Cervical Cancer

Investor and Analyst Day
June 27, 2016, NYC
Forward‐Looking Statements
This presentation contains forward‐looking statements, including, but not limited to: statements regarding Advaxis' ability to develop the next generation of cancer immunotherapies; and the safety and efficacy of Advaxis' proprietary immunotherapy, axalimogene filolisbac. These forward‐looking statements are subject to a number of risks, including the risk factors set forth from time to time in Advaxis' SEC filings, including but not limited to its report on Form 10‐K for the fiscal year ended October 31, 2015, which is available at http://www.sec.gov. Advaxis undertakes no obligation to publicly release the result of any revision to these forward‐
looking statements, which may be made to reflect the events or circumstances after the date hereof or to reflect the occurrence of unanticipated events, except as required by law. You are cautioned not to place undue reliance on any forward‐looking statements.
Welcome Second NYC Analyst and Investor Day • Special thanks to Reed Smith
• Several outstanding oncologist‐Advaxis clinical trials
• Highlight developments over last several months • Axalimogene filolisbac, or AXAL, lead immunotherapy for treatment of HPV‐associated cancers
• AXAL vision = exploit relationship between intracellular pathogen, Listeria monocytogenes or Lm, and “host” APCs
– Educate immune system to recognize and attack cancer cells
• First half 2016 was both important and informative for AXAL – Our original vision manifest in evidence of AXAL having effects  MICROscopic level of tumor microenvironment
 MACROscopic level of patient
• 5 key points for AXAL development
Point #1 – AXAL Is Keeping Good Company
• Data from GOG‐0265, Dr Warner Huh, principal investigator; presented at ASCO, swamped with viewers • AXAL in GOG‐0265 one of very few immunotherapies/ monotherapy to report durable CR in relapsed/refractory metastatic solid cancer of any type – Others were nivolumab (Opdivo®) and pembrolizumab
(Keytruda®) – AXAL was in great company
• Pembrolizumab relapsed/refractory metastatic cervical cancer reported at ASCO
– Unlike in GOG‐0265, there were no CRs reported
– Pembro studies were in patients with high PD‐1 expression
Point #2 – Preliminary Data: AXAL and Durvalumab Shows Feasibility and Resulted in a CR
• Three years ago, Advaxis among first IO companies to combine Lm with other immunotherapies to synergize potential anticancer effects
• Preliminary data combining AXAL and AZ/MedImmune’s durvalumab – AXAL with durvalumab appears feasible – AXAL with durvalumab resulted in a CR in one of the early patients with acceptable safety
– Complete study results will be presented when data mature
Point #3 – SPA Process Worth Time and Effort
• Be as sure as possible that path can ultimately lead to approval
• FDA’s Special Protocol Assessment (SPA) program is great tool
• AIM2CERV protocol in SPA process for past several months • SPA process is rigorous and time‐consuming, generally requiring several 45‐day review cycles • Advaxis proactivity in seeking a SPA will give company stronger footing on the regulatory pathway and will be well worth the time and effort to front‐load the review of our trial design
Point #4 – RTOG Network Interested to Conduct Phase 3 Anal Cancer Study
• Farrah Fawcett Foundation formed to find a cure for anal cancer • Sponsored AXAL in adjuvant anal cancer Brown University Oncology Group • Preliminary data: No recurrence in all 10 patients • RTOG offered to open network of oncologist and radiologist for phase 3 in high‐risk adjuvant anal cancer • Advaxis grateful RTOG is willing to commit network and manpower • Potentially second registration quality study for AXAL in a different tumor type (anal)
Point #5 – Abbreviated AXAL Regimen Switched TME and Mobilized Key Players for Immune Response
• Preliminary preclinical data AXAL affecting TME and making tumors susceptible to immunologic attack
• Patients w/head and neck cancer 5‐week “window” between initial biopsy and surgical resection
• 5‐week window allowed for abbreviated regimen – 2 doses of AXAL
• Post‐treatment tumor tissue analysis showed conversion of TME into site of inflammation
– Infiltration of activated T cells – Increased expression of activation markers
• 2 administrations of AXAL and short 5‐week “window” – AXAL switched on immune system in tumor microenvironment – AXAL recruited key players that would be necessary to mobilize an effective immune response
Beyond AXAL, Milestones and Manufacturing
• Beyond AXAL . . .
– ADXS‐HER2 study underway

Fast‐track designation
– ADXS‐PSA and pembro combo to complete enrollment in 2016 – ADXS‐NEO planning IND for 2016
• Milestones
– AIM2CERV planned initiation 2016
– AXAL/durvalumab combination data planned for SITC
• Manufacturing
– Second most important aspect of cancer immunotherapy – Designed and implemented simple robust process
– Construction new flex suite for GMP clinical and process development
– Additional facility expansion underway for clinical production and future commercial capacity
9
How Has Cancer Been Hiding from the Immune System?
Normal tissue
Multiple mutations*
Myeloid‐Derived Suppressor Cell
Tumor
T Regulatory Cell
Recruitment of suppressor cells
Tumor heterogeneity*
*Means many tumor‐associated antigens (TAA).
Data on file.
How Has Cancer Been Hiding from the Immune System?
Normal tissue
Expression of immunologic checkpoint molecules (eg, PD‐1)
Tumor
Myeloid‐Derived Suppressor Cell
Immuno‐
suppressive TME
T Regulatory Cell
TME, tumor microenvironment.
Data on file.
Immune System Activation by Intracellular Infection
Lm
The immune system has the same attack strategies for cancer cells and cells that are infected with viruses or intracellular bacteria.
As an intracellular bacterium, Lm naturally and effectively triggers many host defense mechanisms.
These responses can be directed toward cancer cells by having Lm express a tumor‐associated antigen (TAA).
Data on file.
Lm Technology™ Overview: Harnessing Unique Life Cycle of Lm in APCs
Lm‐LLO and tumor‐associated antigen (TAA) presented and taken up by dendritic cells (antigen‐
presenting cells or APCs)
2
Some Lm‐LLO is killed and degraded within the phagolysosome
1
Dendritic cells activated to generate an immune response through both the MHC I and MHC II pathways
Robust T‐cell response generated toward antigen secreted by Lm‐LLO and redirected against tumors expressing the same TAA
"Perceived" acute infection stimulates a strong innate immune response through multiple pathways (eg, STING)
Overrides checkpoint inhibitors and negative regulators of cellular immunity
Lm‐LLO is
phagocytosed by APC
5
3
Peptide‐MHC complexes on the APC simulate CD4+ (MHC II) and CD8+ (MHC I) T cells
Some Lm‐LLO escapes the phagolysosome and enters the cytosol
4
tLLO‐TAA fusion protein is degraded by proteasomes into peptides for presentation to the MHC class I pathway
APC, antigen presenting cell; Lm, Listeria monocytogenes; MHC, major histocompatibility complex; tLLO, truncated listeriolysin O. AIM2CERV
Bradley Monk, MD, is the director of the Division of Gynecologic Oncology at St. Joseph’s Hospital and Medical Center in Phoenix, Arizona. Dr Monk is the Lead Cervical Cancer Advisor to Advaxis, and is a key contributor to the development of the planned phase 3 AIM2CERV trial.
GOG‐0265
Warner K. Huh, MD, is a professor and Division Director of Gynecologic Oncology and senior scientist at the University of Alabama in Birmingham. Dr Huh is the lead investigator of GOG‐
0265, a phase 2 clinical study evaluating the potential of AXAL as an immunotherapy for patients.
AXAL + Durvalumab Study
Brian Slomovitz, MD, is the director of the Division of Gynecologic Oncology in the Department of Obstetrics and Gynecology at the University of Miami Miller School of Medicine, as well as co‐leader of the Gynecologic Cancers Site Disease Group at Sylvester Comprehensive Cancer Center.
Dr Slomovitz is an investigator evaluating AXAL in combination with durvalumab, which is currently in its second dose‐
escalation phase.
FAWCETT
Lisa Kachnic, MD, is professor and chair of the Department of Radiation Oncology at Vanderbilt University, and the former associate director of Multidisciplinary Cancer Research at Boston University.
Dr Kachnic plans to evaluate AXAL in a registration quality study in HPV‐associated anal cancer.
ADXS‐PSA
Mark Stein, MD, is a medical oncologist at the Cancer Institute of New Jersey, specializing in prostate cancer. Dr Stein is an investigator in a phase 1/2 trial evaluating ADXS‐PSA in patients with previously treated, metastatic castration‐
resistant prostate cancer (mCRPC).
Agenda
1.30 PM
Introduction
1.45 PM
AXAL Cervical Cancer Panel
Daniel O’Connor
Advaxis President and CEO
AIM2CERV
Bradley Monk, MD
GOG‐0265
Warner Huh, MD AXAL/Durvalumab Combination
Brian Slomovitz, MD 3.15 PM
AXAL in Anal Cancer
Lisa Kachnic, MD
3.45 PM
ADXS‐PSA
Mark Stein, MD
4.15 PM
Question‐and‐Answer Session
All
4.30 PM
Reception
AXAL Cervical Cancer AIM2CERV
Bradley Monk, MD
AXAL Cervical Cancer Panel Discussion:
AIM2CERV
Bradley J. Monk, MD
Director, Division of Gynecologic Oncology
University of Arizona Cancer Center‐Phoenix
Creighton University School of Medicine at
Dignity Health St. Joseph’s Hospital and Medical Center
Human Papillomaviruses and
Human Cancer
•1842: Rigoni-Stern – prostitutes higher incidence of cervical
cancer than nuns
•1928: Georgios Papanicolaou – “Pap smear”
•1951: George Otto Gey – HeLa (Henrietta Lacks) cells
•1983: Harald zur Hausen – discovers HPV (dsDNA
virus)
•2008: Harald zur Hausen – wins Nobel Prize
Harald zur Hausen
HPV and Human Cancer
Approximately 79 million people in the United States are currently infected with HPV1,a
 ~80% of sexually active women will be infected with HPV by age 502,b Most HPV infections clear on their own; however, persistence of certain HPV types can lead to clinically significant diseases2
For HPV‐associated cervical disease, it cannot be reliably predicted which patients with infection or abnormal cytology will progress to clinically significant disease versus spontaneously regress2,3
aEstimates are for 2008 and reflect persons with detectable infection with any of 37 different HPV types,
not just types 6, 11, 16, 18, 31, 33, 45, 52, and 58.4
bBased on modeling estimates.
HPV, human papillomavirus. 1CDC, 2014; 2CDC; 3Woodman et al, 2007; 4Satterwhite et al. Estimated Number of New Cancer Cases Attributable to Human Papillomavirus (HPV) by Anatomic Site and Gender CANCER SITE
Number of
new cases
Number Attributable
Number
attributable
fraction
attributable
to HPV
(%)
to HPV by gender
Males
Females
Cervix uteri
528 000
528 000
100
‐
528 000
Anus
40 000
35 000
88
17 000
18 000
Vagina and Vulva
49 000
20 000
41
‐
20 000
Penis
26 000
13 000
51
13 000
‐
Oropharynx
96 000
29 000
31
24 000
6 000
Oral Cavity and
Larynx
358 000
16 000
4.4
12 000
4 000
1 096 000
641 000
58
66 000
575 000
TOTAL
Plummer et al. Lancet Global Health. 20
Age-Standardized* Cervical Cancer
Rates
*Rates adjusted based on the age distribution of the populations.
Jemal A, et al. CA Cancer J Clin. 2011;61(2):69-90.
Cervical Cancer Epidemiology:
United States
• Median age at diagnosis for cervical cancer is 49 years
• An estimated 12,990 cases of invasive cervical cancer are expected to be diagnosed in 2016
• An estimated 4120 deaths from cervical cancer are expected in 2016
• Incidence rates continue to rise; vaccination and screening are having Incidence ≈ 12,990
little impact
Deaths
≈ 4,120
SEER Stat Fact Sheets: Cervix Uteri Cancer.
American Cancer Society. Cancer Facts & Figures 2016. Atlanta: American Cancer
Society; 2016.
Regional Variation in
Cervical Cancer Mortality • Highest estimated incidence and mortality rates were in areas of Appalachia, the South Atlantic, lower Mississippi Valley, along the Texas‐
Mexico border, and the Oklahoma and Texas panhandles
Homer M-J, et al. Cancer Epidem Biomar.
2014;20:591-599.
Unmet Needs in Cervical Cancer
• HPV vaccination will reduce the incidence of the disease over the course of the next several decades
• After initial surgery and/or chemo‐
radiation, there is no standard adjuvant treatment to reduce the risk of recurrence
• Aside from the approval of bevacizumab in 2014,1 systemic treatment of advanced cervical cancer has been limited to cytotoxic chemotherapy2
– Therapy to prevent disease recurrence after initial treatment is an area of unmet medical need
1. Tewari KS, et al. N Engl J Med. 2014;370(8):7342. Monk BJ, et al. J Clin Oncol. 2009;27(28):4649-46
1994
FIGO Staging
2009 Modification Stage IIA2
FIGO Committee on Gynecologic Oncology. Int J Gynecol Obstet. 2009;105:103‐104.
What Is the Global Standard Therapy for Stage IB2–IVA?
• External beam pelvic radiation (40 to 60 Gy)
• Brachytherapy (8,000 to 8,500 cGy to Point A)
• IV cisplatin chemotherapy
– Cisplatin 40 mg/m2 (max dose 70 mg) IV q wk during RT (6 wk)

GOG 120 (Rose PG, et al. Concurrent cisplatin‐based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med. 1999;340(15):1144‐1153
Monk BJ, et al. J Clin Oncol. 2007;25:2952‐2965.
Standard Anterior and Lateral External‐Beam Irradiation Ports Used to Treat Locally Advanced Cervical Carcinoma Limited to the Pelvis
Monk et al J Clin Oncol 25:2952-2965. 2007
Risk Factors for Recurrence After Chemotherapy and Radiation
1. FIGO stage (III and IV)
2. Lymph node spread
a) Number and location (aortic worse than pelvic)
5‐Year Survival for Advanced Disease
FIGO Stage III
50%
FIGO Stage IV
10%
Why HPV‐Targeted Immunotherapy for Cervical Cancer?
HPV-Associated Cancers Demonstrate Strong Evidence of Immune Evasion
•
MHC class I downregulation
•
Impaired antigen‐processing ability
•
Avoidance of T‐cell–mediated killing
•
Increased immunosuppression due to Treg infiltration
•
Secretion of immunosuppressive cytokines
T‐Cell Infiltration Positively Impacts Cervical Cancer Prognosis
Absence of lymph node (LN) metastases is statistically significantly associated with strong CD8+ T‐cell tumor infiltration n = 59 cervical cancer patients
Vici P, et al. J Exp Clin Cancer Res. 2014;33:29;
Sheu BC, et al. J Obstet Gynaecol Res. 2007;33(2):103‐113;
Piersma SJ, et al. Cancer Res. 2007;67(1):354‐361. Lm Technology Overview: Harnessing Unique Life Cycle of Lm in APCs
Peptide-MHC complexes
on the APC stimulate
CD4+ and CD8+ T cells
Lm-LLO is
phagocytosed by
APC
Lm-LLO is killed
and degraded
within the
phagolysosome
Some Lm-LLO
escapes the
phagolysosome and
releases tLLO-TAA
(fusion protein) into
the cytosol
Fusion protein is degraded by
proteasome into peptides for the
MHC class I pathway
Lm-LLO bacterial
DNA induces an
innate immune
response
through multiple
pathways (TLRs
1, 2, 5, 6, 9;
NOD1; NOD2;
STING)
•
Lm‐LLO and tumor‐associated antigen (TAA) presented and taken up by dendritic cells (antigen‐
presenting cells or APCs)
•
Dendritic cells activated and generate an immune response through both the MHC I and MHC II pathways
•
Robust T‐cell response generated toward antigen secreted by Lm‐LLO and redirected to tumors expressing the same TAA
•
"Perceived" acute infection causes an innate immune response
•
Overrides checkpoint inhibitors and negative regulators of cellular immunity
APC, antigen presenting cell; IFN, interferon; IL, interleukin; Lm, Listeria monocytogenes; MHC, major histocompatibility complex; tLLO, truncated
listeriolysin O.
Hansen K, et al. EMBO J. 2014;33:1654-1666.
AXAL Cervical Cancer Development Plan
Ongoing and Planned Trials for Completion by 2020
AXAL Indication
Stage
2016
Phase 2
Phase 1/2
2017
2018
2019
2020
2021
2022
Sponsor
GOG‐0265
Combination w/ durvalumab
Cervical Cancer
Phase 3
AIM2CERV (Adjuvant)
Recurrent/Metastatic
Phase 3
Ongoing
Planned
Complete Patient Enrollment
http:www.clinicaltrials.gov
ADXS11‐001 (AXAL): Planned Phase 3 Study Schema – ADXS AIM2CERV Study
Randomization 1:2 Between Reference and Treatment Groups
High‐risk, locally advanced cervical cancer • FIGO stage IB2–II with positive pelvic nodes • FIGO stage III–IV • Any FIGO stage with para‐aortic nodes Total sites: 150 in 20 countries • GOG is supporting AIM2CERV by acting as a Site Management Organization Trial timeline (predicted) • First patient enrollment: 3Q16 • Last patient enrollment: 2Q18 • Final data readout: 3Q19 Cisplatin (at least 4 weeks’ exposure) and
radiation (minimum 40 Gy external beam radiation therapy)
RANDOMIZE (N = 450)
1:2
Reference Group
Placebo IV up to 1 year
Treatment Group
ADXS11‐001
(1×109 CFU) up to 1 year
Primary Endpoint: Disease‐free survival
Secondary Endpoint: Overall survival
Participating countries:
Argentina, Brazil, Canada, Chile, Hong Kong, Ireland, Korea,
Malaysia, Mexico, Netherlands, Poland, Romania, Russia,
Serbia, Spain, Taiwan, UK, Ukraine, US
AIM2CERV Phase 3: Strong Rationale for AXAL as an Upfront Therapy
Maximize Clinical
Impact
• Promising outcomes from GOG 0265 lead GOG to recommend positioning AXAL as an upfront therapy in phase 3 studies to maximize impact on cervical cancer management
Favorable
Safety/Tolerability
• AXAL’s favorable safety profile is a significant factor contributing to acceptance by KOLs for upfront use, in contrast to Avastin, which has significant toxicity
Encouraging
Upfront Data in
Anal Cancer
Stronger Immune
System
Expanded
Addressable
Patient Base
• AXAL has demonstrated promising preliminary data in anal cancer as an upfront adjuvant to chemoradiation
• More‐intact immune system and less progressive disease boosts the potential efficacy of immunotherapy approaches due to nature of induced immune response
• Also a need for prevention of cervical cancer recurrence, which is a larger population than post‐recurrence. Upfront positioning could expand the addressable patient base for AXAL for the greatest commercial success
“Immunotherapies, especially targeted ones such as this product, are more amenable in an upfront setting because
of the manageable toxicity profile . . .” - Gyn/Onc KOL
Advaxis, data on file. 2016.
Thank You
[email protected]
AXAL Cervical Cancer GOG‐0265
Warner Huh, MD
AXAL Cervical Cancer Panel Discussion
GOG‐0265
Warner Huh, MD
University of Alabama at Birmingham (UAB)
Cervical Cancer:
Disease Population
• Over 500,000 new cases and 250,000 deaths each year1
• HPV is sexually transmitted and associated with the development of cervical cancer2
– HPV strains 16 and 18 are responsible for 70% of cervical cancers worldwide
• Incidence and mortality for cervical cancer varies worldwide1
– 80% of women diagnosed and 90% of fatal cases are in lower‐
to middle‐income brackets
– Incidence and mortality rates are highest in sub‐Saharan Africa
42
1. De Sanjose S, et al. Lancet Oncol. 2010;11:1048-1056; 2. Globocan 2012.
Cervical Cancer Outcomes:
Opportunity to Improve Patient Survival
National Cancer Database
Cervical Cancer Incidence
by FIGO Stage
FIGO Stage
Stage Definition
Sub‐Stage
5‐Year Survival
100%
IA
Stage I
80%
IB
45%
Stage II
60%
15%
Cervical carcinoma invades beyond uterus but not to pelvic wall or to lower third of vagina
24%
Tumor extends to pelvic wall and/or involves lower third of vagina and/or causes hydronephrosis or nonfunctional kidney
16%
Tumor invades mucosa of bladder or rectum and/or extends beyond true pelvis
40%
Stage III
20%
0%
1
93%
Cervical carcinoma confined to the cervix Stage IV
80%
IIA
63%
IIB
58%
IIIA
35%
IIIB
32%
IVA
16%
IVB
15%
0%
50%
5‐Year Survival Rate
100%
Significant unmet need in Stage III–IV patients and high-risk Stage I–II patients
43
Source: Locust Walk interviews and analysis, American Cancer Society, International Federation of Gynecology and Obstetrics.
Cervical Cancer Treatment:
Lack of Effective Treatment Options
Stage IB2–IV
Stage IA1–IB1
Conization
Trachelectomy
Concomitant Chemoradiation
Simple/Radical Hysterectomy
+/– Pelvic Lymphadenectomy
Regimens include:
Cisplatin
5‐FU
Carboplatin
Paclitaxel
Topotecan
+/– Pelvic Radiotherapy
+/– Concomitant Chemoradiation
Post‐treatment Surveillance: Recurrent or Metastatic
Chemotherapy Regimens +/–
Bevacizumab
Palliative Chemotherapy
44
Pelvic Exenteration
NCCN Clinical Practice Guidelines in Oncology. Cervical Cancer. V1.2016. 12‐Month Survival Rates in Pretreated PRmCC:
The GOG Experience
1. Tewari KS, Monk BJ. Curr Oncol Rep. 2005;7(6):419‐434; 2 Muggia F, et al. Gynecol Oncol. 2004;92(2):639‐643; 3. Plaxe SC, et al. Cancer Chemother Pharmacol. 2002;50(2):151‐154; 4. Armstrong DK, et al. Invest New Drugs. 2003;21(4):453‐457; 5. Fracasso PM, et al. Gynecol Oncol. 2003;90(1):177‐180; 6. Brewer CA, et al. Gynecol Oncol. 2006;100(2):385‐388; 7. Rose P, et al. Gynecol Oncol. 2006;102(2):210‐213; 8. Garcia AA, et al. Am J Clin Oncol. 2007;30(4):428‐431; 9. Miller DS, et al. Gynecol Oncol. 2008;110(1):65‐70; 10. Fiorica JV, et al. Gynecol Oncol. 2009;115(2):285‐289; 11. Monk BJ, et al. J Clin Oncol. 2009;27(7):1069‐1074; 12. Schilder RJ, et al. Int J Gynecol Cancer. 2009;19(5):929‐933; 13. National Cancer Institute. Vaccine therapy in treating patients with persistent or recurrent cervical cancer. http://www.cancer.gov/about‐cancer/treatment/clinical‐trials/search/view?cdrid=691288. Accessed May 25, 2016.
45
Step‐by‐Step Lm‐LLO Immunomodulation
46
APCs, antigen‐presenting cells; CD, cluster of differentiation; CTL, cytotoxic T lymphocyte; LLO, listeriolysin O; Lm, Listeria monocytogenes; MDSCs, myeloid‐derived suppressor cells; TAA, tumor‐associated antigen; tLLO, truncated LLO; TME, tumor microenvironment; Tregs, T‐regulatory cells.
Krupar R, et al. Presented at the 107th Annual Meeting of the American Association for Cancer Research; April 16–20, 2016; New Orleans, LA. Abstract LB‐095.
Preclinical Data Support Lm‐LLO‐E7 MOA Rationale
Tumor Volume (mm3)
ADXS11-001 (AXAL) Induces Complete Regression of Established TC1* Tumor in Mouse Models
47
Lm‐ddA274 (empty control)
PBS (mock
inoculation)
ADXS11‐001
TC‐1 is a cell line with high expression of HPV type 16 E7.
Advaxis, Data on file 2016.
Landmark Randomized Phase II Study of ADXS11‐001 +/– Cisplatin in Relapsed Refractory Cervical Cancer: Survival Analyses at 12, 18, and >24 Months
Patients
12‐Month Survival
18‐Month Survival
≥24‐Month Survival
ADXS11‐001 ALONE (N = 55)
ADXS11‐001 + CISPLATIN (N = 54)
32% 29% 35% (35/109)
(16/55)
(19/54)
22% 22% 22% (24/109)
(12/55)
(12/54)
18% 8% 10%
(16/91)
(7/91)
(9/91)
Overall
(N = 109)
AEs were consistent with established profile for ADXS11‐001 (AXAL)
48
Basu P, et al. J Clin Oncol. 2014; 32(suppl): abstract 5610.
Immunotherapy Checkpoints
Pembrolizumab in PD‐L1+/HPV+ Cervical Cancer
• Data from the second‐line and later cervical cancer cohort of KEYNOTE‐028 phase Ib study were presented at ASCO 2016 (n = 24)
– No CRs; PRs in 4 (17%) patients; stable disease in 3 (13%) patients
– Median PFS, 2 months; median OS, 9 months
Landmark Analysis of Pembrolizumab in Relapsed/Refractory Cervical Cancer Patients, n (%)
PFS
OS
6‐Month Survival
21%
67%
12‐Month Survival
8%
33%
AEs were consistent with established profile for pembrolizumab
49
Presented by Jean‐Sebastien Frenel at 2016 ASCO Annual Meeting.
ADXS11‐001 immunotherapy in squamous or non‐squamous persistent/recurrent metastatic cervical cancer: Results from stage 1 [and stage 2] of the phase II GOG/NRG‐0265 study
NCT01266460
Warner Huh, MD1, Don Dizon, MD2, Matthew A. Powell, MD3, Charles A. Leath III, MD1, Lisa M. Landrum, MD4, Edward Tanner, MD5, Robert Higgins, MD6, Stefanie Ueda, MD7, Michael McHale, MD8, Bradley J. Monk, MD9, Carol Aghajanian, MD10
1University of Alabama Birmingham, Obstetrics/Gynecology, Birmingham, AL; 2Massachusetts General Hospital Cancer Center, Gynecologic Oncology, Boston, MA; 3Washington University School of Medicine, Obstetrics/Gynecology, St. Louis, MO; 4University of Oklahoma Health Sciences Center, Section of Gynecologic Oncology, Oklahoma City, OK; 5Johns Hopkins Medical Institutions, Gynecology and Obstetrics, Baltimore, MD; 6Carolinas Medical Center, Obstetrics/Gynecology, Charlotte, NC; 7UCSF School of Medicine, Obstetrics, Gynecology and Reproductive Sciences, Division of Gynecologic Oncology, San Francisco, CA; 8UC San Diego Moores Cancer Center, Division of Gynecologic Oncology, La Jolla, CA; 9University of Arizona Cancer Center at Dignity Health St. Joseph’s Hospital and Medical Center, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Phoenix, AZ; 10Memorial Sloan Kettering Cancer Center, Gynecologic Medical Oncology Service, New York, NY.
50
ASCO 2016
Monday, June 6, 2016
GOG/NRG‐0265 Study Design and Eligibility
CFU, colony‐forming units; ORR, objective response rate; PFS, progression‐free survival; RECIST, Response Evaluation Criteria In Solid Tumors.
https://www.clinicaltrials.gov/ct2/show/NCT01266460.
Presented by Huh W, et al. ASCO 2016. Abstract 5516.
51
CONSORT Diagram
>3 doses
<3 doses
52
Presented by Huh W, et al. ASCO 2016. Abstract 5516.
Overall Survival
STAGE 1
All Patients
3 Doses of ADXS11‐001
STAGE 2
All Patients
(N = 24)
>3 Doses of ADXS11‐001
(N = 12)
42% (n = 10/24)
67% (n = 8/12)
Median OS (95% CI)
4.8 months (3.8–NR) NR (3.5–NR)
Median PFS (95% CI)
2.6 months (2.0–3.2)
–
6‐month OS
53
CI, confidence interval; NR, not reached. Presented by Huh W, et al. ASCO 2016. Abstract 5516.
GOG/NRG‐0265: Survival in the Context of Historical GOG PRmCC Clinical Trials
1. Tewari KS, Monk BJ. Curr Oncol Rep. 2005;7(6):419‐434; 2 Muggia F, et al. Gynecol Oncol. 2004;92(2):639‐643; 3. Plaxe SC, et al. Cancer Chemother Pharmacol. 2002;50(2):151‐154; 4. Armstrong DK, et al. Invest New Drugs. 2003;21(4):453‐457; 5. Fracasso PM, et al. Gynecol Oncol. 2003;90(1):177‐180; 6. Brewer CA, et al. Gynecol Oncol. 2006;100(2):385‐388; 7. Rose P, et al. Gynecol Oncol. 2006;102(2):210‐213; 8. Garcia AA, et al. Am J Clin Oncol. 2007;30(4):428‐431; 9. Miller DS, et al. Gynecol Oncol. 2008;110(1):65‐70; 10. Fiorica JV, et al. Gynecol Oncol.. 2009;115(2):285‐289; 11. Monk BJ, et al. J Clin Oncol. 2009;27(7):1069‐1074; 12. Schilder RJ, et al. Int J Gynecol Cancer. 2009;19(5):929‐933; 13. National Cancer Institute. Vaccine therapy in treating patients with persistent or recurrent cervical cancer. http://www.cancer.gov/about‐
cancer/treatment/clinical‐trials/search/view?cdrid=691288. Accessed May 25, 2016; 14. GOG/NRG Oncology. Data on file, 2016.
Presented by Huh W, et al. ASCO 2016. Abstract 5516.
54
Objective Response
OBJECTIVE RESPONSE
•
Investigator assessment of tumor best response
Stage 1 (N = 26)
Stage 2 (N = 24)
Complete response
0 (0)
1 (4)
Stable disease
7 (27)
8 (33)
Progressive disease
10 (38)
11 (46)
Not evaluable
6 (23)
4 (17)
Tumor best response, n (%)
55
CR, complete response, NE, no evaluation; PD, progressive disease, SD, stable disease.
Presented by Huh W, et al. ASCO 2016. Abstract 5516.
Safety/Tolerability: Stage 1 Adverse Event Summary (n = 26)
Adverse event (AE)
Patients with ≥1 treatment‐
related AE (TRAE), n (%)
Grade 1–4
Grade 3
Grade 4
24 (92)
4 (15)
1 (4)*
TRAEs occurring in ≥10% of patients
Fatigue
15 (58)
‐
‐
Chills
14 (54)
‐
‐
Fever
11 (42)
‐
‐
Nausea
10 (39)
‐
‐
Headache
9 (35)
‐
‐
Hypotension
7 (27)
2 (8)
‐
Vomiting
6 (23)
‐
‐
Cytokine release syndrome
5 (19)
3 (12)
‐
Myalgia
5 (19)
‐
‐
Abdominal pain
4 (15)
‐
‐
General pain
4 (15)
‐
‐
Flu‐like symptoms
3 (11)
‐
‐
AST elevation
3 (11)
‐
‐
Safety findings among patients enrolled in Stage 2 are similar to those reported in detail for Stage 1.
56
*The observed grade 4 TRAE recorded in 1 patient (lung infection and sepsis from Klebsiella pneumoniae) was considered possibly related to treatment.
AE, adverse event; AST, aspartate aminotransferase; TRAE, treatment‐related AE.
Presented by Huh W, et al. ASCO 2016. Abstract 5516.
GOG/NRG‐0265 Case Study: Durable Complete Response to ADXS11‐001
•
•
66‐year‐old woman diagnosed with squamous cell cancer of the cervix in 2006, surgically treated with radical hysterectomy in 2007
Pelvic recurrence in 2014
‒ Paclitaxel/carboplatin × 8 cycles (6 cycles with bevacizumab) → cispla n (2 cycles) + pelvic radiation. Treatment completed August 2014
•
Systemic recurrence June 2015
‒ Enrolled in GOG/NRG‐0265
GOG/NRG‐0265 GOG/NRG‐0265
ADXS11‐001
ADXS11‐001
Dose 1
Dose 2
GOG/NRG‐0265
ADXS11‐001
Dose 3
CT scan
Confirmed PR
with further ↓
CT scan
PR (>30%↓)
PET/CT scan
NED – CR
PET/CT scan
NED – CR
Jan 2016
May 2016
ADXS11‐001
clinical hold
Oct 2015
July 2015
Aug 2015
Sep 2015
Dec 2015
Application for individual patient IND for ADXS11‐001 . . . ONGOING
ADXS11‐001 well tolerated
Survival to date – second‐line metastatic squamous cell cervical cancer (post‐bevacizumab): 11 months
57
CT, computed tomography; IND, Investigational New Drug; NED, no evidence of disease; PET, positron emission tomography; PR, partial response. This study remains ongoing and this patient's experience may not be typical. Further study is warranted.
Presented by Huh W, et al. ASCO 2016. Abstract 5516.
GOG/NRG‐0265 Case Study: Resolution of LN Mets (PET, Diagnostic CT)
58
LN, lymph node; mets, metastases.
Presented by Huh W, et al. ASCO 2016. Abstract 5516.
Conclusions
• In patients with PRmCC and progression following ≥1 prior lines of systemic therapy, ADXS11‐001 was well tolerated and demonstrated a 38.5% rate of 12‐month survival (n = 10/26)
• Although preliminary, findings from Stage 2 reinforce the rationale for further controlled investigation of ADXS11‐001 in PRmCC, and suggest consistent survival benefit in a heavily bevacizumab‐pretreated population (31% vs 83% in Stage 1 and Stage 2, respectively), particularly among those patients receiving 3 or more doses of immunotherapy
• An international Advaxis‐sponsored phase III study of ADXS11‐001 as adjuvant treatment of high‐risk locally advanced cervical cancer (AIM2CERV) is under development in collaboration with the GOG Foundation
59
PRmCC, progressive recurrent metastatic cervical cancer; GOG, Gynecologic Oncology Group.
Presented by Huh W, et al. ASCO 2016. Abstract 5516.
AXAL Cervical Cancer AXAL/Durvalumab Combination
Brian Slomovitz, MD
AXAL Cervical Cancer Panel Discussion
AXAL + Durvalumab Study
Brian Slomovitz, MD
Director of Gynecologic Oncology University of Miami Miller School of Medicine
Co‐leader of the Gynecologic Cancers Site Disease Group Sylvester Comprehensive Cancer Center HPV‐Associated Cancers Are Prevalent and Can Be Aggressive 62
International Association for Research on Cancer (IARC) Globocan 2008 (4.5-2011).
Cervical and Oropharyngeal Cancers Are Both Associated with HPV Infections
• Increasing prevalence of oropharyngeal cancer
– >80% of cases in US are HPV+
• Rates of cervical cancer are decreasing
– Early diagnosis and treatment of pre‐invasive lesions
– Expected effects of HPV vaccine in young women
– However, cases that do occur are typically aggressive
63
Presented by Joseph Califano at 2016 ASCO Annual Meeting.
Summary of Durvalumab in Head and Neck and Cervical Cancers
• Durvalumab – Study 1108 in PD‐L1+ or PD‐L1– tumors (N = 62)1
– Overall response rate (ORR) = 11%


ORR = 18% in PD‐L1+
ORR = 8% in PD‐L1–
– Treatment‐related AEs in 34% of patients (none grade ≥4)
64
1. Segal NH, et al. Poster presented at ESMO 2014.
ADXS11‐001 (AXAL) Mediates Changes in the Tumor Microenvironment
Window of Opportunity Study in Head and Neck Cancers
Increase in CD8+ T Cells and Decrease in PD-L1
AXAL‐induced changes in T‐cell infiltration and checkpoint expression in tumor microenvironment
Results
▶
AEs included vomiting and hypertension; no AEs grade >3
▶
Detection of HPV E6/E7‐specific T‐cell response in peripheral blood
Potential AXAL‐induced changes in the tumor microenvironment – Decrease in tumor‐infiltrating Tregs observed – T‐cell infiltration – Immune checkpoint molecule expression
▶
Increase in Lymphocyte Infiltration
Tumor-host interface
•
•
•
65
postADXS
preADXS
Tumor-host interface
Phase I in newly diagnosed HPV+ squamous cell carcinoma of the
oropharynx
8 patients treated to determine the tolerability and immunogenicity of
AXAL
Patients who were scheduled for robotic surgery with curative intent
were administered 2 doses of AXAL prior to resection
Krupar R, et al. Presented at AACR 2016. LB‐095.
Preclinical Rationale for ADXS11‐001 (AXAL) + Immune Checkpoint Inhibitors (anti–PD‐1/PD‐L1)
HPV Tumor Model – Response2
Survival Percentage
HPV Tumor Model – Survival1
Days after tumor implantation
Lm immunotherapy is additive and/or synergistic with immune checkpoint inhibitors
66
1. Mkrtichyan M, et al. J Immunother Cancer 2013;1:15. doi:10.1186/2051-1426-1-15.
2. Molli P and Wallecha A. AACR 2015. Abstract 2513.
Immunotherapy Checkpoints:
Pembrolizumab Monotherapy in HPV+ Cervical Cancer
• Data from the second‐line and later cervical cancer cohort of KEYNOTE‐028 phase Ib study were presented at ASCO 2016 (n = 24)
– No CRs; PRs in 4 (17%) patients; stable disease in 3 (13%) patients
– Median PFS, 2 months; median OS, 9 months
Landmark Analysis of Pembrolizumab in Relapsed/Refractory Cervical Cancer Patients, n (%)
PFS
OS
6‐Month Survival
21%
67%
12‐Month Survival
8%
33%
AEs were consistent with established profile for pembrolizumab
67
Presented By Jean‐Sebastien Frenel at 2016 ASCO Annual Meeting.
ADXS11‐001 (AXAL) with Anti–PD‐L1 (Durvalumab)
Patient characteristics
• Diagnosis of cervical cancer or HPV+ squamous cell carcinoma of the head/neck with measurable and/or evaluable disease by RECIST 1.1
Part 1
Phase I/II Study in Recurrent/Persistent Metastatic Cervical or HPV+ Head and Neck Cancer
AXAL + Durvalumab (n = 6–12)
AXAL fixed dose Q 4 weeks +
• 3 mg/kg Q2 weeks (dose level 1)
• 10 mg/kg Q2 weeks (dose level 2)
Expansion phase (n = 20)
AXAL + Durvalumab (RP2D) in H&N only
• ECOG performance status of 0 or 1
• No diagnosis of immunodeficiency
RANDOMIZATION (1:1)
Targeted accrual
Part 2
Cervical cancer only (n = 90)
• 6–12 in Part 1 (dose finding)
• 20 in Part 1 expansion (H&N only)
Durvalumab monotherapy
• 90 in Part 2, phase II (cervical only)
AXAL + Durvalumab
Trial timeline (estimate)
• Part 1 first patient cohort enrollment complete: 1Q16
• Part 1 second patient cohort enrollment complete: 2Q16
• Part 1 expansion initiated: 3Q16
Primary endpoints:
Stage 1: Overall safety
Stage 2: Progression‐free survival/overall safety
• Part 2 first patient enrolled: 3Q16
• Study completion: 2018
68
Company Confidential and Proprietary.
In collaboration with
https://clinicaltrials.gov/ct2/show/NCT02386501.
Proof of Principle: Durable Complete Response in Refractory Cervical Cancer – A Case Study
49-year-old Asian woman with squamous cell carcinoma of the cervix diagnosed 2011
• Prior systemic chemotherapy
–
–
–
Cisplatin/paclitaxel/bevacizumab (Feb 2011 – Nov 2011)
Carboplatin/paclitaxel (Feb 2013 – Jul 2013)
Carboplatin/paclitaxel/bevacizumab (Jan 2015 – May 2015)
Best response: Stable disease
• September 25, 2015 – first dose in phase I/II trial of AXAL + durvalumab
CT scan
Confirmed PR
with further ↓
CT scan
PR (60.5%↓)
CT scan
Ongoing PR
with further ↓
CT scan
NED – CR
AXAL
clinical hold
Sep 2015
Oct 2015
Nov 2015
Dec 2015
Jan 2016
Feb 2016
Mar 2016
Apr 2016
May 2016
Jun 2016
Patient’s survival to date – heavily pretreated metastatic squamous cell cervical cancer (post‐bevacizumab × 2): 9 months
AXAL 1×109 CFU
Durvalumab 3 mg/kg
69
ADXS11‐001 well tolerated by this patient
• Grade 1 transient chills, fatigue, fever, nausea, vomiting, headache, hypotension
• Grade 2 rigors (× 1) This study remains ongoing and this patient's experience may not be typical. Further study is warranted.
Images: Target Lesion 5 (para‐aortic lymph nodes) –
Case Study
5 – 3/16
5 – 1/16
5 – 9/15
5 – 5/16
CT scan
Confirmed PR
with further ↓
CT scan
PR (60.5%↓)
CT scan
Ongoing PR
with further ↓
CT Scan
NED – CR
AXAL
clinical hold
Sep 2015
70
Oct 2015
Nov 2015
Dec 2015
Jan 2016
Feb 2016
Mar 2016
Apr 2016
May 2016
Jun 2016
Images: Target Lesion 1 (axillary lymph nodes) –
Case Study
Lateral left axillary node
Biopsied and confirmed prior to therapy
1 – 3/16
1 – 1/16
1 – 9/15
1 – 5/16
CT scan
Confirmed PR
with further ↓
CT scan
PR (60.5%↓)
CT scan
Ongoing PR
with further ↓
CT Scan
NED ‐ CR
AXAL
clinical hold
Sep 2015
71
Oct 2015
Nov 2015
Dec 2015
Jan 2016
Feb 2016
Mar 2016
Apr 2016
May 2016
Jun 2016
Closing Summary
• Preliminary findings: Combination of AXAL and durvalumab was generally well tolerated
– AE profile to date is consistent with the established tolerability profile of both agents
• Although early in the clinical study, there is some evidence of potential synergy between AXAL and durvalumab – Evidence of activity after cycle 1 in case study with durvalumab at 3 mg/kg*
– PR converted to durable CR following resumption of AXAL treatments
• Stage 2 enrollment now open
72
*Monotherapy dosage of durvalumab is 10 mg/kg.
AXAL in Anal Cancer
Lisa Kachnic, MD
AXAL Anal Cancer Panel Discussion:
Changing the Standard of Care with Immunotherapy
Lisa Kachnic, MD, FASTRO
Professor and Cornelius Vanderbilt Chair
Department of Radiation Oncology
Background
• Anal cancer is fairly rare – much less common than
cancer of the colon or rectum1
– In 2016, approximately 8,080 individuals (5,160 women
and 2,920 men) were diagnosed with anal cancer2
– 1,080 estimated deaths (640 women and 440 men)2
• The number of new anal cancer cases has been rising
for many years1
• Anal cancer is exclusively an HPV-driven disease3;
however, its low prevalence among other GI cancers
(2.5%) makes specialization in this tumor rare
• Anal cancer is an area of relatively limited clinical
research focus
75
1. American Cancer Society. Anal cancer. http://www.cancer.org/cancer/analcancer/detailedguide/analcancer-what-is-key-statistics. Accessed June 23, 2016;
2. American Cancer Society. Cancer Facts and Figures 2016.
http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2016/. Accessed June 23, 2016;
3. Glynne-Jones R, et al. Ann Oncol. 2014;25 (suppl 3):iii10-iii20.
NCCN Anal Cancer Treatment Guidelines
Demonstrate Limited Therapeutic Options
Localized Cancer
5-FU + Mitomycin + RT
Metastatic Cancer
5-FU + Cisplatin
mg/m2/d
Continuous-infusion 5-FU 1000
IV days
1–4 and 29–32
Mitomycin 10 mg/m2/d IV bolus days 1 and 29
Concurrent radiotherapy
Continuous-infusion 5-FU 1000 mg/m2 /d IV
days 1–5
Cisplatin 100 mg/m2 IV day 2
Repeat every 4 weeks
+/– Capecitabine + Mitomycin + RT
Capecitabine 825 mg/m2 PO BID, Monday –
Friday, on each day that RT is given, throughout
the duration of RT (typically 28 treatment days)
Mitomycin 10 mg/m2 days 1 and 29
Concurrent radiotherapy
or
Capecitabine 825 mg/m2 PO BID days 1–5
weekly ×6 weeks
Mitomycin 12 mg/m2 IV bolus day 1
Concurrent radiotherapy
76
?
National Comprehensive Cancer Network. NCCN Guidelines. Anal Carcinoma. V. 1.2016.
No Standard Exists for Metastatic Disease:
IRCI/EORTC/ECOG EA#2133: InterAACT – First-Line Met
SCCA of the Anal Canal (PIs Rao, Eng, Morris)
Arm A
R
•
•
•
•
Cisplatin 75 mg/m2 day 1 +
5-FU 1000 mg/m2 infusion/24 hours/4 days
q28 days
Treatment for 6 mo and continued at the discretion of the investigator
Substratification: HIV+/HIV–, HPV status, and prior RT
CT scans: q3 mo
N = 80
Arm B
Carboplatin (AUC = 5) +
Taxol (weekly) q21d
Objective: Identify best chemotherapy backbone to build for
biologic development
1) Primary endpoint: RR
2) Secondary endpoints: PFS, OS, correlatives, and QOL
77
https://clinicaltrials.gov/ct2/show/NCT02560298.
Standard in Localized Disease Has Been RT/5FU/MMC for Decades
Trial
n
Grade 4/5
Acute AEs
LC
CFS
OS
UKCCCR1
RT
RT/5-FU/MMC
585
39%
61%
EORTC2
RT
RT/5-FU/MMC
110
39%
58%
40%
72%
65%*
72%*
RTOG 87-043
RT/5-FU
RT/5-FU/MMC
310
64%**
83%**
58%**
64%**
65%**
67%**
7%
23%
58%*
65%*
*3-yr; **5-yr; statistically significant.
781. UKCCCR. Lancet. 1996;348:1049-1054; 2. Bartelink H, et al. J Clin Oncol. 1997;15:2040-2049; 3. Flam M, et al. J Clin Oncol. 1996;14:2527-2539.
Strategies to Improve Outcome in Localized
Disease Have Failed
• Adjuvant chemotherapy: RTOG 98-11, UK ACT II
• EGFR inhibition: AMC 045/ECOG
79
RTOG 98-11 (T2–4 Nx M0; no HIV)
Cisplatin 75 mg/m²
5-FU 1 g/m²
T3/4;N+,
T2 with RD
RT: 45 Gy
R
Boost 10–14 Gy
MMC 10 mg/m²
5-FU 1 g/m²
RT: 45 Gy
80
T3/4;N+,
T2 with RD
Boost 10–14 Gy
Primary endpoint: 5-yr DFS increase, from 63% to 73% (n = 682)
Ajani JA, et al. JAMA. 2008;299:1914-1921.
RTOG 98-11: 5-Year Outcomes
CDDP/5-FU –
RT/CDDP/5-FU
n = 320 (%)
RT + MMC/5-FU
n = 324 (%)
P Value
Disease-free survival
57.8
67.8
.006
Local relapse
26.4
20
.087
Colostomy
17.3
11.9
.074
Distant mets
18.1
13.1
.12
Overall survival
70.7
78.3
.026
5-Year Rates
81
Median f/u = 5 years.
Gunderson LL, et al. J Clin Oncol. 2010;30:4344-4351.
ACT II UK (T1–4 Nx M0)
Cisplatin 60 mg/m²
5-FU 1 g/m²
R
RT: 50.4 Gy
R
MMC 12 mg/m²
n = 940
5-FU 1 g/m²
No
maintenance
RT: 50.4 Gy
•
•
•
82
First R endpoint: 5% increase in cCR with CDDP
Second R endpoint: Progression-free survival increase with maintenance 5-FU/CDDP
Median follow-up: 5.1 years
James RD, et al. Lancet Oncol. 2013;14:516-524.
ACT II: 5-Year Outcomes
ACT II
First Randomization
83
RT + CDDP/5-FU RT + MMC/5-FU
P Value
n = 468 (%)
n = 472 (%)
6-mo cCR
89.6
90.5
.64
Colostomy rate 3 yr
11.3
13.7
NS
Gr 3/4 heme AE
16
26
.001
Gr 3/4 non-heme AE
68
62
.22
Second Randomization
CRT + CT
n = 448
CRT Alone
n = 446
P value
Progression-free
survival 3 yr (73%/74%
CDDP/MMC arm)
HR, 0.95; 95% CI: 0.75–1.21
.70
James RD, et al. Lancet Oncol. 2013;14:516-524.
AMC 045 and ECOG 3205 Trials: 5-FU, CDDP,
Cetuximab + RT (IMRT Optional)
AMC045
E3205
Activation (accrual)
Oct 2006
Jan 2007
HIV status
Positive
Negative
None
CDDP/FU × 2
CDDP/FU × 2
CDDP/FU × 2
Concurrent cetuximab
6–8 doses
6–8 doses
Radiation
45–54 Gy
45–54 Gy
50
60
LF at 3 yr
LF at 3 yr
35%  17.5%
35%  17.5%
Induction chemo
Concurrent chemo
Accrual goal
Primary endpoint
Reduction
84
Courtesy of J. Sparano.
AMC 045 and ECOG 3205 Trials: Preliminary
2-Year Results (ASCO 2012 Submission)
AMC045
E3205
No. patients
45
28
Stage I/II/III
24%/42%/34%
11%/50%/39%
37 (82%)
22 (79%)
Type I/II adverse events
CDDP/FU × 2
22 (79%)
Colostomy rate (95% CI)
7% (1%–18%)
14% (4%–33%)
7%
13%
89% (73%–96%)
93% (83%–100%)
Completed therapy
2-yr LRF
2-yr OS (95% CI)
85
Courtesy of J. Sparano.
RTOG 9811 ≥4 cm Tumor Size Is Predictive of
Locoregional Failure and DFS
Loco-regional Failure
DFS
3-Year Local
Failure, %
(95% CI)
5-Year Local
Failure, %
(95% CI)
3-Year Alive
Without Failure, %
(95% CI)
5-Year Alive
Without Failure, %
(95% CI)
T2 (n = 204)
11
(7–16)
13
(8–18)
78
(72–84)
75
(68–81)
T3 (n = 87)
25
(16–35)
25
(16–35)
67
(56–75)
59
(48–69)
T4 (n = 34)
45
(27–62)
48
(31–66)
52
(34–68)
45
(27–61)
N0/NX (n = 240)
14
(9–18)
15
(11–20)
78
(72–83)
73
(67–78)
N+ (n = 85)
32
(22–42)
34
(23–44)
57
(46–67)
53
(42–63)
Tumor size <4 cm (n = 141)
11
(6–16)
13
(7–19)
80
(73–86)
76
(68–83)
Tumor size ≥4 cm (n = 184)
25
(18–31)
25
(19–32)
66
(59–73)
61
(54–68)
T2 N0/NX and size <4 cm
(n = 101)
7
(2–12)
9
(3–15)
84
(75–90)
79
(70–86)
T2 N0/NX and size ≥4 cm, T2N+,
T3, T4 (n = 224)
24
(18–29)
25
(19–31)
67
(61–73)
63
(56–69)
86
Opportunity for Treatment Improvements in
Locally Advanced Anal Cancer
• High-risk locally advanced anal cancer includes
T2 ≥4 cm, T3, T4, and/or node-positive disease
• Five-year DFS of RTOG 98-11 (5-FU/MMC/RT)
– 45% T4
– 59% T3
– 63% T2 ≥4 cm
– 53% N+
87
Ajani JA, et al. JAMA. 2008;299:1914-1921.
Immunotherapy May Fill This Unmet Need
APC
T Cell
CTLA-4
PD-1
Anti–CTLA-4
Anti–PD-L1/PD-1
Tumor Lysis
• Chakravarty, Cancer
Res 1999
• Demaria, Clin Cancer
Res 2005
• Zeng, IJROBP 2013
• Bos, JEM 2013
• Deng, JCI 2014
DNA
Damage
Cancer Cell
88
Courtesy of A. Minn.
Investigational Immunotherapeutic Approaches
to Anal Cancer Treatment
89
Clinical Trial
Population
Sponsor/CTN
Status
Phase
Intervention/
Immunotherapy
Refractory
metastatic anal
cancer
NCI
NCT02314169
Recruiting
2
Nivolumab (PD-1 inhibitor)
Metastatic anal
cancer
Advaxis
NCT02399813
Recruiting
1/2
Axalimogene filolisbac
Lm-LLO immunotherapy
Locally
advanced anal
cancer with
chemoradiation
Brown University
NCT01671488
Recruiting
1/2
Axalimogene filolisbac
Lm-LLO immunotherapy
Anal
intraepithelial
neoplasia
Academisch Medisch
Centrum – Universiteit van
Amsterdam NCT01923116
1/2
SLP-HPV-01® vaccine with
or without interferon-α
injections
Recruiting
CTN, clinical trial number.
www.clincialtrials.gov.
NCI9673: Phase 2 Study of Nivolumab in
Metastatic Anal Cancer
Simon optimal 2-stage phase 2 study in patients with ≥1 prior therapy for
metastatic squamous cell carcinoma of the anal canal and no prior
immunotherapy
Response
Patients, n (%)
CR
2 (5.4)
PR
7 (18.9)
SD
17 (45.9)
PD
8 (21.6)
Unevaluable
3 (8.1)
Median PFS = 3.9 months
Adverse events were
consistent with established
profile of nivolumab
ORR:
90
ITT, N = 37
9 (24.3)
Evaluable, n = 34
9 (26.5)
Presented by Van Morris at 2016 ASCO Annual Meeting.
Investigational Immunotherapeutic Approaches
to Anal Cancer Treatment
91
Clinical Trial
Population
Sponsor/CTN
Status
Phase
Intervention/
Immunotherapy
Refractory
metastatic anal
cancer
NCI
NCT02314169
Recruiting
2
Nivolumab (PD-1 inhibitor)
Metastatic anal
cancer
Advaxis
NCT02399813
Recruiting
1/2
Axalimogene filolisbac
Lm-LLO immunotherapy
Locally
advanced anal
cancer with
chemoradiation
Brown University
NCT01671488
Recruiting
1/2
Axalimogene filolisbac
Lm-LLO immunotherapy
Anal
intraepithelial
neoplasia
Academisch Medisch
Centrum – Universiteit van
Amsterdam NCT01923116
1/2
SLP-HPV-01® vaccine with
or without interferon-α
injections
Recruiting
CTN, clinical trial number.
www.clincialtrials.gov.
Phase 1/2 FAWCETT Study in Metastatic
Anal Cancer
Two-part study of AXAL monotherapy
• Primary endpoints: Overall response rate, 6-month
PFS, and safety and tolerability
Treatment naive in metastatic setting or
progressed after platinum-based therapy
• Secondary endpoints: Duration of response, PFS,
and overall survival
• Proceed to stage 2 if stage 1 response rate ≥10%
or if 6-month PFS ≥25%
• Note: Stage 2 may include checkpoint inhibitor
combination
Patient characteristics
• Persistent/recurrent, locoregional, or metastatic
squamous cell cancer of the anorectal canal
AXAL monotherapy
Every 3 weeks for up to 2 years
Primary endpoints:
Overall response rate
6-month PFS
• Stage 1 enrollment: 31 patients
• Stage 2 enrollment: 24 additional patients
Interim analysis and stage 2 enrollment
Additional 24 patients if ≥10% RR or ≥ 25%
6-month PFS
Trial timeline (projected)
• First patient enrollment: 3Q16
• Study completion: 2021
92
Company Confidential and Proprietary.
https://clinicaltrials.gov/ct2/show/NCT02399813.
Investigational Immunotherapeutic Approaches
to Anal Cancer Treatment
93
Clinical Trial
Population
Sponsor/CTN
Status
Phase
Intervention/
Immunotherapy
Refractory
metastatic anal
cancer
NCI
NCT02314169
Recruiting
2
Nivolumab (PD-1 inhibitor)
Metastatic anal
cancer
Advaxis
NCT02399813
Recruiting
1/2
Axalimogene filolisbac
Lm-LLO immunotherapy
Locally
advanced anal
cancer with
chemoradiation
Brown University
NCT01671488
Recruiting
1/2
Axalimogene filolisbac
Lm-LLO immunotherapy
Anal
intraepithelial
neoplasia
Academisch Medisch
Centrum – Universiteit van
Amsterdam NCT01923116
1/2
SLP-HPV-01® vaccine with
or without interferon-α
injections
Recruiting
CTN, clinical trial number.
www.clincialtrials.gov.
Preclinical Evidence of Synergy with
Lm-LLO Immunotherapy and Radiation
Lm-LLO immunotherapy can be
combined with radiation therapy and
demonstrates synergy
94
Combination therapy results in
protective immunity against
rechallenge
Hannan R, et al. Cancer Immunol Immunother. 2012;61:2227-2238.
ADXS11-001 with Mitomycin/5-FU/IMRT for Locally
Advanced Anal Cancer: Brown University Study
Open-Label Phase 1–2 Study
•
•
•
•
Biopsy
Diagnosis
N = 25
Primary stage II–III anal cancer
High risk of recurrence
HPV positive
ADXS11-001
1×109 CFU × 4 (1 prior to chemoRT and 3 post, q28 days) as a 500-mL infusion
over 30 min
Biopsy
6 months
5.5 weeks IMRT
Mito/5-FU
ADXS11-001 #1
Day –10 to 14
•
95
28 days
28 days
Follow-up
Primary efficacy
endpoint:
6-month CR rate
Mito/5-FU
ADXS11-001 #2
ADXS11-001 #3
Day +10 post-IMRT
ADXS11-001 #4
Premeds with naproxen (500 mg BID, day –1 and 0) and promethazine (25 mg BID, predose 8 hr)
https://www.clinicaltrials.gov/ct2/show/NCT02002182.
Statistical Considerations
• Goal accrual = 25
• Based on the Simon's two-stage design, the null
hypothesis that the true response rate is 50% (p0)
will be tested against a one-sided alternative. In
the first stage, 16 patients will be accrued. If there
are 10 or fewer responses in these 16 patients,
the study will be stopped early for futility
96
https://www.clinicaltrials.gov/ct2/show/NCT02002182.
Major Eligibility Criteria
• Newly diagnosed locally advanced anal cancer
• Stages: T ≥4 cm or node +
• PS 0–1
• Staging by CT/MRI or PET scan
• No significant cardiac or pulmonary disease
• Adequate bone marrow and renal function
• No HIV thus far
97
https://www.clinicaltrials.gov/ct2/show/NCT02002182.
Patient Characteristics (N = 11)
Characteristic
Age, years
<50
≥50 but <75
Median
Range
Sex
Male
Female
Stage
II
III
Lymph node involvement
N0
N1
N2
N3
98
Number
1
9
62
37–71
5
6
4
7
6
0
1
4
Personal communication: L. Kachnic, MD.
Pilot Outcomes
• Ten patients treated and alive on study since April 2013
(40% N2/N3)
• Acute grade 3 flu-like symptoms post-vaccine in 5 (gone in
24 hr); 1 patient with cardiac event from 5-FU unrelated to
vaccine
• ADXS11-001 did not worsen the toxicity profile due to
chemoradiation
• Ten patients experienced clinical CR
• One recurrence to date (systemic) at 10 months posttreatment (median follow-up for entire cohort: 2 years)
99
Personal communication: L. Kachnic, MD.
Preliminary RFS Data
RFS
T4N3
11
T3N0
10
T3N0
9
T3N3
8
T2N0
7
T4N0
6
T3N3
5
T4N0
4
T2N2
3
T3N3
2
Patient progressed systemically
Patient expired unrelated to study treatment
0
200
400
600
800
1000
1200
Relapse-Free Survival (Days)*
Median Follow-up 741.5 Days (IQR 1063)
10
0
Note: Patient #1 enrolled but was never treated on study.
*As of Mar 27, 2016.
Personal communication: L. Kachnic, MD.
A Phase 2–3 Trial Evaluating
ADXS11-001 with Mitomycin, 5-Fluorouracil
(5-FU), and IMRT for Locally Advanced
Anal Cancer
Hypothesis: ADXS11-001, utilizing Listeria as a vector
to deliver a fusion protein of listeriolysin with HPV E7,
will stimulate MHC class I and II pathways, activating
CD4+ and CD8+ T cells, decreasing locoregional
failure (LRF) and increasing disease-free survival
(DFS) as compared to chemoradiation (CRT) alone
10
1
Primary Objective
• Phase 2-R: Determine if the addition of ADXS11-001
will provide a sufficient signal for reduced LRF when
added to standard CRT for patients with locally
advanced anal cancer, to warrant the full phase 3
trial
• Phase 3: Determine if the addition of ADXS11-001
will improve DFS when added to standard CRT for
patients with locally advanced anal cancer
10
2
Secondary Objectives
•
Overall survival (Failure: Death due to any cause)
•
ADXS11-001–related adverse events (per CTCAE v4.0 criteria)
•
Adverse events (per CTCAE v4.0 criteria)
– ADXS11-001 impact on chemoRT AEs
– ADXS11-001 related
– All AEs
•
To evaluate immune markers with ADXS11-001 treatment and correlate with
DFS and OS
– Serum cytokines
– PBMC phenotype characterization
– HPV subtyping correlated to outcomes
•
To evaluate PROs
– EORTC QLQ-CR29
– PROMIS Fatigue (sample size information)
– Sexual function; vaginal function
103
Eligibility Criteria
•
Histologically proven, invasive primary squamous, basaloid, or cloacogenic
carcinoma of the anal canal
•
AJCC 2009 TN stage T1 N2–N3; T2 (<4 cm) N1–N3; T2 (≥4 cm) N0–N3, T3
N0–N3, T4 N0–N3; based on the following diagnostic workup
– Physical exam
– Anal exam by one of the following: anoscopy, sigmoidoscopy, rigid proctoscopy, or
colonoscopy
– Biopsy confirmation within 42 days before registration
– CT scan, MRI, or PET/CT scan of the abdomen/pelvis
104
•
ECOG performance status ≤1
•
Age >18
•
Lab data with adequate bone marrow, hepatic, and renal function
•
HIV NOT eligible (Advaxis Inc. will perform own pilot)
Schema
Arm 1 Standard Treatment Schedule
5-FU: 1 g/m2/day × 96 hours beginning on day 1–4 and day 29–32 +/– 72 hours
Mitomycin: 10 mg/m2, day 1 and 29 (day 29 can be +/– 72 hours)
IMRT: Primary tumor PTV (PTVA) will receive 54 Gy in 30 fxs
If N0, nodal PTVs will receive 45 Gy in 30 fxs at 1.5 Gy per fxs
If N+ involved nodes PTV (PTV54) will receive 54 Gy in 30 fxs
Arm 2 Experimental Treatment Schedule
The first dose of ADXS11-001 will be given 6–14 days prior to CRT
The 2nd–4th dosages of ADXS11-001 will be given after completion of CRT at 28 day
intervals (/+7 days)
ADX #1
6–14 days
pre-RT
Biopsy
ADX #2
Mito/5-FU
Day 1–4
Mito/5-FU
Day 29–32
+/– 72 hr
ADX #3
ADX #4
Biopsy at
6 months
IMRT for 5.5 weeks
Targeted accrual, N~264
105
Statistical Design
106
•
Patients will be stratified by gender and nodal status
•
Randomized 1:1 to chemoradiation with or without ADX
•
Phase 2: Two-year LRF for the chemoradiation alone arm is assumed to be
25% (98-11/0529 high-risk pts) and it is hypothesized that the addition of ADX
will decrease 2-year LRF to 13%, corresponding to a HR of 0.48 (1-sided type 1
error 0.05; 85% power); 170 pts
•
Phase 3: Three-year DFS for the chemoradiation alone arm is assumed to be
58% (98-11/0529) and it is hypothesized that the addition of ADX will increase
3-year DFS to 72%, corresponding to a HR of 0.60 (2-sided type 1 error 0.05;
85% power); 94 additional pts (total 264)
•
Accrual projected to be 5 pts/month (98-11/0529 high-risk pts); 5 years
•
Two interim analyses per year (w/significance testing for early termination or
reporting)
Updates/Next Steps
• Advaxis support for all endpoints including
correlatives
• Approved by NRG research strategy
• Approved by NCI Rectal Anal Task Force
• Approved by NCI IRCI
• Under discussion as RTOG Foundation Study
107
AXAL in Anal Cancer: Summary and Conclusions
• For metastatic disease, no standard
– InterAACT trial underway
– AXAL may be first- or second-line therapy
– Role of dual immuno-inhibition prime for evaluation
• For locally advanced disease, RT/5-FU/MMC still remains
standard, but local control is suboptimal
– RTOG 98-11/ACT II showed adjuvant chemotherapy of no
benefit
– EGFR inhibition is no longer being evaluated
– AXAL in cervical cancer and anal pilot encouraging
– Discuss next steps for initiating a study in this population
108
ADXS‐PSA
Mark Stein, MD
ADXS-PSA in prostate cancer
Mark Stein M.D.
Associate Professor of Medical Oncology
Rutgers Robert Wood Johnson Medical School
Advaxis Investor & Analyst Meeting June 28, 2016
Burden of prostate cancer
• Prostate cancer is the
second most common cancer
in men in the United States
and the second leading
cause of cancer death in
men1
– Occurs more often, and has
a higher mortality rate, in
African-American men than
in other racial/ethnic
groups2
1. http://www.cancer.gov/types/prostate; 2. http://www.cancer.gov/research/progress/snapshots/prostate.
Clinical States Model of Prostate Cancer
59,000/yr
*Estimated incidence in 2020
260,0000/yr
Localized
Prostate
Cancer
Non-metastatic
Castrate Resistant PC
(nmCRPC)
98,000/yr
13,000/yr
Non-metastatic
Rising PSA
(nmHSPC)
Metastatic
Androgen sensitive
PC (mHSPC)
Treatment
Androgen deprivation (ADT)
Salvage Radiation
Observation
Trial
Stein M, Jang T Journal Clinical Oncology 2016
Scher H et al Plos One 2015
Treatment
Androgen deprivation +/docetaxel chemotherapy
57,000/yr
ADT
1st line metastatic
Castrate Resistant PC
(mCRPC)
21,000/yr
2nd Line
mCRPC
(and beyond)
Treatment
ADT plus
Androgen receptor targeted therapy
--enzalutamide/ abiraterone
Sipuleucel-T
Docetaxel
Cabazitaxel (approved for use after docetaxel)
Radium-223
Mitoxantrone
Trial
Survival in Patients With mCRPC
•
nmCRPC
Survival (months)
45
Metastatic
CRPC
35
Patients with metastatic and/or
castration-resistant prostate
cancer (CRPC) have a poor
prognosis
– Median survival ranged from 45
months for nmCRPC in 20101
– Median survival 35 mos
metastatic prostate cancer
2015 2
–
5-year survival was 28% with
metastatic disease, compared to
~100% for locoregional disease3
0
1. Smith MR. Lancet 2012:39; 2. Enzalutamide (ENZA) in men with chemotherapy-Naïve metastatic castration-resistant
prostate cancer (mCRPC): Final analysis of the phase 3 PREVAIL study; ASCO 2015;
3. http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-survival-rates.
Why Immunotherapy
Verdeil G et al 2015 Acta Biochemica et Biophysica acta
Therapeutic Vaccines vs. Conventional Therapy
Target
Conventional Therapy
Therapeutic Vaccines
Tumor or its
microenvironment
Immune system
Pharmacodynamics Often immediate action
Delayed
Memory Response
No
Yes
Tumor Evolution /
new mutations
Resistance to therapy
New immunogenic targets
Limitations
Toxicity
Requires adequate immune
system function (both
systemically and at tumor site)
Gulley et al., ASCO Education Book, 2013.
Overcoming Tumor Immune Evasion
Pico de Coana Trends in Molecular Medicine, August 2015.
Training a T-cell
T-cell Checkpoints and Agonists
Melero I et al. Clin Cancer Res. 2013;19:997-1008.
Sipuleucel-T (Provenge) Proposed
Mechanism of Action
119
Sipuleucel-T (Provenge)
DAY 1
LEUKAPHERESIS
DAY 2–3
PROVENGE (SIPULEUCEL-T)
DAY 3–4
PATIENT IN INFUSED
IS MANUFACTURED
The patient gets standard blood
collection where white blood
cells are extracted for treatment.
120
The patient’s peripheral blood
mononuclear cells (PMBCs) are
separated from other white blood
cells using proprietary
technology.
The physician administers the
patient’s PROVENGE
intravenously.
Complete course of therapy: 3
cycles
Sipuleucel-T
First Cancer Vaccine Approved by the US FDA
P = 0.03 (Cox model)
HR = 0.78 [95% CI: 0.614, 0.979]
Median Survival Benefit = 4.1 Mos.
No Change in
Time to
Progression
Sipuleucel-T (n = 341)
Median Survival: 25.8 Mos.
Placebo (n = 171)
Median Survival: 21.7 Mos.
Kantoff et al. NEJM 2010.
PSA-TRICOM (PROSTVAC-VF) Proposed Mode of Action
Tumor antigen gene
PSA
Costimulatory molecule genes
LFA-3
ICAM-1
B7-1
(TRIad of COstimulatory Molecules)
Induction of tumorspecific immune
responses (T-cells)
Vaccines:
PROSTVAC-V
PROSTVAC-F
Developed at NCI
CRADA with BNIT
122
122
PSA-TRICOM: Overall Survival
Overall survival (% patients)
100
80
N
Deaths
Median
Control
40
37
16.6
PSA-TRICOM
82
65
25.1
60
∆ 8.5
months
Hazard ratio:
0.56 (95% CI 0.37–0.85)
p=0.0061
40
20
PSA-TRICOM
Control
0
0
12
24
36
Months
Kantoff…Schlom, Gulley et al. J Clin Oncol 2010.
48
No Change in
Time to
Progression
60
Phase 3 PROSPECT Trial Design
Asymptomatic/
minimally
symptomatic
mCRPC
patients
R
a
n
d
o
m
i
z
a
t
i
o
n
Long-term Follow-up
(every 6 mo for 5 yr)
Treatment Phase
(5 mo)*
PSA-TRICOM + GM-CSF**
(n = 400)
PSA-TRICOM (n = 400)
Vector Placebo
(n = 400)
1 3
Prime
5
9
13
17
S
U
R
V
I
V
A
L
21
Boosts
Vaccination Weeks
124
*at the end of the 5 month treatment phase, use of other therapies for mCRPC is at the discretion of the investigator
**low-dose adjuvant (100 µg) SC days 1-4 of each vaccination
Vaccines in Combination with Other Therapies May
Improve Time To Progression
†
†
†
Tumor Burden
Vaccine
Cytotoxic Therapy
Combination
Time
Stein WD, Clin Cancer Res, 2010.
Madan RA, Semin Oncol, 2012.
Progression
Progression
Immunotherapy for Prostate Cancer
•
•
•
Phase I Study of PDA/IL-2/GM-CSF-containing prostate cancer vaccine
in PSA-defined biochemical recurrent prostate cancer1
–
8 of 11 patients who received all 6 vaccines had increased immune responses to PSA in
lymphocyte blastogenesis assay by week 19
–
6 of 10 evaluable patients had an increase in serum PSA doubling time
Ongoing Phase I/2 Study of ipilimumab with abiraterone acetate plus
prednisone in chemotherapy- and immunotherapy-naïve patients with
progressive castration-resistant prostate cancer (CRPC)2
–
2 of 5 patients treated with the lead-in schedule had PSA decreases
–
2 of 4 patients receiving concomitant treatment had PSA decreases
Phase I Study of nivolumab in solid tumors (N=296; CRPC, n=17)3
–
No objective response among CRPC cohort; 2 of 2 tested biopsy samples were PD-L1negative
1. Daniels G, et al. ASCO 2016. Abstract e14584; 2. Danila, DC, et al. ASCO 2016. Abstract e16507; 3. Topalian S, et al. N Engl J
Med. 2012;366:2443-2454;.
Rational behind Use of Lm System
Advaxis LM Technology™ stimulates a tumortargeted immune response directed by plasmids
...so that cancer can be recognized
...and killed
PSA
PSA
Attenuated Lm trigger a robust immune
response and bioengineered plasmids
generate a fusion protein, tLLO-PSA
PSA activates cytotoxic
T-cells targeted against the tumor
T-cells target PSA on
tumor cells and tLLO
causes inhibition of Treg
and MDSC function in
the TME, reducing the
tumor’s protective shield
APC, antigen presenting cell; Lm, Listeria monocytogenes; MHC, major histocompatibility complex; TCR, T-cell receptor; MDSC, myeloid-derived
suppressor cells; TAA, tumor-associated antigen; tLLO, truncated listeriolysin O; Treg, regulatory T cell; TME, tumor microenvironment
127
Copyright Advaxis 2016.
Lm-LLO-PSA (ADXS-PSA) Recruits Antitumor
Response Against Experimental Prostate Tumors
IFN-γ
•
ADXS-PSA is more active in shrinking prostate tumors in mice than
existing anti-PSA pDNA and vaccinia vaccines
Shahabi V, et al. Cancer Gene Ther. 2011;18(1):53-62.
Combined ADXS-PSA + Radiation Recruits
Antitumor Response > Monotherapy
IFN-γ
Augmented antitumor response with combination RT + ADXS-PSA
• Increased enrichment of PSA-specific CD8+ T cells
• Increased IFN-γ secretion capacity
Hannan R, et al. Cancer Immunol Immunother. 2012;61(12):2227-2238.
Rationale for Lm
Technology + Anti-PD-1
Lm Technology seeks to increase
tumor antigen specific T-cells
•
Goal = production of tumor-infiltrating
lymphocytes against the cancer
Interaction of PD-1 receptor
expressed on T cells with its
ligand, PD-L1, expressed by
tumor cells, can dampen T-cell
receptor signaling
•
•
Molli P, Wallecha A. AACR 2015. Abstract 2513.
Suppresses activation and proliferation of
T cells
Inhibits the potential infiltration of activated
lymphocytes into the tumor
Preclinical Rationale for Combination Trials of
Lm-LLO and Checkpoint Inhibitors
HPV Tumor Model
TC-1 tumor
implantation
Percent Survival
0
Tx 1
Tx 2
8
Days
15
Treatments:
Lm-LLO-E7 (AXAL):
5x106 cfu
CT-011 mAb:
50 μg
Days after tumor implantation
Lm immunotherapy is synergistic with checkpoint
inhibitors
Data from Mkrtichyan M, et al. J Immunother Cancer 2013, 1:15 doi:10.1186/2051-1426-1-15.
ADXS-PSA: Phase 1/2 Dose Escalation and Safety Study Alone and Combined with anti-PD-1
(Pembrolizumab)
•
N = 21 (Part A); N = 30 (Part B) [Total N = 51]
•
•
Pretreated metastatic castration-resistant
prostate cancer (CRPC)
mTPI Design (Part A) to determine recommended Phase 2
dose (RP2D)
•
Following the completion of enrollment and the safety
evaluation of ADXS-PSA in Part A, Part B combination arm
with pembrolizumab will commence
•
Part B ADXS-PSA Dose = Part A recommended Phase 2
dose (DL-1) + Pembrolizumab
•
No more than 3 prior systemic treatment
regimens with chemotherapy, hormonal, or
immunotherapy or >1 prior chemotherapeutic
regimen in the metastatic setting
WEEK 1
Part A
WEEK 4
WEEK 7
REPEAT Q 12 WEEK CYCLES
ADXS-PSA Monotherapy
Up to PD or
2 years
Dose escalation (3 dose levels)
Endpoints: To determine safety and RP2D
ADXS-PSA
N = 21
Part B
ADXS-PSA
ADXS-PSA
WEEK 1
ADXS-PSA
WEEK 4
WEEK 7
Dose determination and confirmation
ADXS-PSA
ADXS-PSA
ADXS-PSA
Endpoints: To determine safety and RP2D of the
combination
Up to PD or
2 years
N = 30
Keytruda®
In collaboration with
132
REPEAT Q 12 WEEK CYCLES
+ Keytruda®
Keytruda®
Keytruda®
https://clinicaltrials.gov/ct2/show/NCT02325557
KEYTRUDA® is a registered trademark of Merck & Co., Inc.
ADXS-PSA: Phase 1/2 Dose Escalation and Safety Study
Alone and Combined with anti-PD-1 (Pembrolizumab)
Dose level 1 - 1 x 109 cfu of ADXS-PSA – 4 patients
Dose level 2 - 5 x 109 cfu of ADXS-PSA – 3 patients
Dose level 3 - 1 x 1010 cfu of ADXS-PSA – 3 patients
Planned Expansion — Dose level 1 (1 x 109 cfu of ADXS-PSA) in combination with
pembrolizumab 200 mg
Dose-limiting toxicities:
Dose level 3 – hypotension; hypertension
Common AEs: rigor, fevers, nausea
Longest Duration on study dose level 1 – 3.5 months*
*clinical hold – came off treatment
133
Future directions for ADXS-PSA
Non-metastatic
Castrate Resistant
PC
(nmCRPC)
Localized
Prostate
Cancer
Non-metastatic
Rising PSA
(nmHSPC)
Treatment
Androgen deprivation (ADT)
Salvage Radiation
Observation
Trial
134
Metastatic
Androgen sensitive
PC (mHSPC)
Treatment
Androgen deprivation (ADT)
+/- chemotherapy
ADT
1st line metastatic
Castrate Resistant
PC
(mCRPC)
2nd Line
mCRPC
(and beyond)
Treatment
ADT plus
Androgen receptor targeted therapy
--enzalutamide/ abiraterone
Sipuleucel-T
Docetaxel
Cabazitaxel (approved for use after
docetaxel)
Radium-223
Mitoxantrone
Trial
E9802:Vaccinia/Fowlpox-PSA/TRICOM/GMCSF in patients
with PSA Progression after local therapy
Progression
Progression
PROSTVAC-V/TRICOM (Vaccinia) on
cycle 1 followed by PROSTVACF/TRICOM (Fowlpox) on further
cycles each with GM-CSF s.c. on
days 1-4 q4 wks for 4 cycles then q
3 months
Addition of
Bicalutamide 50mg
PO q day and
LHRH agonist to
vaccine therapy
Primary endpoint: progression at 6 mo and
characterization of change in PSA velocity
pretreatment to post-treatment
Discontinue protocol
vaccine therapy
SD or Resp
Continue LHRH agonist
with continued vaccine
therapy with GM-CSF on
days 1-4 q 3mo until
progression
Progression:
• PSA progression was defined as an increase in PSA value >50% of baseline (on trial) or nadir PSA,
whichever was lower, confirmed by a repeat PSA 2 wk later. The PSA must have risen by at least 5 ng/ml.
• Metastasis/death
135
Median PFS was 12.0 mo (95% CI, 7.4–14.7)
Figure 2: Log-Transformed PSA over Time. To determine the change in
PSA velocity pre-treatment to post-treatment, a linear mixed effects
model was fitted. Black lines are PSA values for each patient prior to
registration and during treatment; blue line is the average trend using
a lowess smoothed curve.
The PSA slope prior to registration was 0.13 log PSA/month
PSADT 5.3 months
post-registration slope of 0.09 log PSA/month
PSADT 7.7 months; p=0.002
DiPaola, Chen, Bubley, Stein et al. Eur Urol. 2015:365.
Combining androgen deprivation and
immune therapy
•
•
•
Mouse model data have suggested that enzalutamide can also enhance thymic
production of naive T cells
TRAMP mice +/-enzalutamide +/-vaccine
Study demonstrated the immunogenic modulation property of enzalutamide and
improved OS in mice treated with combination enzalutamide and vaccine compared
to no treatment, vaccine alone, or enzalutamide alone
Ardiani et al Clin Ca Res 2013:6205.
ADT stimulates T-cells in humans
Androgen ablative therapy to induce Tcell infiltration of prostate tissue was demonstrated in a
study by Mercader (Proc Natl Acad Sci U S A 2001)
Increase in naive T-cell production by the thymus after testosterone suppression therapy is
initiated (Williams Blood 2008:3263)
Enzalutamide increases population of naïve T-cells in thymus (Madan GU ASCO 2016)
Mercader M et al. Proc Natl Acad Sci U S A 2001
Testing ADXS-PSA for rising PSA
R (2:1)
N=100
ADT
Primary objective: To determine if ADXS-PSA plus ADT will
improve recurrence free survival compared to ADT alone
Secondary objectives:
- To determine if ADXS-PSA will improve metastasis free
survival compared to historical controls
- To determine if initial ADXS-PSA plus ADT will improve
metastasis free survival compared to ADT
J Clin Oncol. 2016 Jun 1;34(16):1913.
PSA Recurrence free survival
PSA
Recurrece
PSADT
≤ 9 mo
ADXS-PSA x 7 mo
ADT x 6mo
(starting month 1)
ADXS-PSA x 7 mo
ADXS-PSA x 7 mo
M
E
T
A
S
T
A
S
I
S
(M1)
Assume median time to PSA relapse will be 6 months
among patients treated with ADT alone and 12 months
among patients treated with ADT+B (HR = 0.50 ADT+B :
ADT). Total of 68 events will be required to provide 80%
power with one-sided a=0.025 and allowing one interim
analysis. A total of 100 patients will be enrolled and
randomized (67:33)
ADT=androgen deprivation therapy
Testing ADXS-PSA with salvage radiation
140
N to be determined based on statistical assumptions.
Testing ADXS-PSA with salvage radiation
N=110
2:1
Primary objective: To determine if ADXS-PSA
plus salvage RT and ADT will improve
recurrence free survival compared to RT and
ADT for 6 months
Assume the median PFS is 36 months. A total
of 110 patients will be enrolled and randomized
to detect 50% improvement in median PFS
with 80%.power
141
Arm B: combined androgen blockade (LHRH
agonist + oral anti-androgen) given for 24
weeks with external beam radiation therapy to
the prostate bed beginning week 9.
PSA Recurrence free survival
1) Randomize
2) Stratify by Gleason
7 (3+4) or lower vs
7 (4+3) or higher
Arm A: combined androgen blockade (LHRH
agonist + oral anti-androgen) given for 24
weeks with external beam radiation therapy to
the prostate bed beginning week 9.
plus
ADXS-PSA 25 weeks starting with the initiation
of combined androgen blockade as described
above.
305 College Road East
Princeton, NJ
www.advaxis.com [email protected]
142
Thank you
Evolution of Immunotherapy Response: Patient Example
Screening
Week 12
Increased inflammation, fungating appearancen new
small lesion evident
Week 16
Responding
Week 72
Durable & ongoing response