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Game plan for therapeutic cancer vaccines
 

Game plan for therapeutic cancer vaccines

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Pioneering novel therapeutics is always an uncertain endeavor. Thus, the story of therapeutic cancer vaccine development has been a story of challenges, but they are not insurmountable.

Pioneering novel therapeutics is always an uncertain endeavor. Thus, the story of therapeutic cancer vaccine development has been a story of challenges, but they are not insurmountable.

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    Game plan for therapeutic cancer vaccines Game plan for therapeutic cancer vaccines Presentation Transcript

    • Game Plan for Therapeutic Cancer Vaccines style Click to edit Master title Presented by: Mark Shapiro, MBA, MA, RAC Click to edit Master title style Nikolas Burlew, RQAP-GLP Todd Clark, MBA Catherine McCall, D. Phil
    • Sponsors Clinipace Worldwide: Oncology Drug Development Drug Development Regulatory Clinical Development Pharmacovigilance Post-Approval clinipace.com Click to edit Master title style VOI Consulting: Oncology Consulting & Publishing Value of Insight Consulting, Inc. (VOI) is a pharmaceutical consulting and publishing company dedicated to providing pharmaceutical and biopharmaceutical clients with Click to edit Master title style fact-based analysis and business intelligence to meet market challenges in today’s highly competitive global environment. VOI Publications The Oncology Roadmap pharmahandbook® voiconsulting.comRIGHT-SIZEDTM CLINICAL RESEARCH SERVICES www.clinipace.com
    • Types of Therapeutic Anti-Cancer Vaccines Vaccine Type Viral Vector / Antigen/Adjuvant Whole Cell Vaccines DNA-based Vaccines Vaccines Click to edit Master title style Autologous Allogeneic GM2 ganglioside vaccine combined with the QS- 21 adjuvant (GMK) plasmid DNA vaccine expressing the Melan- A/MART antigen Effective, but inferior to high- Melan-A/MART-1 specific T Dendritic Cell Vaccines Click to edit Master title style CanVaxin™, irradiated allogeneic melanoma cell line dose IFN (another cell responses were evident immunotherapy) in Phase III by ELISPOT, but no HBsAg- plus BCG ) trial specific antibodies detected Provenge (sipuleucel-T), isthe first approved cell-based vaccineRIGHT-SIZEDTM CLINICAL RESEARCH SERVICES www.clinipace.com
    • Click to edit Cancer Vaccine Trends in Master title style Development title style Click to edit Master & Lessons Learned
    • Status of Cancer Vaccine Research ~230 vaccines are in Melanoma, breast, and lung have Lung cancer has more clinical development the highest overall activity late-stage candidates 90 81 4 80 Phase III 4 75 45 70 40 Phase II/III 65 35 Phase II 3 60 30 Phase I/II Click to edit Master title style 50 25 Phase I 2 40 2 20 30 15 1 1 1 20 1 10 10 8 Click to edit Master title style 5 2 0 0 0Source: Dayoub, E., Davis, MM. Relationship of therapeutic cancer vaccine development to population disease burden and five-year survival. Human Vaccines Nov 2011; Data H1 2011 RIGHT-SIZEDTM CLINICAL RESEARCH SERVICES www.clinipace.com
    • Geography of Cancer Vaccine Research Site Locations for Phase III Cancer Trials 45% 40% 39% 36% Non-Vaccine Phase III Pivotal Trials (2005-2011) Vaccine Phase III Trials 35% 32% 30% 28% 25% 20% 15% 10% Click to edit Master title style 9% 14% 7% 6% 4% 5% 4% 3% 5% 3% 2% 3% 1% 1% 1% 0% Click to edit Master title styleSources: Pivotal trial data from Oncology Clinical Trials: The Roadmap to FDA Approval. VOI Consulting / insiteinvestigator database; Vaccine trial locations from clinicaltrials.gov andpublished articles on Phase III trials RIGHT-SIZEDTM CLINICAL RESEARCH SERVICES www.clinipace.com
    • Trial Design PRIMARY ENDPOINT COMPARISON ARM Vaccine trials are much more likely than other cancer Placebo controls are also much more studies to feature overall survival as a primary endpoint: common: 70% 62% 60% 69% 60% Non-vaccine Non-vaccine Phase III 50% Pivotal Trials (2005-2011) 40% Vaccine 30% 24% 20% 20% 20% Click to edit Master title style 14% 37% 10% 0% Active Passive Placebo 22% 15% 15% 12% 10% 12% Click to edit Master 6% style title 0% 0% 0% Progression Free Survival Overall Survival Time to Progression Disease Free Survival Response Rate Other RANDOMIZATION Vaccine trials also tend to overweight the investigative arm: ~75% of Phase III studies have 2:1 randomization as compared to >10% of non-vaccine pivotal cancer trials.Sources: Pivotal trial data from Oncology Clinical Trials: The Roadmap to FDA Approval. VOI Consulting / insiteinvestigator database; Vaccine trial data from clinicaltrials.gov andpublished sources. Passive controls can take the form of comparisons to best supportive care or the lack of investigational drug in the comparison arm. RIGHT-SIZEDTM CLINICAL RESEARCH SERVICES www.clinipace.com
    • Trial Size Cancer vaccine trials, on average, are smaller than Phase III pivotal trials for other cancer drugs. However, cancer vaccine trials currently underway are very similar in terms of # of patient & sites. Parameter Phase III Trial Type Average Median Min Max Number Patients Non-Vaccine (Actual) 667 571 100 3387 Click to edit Master title style Vaccine (Actual) 256 177 98 512 Vaccines (Projected) 687 568 230 1476 Number of Sites Non-Vaccine (Actual) Master title style Click to edit 106 88 19 476 Vaccine (Actual) 40 27 17 75 Vaccines (Projected) 108 76 10 295Sources: Actual trial data from Oncology Clinical Trials: The Roadmap to FDA Approval. VOI Consulting / insiteinvestigator database; Projected vaccine trials data from clinicaltrials.gov. RIGHT-SIZEDTM CLINICAL RESEARCH SERVICES www.clinipace.com
    • Randomization Rates To date, Phase III cancer vaccine trials have experienced substantially lower randomization rates. This problem has led to a discontinuation of at least one trial (i.e. BiovaxID had a 563 patient target but enrolled only 234 after ~8 years). 0.25 Accrual Rates (Number of Randomized Patients per Site per Enrollment Month) 0.23 -14% 0.21 0.20 0.19 -29% 0.15 Click to edit Master title style 0.15 0.10 Non-Vaccine (Actual) Click to edit Master title style Vaccine (Actual) 0.05 0.00 Average MedianSources: Oncology Clinical Trials: The Roadmap to FDA Approval. VOI Consulting / insiteinvestigator database. BiovaxID information from Schuster, S. Vaccination With Patient-SpecificTumor-Derived Antigen in First Remission Improves Disease-Free Survival in Follicular Lymphoma. Journal of Clinical Oncology Jul 10 2011 RIGHT-SIZEDTM CLINICAL RESEARCH SERVICES www.clinipace.com
    • Screening Rates Slow accrual may be due in part to high screen failure rates for vaccine trials (average = 29% as compared to <20% for pivotal trials of other cancer drugs). Provenge (D9901) Provenge (D9902A) Provenge (D9902B) Screened = 186 Screened = 116 Screened = 926 Excluded = 59 Excluded = 18 Excluded = 414 (32%) (16%) (45%) Click to edit Master title style Randomized = 127 (68%) Randomized = 98 (84%) Randomized = 512 (55%) BiovaxID mitumprotimut-T Screened = 495 Click to edit Master title style Screened = 234 Excluded = 57 Excluded = 131 (24%) (26%) Randomized = 177 Randomized = 364 (76%) (74%)Source: Oncology Clinical Trials: The Roadmap to FDA Approval. VOI Consulting / insiteinvestigator database RIGHT-SIZEDTM CLINICAL RESEARCH SERVICES www.clinipace.com
    • Cancer Vaccine Development Lessons Learned In comparison to the design and execution of other types of cancer trials, vaccine studies show more similarities than differences (e.g. number patients, number sites, locations). Nonetheless, there are important differences: Overall survival strongly preferred as primary endpoint. Click to edit Master title style Placebo controls and 2:1 randomization are the norm. Expect high screen failure and slower randomization rates. Fewer sites with vaccine experience  particularly in developing markets (with the exception of Central/Eastern Europe). Click to edit Master title style Expect strict regulatory scrutiny regarding efficacy and labeling that reflects the studied population.RIGHT-SIZEDTM CLINICAL RESEARCH SERVICES www.clinipace.com
    • Click Regulatory Strategy style to edit Master title Click to edit Master title style
    • FDA Regulatory Framework Regulated by FDA’s Center for Biologics Evaluation and Research Reviewed by Office of Cellular, Tissue and Gene Therapy (CBER) CDER and CDRH may be involved in product review Click to edit Master title style Investigational New Drug (IND) application required for clinical trials in humans. FDA strongly recommends a pre-IND meeting to discuss study design, CMC and nonclinical (toxicology) plans Click to edit Master title style Biologics License Application (BLA) required for marketing approval In parallel, device approval may be required for delivery device, companion diagnosticRIGHT-SIZEDTM CLINICAL RESEARCH SERVICES www.clinipace.com
    • Regulatory Challenges CMC can be very difficult Patient selection Conventional dose-escalation to reach MTD not relevant Use of adjuvants, companion diagnostic, delivery device Clinical response is often delayed Click to edit Master title style Need to develop standardized assays Importance of placebo vs. active comparator group Standard clinically meaningful endpoint may not be relevant Click to edit Master title styleRIGHT-SIZEDTM CLINICAL RESEARCH SERVICES www.clinipace.com
    • Regulatory Considerations {EU vs. USA} Overview of ATMPs • European Legislation differentiates between Small Molecule Entities (SMPs) and Advanced Click to edit Master title style Therapy Medicinal Products (ATMPs) • Different Competent Authority (CA) and Ethics Committee (EC) approval timelines Click to edit Master title style • Separate GCP Guidelines for ATMPsRIGHT-SIZEDTM CLINICAL RESEARCH SERVICES www.clinipace.com
    • EU Study Start-up TimelineThrough the EMEA, there is a common framework for initiating clinicaltrials in EU Member States. ID Task name Duration Month 1 Month 2 Month 3 Month 4 Month 5 Month 6 1 Total elapsed time 24W Compilation of 2 5W Click to edit Master title style submission 3 Competent Authority 5W 4 to 6 weeks 4 Ethics Committee 10W 5 Site-specific assessment 8W 6 to 12 weeks Click to edit Master title style 6 CTA negotiations 16W 7 R&D (UK only) 5W 6 to 12 weeks 8 Importation & Initiation 3W 4 to 6 w 2 to 4 wRIGHT-SIZEDTM CLINICAL RESEARCH SERVICES www.clinipace.com
    • Voluntary Harmonisation Procedure Voluntary Harmonization Procedure •Launched as a EU pilot project in February 2009 •Amended guidelines issued in March 2010 •Facilitates multinational Competant Authority (CA) Click to edit Master title style submissions across the EU •A coordinated assessment of an application for a clinical trial •The trial must still be authorized at national level •Consists of 3 phases to edit Master title style Click •Centralized assessment but not centralized approval •MINIMUM TIMELINE: 45 DAYS •MAXIMUM TIMELINE: 75 DAYS* * IF ASSESSMENT OF LOCAL DOCUMENTATION IS SATISFACTORYRIGHT-SIZEDTM CLINICAL RESEARCH SERVICES www.clinipace.com
    • Expected Approval Timelines ATMP *** VHP max * ** Click to edit Master title style VHP min Click to edit Master title style AT FR DE IT NL SE ES UK* ES: VHP tbc; non ATMP** UK: 30 to 60 days*** FR: 60 to 90 days RIGHT-SIZEDTM CLINICAL RESEARCH SERVICES www.clinipace.com
    • Click to editDevelopment Clinical Master title style Click to edit Master title style
    • Selection of Tumor Tumor Selection Many Types with Known Responsiveness to Immunotherapies Click to edit Master title style Solid Tumors edit Master title style Click to Hematologic tumors Melanoma: IFN, IL-2, autologous LAK/TIL, anti- CTLA-4 (Yervoy) NHL/CLL: Rituxan Renal cell : IL-2, autologous LAK/TIL CML: Interferon alpha Colon cancer: Levamisole Bladder cancer: BCGRIGHT-SIZEDTM CLINICAL RESEARCH SERVICES www.clinipace.com
    • Key Study Design Issues Indication Regimen Randomization Control Endpoint Placebo Click to edit Master title style Tumor Stage Single-agent TTP Non-randomized Control PFS Treatment Combination Randomized Active line Comparator DFS Click to edit Master title style OSRIGHT-SIZEDTM CLINICAL RESEARCH SERVICES www.clinipace.com
    • Definition of the Patient Population Inclusion Exclusion • Early- vs. late- • Poor functional Click to edit Master title style stage disease? • Resectable tumor status (ECOG >1) • Prior immunotherapy • Histopathology Click to edit Master title Autoimmune • style • Tumor genotype? diseases? • Prior treatment? • NeutropeniaRIGHT-SIZEDTM CLINICAL RESEARCH SERVICES www.clinipace.com
    • Randomized Trials in Phase II Design Phase 3 Study • Select measurable and clinically meaningful endpoint • Define a clinically relevant risk • Determine number of events based on 90% power Click to edit Master title style Design Phase 2b Screening Study • Randomized, controlled design using the phase 3 study endpoint • Determine number of events (approximately 25% of phase III) • Determine threshold for phase 2 success, e.g. RR = 0.82 Conduct Phase 2b Screening Study edit Click to Master title style • Pre-determine decision-making criteria, e.g. • Observed RR > 0.82  “no go” • Observed RR between 0.71 and 0.82  further evaluation required • Observed RR < 0.71  “clear signal, green light phase 3RIGHT-SIZEDTM CLINICAL RESEARCH SERVICES www.clinipace.com
    • Endpoint Selection Overall Survival PFS/TTP/DFS Faster trial, especially good for slow Rapid disease progression of pivotal study disease progression or POC studies Requires less frequent subject visits Imaging becomes pivotal thus greater cost meaning less complicated and costly associated with IAC, independent reads, Click to edit Master title style studies Requires longer duration studies than PFS and image management Imaging more frequent than SOC which and other endpoints based on tumor size means more expense and complexity for or progression sites In a pivotal study, OS provides a strongerto Click edit Master title Immune recruitment to tumor sites can style basis for approval than PFS or TTP appear as progression under RECIST 1.1RIGHT-SIZEDTM CLINICAL RESEARCH SERVICES www.clinipace.com
    • Click to edit & Site Selection Feasibility Master title style Click to edit Master title style
    • Country Selection Country selection based on a robust feasibility will provide the best chance of success for a trial where there is little precedent in most countries for anti-cancer vaccines Regulators outside the US may be unfamiliar and thus slower to approve trials with cell-based immunotherapy Click to edit Master title style Exportation of tissue samples for vaccine production is highly regulated in certain countries Importation and customs delays can put vaccine shipments at risk Concentrating sites in emerging markets will hurt uptake at product launch because the complexClick to of anti-cancer vaccines means that nature edit Master title style prescribers need significant experience during clinical trials to establish commercial useRIGHT-SIZEDTM CLINICAL RESEARCH SERVICES www.clinipace.com
    • Site Selection Site selection can include identification and evaluation of surgeons, pathologists, leukapherisis centers, and medical oncologist Site-specific capabilities and regulations, e.g. dedicated glove box for adjuvants, e.g. BCG OS trials following a series of inoculations tend to be easy for sites, Click to edit Master title style opening up the possibility of community-based oncologists (e.g. CCOP) and central IRB sites Click to edit Master title styleRIGHT-SIZEDTM CLINICAL RESEARCH SERVICES www.clinipace.com
    • Click to editOperations, and Logistics, Master title style CMC style Click to edit Master title
    • Logistical and Operation Issues for Autologous Cell-Based Vaccines Shipping Tracking Click to edit Master title style • Coordination between surgeons, • Intradermal injection pathologists, training • Importation/export of • Handling, processing, leukapherisis centers, tissue samples and and shipping of tumor and oncologists cell-based therapy samples should comply with GMP and SOPs Production Administration Click to edit Master title styleRIGHT-SIZEDTM CLINICAL RESEARCH SERVICES www.clinipace.com
    • Chemistry, Manufacturing and Controls Autologous product Allogeneic product - Culture period < 1 wk - Extensive culture period - <20 final product vials/lot - ~100 final product vials/lot - No cryopreservation - Cryopreservation used Bulk Click to edit Master title style Bulk -Sterility and LAL Not performed -Hold lot until all results available Final Release -Gram stain andClick to edit Master title style Final Release LAL -Pre-release -Gram stain and LAL -Sterility -Results pre-release -2 d read, pre-release -Sterility -Final read, post-release -Results post-releaseRIGHT-SIZEDTM CLINICAL RESEARCH SERVICES www.clinipace.com
    • Chemistry, Manufacturing and Controls Sterility Testing Failures •Must define actions in procedures – including notifications, investigation, etc. •Must perform susceptibility testing and report results to clinician Click to edit Master title style LAL Testing: False positives / Interference • (1,3)-β-D glucan molecules; Found in cell walls of most yeasts, molds, culture media, cellulose filters, gloves, and uniforms • High rates of invalid tests due to interference Click to edit Master title style Aseptic Processing: Media Fills • Recommend completing in support of Phase II and later (earlier if high risk manipulations required)RIGHT-SIZEDTM CLINICAL RESEARCH SERVICES www.clinipace.com
    • FDA Guidance Guidance for Industry: Clinical Considerations for Therapeutic Cancer Vaccines; Availability http://www.federalregister.gov/articles/2011/11/07/2011- 28726/guidance-for-industry-clinical-considerations-for-therapeutic- cancer-vaccines-availability Click to edit Master title style Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics Click to edit Master title style http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulator yInformation/Guidances/ucm071590.pdfRIGHT-SIZEDTM CLINICAL RESEARCH SERVICES www.clinipace.com
    • Thank You Questions & Answers Please submit your questions via the Q&A box on the left side of your screen Click to edit Master title style Clinipace Worldwide: Oncology Drug Development clinipace.com Click to edit Master title style VOI Consulting: Oncology Consulting & Publishing voiconsulting.comRIGHT-SIZEDTM CLINICAL RESEARCH SERVICES www.clinipace.com