Looking Beyond the Standard-of- Care : The Clinical Trial Option

Transcription

1 1 Looking Beyond the Standard-of- Care : The Clinical Trial Option Terry Mamounas, M.D., M.P.H., F.A.C.S. Medical Director, Comprehensive Breast Program UF Health Cancer Center at Orlando Health Professor of Surgery, University of Central Florida College of Medicine Clinical Professor of Clinical Sciences, Florida State University College of Medicine

2 Rethinking Our Approach to Cancer Therapy Advances in genomic technology have lead to an unprecedented pace in discovery of new molecular and genomic cancer targets that underscore the complexity of the disease A multitude of drugs against these targets has already been developed with many more being developed at a rapid pace How to make these new molecules the new standard of care represents a major challenge and requires a change in our clinical trial development strategy both in advanced disease and in earlystage

3 Genomic Alterations in 128 Clinically Relevant Genes in 962 TCGA Breast Cancer Samples

4 Potential Genomic Targets in Breast Cancer Selected genes with Mutations, Amplifications/Deletions, Rearrangements in BC ERBB2 PIK3CA PTEN AKT1 AKT2 AKT3 PIK3R1 INPP4B MTOR TSC1 TSC2 KRAS NRAS BRAF MAP2K1 MAP3K1 NF1 FGFR1 FGFR2 FGFR3 CDKN2A CDKN1B CCND1 CCNE1 CDK4 RB1 BRCA1 BRCA2 ATM EGFR TP53 MDM2 MYC KIT NTRK3 NOTCH1 Anti-Her2 Therapies FGFR Inhibitors EGFR Inhibitors Anti-p53 Strategies PI3k / AKT / MTOR Inhibitors CDK Inhibitors Nutlins Anti-MYC Strategies RAF / MEK / ERK Inhibitors PARP Inhibitors Platinums Others

5 Categorizing Modern Oncology Clinical Trial Designs Berry D: Molecular Oncology 2015

6 Examples of Platform Clinical Trials The I-SPY 2 Trial in breast cancer The BATTLE Trial in NSCLC The CUSTOM Trial in NSCLC The LUNG MAP Trial in Squamous Cell Lung Cancer

7 Breast Cancer: The I-SPY2 Trial (and other Neoadjuvant Trials Tailoring Therapy)

8 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 I-SPY2 & 3 as a Model I-SPY2: Randomized phase II screening trial Identify new agents/ biomarker combinations that improve pcr Graduation threshold from I- SPY 2: 85% probability of success in Phase 3 I-SPY3: Randomized phase III trial Rapidly and efficiently validate I-SPY 2 biomarkerlinked efficacy signals and create a fluid phase 2-3 platform Similar eligibility criteria as I- SPY 2 to allow confirmation in same patient population I-SPY2 I-SPY3

9 I-SPY 2 TRIAL: Learn, Drop, Graduate, and Replace Agents Over Time Paclitaxel+ Trastuzumab Randomize HER 2 (+) Paclitaxel + Trastuzumab* + New Agent A Paclitaxel + Trastuzumab* + New Agent B Paclitaxel + Trastuzumab* + New Agent F C A C Surgery Learn and adapt from each patient as we go along Key MRI Patient is on Study Residual Disease (Pathology) Randomize HER 2 ( ) Paclitaxel Paclitaxel + New Agent C F Paclitaxel + New Agent GH D Paclitaxel + New Agent E A C Surgery *Investigational agent may be used in place

10 The I-SPY 2 Trial Design Is Novel Adaptive randomization Uses a prespecified and automated algorithm Randomization probabilities update as study proceeds By signature, and based on MRI and pcr results Algorithm triggers the decision to graduate when patients are enrolled Berry DA. Nat Rev Clin Oncol. 2011;9(4): Rugo HS, et al. Cancer Res. 2013;73(24 Suppl): Abstract S5-02.

11 I-SPY 2 Eligibility Tumor size 2.5 cm Patient is eligible and randomized Screening consent Assess eligibility Treatment consent, patient on study Is patient eligible? (based on stratifying biomarkers) MammaPrint Low MammaPrint High HR+ HR- HR+ HR HER2+ Eligible Eligible Eligible Eligible HER2 Not eligible* Eligible Eligible Eligible *May be eligible to participate in low-risk registry trial (supplement 1) Rugo HS, et al. Cancer Res. 2013;73(24 Suppl): Abstract S5-02.

12 Experimental Arm 1: Veliparib/Carboplatin Veliparib (ABT888) is a potent PARP inhibitor For this analysis, patients were ADAPTIVELY randomized to receive: Veliparib 50 mg po BID x 12 weeks/carboplatin AUC 6 q 3 weeks x 4 with weekly paclitaxel followed by AC OR Weekly paclitaxel followed by AC Enrollment open only to patients with HER2-negative disease Eligible to graduate in 3 signatures: All HER2-, HR+/HER2-, TN R Screening MRI Biopsy Blood Draw Consent #1 Screening Consent A N D O M I Z E O N S T U D Y Consent #2 D Treatment Consent Paclitaxel +/- veliparib /carbo (12 weekly cycles) MRI Biopsy Blood Draw AC (4 cycles q 2-3 weeks) MRI with G-CSF support Blood Draw MRI Blood Draw S U R G E R Y Tissue Rugo HS, et al. Cancer Res. 2013;73(24 Suppl): Abstract S5-02.

13 Veliparib/Carboplatin GRADUATES in the Triple Negative Signature SIGNATURE All HER2- Estimated pcr Rate (95% probability interval) Veliparib/ Carbo 33% (22-43%) ConcurrentC ontrol Probability Veliparib + Carbo is Superior to Control Predictive Probability of Success in Phase 3 22% (10-35%) 92% 55% HR+/HER2- HR-/HER2-14% (4-27%) 52% (35-69%) 19% (6-35%) 28% 9% 26% (11-40%) 99% 90% Ongoing phase III 3 arm neoadjuvant TNBC trial (n=624): Pac/carbo/veliparib vs pac/carbo vs pac Rugo et al, SABCS 2013

14 How Do Utilize pcr to Maximize the Clinical Impact Of NC? Use pcr as a surrogate endpoint for long-term outcome (potential pathway for new drug approval) Identify better predictors of pcr: Baseline Early During treatment Use primary tumor response as a guide for tailoring systemic therapy and loco-regional therapy

15 NSABP B-50I: KATHERINE Study Schema SURGERY Preoperative therapy: Trastuzumab/ Taxane ± Anthracycline Residual invasive tumor Herceptin T-DM1 Radiation per standard guidance; hormone therapy if ER or PgR pos

16 NSABP B-54-I: Penelope N=800 pts. with HR+/HER2- breast cancer No pcr and CPS-EG score 3 : Palbociclib 125 mg once daily p.o. d1-21, q29 for 12 cycles Neoadjuvant Chemotherapy Surgery +/- Radiotherapy R Placebo d1-21, q29 for 12 cycles Concomitant endocrine therapy according to local standards

17 Recently Activated U.S. Clinical Trials Tailoring Loco-Regional Therapy with NC 17

18 Lung Cancer: BATTLE Trial CUSTOM Trial The Lung MAP Trial

19 Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination Trial (BATTLE) BATTLE establishes the feasibility of a new paradigm for a personalized approach to lung cancer clinical trials First completed prospective, biopsy mandated, biomarker-based, adaptively randomized study 255 pretreated lung cancer patients Edward S. Kim et al. Cancer Discovery 2011;1:44-53

20 Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination Trial (BATTLE) Following an initial equal randomization period, chemo-refractory non small cell lung cancer (NSCLC) patients were adaptively randomized based on relevant molecular biomarkers analyzed in fresh core needle biopsy specimens to: Erlotinib Vandetanib Erlotinib plus bexarotene Sorafenib Edward S. Kim et al. Cancer Discovery 2011;1:44-53

21 CONSORT Diagram of the BATTLE Study 2011 by American Association for Cancer Research Edward S. Kim et al. Cancer Discovery 2011;1:44-53

22 BATTLE Results Overall results include: A 46% 8-week disease control rate (primary end point) Confirm pre-specified hypotheses Show an impressive benefit from sorafenib among mutant-kras patients

23 Achieved 8 week DC (%) EGFR and KRAS Marker Groups Primary Endpoint: Overall DCR at 8 weeks was 46% EGFR Group - Mutation - Copy number KRAS Group - KRAS mutation - BRAF mutation 79% % 41% 55% 39% 33% Erlotinib Vandetanib Erlotinib + bexarotene Sorafenib N = EGFR Group 14% 0% N = KRAS Group Kim ES et al. AACR Plenary Session LBA #1

24 Achieved 8 week DC (%) EGFR and KRAS Mutations: Novel Discovery Findings Erlotinib Vandetanib Erlotinib + bexarotene Sorafenib 71% EGFR Mutation 29% 64% 23% 22% KRAS Mutation 37% 61% 56% 0 N = N = Kim ES et al. AACR Plenary Session LBA #1

25 The CUSTOM Trial A basket clinical trial to test the feasibility of this design strategy Independently evaluated the effects of multiple targeted agents against specific molecular aberrations in multiple histologic subtypes concurrently Patients with advanced NSCLC, small-cell lung cancer, and thymic malignancies were enrolled and underwent genomic characterization of oncogenic drivers Lopez-Chavez, A: J Clin Oncol, 2015

26 The CUSTOM Trial: Frequency of Gene Alterations in NSCLC Lopez-Chavez, A: J Clin Oncol, 2015

27 The CUSTOM Trial Patients were enrolled onto a not-otherwise-specified arm and treated with standard-of-care therapies or one of the following five biomarker-matched treatment groups: Erlotinib for EGFR mutations Selumetinib for KRAS, NRAS, HRAS, or BRAF mutations MK2206 for PIK3CA, AKT, or PTEN mutations Lapatinib for ERBB2 mutations or amplifications Sunitinib for KIT or PDGFRA mutations or amplification Lopez-Chavez, A: J Clin Oncol, 2015

28 The CUSTOM Trial: Results 647 patients were enrolled, and 88% had their tumors tested for at least one gene EGFR mutation frequency was 22.1% in NSCLC, and erlotinib achieved a response rate of 60% KRAS mutation frequency was 24.9% in NSCLC, and selumetinib failed to achieve its primary end point, with a response rate of 11% Completion of accrual to all other arms was not feasible Lopez-Chavez, A: J Clin Oncol, 2015

29 The CUSTOM Trial: Results Median Survival: EGFR mutations: 3.51 yrs ALK rearrangements: 2.94 yrs KRAS mutations: 2.3 years Other genetic abnormalities: 2.17 years Without an actionable mutation: 1.85 years Lopez-Chavez, A: J Clin Oncol, 2015

30 The CUSTOM Trial: Conclusion This basket trial design was not feasible for many of the arms with rare mutations It allowed the study of the genetics of less common malignancies Lopez-Chavez, A: J Clin Oncol, 2015

31 Rationale for Master Lung-1 Protocol Design Multiple and often independent mutations and potential therapeutic targets Lung SCCA: No substantial therapeutic developments Refined strategy for subgroup selection (driven by genotype or phenotype) in a multiarm Master Protocol Improved operational efficiency Homogeneous patient populations & consistency in eligibility from arm to arm

32 Rationale for Master Lung-1 Protocol Design Phase II-III design: Rapid drug/biomarker testing for detection of large effects Grouping multiple studies: Reduces overall screen failure rate Multi-target screening by NGS platform: Sufficient hit rate and uninterrupted accrual Bring safe and effective drugs to patients faster Ineffective drugs are replaced by new improved candidates Designed for FDA approval of new therapeutics

33

34 Study design within each biomarker defined subgroup

35 Questions? 35

36