Flexibility, Resilience, Understanding the Science: Phase 1 and Beyond?

Transcription

1 Clinical Operations in Oncology Trials Boston, July 15 th 2015 Flexibility, Resilience, Understanding the Science: Phase 1 and Beyond? Giovanni Abbadessa, MD, PhD Vice President Clinical Development, Translational Research, Medical Affairs ArQule, Inc

2 Origin: Dogma An official system of principles or tenets concerning faith, morals, behavior, etc. A specific tenet or doctrine authoritatively laid down Prescribed doctrine proclaimed as unquestionably true by a particular group A settled or established opinion, belief, or principle ; Greek: dokein to seem, think, seem good, seem tru A reminder to English speakers that now established principles and doctrines were once simply thoughts and opinions of ordinary people that gained popularity. Twentieth-century American academic and aphorist Mason Cooley observed that Under attack, sentiments harden into dogma, suggesting that dogma is spawned as a defensive act. This implies that for every dogma there is a counter dogma. With so many truths out there, there is sure to be a dogma to conveniently fit every set of beliefs. Dictionary.com

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4 Dolores Umbridge Head of the Improper Use of Magic Office (formerly) Department of Magical Law Enforcement (formerly) Senior Undersecretary to the Minister for Magic (before ) Professor of Defence Against the Dark Arts at Hogwarts ( ) High Inquisitor of Hogwarts ( ) Headmistress of Hogwarts (1996) Head of the Muggle-Born Registration Commission ( ) Harry Potter Wiki

5 Flexibility Capable of being bent, usually without breaking; easily bent Susceptible of modification or adaptation; adaptable Willing or disposed to yield; pliable Origin: Of physical things, from 1610s From French: flexibilité From Late Latin: flexibilitas From Latin: flexibilis Of immaterial things, from Dictionary.com

6 Resilience The power or ability to return to the original form, position, etc., after being bent, compressed, or stretched; elasticity Ability to recover readily from illness, depression, adversity, or the like; buoyancy Origin: 1620s, "act of rebounding" from Latin: resiliens, present participle of resilire "to rebound, recoil," from re- "back" + salire "to jump, leap" Meaning "elasticity" is from Dictionary.com

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8 Understanding the Science In 2015, almost every clinical trial in oncology is based on preclinical (and clinical) rationale, pathway knowledge increases by the year (by the day!) but In 2015, cell cultures are still cells in plastic, mice are still mice, and patients are still patients Challenges: Identify clinical consequences of preclinical findings Keep preclinical findings in perspective, when making clinical decisions

9 Case Study 1

10 ARQ : Phase 1 Clinical Study PRIMARY ENDPOINTS Safety and tolerability in subjects with advanced solid tumors SECONDARY ENDPOINTS Pharmacokinetic profile Pharmacodynamic activity (in blood and eventually in tumor) MTD and RP2D Preliminary evidence of activity Open label Cohorts 1-5: dose doubled From cohort 6: modified Fibonacci scheme (increase by 30% until RP2D) 3+3* subjects per cohort (*if DLT) Intra-subject dose escalation not allowed Cycle 1: DLT window Cycle 2 EXPLORATORY ENDPOINTS Association between markers of the AKT signaling pathway, toxicity and clinical activity Changes in different pathways and potential combinations of interest PK SAMPLING PD SCHEDULE TUMOR ASSESSMENT 1,2 8 15, Saleh M, et al. AACR 2013

11 ARQ : Phase 1 Clinical Study Cohort # 1000 Dose mg mg mg mg mg mg mg QD mg QD mg QD mg QD mg QD mg BID mg BID mg BID Schedule QOD QD QD QD QD QD QOW QOW 600 QOW QOW QOW Weekly Weekly Weekly No. Pts Planned 400 No. Pts * 7* * * 7* 7 Actual 200 *One of the first three subjects experienced a DLT, the cohort was expanded to enroll at least 6 subjects Mean Plasma Concentration (±SD) 0 C1D Time post- dose (hr) Dose (mg/day) mg BID Weekly Saleh M, et al. AACR 2013

12 ARQ : Phase 1 Clinical Study Cohort # 1000 Dose mg mg mg mg mg mg mg QD mg QD mg QD mg QD mg QD mg BID mg BID mg BID Schedule QOD QD QD QD QD QD QOW QOW 600 QOW QOW QOW Weekly Weekly Weekly No. Pts Planned 400 No. Pts * 7* * * 7* 7 Actual 200 *One of the first three subjects experienced a DLT, the cohort was expanded to enroll at least 6 subjects Mean Plasma Concentration (±SD) 0 C1D Time post- dose (hr) Dose (mg/day) mg BID Weekly Saleh M, et al. AACR 2013

13 ARQ : Phase 1 Clinical Study Cohort # 1000 Dose mg mg mg mg mg mg mg QD mg QD mg QD mg QD mg QD mg BID mg BID mg BID Schedule QOD QD QD QD QD QD QOW QOW 600 QOW QOW QOW Weekly Weekly Weekly No. Pts Planned 400 No. Pts * 7* * * 7* 7 Actual 200 *One of the first three subjects experienced a DLT, the cohort was expanded to enroll at least 6 subjects Mean Plasma Concentration (±SD) 0 C1D Time post- dose (hr) Dose (mg/day) mg BID Weekly Saleh M, et al. AACR 2013

14 ARQ : Phase 1 Clinical Study Continuous Intermittent Weekly Cohort # Dose Schedule mg mg mg mg mg mg mg QD mg QD mg QD mg QD mg QD mg BID mg BID mg BID mg BID QOD QD QD QD QD QD QOW QOW QOW QOW QOW Weekly Weekly Weekly Weekly No. Pts Planned No. Pts Actual * 7* * * 7* 7 *One of the first three subjects experienced a DLT, the cohort was expanded to enroll at least 6 subjects; # Food-effect cohort Saleh M, et al. AACR-EORTC-NCI 2014

15 ARQ : Phase 1 Clinical Study Two subjects (lymphoma and endometrial) experienced a durable partial response. Both subjects had activating mutations in the PIK3CA gene In addition, 31 subjects had stable disease including 4 (13%) who had a >10% tumor reduction and 16 (52%) who remained on treatment for 16 weeks Tolcher A, et al. ESMO 2015

16 Case Study 2

17 ARQ 092: Proteus Syndrome Proteus syndrome is a rare disorder (incidence <1 in 1 Million people worldwide) characterized by non-cancerous overgrowth of skeleton, skin, adipose tissue and central nervous system Approximately 100 patients are being actively followed clinically in the US and ~200 in West

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19 ARQ 092: Proteus Syndrome Biesecker LG, et al. ASHG 2014

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21 Case Study 3

22 HCC Drug Development: a Series of (repeated) Failures Fornaro L, et al. Future Oncology 2014

23 HCC Drug Development: a Series of (repeated) Failures Fornaro L, et al. Future Oncology 2014

24 HCC Drug Development: a Series of (repeated) Failures Llovet J, et al. JCO 2013 Fornaro L, et al. Future Oncology 2014

25 HCC Drug Development: a Series of (repeated) Failures Everolimus (362): 7.6 mo Placebo (184): 7.3 mo Zhu AX, et al. JAMA 2014 Llovet J, et al. JCO 2013 Fornaro L, et al. Future Oncology 2014

26 HCC Drug Development: a Series of (repeated) Failures Everolimus (362): 7.6 mo Placebo (184): 7.3 mo Zhu AX, et al. Lancet Oncol 2015 Zhu AX, et al. JAMA 2014 Llovet J, et al. JCO 2013 Fornaro L, et al. Future Oncology 2014

27 ARQ 197 (tivantinib) in HCC

28 ARQ 197 (tivantinib) in HCC

29 ARQ 197 (tivantinib) in HCC TTP: 11.7 vs 6.1 wks HR: 0.43, P=0.03 PFS: 9.6 vs 6.0 wks HR: 0.45, P=0.02 DCR: 50% vs 20% OS (MET Low patients): no statistical difference, with curves crossing: HR: 1.33, P=0.50 Rimassa L, et al. J Clin Oncol. 2012;30s; abstr 4006

30 ARQ 197 (tivantinib) in HCC Santoro A, et al. Hepatic Oncol. 2014

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33 Flexibility, Resilience, Understanding the Science:

34 Clinical Operations in Oncology Trials Boston, July 15 th 2015 Flexibility, Resilience, Understanding the Science: Phase 1 and Beyond! Giovanni Abbadessa, MD, PhD Vice President Clinical Development, Translational Research, Medical Affairs ArQule, Inc