1. Alex A. Adjei, MD, PhD Designing Phase I Trials with Targeted Agents: Challenging Tradition

2. Definition of a Phase I Study First evaluation of a new cancer therapy in humans First in-human single-agent study Combination of novel agents Combination of novel agent and approved agent Combination of novel agent and radiation therapy Eligible patients usually have refractory solid tumors of any type

3. The 3 Basic Tenets of Phase I Studies Define a recommended dose: –SAFELY (minimum number of serious toxicities) –EFFICIENTLY (smallest possible number of patients) –RELIABLY (high statistical confidence) –SAFETY TRUMPS EVERYTHING ELSE

4. Preclinical Toxicology Typically, a rodent (mouse or rat) and non-rodent (dog or non-human primate) species Very few animal organ-specific toxicities predict human toxicity –Bone marrow and GI toxicity more predictable –Hepatic and renal toxicities – large false-positives –Toxicologic parameters LD10 – lethal dose in 10% of animals TDL (toxic dose low) – lowest dose that causes any toxicity in animals

5. Phase I Trials: Starting Dose 1/10 of the LD10 in rodents or 1/3 of the TDL in large animals Expressed as mg/m 2 These have historically been safe doses

6. Equivalent Surface Area Dosage Conversion Factors Mouse 20 g Rat 150 g Monkey 3 kg Dog 8 kg Man 60 kg Mouse 11/21/41/61/12 Rat 211/21/41/7 Donkey 4213/51/3 Dog 645/311/2 Man 127321 Freireich EJ et al. Cancer Chemother Rep. 1966;50:219-244.

7. Phase I Dose Escalation CohortDoseEscalation (%) 1nFirst dose 22 n100 33.3 n67 45 n50 57 n40 6 and higher25-33 The modified Fibonacci schedule

8. Phase I Study End Points Dose, toxicity, pharmacology (efficacy?) Classical goals –Identify DLTs –Identify the MTD –Assess pharmacokinetics Evaluate target modulation

9. Defining Toxicities: NCI Common Toxicity Criteria Grade 1 = mild Grade 2 = moderate Grade 3 = severe Grade 4 = life-threatening Grade 5 = fatal

10. Maximum Tolerated Dose Inconsistently defined as either: –Dose at which  33% of patients experience unacceptable toxicity (DLT in  2 of 3 or  2 of 6) or –1 dose level below that MTD = level @ DLT (in Europe or Japan) MTD = level below DLT (in US) 6-10 patients treated at the recommended phase II dose (MTD or 1 dose level below)

11. Recap: Transatlantic Differences in Terminology Important to note that “Maximum tolerated dose” (MTD): –Usually means “recommended phase 2 dose (RP2D)” in US –Usually means dose level above RP2D in Europe and some other countries

12. Dose-Limiting Toxicities Toxicities that are considered to be unacceptable and limit further dose escalation Defined in advance of starting trial Classically based on cycle 1 toxicity Examples –ANC <500 for  5 or 7 days –ANC <500 of any duration with fever –PLT <10,000 or 25,000 –Grade 3 or greater non-hematologic toxicity –Inability to re-treat patient within 2 weeks of scheduled treatment

13. Definition of DLT Is Dynamic Examples: DLTs in 2014 –Diarrhea: ≥ Grade 3 in spite of adequate antidiarrheal therapy (loperamide) –Nausea and vomiting: ≥ Grade 3 in spite of adequate antiemetic prophylaxis and therapy (steroids, 5HT3 antagonists) –Hypertension: ≥ Grade 3 in spite of adequate antihypertensive therapy –Rash : ≥ Grade 3 in spite of adequate therapy –Hyperglycemia : ≥ Grade 3 in spite of adequate therapy –Inability to take at least 90% of drug doses in a cycle (continuous oral meds) –Grade 2 chronic unremitting toxicity

14. 3 pts Dose 3 pts Recommended dose DLT Starting dose 3 pts + DLT Phase I Standard 3 + 3 Design Eisenhauer EA et al. J Clin Oncol. 2000;18:684-692.

15. Classic Phase I Trial Design Limitations Wide confidence intervals Patients treated at ineffective doses in first cohorts High risk of severe toxicities in late cohorts

16. Intrapatient Dose Escalation Treat patients at dose level 1 Dose level 2 is well tolerated and patients at dose level 1 have no toxicities Patients at level 1 are escalated to level 2 WHY NOT ALWAYS DO THIS? Makes evaluation of chronic toxicities difficult The proverbial 1 responder at dose level 1

17. Pre-FTI 3 Months Response to lonafarnib and EKB569 March 29, 2001 September 19, 2001

18. Novel Designs – Wish List Maximise safety –  patients exposed to DLT –Safe RP2D Maximise chance benefit –  patients exposed to likely subtherapeutic doses of drugs Efficiency (  N patients,  speed) Reduce time trial is on hold Bayesian Model-based Frequentist Rule-based

19. Frequentist Designs DesignDose PK-guided Double until target AUC (40% of murine at LD10) then modified Fibonacci Accelerated titration Double dose until target toxicity (<DLT) then switch to more conservative (eg, Fibonacci until MTD)

20. 1 pt Dose 1 pt 3 pts Recommended dose DLT Starting dose 3 pts + DLT Accelerated Titrated Design GR 2 Toxicity Eisenhauer EA et al. J Clin Oncol. 2000;18:684-692.

21. Bayesian Designs Escalation SchemeDescription Modified continual reassessment method (mCRM) Preset estimated MTD and dose levels. Update MTD statistically on basis of each pt’s data http://www.cancerbiostats.onc.jhmi.edu/software.cfm TriCRM Incorporates both toxicity and efficacy data into the estimation of the biologically optimal dose – but OR takes time to mature… (phase I/II better?) EWOC (escalation with overdose control) Uses real-time toxicity data to make decisions http://sisyphus.emory.edu/software_ewoc.php Many more variations, some including PK

22. Phase I Trial Design: Targeted Agents MTD may not be the goal of phase I, as specificity of effect may be lost at MTD Pharmacologic effect may not equal biologic effect Goal: Identify optimal biologic dose (OBD) Biomarkers can guide dose escalation and dose selection

23. Erlotinib PK Patnaik A et al. Clin Cancer Res. 2006;12:7406-7413.

24. Phase II Study of the MEK Inhibitor, CI-1040 Rinehart et al. J Clin Oncol. 2004;22:4456-4462.

25. What’s the Target? Sorafenib (Raf kinase inhibitor) VEGFR1–3 5-Azacytidine (antimetabolite) methylation Imatinib (PDGFR) Bcr-Abl, kit Crizotinib (MET) EML4-ALK Iniparib (PARP) ??? alkylating agent forming adducts with cysteine-rich proteins Tivantinib (MET) anti-tubulin

26. UNUSUAL TOXICITIES OF TARGETED AGENTS

27. Signal Transduction Inhibitors (Dy and Adjei, CA-A, 2013) Courtesy of Alex Adjei, MD, PhD.

28. Cutaneous Toxicities Courtesy of Alex Adjei, MD, PhD. Radiation dermatitis Trichomegaly ParonychiaOnycholysis

29. RASopathic Skin Toxicities Photosensitivity Radiation recall

30. Vatalanib Bevacizumab Sorafenib Posterior Reversible Encephalopathy Syndrome (PRES)

31. MEK Inhibitor – Blurred Vision 2005 CSR: Subretinal fluid - 2012

32. SHOULD WE BE TREATING GENOMIC SUBSETS IN PHASE I?

33. Somatic Mutations: Recurrent in Common Cancers Dancey et al. Cell. 2012;148:409-420.

34. Phase I Study Design – Unselected Patients in Dose Escalation Followed by Specific Expansion Cohorts Dose Escalation Cohort Expansion PharmacodynamicsTargeted Tumour Types PK, safety Define MTD Biopsies Functional imaging Molecular enrichment Histologic enrichment

35. PLX4032: Novel, Small-Molecule Inhibitor Selective for BRAF V600E kinase among 70 kinases screened Selective in cellular assays Selective regression of V600EKinase domain binding PLX4720 co-structure with kinase domain of BFAF V600E IC 50 (nM) 10−100 100−1000 1000−10,000 Phospho-ERKIC 50 (nM) V600E A375 COLO829 COLO205 20 10 30 WT SW620 SKMEL2 >40,000 14,000 Flaherty et al. ASCO 2009. Tsai J et al. Proc Natl Acad Sci USA. 2008;105:3041-3046. Selectivity for BRAF V600E in vitro and in vivo 10 5 0 Tumour Size 100 mm 3

36. Vemurafenib (PLX4032) in Melanoma: Phase I Studies Flaherty et al. ASCO 2009. Tsai J et al. Proc Natl Acad Sci USA. 2008;105:3041-3046.

37. Phase I Study Design – Only Molecularly Enriched Patients Dose Escalation Cohort Expansion PharmacodynamicsTargeted Tumour Types PK, safety Define MTD Biopsies Functional imaging Histologic enrichment

38. Oral, once-daily BYL719, 28-day cycle (n=36) Dose-escalation phase PIK3CA altered solid tumours MTD expansion phase PIK3CA altered solid tumours Declaration of MTD 400 mg QD BYL719 (Approximately 45 patients) in PIK3CA-altered solid tumors Dose levels Phase I Trial of BYL719: Study Design 30 mg/day60 mg/day90 mg/day 180 mg/day 270 mg/day400 mg/day450 mg/day Juric et al. AACR 2012.

40. Number of Patients Needed to be Screened for 70 Marker + Patients Prevalence of MarkerExpected Number to be Screened 0.05 1394 0.1 697 0.2 349 0.3 232 0.4 174 0.5 139 0.6 116 0.7 100 0.8 87 1 70 Sleijfer S et al. J Clin Oncol. 2013;31:1834-1841.

41. Molecular Selection of Patients for Phase I Trials Multiplexed molecular prescreening at local site Reduces change of tissue exhaustion from multiple trial demands Underscores the importance to have validated broad molecular profiling capacity of actionable mutations and other aberrations in local validated laboratory Multicentre participation – especially if seeking rare molecular subsets Nested clinical trial

42. N-of-1 Trials: A Possible Design for Personalized Medicine? Drug A Drug B Average treatment effect of Drug A Average treatment effect of Drug B vs Crossover study performed within a single individual

43. 70 year old man with Lung Cancer and a Braf Mutation : Vemurafenib after Progression on Pemetrexed/Carboplatin October 30, 2013 August 25, 2013

44. Conclusions Alternate designs are important but not the solution –For most drugs, an MTD can be defined –It may be chronic toxicity rather than classical cycle 1 DLTs –Evaluate intermediate doses –Biomarker end points are necessary for the few agents, such as antibodies, with no dose-dependent toxicities Phase I trials in molecular subsets should be the exception at this time –May miss other populations who will benefit –Study can be slow and expensive –May be more informative to treat a small subset of “wild-type” patients (eg, escalate quickly and expand in molecular subset)