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Alex A. Adjei, Roswell Park Cancer Institute, Buffalo, NY CHALLENGES IN DESIGNING PHASE I CLINICAL TRIALS IN THE ERA OF TARGETED THERAPIES Phase I study endpoints have not changed •To define : •Dose, toxicity, pharmacology (efficacy) –Identify DLTs –Identify the MTD –Assess pharmacokinetics •Evaluate target modulation Pharmacology is Important ! Phase I – Classical Eligibility Criteria •“Conventional” eligibility criteria – examples: –Refractory advanced solid tumors –Good PS ( ECOG 0 or 1) –Adequate organ function ( bone marrow, liver, kidney) –Specification about time interval between prior therapy and initiation of study treatment –No serious uncontrolled medical disorder or active infection Phase I – Eligibility Criteria in the Targeted Therapy Era • “Agent-specific” eligibility criteria – examples: – Specific organ function: • Cardiac function restrictions (e.g. QTc <450–470 ms, LVEF >45%, etc.) • uncontrolled hypertension • proteinuria • hyperlipidemia • Hgb A1c < 7% • Retinal disease – Prohibited medications - risk of interaction with study drug • Anticoagulants (coumadin, low molecular weight heparin) • Steroids (immunotherapeutic agents) • Potent CYP inhibitors/inducers 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-hematological toxicity Definition of DLT in the era of targeted agents –Diarrhea: ≥ Grade 3 in spite of adequate antidiarrheal therapy (loperamide) –Nausea and vomiting: ≥ Grade 3 in spite of adequate anti-emetic prophylaxis and therapy (steroids, 5HT3 antagonists) –Hypertension: ≥ Grade 3 in spite of adequate therapy –Hyperglycemia: ≥ Grade 3 in spite of adequate therapy (metformin) –Triglycerides/Cholesterol ≥ 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 How quickly do you escalate? Phase I trial design: Dose escalation •Attributed to a merchant from Pisa in the 13th century –Leonardo Bonacci, 1170–1240; aka Fibonacci •Outlined series (0,1, 1, 2, 3, 5, 8, 13, 21, 34, 55, 89, 144…) in a book, “Liber abacus” Phase I trials: Dose escalation The modified Fibonacci schedule Cohort 1 2 3 4 5 6 and higher Dose n 2n 3.3 n 5n 7n Escalation (%) First dose 100% 67% 50% 40% 25–33% Phase I standard 3 + 3 design DLT Dose Recommended dose 3 pts 3 pts 3 pts 3 pts 3 pts Eisenhauer EA, et al. J Clin Oncol 2000;18:684–692. Starting dose + 3 pts DLT 3 pts Classic Phase I trial design limitations • Wide confidence intervals •Patients treated at ineffective doses in first cohorts • High risk of severe toxicities at late cohorts • Chronic toxicities usually cannot be assessed • Cumulative toxicities usually cannot be identified •Uncommon toxicities will be missed Phase I Studies and Infrequent Toxicities Probability of NOT observing a serious toxicity occuring at a rate of: Number of patients 10% 20% 1 0.90 0.80 2 0.81 0.64 3 0.73 0.51 6 0.53 0.26 10 0.35 0.11 15 0.21 0.04 Probability of overlooking a toxicity: POT(p) = (1-p)n; n = sample size, p = true toxicity rate Intra-patient 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 isn’t IPDE more widely used? • Makes evaluation of chronic toxicities difficult • The proverbial 1 responder at dose level 1 Phase I study of EKB569 March 29, 2001 September 19, 2001 Problem : Inadequate Pharmacology for Oral Targeted Agents in Phase I -Relevant Drug Interactions -Food Effects DA Smith el al, BJCP, 2009 INDIVIDUAL AUC’S – CBZ AND KTZ DA Smith el al, BJCP, 2009 LAPATINIB – FOOD EFFECT Koch el al, JCO, 2009 • Do innovative phase I designs make a significant difference in novel drug development ? Novel designs – wish list •Maximize safety – patients exposed to DLT –Safe RP2D •Maximize chance of benefit – patients exposed to likely sub-therapeutic doses of drugs • Efficiency ( N patients , speed) • Reduce time trial is on hold Frequentist Rule-based Bayesian Model-based Lots of pushing and shoving amongst the statisticians !!! Frequentist designs design Description ROLLING 6 2-6 PATIENTS ADDED TO Dl- Dl dependent on N enrolled evaluable / with DLT 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 (e.g. fibonacci until MTD. N INC IPDE Switch rule 1A 3 40 N NA 2B 1 40 Y C1 3B 1 100 Y C1 4B 1 100 Y Any Adaptive - Grade dependent increments Phase I trial design Accelerated Titrated Design (Rule-based) • First proposed by Simon et al (J Natl Cancer Inst 1997) • Several variations exist: –usual is doubling dose in single-patient cohorts till Grade 2 toxicity –then revert to standard 3+3 design using a 40% dose escalation –Intra-patient dose escalation allowed in some variations • More rapid initial escalation Accelerated Titrated Design DLT Dose Recommended dose GR 2 Toxicity 3 pts 3 pts 1 pt 1 pt 1 pt Eisenhauer EA, et al. J Clin Oncol 2000;18:684–692. Starting dose + 3 pts DLT 3 pts Bayesian designs Escalation Scheme Description Modified continual reassessment method (mCRM) Preset estimated MTD and dose levels. Update MTD statistically on basis of each pt’s data. 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://www.cancerbiostats.onc.jhmi.edu/software.cfm http://sisyphus.emory.edu/software_ewoc.php Many more variations, some including pk Phase I trial design: Non-cytotoxic agents • MTD may not be the goal of Phase I as specificity of effect may be lost at MTD • Pharmacological effect may not equal biological effect • Goal: Identify OBED • Paradox: Requires early development and integration of (usually unvalidated) measures of biological effect into Phase I OBED = optimal biologically effective dose. Optimum biological dose • An inherently flawed concept for most oral agents • Flat doses are typically administered • Variable absorption • Variable transport • Variable metabolism • Variable exposure • Small numbers of patients studied • Are we sure of the target ? biomarker ? • Agent may not have a classical first-cycle DLT but easy to identify an intolerable chronic dose (2-6 cycles) What’s the target? • Sorafenib (Raf kinase inhibitor) VEGFR1–3 • 5-Azacytidine (antimetabolite) methylation • Lenalinomide (angiogenesis) IMID • Imatinib (PDGFR) bcr-abl, kit • Crizotinib (MET) EML4/ALK • Iniparib (PARP) ?????? Erlotinib PK Patnaik A, et al. Clin Cancer Res 2006;12:7406–7413. Phase II study of the MEK inhibitor, CI-1040 Steady State CI-1040 Plasma Concentration Concentration (ng/mL) 1000 100 10 Course 1 Course 2 Course 3 Course 4 or later Expected Concentration 1 0 4 8 12 Time (hr) Rinehart et al. J Clin Oncol. 2004;22:456-62. 16 20 24 Enzastaurin, an Oral Protein Kinase C Inhibitor Carducci et al, JCO, 2006 Average Steady State Concentrations of Individual Patients Carducci et al, 2006 Phase III study of Enzastaurin vs Lomustine in GBM Wick et al, JCO, 2010 Unusual Toxicities of Targeted Agents Signal Transduction Inhibitors (Dy and Adjei, CA-A, 2013 in press) Cutaneous toxicities Radiation dermatitis Paronychia Trichomegaly Onycholysis Posterior Reversible Encephalopathy Syndrome (PRES) Vatalanib Bevacizumab Sorafenib MEK inhibitor – Blurred vision 2002 CSR: Subretinal fluid 2112 Combination Phase I Studies Energy stress GF GF GRs GRs LKB IRS RAS PI3K AMPK PIP3 Raf PDK TSC2 Akt PI3K inhibitors (e.g., BEZ235) ERK Rheb MEK RSK SIN1 Rictor mTOR mLST8 PRAS40 Raptor mTOR Rapalogs (e.g., Rapamycin) p70S6K 4EBP1 mLST8 S6 eIF4E Protein synthesis (Cyclin D, c-Myc, etc) Combinations will be Key to “Cure” of Epithelial Cancers Common DLTs Other “Challenging” Combinations •IGF-1R inhibitors + Erlotinib •Erlotinib + PI3-Kinase/mTOR inhibitors •Sorafenib/VEGFR Inhibitors + mTOR inhibitors •Proteasome Inhibitors + HSP 90 Inhibitors Phase I Study of Drug A combined with Drug B Single agent doses (100 mg for drug A; 80mg for drug B) Dose Level Drug A 1 2 3 4 5 aC-raf-truncated cwt (305–680), bFull length (1–680); and V599E-truncated BRAF (410–765). 50 mg 75 mg 75 mg 100 mg 100 mg Drug B 40 mg 40 mg 60 mg 60 mg 80 mg Phase I Study of Sorafenib combined with Gefitinib Part A Part B n=12 n=20 Randomization Randomization 400 mg bid sorafenib (n=9)* Cohort 1 Cohort 2 (n=6) 200 mg bid sorafenib plus 250 mg qd gefitinib (n=6) 400 mg bid sorafenib plus 250 mg qd gefitinib 250 mg gefitinib (n=10) Run-in phase 250 mg gefitinib (n=6) 400 mg bid sorafenib (n=10)** 400 mg bid sorafenib plus 250 mg gefitinib (n=10)*** *three of these patients discontinued treatment after receiving sorafenib 400 mg bid **three of these patients received 200 mg bid due to a dosing error ***n=9 for sorafenib and n=1 for gefitinib Adjei AA et al, CCR, 2007 Pharmacologic Principles of Drug Combination •Therapeutic Index is important •Agents should have non-overlapping DLTs •Ability to administer full doses of each agent •Schedule and sequence may be important •True cytotoxic synergy is important