Topics in Clinical Trials (4) -2012

1. Topics in Clinical Trials (4) -2012 J. Jack Lee, Ph.D. Department of Biostatistics University of Texas M. D. Anderson Cancer Center

2. Objectives of Phase I Trials • Determine • Maximum tolerated dose (MTD) • Optimal biological dose (OBD) • Recommend phase II dose (RPTD) • Define toxicity profiles • Dose limiting toxicities (DLT) • NCI Common Toxicity Criteria (CTC 2.0), CTCAE v3.0 and 4.0 • http://ctep.cancer.gov/reporting/ctc.html • WHO Common Toxicity Criteria • Study PK/PD • Pharmacokinetics: body does to the drug • Pharmacodynamics: drug does to the body • Initial assessment of treatment efficacy

3. Key Elements of Phase I Trials • Choose a promising agent or combination • Administration route / Schedule • Define patient population • Inclusion criteria / Exclusion criteria • Choose a starting dose • First human trial • Lower dose of 1/10 of mouse LD10, 1/3 of dog Toxic Dose Low • Human data available • Start with a safe dose • Define Dose Limiting Toxicities (DLT) • ≥ Grade 3 non-hematologic or ≥ Grade 4 hematologic toxicities • Define dose escalation scheme • Dose spacing • Dose assignment • Cohort size • Determine MTD and/or RPTD • Collect and analyze PK/PD data

4. Dose Spacing • Fibonacci sequence: 1, 1, 2, 3, 5, 8, 13, 21, 34, … • % increase: 100, 50, 67, 60, 63, 62, 62, … converge to ‘golden ratio.’ • Modified Fibonacci Scheme: 100, 67, 50, 40, 33, 33, … • Adaptive increment scheme • No toxicity: 100% increase • Minor tox (gr.2 ) 50% increase • Major tox (DLT) 25% increase • Fixed increment scheme • Always 33% increase • Always increase by, say, 25 mg/m2

5. Available Phase I Designs • Algorithm based • 3+3 Design • Up and Down Design • Pharmacologically Guided Dose Escalation (PGDE) • Collins et al. Cancer Treat Rep 1986; JNCI 1990 • Model based • Accelerated Titration Design • Simon et al. JNCI 1997 • Continual Reassessment Method (CRM) • O’Quigley et al. Biometrics 1990 • Escalation With Overdose Control (EWOC) • Babb et al., Stat in Med 1998 • Bayesian Model Average CRM (BMA-CRM) • Yin and Yuan, JASA 2009

6. Conventional 3 + 3 Design • Algorithm based • Enter 3 pts at the lowest dose level • If 0/3 DLT → Next 3 pts at next higher dose • If 1/3 DLT → Next 3 pts at the same dose • 1/3 + 0/3 DLT → next 3 pts at next higher dose • 1/3 + 1/3 DLT →MTD or exceed MTD • 1/3 + 2/3 or 3/3 DLT→exceed MTD • If 2/3 or 3/3 DLT →exceed MTD • If MTD not reached, repeat the above steps • MTD defined with ≤ 1/6 DLT or ≤ 2/6 DLT • Generally targeted at 20 to 30% DLT level

7. Example 1

8. Example 2

9. Example 3

10. Properties of 3+3 Design • Ad-hoc • Based on a pre-set algorithm without a clearly defined scientific objective • Generally yield a dose with 20% to 30% target toxicity level • Lin and Shih, Biostatistics 2001 • An OK design • Rigid, not flexible • Inefficient

15. PGDE Design • Choose the starting dose based on relevant pre-clinical data • Measure PK data, 100% dose escalation until AUC within 40% of target AUC • Then, switch to modified Fibonacci scheme

16. Model-based Design

17. Accelerated Titration Design • Scheme (Design 4 in the paper) • Enter 1 pt at the lowest dose level • Accelerated Titration Phase • Allow 100% inter- and intra- patient dose escalation with < grade 2 toxicity • Standard Design Phase • After observing grade 2 toxicity during any course of the treatment, then, switch to 3+3 design with 40% dose escalation • Intra-patient dose escalation • No tox or grade 1 tox → Next course 100% increase • Grade 2 tox → Next course at the same level • Grade 3 or 4 tox → Next course decrease by 1 level • All toxicity information is used to model the dose-toxicity curve

20. CRM • A Bayesian model-based method to estimate the dose-toxicity curve and to assign pt at a level closest to the current estimate of MTD • Choose a family of dose-toxicity curve • p = Prob(DLT at dose d) • Hyperbolic tangent model: p = [ed/ (ed+e-d)]a • Logistic model: p = e3+a∙d / (1+e3+a∙d) • Power model: p = dexp(a) • Estimate the parameter a with data

24. CRM Scheme • Assume a vague or non-informative prior of a • Treat 1 patient at the level closest to the current estimate of MTD • Observe the toxicity outcome • Update the information of a by computing its posterior distribution • Repeat the above steps until a reasonable estimate of a or maximum N is reached

25. Properties of CRM • Advantage • Model-based method with a clearly defined objective • Treat more pts at close to the target MTD level, hence, reduce the number of pts treated at low or ineffective dose levels • Disadvantage • May be too aggressive • The success depends on a proper choice of the dose-toxicity curve and prior distribution of a • Need special computer programs to implement the design

26. Modified CRM • Start at the lowest dose level • Do not skip doses • Use cohort size of 2 or 3 • Add stopping rules e.g. no more than 2 of 6 developed MTD • Available programs • http://biostatistics.mdanderson.org/SoftwareDownload/ • http://www.cancerbiostats.onc.jhmi.edu/software.cfm • http://linus.nci.nih.gov/~brb/Methodologic.htm • http://www.biostats.upci.pitt.edu/biostats/ClinicalStudyDesign/ • http://www.crab.org/Statistools.asp

27. Example • 6 dose levels to be studied with a target toxicity level = 0.2 • Assume the dose-toxicity curve is hyperbolic tangent • Assume the prior distr. of a is unit exponential • The prior belief of Prob(tox) at each dose level is: • Enter 1 pt at a time at the current estimate of the MTD • Observe the toxicity outcome • Update the distribution of a accordingly • Treat the next pt at the current estimate of the MTD • Repeat Steps 6-9 until the max. number of pts or a pre-specified precision of the parameter estimation is reached

38. Case Study #1Ramnath et al., Cancer Chemother Pharmacol, 2003 • Drug: Anhydrovinblastine (AVLB) • Patient population: solid tumors • Starting dose: 2.5 mg/m2 • MTD in rats: 17.5 mg/m2 • MTD in dogs: 40 mg/m2 • 1/7 of MTD in rats (more sensitive species) • DLT • Grade 4 neutropenia for more than 7 days • Febrile neutropenia • Grade 4 thrombocytopenia • Grade 3 non-hematologic toxicity except for controllable nausea/vomiting or diarrhea

39. Case Study #1 (cont.) • Dose escalation scheme • Modified CRM • 1 pt/cohort until grade 1 tox, then, 3 pt/cohort • Doses • 2.5, 5.0, 10.0, 16.5, 21.0, 25.0, 30.0 (100) (100) (65%) (50%) (20%) (20%) • Determination of MTD • Highest dose with ≤ 1/6 DLT • PK/PD

40. Case Study #1: Result

41. Case Study #2Fox et al., The Oncologist, 2002 • Two Types of Phase I Studies

43. EWOC Design Babb et al., Stat in Med 1998 • Prob {DLT | Dose = MTD} =  • Start at the lowest dose level • Before treating kth patient, define Dk as the cumulative data currently available and  be any dose • Let k()= Prob{MTD   | Dk} be the probability that dose  exceeds MTD. EWOC selects for the kth patient the dose level xk such that k(xk)= . • For pre-selected doses, choose max{d1 ,…, dr : di-xkT1 and k(xk) - T2 } • Positive tolerance T1 and T2 allow treating pts at dose levels above yet sufficiently close to the optimal Bayesian dose xk.

44. Bayesian Model Average - CRM

46. Homework #5 (due 2/9) In a first in human study, suppose the new agent will be tested in 5 doses. The expected probability of dose limiting toxicity (DLT) are characterized in the following 2 scenarios: Dose 1Dose 2Dose 3Dose 4Dose 5 Scenario 1 0.05 0.15 0.30 0.50 0.70 Scenario 2 0.10 0.35 0.60 0.75 0.95 The goal is to determine the maximum tolerated dose defined as the dose which yield 30% DLT. 1. Please evaluate the operating characteristics (OC) with at least 1,000 simulations using (a) The standard 3+3 design with a cohort size of 3. (b) The modified continual reassessment methods with a cohort size of 3. Assume the maximum sample size is 30. [NOTE: for (b), please specify the parametric form of the CRM and give the prior distribution. You may choose logistic, hyperbolic, or power functions.] (c) The BMA-CRM with a cohort size of 3. Assume the maximum sample size is 30. Please list the skeletons used. The OC should include at least: (i) Number and percent of patients treated at each dose (ii) Number and percent of toxicities observed at each dose (iii) Percentage of recommended MTD at each dose (iv) Average number of patients treated (v) Overall toxicity rate You may use the program phaseIsim, CRM Simulator, BMA-CRM Simulator 2. Compare the results in (a), (b), and (c). Which method do you recommend?