Design and Analysis of Phase I Clinical Trials in Cancer Therapy

1. Design and Analysis of Phase I Clinical Trials in Cancer Therapy

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

3. �Conventional� eligibility criteria- examples: Advanced solid tumors unresponsive to standard therapies or for which there is no known effective treatment Performance status (e.g. ECOG 0 or 1) Adequate organ functions (e.g. ANC, platelets, Creatinine, AST/ALT, bilirubin) Specification about prior therapy allowed Specification about time interval between prior therapy and initiation of study treatment No serious uncontrolled medical disorder or active infection

4. �Agent-specific� eligibility criteria - examples: Restriction to certain patient populations � must have strong scientific rationale Specific organ functions: For example � cardiac function restrictions (e.g. QTc < 450-470 ms, LVEF > 45%, etc) if preclinical data or prior clinical data of similar agents suggest cardiac risks For example � no recent (6-12 months) history of acute MI/unstable angina, cerebrovascular events, venous thromboembolism; no uncontrolled hypertension; no significant proteinuria, for antiangiogenic agents Prohibited medications if significant risk of interaction with study drug

5. A New Agent Merits Clinical Study if� It is biologically plausible that the agent may have activity in cancer (target seems valid and agent affects it) There is reason to expect benefit for patients (preclinical or other evidence of efficacy) There is reasonable expectation of safety (toxicology) Sufficient data on which to base starting dose Hirschfeld S, 2004

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

7. Phase I Study Basic Design Principles Start with a safe starting dose Minimize # of pts treated at sub-toxic doses Escalate dose rapidly in the absence of toxicity Escalate dose slowly in the presence of toxicity Expand patient cohort at recommended phase II dose

8. Phase I Trials: Fundamental Questions At what dose do you start? What are the endpoints? How many patients per cohort? How quickly do you escalate?

9. At what dose do you start ?

10. Typically a rodent (mouse or rat) and non-rodent (dog or non-human primate) species Reality of animal organ specific toxicities � very few predict for human toxicity Myelosuppression and gastrointestinal toxicity more predictable Hepatic and renal toxicities � large false positive Toxicologic parameters LD10 � lethal dose in 10% of animals TDL (toxic dose low) � lowest dose that causes any toxicity in animals

11. Phase I Trials : Starting Dose 1/10th of the LD10 in rodents, or 1/3rd of the minimal toxic dose in large animals Expressed as mg/m2 These have historically been safe doses

13. What are the endpoints / objectives ? First of all...does this drug have an effect on the tumor? Look at techniques to monitor metabolism andexcretion of the drug. Develop an assay to see if the drug is hitting the target. What kind of toxicities are there? Determine a therapeutic index using tumor bearing animals. Need to ID methods to manufacture the drug.First of all...does this drug have an effect on the tumor? Look at techniques to monitor metabolism andexcretion of the drug. Develop an assay to see if the drug is hitting the target. What kind of toxicities are there? Determine a therapeutic index using tumor bearing animals. Need to ID methods to manufacture the drug.

14. Phase I Study Endpoints Dose, toxicity, pharmacology (efficacy ? ) Classical goals Identify dose-limiting toxicities (DLTs) Identify the maximally tolerated dose (MTD) Assess pharmacokinetics (drug metabolism and clearance) Evaluate target modulation

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

16. Dose-Limiting Toxicities (DLT) Toxicities that, due to their severity or duration, are considered unacceptable, and limit further dose escalation Defined in advance of beginning 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 wks of scheduled treatment

17. Definition of DLT is Dynamic Examples: DLTs in 2008 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 anti-hypertensive therapy Inability to take at least 90% of drug doses in a cycle (continuous oral meds) Grade 2 chronic unremitting toxicity

18. Maximally Tolerated Dose (MTD) Inconsistently defined as either: Dose at which ? 33% of pts 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 pts treated at the recommended Phase II dose (MTD or 1 dose level below)

19. Recap : Trans-AtlanticDifferences in Terminology Important to note that: �Maximum tolerated dose� (MTD): Usually means �recommended dose� in US Usually means dose level above recommended dose in Europe and some other jurisdictions

20. How many patients per cohort?

21. Patients per Cohort : Guiding Principles Minimum needed to provide adequate toxicity information Classically 3 patients per cohort In some designs �1 patient per cohort� until toxicity seen If correlative studies are a major aim, may increase up to 6 patients per cohort

23. How quickly do you escalate?

24. Phase I Trial Design : Dose Escalation �Escalation in decreasing steps� (Hansen HH et al. Cancer Res. 1975) Attributed to a merchant from Pisa in the 13th century (Leonardo Bonacci, 1170-1240; aka Fibonacci) Outlined a number of problems including �how many pairs of rabbits can be produced from a single pair under specified conditions?� (1, 1, 2, 3, 5, 8, 13, 21, 34, 55, 89, 144�..) in a book, �Liber abacus�

25. Phase I Trials: Dose Escalation

26. Cohort Dose Escalation

27. Problems and Pitfalls

28. Phase I Study Assumptions The higher the dose, the greater the likelihood of efficacy Dose-related acute toxicity is regarded as a surrogate for efficacy The highest safe dose is the dose most likely to be efficacious

29. Dose-response: Efficacy and Toxicity

30. Modified Fibonacci Dose Escalation Problems: Requires many patients Takes a long time May expose a substantial proportion of patients to low, ineffective doses

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

32. Classic Phase I Trials Design Limitations Chronic toxicities usually cannot be assessed Cumulative toxicities usually cannot be identified Uncommon toxicities will be missed

33. Phase I Studies and Infrequent Toxicities

34. Alternate Designs Starting dose Number of patients per dose level Method/rapidity of dose escalation

35. Selection of Starting Dose for Phase I Trials: Retrospective analysis of 21 trials using modified Fibonacci dose escalation

36. 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 NOT DO THIS ALWAYS ? Makes evaluation of chronic toxicities difficult The proverbial 1 responder at dose level 1

37. 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 intrapatient dose escalation allowed in some variations More rapid initial escalation

39. Accelerated Titrated Design : Phase I Study of Lonafarnib (SCH66336)

40. Bayesian method Pre-study probabilities based on preclinical or clinical data of similar agents At each dose level, add clinical data to better estimate the probability of MTD being reached Fixed dose levels, so that increments of escalation are still conservative

41. Example: Pre-set dose levels of 10, 20, 40, 80, 160, 250, 400 If after each dose level, the statistical model predicts a MTD higher than the next pre-set dose level, then dose escalation is allowed to the next pre-set dose level Advantages: Allows more dose levels to be evaluated with a smaller number of patients More patients treated at or closer to �therapeutic� dose Disadvantages: Does not save time, not easily implemented if without access to biostatistician support

42. Bayesian method After each cohort of patients, the posterior distribution is updated with DLT data to obtain ?d (probability of DLT at dose d). The recommended dose is the one with the highest posterior probability of DLT in the �ideal dosing� category The overdose control mandates that any dose that has > 25% chance of being in the �over-dosing� or �excessive over-dosing� categories, or > 5% chance of being in the �excess-overdosing� category, is not considered for dosing

43. Estimated MTD Based on Bayesian Logistic Method (2-parameter evaluation with over-dose control)

44. Phase I trial design � Bayesian EWOC model exampleScenario 0/3 DLTs

45. Phase I trial design � Bayesian EWOC model exampleScenario 1/4 DLTs

46. General requirement for long-term administration: pharmacology and formulation critical Difficulty in determining the optimal dose in phase I: MTD versus OBD Absent or low-level tumor regression as single agents: problematic for making go no-go decisions Need for large randomized trials to definitively assess clinical benefit: need to maximize chance of success in phase III

47. Phase I Trial Design: Non-Cytotoxic Agents MTD may not be the goal of Phase I since specificity of effect may be lost at MTD Pharmacologic effect may not equal biologic effect Goal: identify optimal biologically effective dose (OBED) Paradox: requires early development and integration of (usually unvalidated) measures of biologic effect into Phase I

48. Conventional cytotoxic drugs have led to predictable effects on proliferating tissues (neutropenia, mucositis, diarrhea), thus enabling dose selection and confirming mechanisms of action Targeted biological agents may or may not have predictable effects on normal tissues and often enter the clinic needing evidence/proof of mechanisms in patients

49. Therefore, biological correlative studies may be used to derive the best dose and schedule of an agent, and To determine whether the drug is inducing the intended biological effect in the patient, and To predict clinical benefit, although this generally requires testing in large randomized studies.

50. Alternative Endpoints Minimum blood levels/AUC or other PK measure Inhibition of target In normal tissue In tumor tissue Need enough preclinical evidence to suggest that the above are reasonable endpoints with �sufficient� clinical promise Must also pay attention to toxicity

51. Phase I Trial Design : Non-Cytotoxic Agents - Examples Pre-clinically define target drug exposure � Matrix Metalloproteinase Inhibitors Define pharmacodynamic endpoint � Bortezomib (70% of 26S proteasome inhibition in PBMCs) Use functional imaging as endpoint � Vatalanib (DCE-MRI) Use cumulative toxicities � CI-1040 MEK Inhibitor, 800mg TID intolerable after 3 cycles of therapy Problem : If drug works, you�re a genius. If it doesn�t, you�re a goat

52. Vatalanib (PTK/ZK) : VEGF Receptor Tyrosine Kinase Inhibitor The purpose of this slide is to illustrate the mechanism of action of PTK/ZK PTK/ZK binds to the intracellular tyrosine kinase domain of all VEGF receptors (VEGFR-1, VEGFR-2, VEGFR-3) and prevents their activation by members of the VEGF family1,2 Disruption of VEGF receptor activity by PTK/ZK occurs despite the extracellular presence of VEGF family members, resulting in inhibition of tumor angiogenesis and lymphangiogenesis1,2 1. Bold G, Altmann KH, Frei J, et al. New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis. J Med Chem. 2000;43(12):2310-23. 2. Wood JM, Bold G, Buchdunger E, et al. PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res. 2000;60:2178-2189. The purpose of this slide is to illustrate the mechanism of action of PTK/ZK PTK/ZK binds to the intracellular tyrosine kinase domain of all VEGF receptors (VEGFR-1, VEGFR-2, VEGFR-3) and prevents their activation by members of the VEGF family1,2 Disruption of VEGF receptor activity by PTK/ZK occurs despite the extracellular presence of VEGF family members, resulting in inhibition of tumor angiogenesis and lymphangiogenesis1,2 1. Bold G, Altmann KH, Frei J, et al. New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis. J Med Chem. 2000;43(12):2310-23. 2. Wood JM, Bold G, Buchdunger E, et al. PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res. 2000;60:2178-2189.

53. PTK/ZK Induced Significant Reduction in Tumor Blood Flow in Metastatic Colorectal Cancer by DCE-MRI The purpose of this slide is to demostrate the utility of DCE-MRI as a biomarker for PTK/ZK clinical efficacy A case report of positive tumor response by DCE-MRI Changes in tumor blood flow are quantified and expressed by the value MRI-Ki, which incorporates tumor blood flow, perfusion, and permeability measures MRI-Ki was significantly reduced from baseline with the administration of PTK/ZK as measured by DCE-MRI; liver metastases seen here; and significantly correlated with improved early clinical outcome defined as lack of progression: SD>2 months Thomas AL, Morgan B, Drevs J, et al. Vascular endothelial growth factor receptor tyrosine kinase inhibitors: PTK787/ZK 222584. Semin Oncol. 2003;30:32-38. Morgan B, Drevs J, Steward W, et al. Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies. J Clin Oncol. 2003;21:3955-3964.The purpose of this slide is to demostrate the utility of DCE-MRI as a biomarker for PTK/ZK clinical efficacy A case report of positive tumor response by DCE-MRI Changes in tumor blood flow are quantified and expressed by the value MRI-Ki, which incorporates tumor blood flow, perfusion, and permeability measures MRI-Ki was significantly reduced from baseline with the administration of PTK/ZK as measured by DCE-MRI; liver metastases seen here; and significantly correlated with improved early clinical outcome defined as lack of progression: SD>2 months Thomas AL, Morgan B, Drevs J, et al. Vascular endothelial growth factor receptor tyrosine kinase inhibitors: PTK787/ZK 222584. Semin Oncol. 2003;30:32-38. Morgan B, Drevs J, Steward W, et al. Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies. J Clin Oncol. 2003;21:3955-3964.

54. Using DCE-MRI to Establish the Optimal Therapeutic Dose for Vatalanib The purpose of this slide is to illustrate the optimal therapeutic dose for PTK/ZK A decrease to 60% or less of baseline MRI-Ki was significantly correlated with improved early clinical outcome, defined as lack of progression Analysis of AUC versus Ki shows that an AUC of 90 hr��M is correlated with a 60% decrease from baseline Ki (left panel) Plotting mean AUC at day 28 against PTK/ZK dose suggests that a dose of approximately 1,200 mg/day is required to achieve an exposure of 90 hr��M even at the lower end of the confidence interval (right panel) Based on these pharmacokinetic analyses, as well as the MRI-DCE and safety and preliminary efficacy data in phase I/II trials, the selected dose for phase III trials is 1,250 mg/day Morgan B, Drevs J, Steward W, et al. Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies. J Clin Oncol. 2003;21:3955-3964.The purpose of this slide is to illustrate the optimal therapeutic dose for PTK/ZK A decrease to 60% or less of baseline MRI-Ki was significantly correlated with improved early clinical outcome, defined as lack of progression Analysis of AUC versus Ki shows that an AUC of 90 hr��M is correlated with a 60% decrease from baseline Ki (left panel) Plotting mean AUC at day 28 against PTK/ZK dose suggests that a dose of approximately 1,200 mg/day is required to achieve an exposure of 90 hr��M even at the lower end of the confidence interval (right panel) Based on these pharmacokinetic analyses, as well as the MRI-DCE and safety and preliminary efficacy data in phase I/II trials, the selected dose for phase III trials is 1,250 mg/day Morgan B, Drevs J, Steward W, et al. Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies. J Clin Oncol. 2003;21:3955-3964.

56. Initial dose-finding component often needed if you are planning a new combination for a phase II trial Patients for dose-finding phase: Advanced solid tumors (all comers): Advantage: fast accrual Disadvantage: may not be representative of your patient population of interest Specific patient population (e.g. same as phase II cohort): Advantage: population of interest, and early glimpse at antitumor activity in disease of interest Disadvantage: slow down accrual especially if rare/uncommon tumors

57. Dose escalation: New drug A + Standard combination BC Ideally keep standard combo doses and escalate the new drug (e.g. 1/3, 2/3, full dose) Need to provide rationale: why add A to BC? Need to think about overlapping toxicity in your definition of DLT Do you need PK assessment to determine if A, B and C interact with each other?

58. How are Phase I Studies Designed Now ? 31 targeted agents: representative of most common targets Reports (papers or abstracts) of completed single agent phase I trials in non-hematologic malignancies 57 phase I reports identified  Parulekar and Eisenhauer JNCI July 2004

59. Agents/Targets

60. Results: Reason for Halting Dose Escalation

61. Basis for Recommending Phase II Dose

62. Secondary Information to Support Dose Recommendation

63. Laboratory and Imaging Studies

64. Summary: ReviewPhase I Trials �Targeted� Agents Toxicity Most common reason to halt escalation and primary basis for dose recommendation (35/50 trials) PK (Blood levels) Second most common basis for dose recommendation (9/50 trials) Laboratory studies May provide information to support dose recommendation

65. Phase I Study - Ethics

66. Phase I Study - Ethics Patient benefit or antitumor activity is not a primary goal of the study, but �therapeutic intent� is an important feature Desperate patients cannot make a truly informed decision Historically low probability of response in Phase I trials < 5% response rate Majority of responses occur within 80%-120% of the recommended phase II dose

68. Phase I Study - Ethics Investigators have an inherent conflict of interest Funding Academic promotion Publicity

69. Phase I Study Ethics : Partial Solutions to the Dilemma You�re the patients physician 1st and a scientist 2nd Scientific goals should never take precedence over the patient�s best interest Only pts for whom no life-prolonging or curative therapy exists are eligible for Phase I trials Informed consent is obtained from every patient No new agent can hit the pharmacy shelves without going through Phase I clinical evaluation

70. Phase I Clinical Trials - Summary Most drugs tend to follow the MTD/DLT paradigm Alternative designs continue to be explored. Most times they are more complex. Correlative studies are increasingly important in the comprehensive evaluation of new agents Patient benefit/wellbeing trumps all the science Being a good phase I trialist is not as simple as you may think