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Oncology Early Clinical Trials’ Designs and their Challenges Pamela N Munster, MD TICR 4-18-2012.

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Presentation on theme: "Oncology Early Clinical Trials’ Designs and their Challenges Pamela N Munster, MD TICR 4-18-2012."— Presentation transcript:

1 Oncology Early Clinical Trials’ Designs and their Challenges Pamela N Munster, MD TICR

2 Phase I Safety/Phase II dose Phase III Compare new vs. standard Phase IV long term safety FDA Approval IND granted Cell culture, signaling studies, combinations, xenografts and animal models Animal Tox Molecular Screens 2554 Phase I trials currently accruing Historical Drug Development Snapshot 3908 NCI listed 1872 NCI listed Phase 0 Phase II Efficacy/Tox

3 Testing of a novel strategy/compound –New single agent First in Man, Proof of Concept New formulations, schedules or doses –Combinations of novel agents with existing agents X combined with chemotherapy X combined with hormonal therapies –Novel agent as biological response modifier Inhibition of Histone deacetylase, Inhibition of DNA repair (e.g. PARP, Chk1, wee1) Inhibition of chaperone proteins, (e.g. HSP90) Types of Treatments in Phase I Clinical Trials (I)

4 Testing of a novel strategy/compound –Different Modalities Small molecules Immune modifiers electroporation of inhibitory genes siRNA, anti-sense Types of Treatments in Phase I Clinical Trials (II)

5 Terms and Definitions –Safety, Toxicity and Tolerability –Dose limiting toxicities (DLT) –Maximally Administered Dose (MAD) –Maximally Tolerated Dose (MTD) –Recommended Phase II dose (RPTD) –Dose Escalation Rules –Pharmacokinetics and Pharmacodynamics Early Phase Clinical Trials’ Design

6 Terms and Definitions –Safety, Toxicity and Tolerability Standard toxicity assessment by Common Terminology Criteria for Adverse Events (CTCAE) v ) Grading »0-5 2) Causality determination: »treatment-emergent vs treatment-related Early Phase Clinical Trials’ Design

7 Example: Toxicity Assessment Presentation: A 47 year old Caucasian male starts an investigational agent on , Four days later he presents with a new rash over his entire right arm with itching. He continues to have mild fatigue, but now has an unquenchable thirst. He is able to do his daily chores. His fasting blood glucose is 271 mg/dL. Baseline criteria included Grade I fatigue, but otherwise no symptoms. Assessment: Grading and Relatedness (CTCAE IPhone App, or (ctep.cancer.gov/protocoldevelopment/electronic.../ctcaev3.pdf) Fatigue: Rash: Fasting Blood Glucose:

8 Example: Toxicity Assessment Presentation: A 47 year old Caucasian male starts an investigational agent on , Four days later he presents with rash over the arms and chest, fatigue, and unquenchable thirst. He is able to do his daily chores and has otherwise no symptoms. His fasting blood glucose is 271. Baseline criteria included Grade I fatigue, but otherwise no symptoms. Assessment:

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11 Example: Toxicity Assessment Presentation: A 47 year old Caucasian male starts an investigational agent on , Four days later he presents with rash over the arms and chest, fatigue, and unquenchable thirst. He is able to do his daily chores and has otherwise no symptoms. His fasting blood glucose is 271. Baseline criteria included Grade I fatigue, but otherwise no symptoms. Assessment: Fatigue: Grade 1, not related Rash: Grade 2, related Fasting Blood Glucose: Grade 3, related

12 Terms and Definitions Dose limiting toxicities (DLT) within window (usually 3-4 weeks) –Grade 3 non-hematological toxicities –Grade 4 hematological –Protocol-specific definitions E.g. allow for grade 3 –Diarrhea despite optimal care, –Nausea despite optimal care –Hyperglycemia (with treatment for more than 14 days) (PI3k, mTOR) –Hypertension (VEGF inhibitors, VEGFR inhibitors) Classical Phase I Clinical Trials’ Design

13 Terms and Definitions –Maximally Administered Dose (MAD) Highest administered dose (>2/6 pts with DLT) –Maximally Tolerated Dose (MTD) Highest tested dose where 0/6 or 1/6 patients experienced DLT –Recommended Phase II dose (RPTD) The dose to be tested in phase II Classical Phase I Clinical Trials’ Design

14 Dose escalation designs Leonardo di Pisa (ca.1202) (Fibonacci) First mentioned in Pingala (200 BC)Pingala

15 Dose escalation designs –Fibonacci (0, 1, 1, 2, 3, 5, 8, 13, 21, …) –Modified Fibonacci –Dose doubling Designs –Adaptive Designs real time pharmacokinetics, statistical adaptations –Combinations of designs Early Phase Clinical Trials’ Design

16 Dose escalation CohortsFibModified Fib Percent increase Example (mg) 1 D D x D 100%2 33 x D3.3 x D66% x D 50%5 58 x D7 x D 40 %7 613 x D9 x D29%9 721 x D12 x D33 % x D16 x D33 %16 Fibonacci and modified Fibonacci Dose escalations

17 Dose escalation CohortsDose Increase 12 mg D 24 mg2 x D100% 38 mg4 x D100% 4 (1/6 DLT)16 mg8 x D100% 524 mg12 x D40%-50% 636 mg18 x D40%-50% Dose doubling

18 Dose escalation with fixed tablets: e.g. 100 mg tablets CohortsDose% IncreaseMod Fib 1100 mg mg100% 3300 mg50%66% 4400 mg33%50% 5500 mg25% 40 % 6600 mg20%29% 7700 mg17%33% Other Dose Escalation schemes

19 Adaptive Dose escalation with fixed tablets: e.g. 100 mg tablets CohortsDoseIncrease 1100 mg qd 2100 mg bid100% 3100 mg tid50% 4200 mg qd25% 5200 mg bid100% 6200 mg tid50% Adaptive Designs (Example)

20 Cohort Size Patient Escalation 1+1 (occ. used for lowest doses) 3+3 (most common) 6+6 Cohorts and Sample Size

21 –Dose Escalation Rules PRE-DEFINED CONDITIONS FOR DOSE ESCALATION –(standard and specific to the individual protocol) Early Phase Clinical Trials’ Design Terms and Definitions

22 Dose Escalation Rules (3+3 design) # patients with DLT at a Given Dose Level Escalation Decision Rule 0 out of 3Dose escalate to next higher dose level >2 out of 3Dose escalation will be stopped. This dose level will be declared the maximally administered dose (highest dose administered). The next lower cohort will be expanded to 6 patients. If no DLTs are seen consider an intermediate dose level between this dose and the MAD dose. 1 out of 3Enter at least 3 more patients at this dose level.  If 0 of these 3 patients experience DLT, proceed to the next dose level.  If 1 or more of this group suffer DLT, then dose escalation is stopped, and this dose is declared the maximally administered dose. <1 out of 6 at highest dose level below the maximally administered dose This is the recommended Phase II dose. If 0 out of 3 at the highest dose Consider protocol amendment to dose escalate further

23 Dose expansion Purpose: Estimation of toxicities in larger sample set Estimation of PK and PD markers Preliminary Efficacy Sample size Minimum 6 General 12-15

24 Dose expansion Purpose: Estimation of toxicities in larger sample set Estimation of PK and PD markers Preliminary Efficacy Sample size Minimum 6 General 12-15

25 Pharmacokinetics and Pharmacodynamics

26 “Drug Behavior in the Subject” Pharmacokinetics

27 Free Drug Plasma ↕ Metabolites Bound Drug TARGET SITE (Receptor) Free Drug ↕ Bound Drug TISSUE SITE Free Drug ↕ Bound Drug Metabolism Absorption Pharmacokinetics EliminationExcretion Polymorphism P. Munster

28 Measurables Routinely done: albeit often limited Half-life (t 1/2 ) Distribution volume Peak concentrations (C max ) Time to peak concentration (T max ) Area under the curve Food effects Not routinely done Polymorphisms Drug-drug interactions PK-PD interactions Pharmacokinetics

29 Example of PK sampling in Phase I trial Heparinized blood samples (10 mL) will be collected on Day1 at 0, 0.5, 1, 2, 4, 6, 8, 24, 48, and 72 hours after the first dose of LY Day 15 at 0, 0.5, 1, 2, 4, 6, 8, and 24 hours after that day’s dose Day 57 at 0, 0.5, 1, 2, 4, 6, 8, and 24 hours after that day’s dose. Single blood samples for pharmacokinetic studies for the desmethyl metabolite were also collected on days 8, 15, 22, 29, 43, 71, and 85.

30 Example: Plasma concentration: dose escalations ASCO 2008, J Infante

31 Munster et al CCR 2009 VPA dose level (mg/kg/day) VPA level (μg/ml) 0.25 h 24 h 48 h 168 h Epirubicin level (ng/ml) C Example: Plasma Concentrations – Drug Interactions

32 Metabolism and Polymorphism

33 [Kirchheiner, 2003] Polymorphisms in the CYP2D6 gene changes Metabolizers status PM: Poor metabolizers IM: Intermediate metabolizer EM: Extensive metabolizer UM: Uebermetabolizer

34 Pharmacodynamics

35 “Drug Effects on the subjects and tumors” Symptoms Signs Changes in Lab values (e.g effects on glucose metabolism) Molecular and Biological effects

36 Munster P et al. Clin Cancer Res 2009;15: ©2009 by American Association for Cancer Research Pharmacodynamics: Effects on Lab Parameters DIRECT EFFECTS

37 Munster, P. et al. J Clin Oncol; 25: Fig 1. Valproic acid (VPA) effects on epirubicin-associated toxicities Indirect effects Pharmacodynamics: Effects on Lab Parameters INDIRECT EFFECTS

38 HORMONE RECEPTOR STATUS HER2 STATUS VISCERA DISEASE PRIOR AROMATASE INHIBITORS PRIOR TAMOXIFEN  ACET- H4 DOSE MOD Patients with Partial Response: 8/43 (19%) Pt 1 Pt 2 Pt 3 Pt 4 Pt 5 Pt 6 Pt 7 Pt 8 ER+ / PR+ ER+ / PR- ER+ / PR+ Not ampl Yes No Yes No Letrozole Anastrozole, Exemestane Letrozole, Exemestane Anastrozole Letrozole, Exemestane Anastrozole, Exemestane Letrozole Tamoxifen Tamoxifen Yes No Yes - Yes Patients with Stable Disease > 24 weeks: 9/43 (21%) Pt 1 Pt 2 Pt 3 Pt 4 Pt 5 Pt 6 Pt 7 Pt 8 Pt 9 ER+ / PR- ER+ / PR+ ER+ / PR- ER+ / PR+ ER+ / PR- ER+ / PR+ Not ampl Ampl Not ampl No Yes No Yes No Yes No Letrozole, Anastrozole Letrozole, Exemestane, Anastrozole, Letrozole Letrozole Anastrozole Anastrozole, Letrozole Letrozole, Exemestane Letrozole Tamoxifen Tamoxifen Tamoxifen Yes - Yes Pharmacodynamics: PD effects (histone acetylation) and Responses

39 H4 acetylation occurred only in 58% of treated patients % change in histone acetylation Acetyl-H4 Day 1 Day 8

40 H3 and H4 acetylation more commonly seen in patients with clinical benefits % change in histone acetylation ALL R NR % change in acetyl-H4 * P=0.022, n=36

41 Correlative studies: Histone acetylation biomarker in responders vs non-responders Change in H4 histone acetylation (%) All R NR % change in histone acetylation

42 No clear relationship between dose and toxicity No definite threshold toxicity (DLT) No clear relationship between efficacy and dose No clear target modulation Unrecognized down-target effects –Activating or inhibitory Efficacy not likely Difficult to choose dose or schedule in these circumstances Emerging Challenges

43 Imaging –PET scanning Tissue Perfusion Blood Volume Glucose metabolism Estrogen metabolism –DCE-MRI Pharmacodynamic Studies –Target inhibition in end-organ Tumor biopsies Circulating tumor cells –Target inhibition in surrogate tissue Peripheral Blood Mononuclear Cells Pharmacokinetics –Targeted Drug Levels: Serum Markers Alternative and/or Additional Endpoints

44 Traditional Phase I designs are valid for novel chemotherapy drugs and for some novel agents but…. Many targeted agents require careful assessment and incorporation of correlative endpoints or novel imaging modalities to decide the dose, schedule, and optimal therapeutic partners Availability of real-time PK and PD (biomarkers) Validation of endpoints in larger studies with enriched populations Conclusion

45 Thank you


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