PF-06821497 Treatment Of Relapsed/Refractory SCLC, Castration Resistant Prostate Cancer, and Follicular Lymphoma

Study Overview
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Brief Summary
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A Phase 1 Dose Escalation and Expanded Cohort Study Of PF-06821497 In The Treatment Of Adult Patients With Relapsed/Refractory Small Cell Lung Cancer (SCLC), Castration Resistant Prostate Cancer (CRPC) And Follicular Lymphoma (FL).

Detailed Description
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This is an open label, multi center, Phase 1 dose escalation and dose expansion study of PF-06821497 administered orally BID as a single agent or in combination with SOC to patients with CRPC, SCLC, and FL. Part 1A will evaluate safety and target modulation of PF-06821497 monotherapy in patients with SCLC, FL and CRPC. PF-06821497 will be administered as monotherapy in patients with FL in Part 1B dose escalation and to patients with CRPC in Part 1C dose escalation. For Part 2A (dose escalation combination therapy), PF-06821497 will be administered in combination with SOC in patients with CRPC and SCLC. For Part 2B (dose expansion), patients with mCRPC will be randomized (1:1 ratio) to receive either SOC or PF-06821497 in combination with SOC. Once safety and adequate target modulation has been established in Part 1A, Parts 1B and 2A of the trial will be initiated. Part 1C (monotherapy dose escalation) will determine the MTD of single agent PF-06821497 in patients with mCRPC. Japan and China monotherapy cohorts will evaluate the safety, antitumor activity and PK of single agent PF-06821497 in Japanese and Chinese patients. Part 2A (escalation RP2D finding for combination) will determine the MTD of the combination with SOC in patients with CRPC. Part 2B (dose expansion) will assess the efficacy of PF-06821497 at the RP2D in combination with SOC in patients with mCRPC in comparison to SOC alone. The study is currently enrolling Part 2B.

Official Title
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A PHASE I DOSE ESCALATION AND EXPANDED COHORT STUDY OF PF-06821497 IN THE TREATMENT OF ADULT PATIENTS WITH RELAPSED/REFRACTORY SMALL CELL LUNG CANCER (SCLC), CASTRATION RESISTANT PROSTATE CANCER (CRPC) AND FOLLICULAR LYMPHOMA (FL)

Conditions
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Castration Resistant Prostate Cancer (CRPC), Small Cell Lung Cancer (SCLC), Follicular Lymphoma (FL)

Intervention / Treatment
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* Drug: PF-06821497


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Histological or cytological diagnosis of advanced / metastatic solid tumor with the following tumor types in individual study parts: Part 1A (closed to enrollment): Part 1B (closed to enrollment): Part 1C: Castration resistant prostate cancer. Patients should have received either abiraterone and/or enzalutamide treatment and have evidence of prostate cancer progression (per PCWG3) Japan cohort Castration resistant prostate cancer that is resistant to SOC or for which no local regulatory approved SOC is available that would confer significant clinical benefit in the medical judgement of the investigator. Patients should have received either abiraterone and/or enzalutamide treatment and have evidence of prostate cancer progression (per PCWG3) China cohort Castration resistant prostate cancer that is intolerant/resistant to SOC or for which no local regulatory approved SOC is available that would confer significant clinical benefit in the medical judgement of the investigator. Patients who refused SOC may be eligible. Patients should have received either abiraterone and/or enzalutamide treatment and have evidence of prostate cancer progression (per PCWG3) Part 2A: • Castration resistant prostate cancer. Patients should have received either abiraterone and/or enzalutamide treatment, may have received up to 1 line of chemotherapy and have evidence of prostate cancer progression (per PCWG3) Part 2B: Castration resistant prostate cancer. Patients should have received abiraterone treatment, may have received up to 1 prior line of chemotherapy, have not received prior enzalutamide, apalutamide or darolutamide and have evidence of prostate cancer progression (per PCWG3) Patients must have radiographic evidence of disease Other inclusion criteria: Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1. Adequate organ function Key Exclusion Criteria: - Prior Chemotherapy: Part 1C , Japan cohort and China cohort (CRPC): no more than 2 previous regimens of chemotherapy Part 2A: CRPC: no more than 1 previous regimen of systemic chemotherapy Part 2B (CRPC): no more than 1 previous regimen of chemotherapy Prior irradiation to >25% of the bone marrow. QTcF interval >480 msec at screening. Hypertension that cannot be controlled by medications (>150/90 mmHg despite optimal medical therapy). Known or suspected hypersensitivity to PF 06821497 or any components or enzalutamide (CRPC) Active inflammatory gastrointestinal disease, chronic diarrhea, known diverticular disease or previous gastric resection or lap band surgery. Gastroesophageal reflux disease under treatment with proton pump inhibitors is allowed. Current use or anticipated need for food or drugs that are known strong CYP3A4/5 inducers or inhibitors, including their administration within 10 days or 5 half lives of the CYP3A4/5 inhibitor, whichever is longer prior to first dose of investigational product.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation (Part 1A)<br>Participants with SCLC, CRPC and FL will receive PF-06821497 at escalating dose levels | Drug: PF-06821497<br>* Oral continuous<br>* Other names: EZH2i;|
| Experimental: Dose Escalation (Part 1B)<br>Participants with FL will receive PF-06821497 at escalating dose levels | Drug: PF-06821497<br>* Oral continuous<br>* Other names: EZH2i;|
| Experimental: Dose Escalation (Part 1C)<br>Participants with CRPC will receive PF-06821497 at escalating dose levels. | Drug: PF-06821497<br>* Oral continuous<br>* Other names: EZH2i;|
| Experimental: Dose Escalation (Part 2A)<br>Participants with CRPC and SCLC will receive PF-06821497 at escalating dose levels in combination with SOC. | Drug: PF-06821497<br>* Oral continuous<br>* Other names: EZH2i;|
| Experimental: Dose Expansion (Part 2B)<br>Participants with CRPC will receive PF-06821497 in combination with SOC or SOC alone. | Drug: PF-06821497<br>* Oral continuous<br>* Other names: EZH2i;|
| Experimental: Japan Cohort<br>Participants with CRPC will receive PF-06821497 at one or two doses | Drug: PF-06821497<br>* Oral continuous<br>* Other names: EZH2i;|
| Experimental: China cohort<br>Participants will receive PF-06821497 at one or two doses | Drug: PF-06821497<br>* Oral continuous<br>* Other names: EZH2i;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with dose limiting toxicities (DLTs) to determine the maximum tolerated dose (MTD) | First cycle DLTs will be utilized to determine the MTD | Baseline up to 90 days | 
| Overall safety profile including adverse events | Adverse Events will be graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version [4.03]) | Baseline up to approximately 2 years | 
| Preliminary efficacy determination as evaluated by disease specific response criteria | Objective response using Response Evaluation Criteria in Lymphoma (RECIL) for lymphoma, Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for solid tumors including Small Cell Lung Cancer (SCLC) and Prostate Cancer Working Group 3 (PCWG3) for Castration Resistant Prostate Cancer (CRPC). Progression-free survival in Part 2B in patients with CRPC. | Through study completion, approximately 2 years past last patient first visit. | 
| Overall safety profile including laboratory abnormalities | Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE version [4.03]), and timing. | Baseline up to approximately 2 years | 
| Overall safety profile including vital signs | Vital sign changes from baseline including blood pressure, heart rate, ECG changes. | Baseline up to approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate time to event anti-tumor activity of PF-06821497 including progression-free survival (PFS), PSA50, Duration of Response (DoR), Time to first skeletal related event and Time to symptomatic skeletal related event, depending on tumor type. | Time to event endpoints based on Response Evaluation Criteria in Lymphoma (RECIL) for lymphoma, Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for solid tumors including Small Cell Lung Cancer (SCLC) and Prostate Cancer Working Group 3 (PCWG3) for Castration Resistant Prostate Cancer (CRPC) | Baseline and every 21 days through time of confirmed disease progression, unacceptable toxicity, or through study completion, approximately 2 years. | 
| Evaluate overall survival | Median time to death proportion of patients alive at 6 months, 1 year, and 2 years. | Baseline up to approximately 2 years | 
| Pharmacokinetic Parameters: Maximum Observed Plasma Concentration (Cmax) | Single dose and multiple dose PK will be calculated as data permits | At specific timepoints from Cycle 1 day 1 to End of Treatment visit | 
| Pharmacokinetic Parameters: Time to Reach Maximum Observed Plasma Concentration (Tmax) | Single dose and multiple dose PK will be calculated as data permits | At specific timepoints from Cycle 1 day 1 to End of Treatment visit | 
| Pharmacokinetic Parameters: Area Under the Curve (AUC) | Single dose and multiple dose PK will be calculated as data permits | At specific timepoints from Cycle 1 day 1 to End of Treatment visit | 
| Pharmacokinetic Parameters: Apparent Oral Clearance (CL/F) | Single dose and multiple dose PK will be calculated as data permits | At specific timepoints from Cycle 1 day 1 to End of Treatment visit | 
| Pharmacokinetic Parameters: Apparent Volume of Distribution (Vz/F) | Single dose and multiple dose PK will be calculated as data permits | At specific timepoints from Cycle 1 day 1 to End of Treatment visit | 
| Pharmacokinetic Parameters: Plasma Decay Half-Life (t1/2) | Singe dose and multiple dose PK will be calculated as data permits | At specific timepoints from Cycle 1 day 1 to End of Treatment visit | 
| Evaluate the impact of PF-06821497 on patient reported outcomes. | Quality of Life and Time to Functional Status Deterioration as assessed by FACT-P. | At specific time-points from Cycle 1 Day 1 to End of Treatment visit. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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EZH2, enhancer of zeste homolog 2, castrate resistant prostate cancer, prostatecancer-study.com, CRPC, efficacy, safety, pharmacokinetics, pharmacodynamics, dose escalation, dose expansion, open-label, small cell lung cancer, SCLC, follicular lymphoma, FL, relapsed, refractory