A Dose Escalation Study Of PF-06939999 In Participants With Advanced Or Metastatic Solid Tumors

Study Overview
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Brief Summary
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This is a Phase 1, open label, multi center, dose escalation and expansion, safety, tolerability, PK, and pharmacodynamics study of PF 06939999 in previously treated patients with advanced or metastatic cancer.

Official Title
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A PHASE 1 STUDY TO EVALUATE THE SAFETY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF ESCALATING DOSES OF PF-06939999 (PRMT5 INHIBITOR) IN PARTICIPANTS WITH ADVANCED OR METASTATIC NON-SMALL CELL LUNG CANCER, HEAD AND NECK SQUAMOUS CELL CARCINOMA, ESOPHAGEAL CANCER, ENDOMETRIAL CANCER, CERVICAL CANCER AND BLADDER CANCER

Conditions
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Advanced Solid Tumors, Metastatic Solid Tumors

Intervention / Treatment
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* Drug: PF-06939999 dose escalation
* Drug: PF-06939999 monotherapy
* Drug: PF-06939999 in combination with docetaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed locally advanced or metastatic NSCLC, urothelial carcinoma or HNSCC Progressed after at least 1 line of treatment and no more than 3 lines of treatment At least one measurable lesion as defined by RECIST version 1.1 ECOG Performance Status 0 or 1 Adequate Bone Marrow Function Adequate Renal Function Adequate Liver Function Resolved acute effects of any prior therapy Exclusion Criteria: Known active uncontrolled or symptomatic CNS metastases. Major surgery, radiation therapy, systemic anti-cancer therapy or investigational drug(s) within 4 weeks prior to study entry. Active, uncontrolled infection, including COVID-19 Known or suspected hypersensitivity to PF-06939999 Inability to consume or absorb study drug

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: Parallel Assignment
Interventional Model Description: Dose Escalation and Dose expansion
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation<br>Participants will receive PF-06939999 orally at escalating doses in 28 day cycles on a continuous basis | Drug: PF-06939999 dose escalation<br>* PF-06939999 orally at escalating doses on a continuous basis<br>* Other names: PRMT5 inhibitor;|
| Experimental: Non small cell lung cancer monotherapy<br>Participants will receive PF-06939999 at the recommended Phase 2 dose in 28 day cycles on a continuous basis | Drug: PF-06939999 monotherapy<br>* PF-06939999 at the recommended Phase 2 dose orally on a continuous basis<br>* Other names: PRMT5 inhibitor;|
| Experimental: Urothelial carcinoma<br>Participants will receive PF-06939999 at the recommended Phase 2 dose in 28 day cycles on a continuous basis | Drug: PF-06939999 monotherapy<br>* PF-06939999 at the recommended Phase 2 dose orally on a continuous basis<br>* Other names: PRMT5 inhibitor;|
| Experimental: Head and neck squamous cell carcinoma<br>Participants will receive PF-06939999 at the recommended Phase 2 dose in 28 day cycles on a continuous basis | Drug: PF-06939999 monotherapy<br>* PF-06939999 at the recommended Phase 2 dose orally on a continuous basis<br>* Other names: PRMT5 inhibitor;|
| Experimental: Non small cell lung cancer PF-06939999 plus docetaxel<br>Participants will receive PF-06939999 on a continuous basis in combination with docetaxel | Drug: PF-06939999 in combination with docetaxel<br>* PF-06939999 orally on a continuous basis in combination with docetaxel<br>* Other names: PRMT5 inhibitor;|
| Experimental: Non small cell lung cancer dose finding<br>Participants will receive PF-06939999 on a continuous basis at escalating doses in combination with docetaxel | Drug: PF-06939999 in combination with docetaxel<br>* PF-06939999 orally on a continuous basis in combination with docetaxel<br>* Other names: PRMT5 inhibitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with dose limiting toxicities (DLTs) | DLTs will be evaluated during the first cycle. The number of DLTs will be used to determine the maximum tolerated dose (MTD) | Baseline through day 28 | 
| Number of participants with treatment emergent adverse events (AEs) | Adverse events as characterized by type, frequency, severity, timing, seriousness and relationship to study therapy | Baseline through up to 2 years or until disease progression | 
| Number of participants with laboratory abnormalities | Laboratory abnormalities as characterized by type, frequency, severity, and timing. | Baseline through up to 2 years or until disease progression | 
| Objective Response Rate | Best Overall Response by RECIST 1.1 | Baseline through up to 2 years or until disease progression | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic Parameters: Maximum Observed Plasma Concentration (Cmax) | Single dose PK will be calculated including Maximum Observed Plasma Concentration (Cmax). | Cycle 1 Days 1 and 15, predose, 0.5, 1, 2, 4, 6 and 12 hours post dose; predose on Cycle 1 Days 2, 8, 16 and 22 and predose on Day 1 of every Cycle (each cycle is 28 days) thereafter until month 24 | 
| Pharmacokinetic Parameters: Time to reach Maximum Observed Plasma Concentration (Tmax) | Single dose PK will be calculated including Time to reach Maximum Observed Plasma Concentration (Tmax). | Cycle 1 Days 1 and 15, predose, 0.5, 1, 2, 4, 6 and 12 hours post dose; predose on Cycle 1 Days 2, 8, 16 and 22 and predose on Day 1 of every Cycle (each cycle is 28 days) thereafter until month 24 | 
| Pharmacokinetic Parameters: Area Under the Curve from time 0 to the last sampling time point within the dose interval (AUClast) | Single dose PK will be calculated including Area Under the Curve from time 0 to the last sampling time point within the dose interval (AUClast) | Cycle 1 Days 1 and 15, predose, 0.5, 1, 2, 4, 6 and 12 hours post dose; predose on Cycle 1 Days 2, 8, 16 and 22 and predose on Day 1 of every Cycle (each cycle is 28 days) thereafter until month 24 | 
| Pharmacokinetic Parameters: Terminal elimination half life (t1/2) | Single dose PK will be calculated including, as data permit, terminal elimination half life (t1/2) | Cycle 1 Days 1 and 15, predose, 0.5, 1, 2, 4, 6 and 12 hours post dose; predose on Cycle 1 Days 2, 8, 16 and 22 and predose on Day 1 of every Cycle (each cycle is 28 days) thereafter until month 24 | 
| Pharmacokinetic Parameters: AUC from time 0 extrapolated to infinity (AUCinf) | Single dose PK will be calculated including, as data permit, Area Under the Curve from time 0 extrapolated to infinity (AUCinf) | Cycle 1 Days 1 and 15, predose, 0.5, 1, 2, 4, 6 and 12 hours post dose; predose on Cycle 1 Days 2, 8, 16 and 22 and predose on Day 1 of every Cycle (each cycle is 28 days) thereafter until month 24 | 
| Pharmacokinetic Parameters: Apparent oral plasma clearance (CL/F) | Single dose PK will be calculated including, as data permit, apparent oral plasma clearance (CL/F) | Cycle 1 Days 1 and 15, predose, 0.5, 1, 2, 4, 6 and 12 hours post dose; predose on Cycle 1 Days 2, 8, 16 and 22 and predose on Day 1 of every Cycle (each cycle is 28 days) thereafter until month 24 | 
| Pharmacokinetic Parameters: Apparent volume of distribution (Vz/F) | Single dose PK will be calculated including, as data permit, apparent volume of distribution (Vz/F) | Cycle 1 Days 1 and 15, predose, 0.5, 1, 2, 4, 6 and 12 hours post dose; predose on Cycle 1 Days 2, 8, 16 and 22 and predose on Day 1 of every Cycle (each cycle is 28 days) thereafter until month 24 | 
| Pharmacokinetic Parameters: Maximum Observed Steady State Plasma Concentration (Css,max) | Multiple dose PK will be calculated including Maximum Observed Steady State Plasma Concentration (Css,max). | Cycle 1 Days 1 and 15, predose, 0.5, 1, 2, 4, 6 and 12 hours post dose; predose on Cycle 1 Days 2, 8, 16 and 22 and predose on Day 1 of every Cycle (each cycle is 28 days) thereafter until month 24 | 
| Pharmacokinetic Parameters: Time to reach Maximum Observed Steady State Plasma Concentration (Tss,max) | Multiple dose PK will be calculated including Time to reach Maximum Observed Steady State Plasma Concentration (Tss,max). | Cycle 1 Days 1 and 15, predose, 0.5, 1, 2, 4, 6 and 12 hours post dose; predose on Cycle 1 Days 2, 8, 16 and 22 and predose on Day 1 of every Cycle (each cycle is 28 days) thereafter until month 24 | 
| Pharmacokinetic Parameters: Area Under the Curve within one dose interval (AUCss,t) | Multiple dose PK will be calculated including Area Under the Curve within one dose interval (AUCss,t) | Cycle 1 Days 1 and 15, predose, 0.5, 1, 2, 4, 6 and 12 hours post dose; predose on Cycle 1 Days 2, 8, 16 and 22 and predose on Day 1 of every Cycle (each cycle is 28 days) thereafter until month 24 | 
| Pharmacokinetic Parameters: Steady state apparent oral plasma clearance (CL/F) | Multiple dose PK will be calculated including, as data permit, steady state apparent oral plasma clearance (CL/F) | Cycle 1 Days 1 and 15, predose, 0.5, 1, 2, 4, 6 and 12 hours post dose; predose on Cycle 1 Days 2, 8. 16 and 22 and predose on Day 1 of every Cycle (each cycle is 28 days) thereafter until month 24 | 
| Pharmacokinetic Parameters: Steady state apparent volume of distribution (Vss/F) | Multiple dose PK will be calculated including, as data permit, steady state apparent volume of distribution (Vss/F) | Cycle 1 Days 1 and 15, predose, 0.5, 1, 2, 4, 6 and 12 hours post dose; predose on Cycle 1 Days 2, 8, 16 and 22 and predose on Day 1 of every Cycle (each cycle is 28 days) thereafter until month 24 | 
| Pharmacokinetic Parameters: Accumulation ratio (Rac) | Multiple dose PK will be calculated including, as data permit, accumulation ratio (Rac) | Cycle 1 Days 1 and 15, predose, 0.5, 1, 2, 4, 6 and 12 hours post dose; predose on Cycle 1 Days 2, 8, 16 and 22 and predose on Day 1 of every Cycle (each cycle is 28 days) thereafter until month 24 | 
| Duration of response (DOR) | DOR as assessed using RECIST 1.1 | Baseline through up to 2 years or until disease progression | 
| Progression free survival (PFS) | PFS as assessed using RECIST 1.1. | Baseline through up to 2 years or until disease progression | 
| Time to progression (TTP) | TTP as assessed using RECIST 1.1. | Baseline through up to 2 years or until disease progression | 
| Overall Survival (OS) | Proportion of participants alive at 6 months, 1 year and 2 years. | Baseline through up to 2 years |