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

Phase 1TerminatedNCT03854227

Pfizer54 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Advanced Solid Tumors Metastatic Solid Tumors

Interventions

PF-06939999 dose escalationDRUG

PF-06939999 orally at escalating doses on a continuous basis

PF-06939999 monotherapyDRUG

PF-06939999 at the recommended Phase 2 dose orally on a continuous basis

PF-06939999 in combination with docetaxelDRUG

PF-06939999 orally on a continuous basis in combination with docetaxel

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (22)

Scottsdale Healthcare Hospitals d/b/a HonorHealth

Scottsdale, Arizona, United States

Outcomes

Primary Outcomes

Part 1A: Number of Participants With Dose-Limiting Toxicities (DLT)

DLTs=any of the following adverse events (AEs) occurring in the DLT observation period (first treatment cycle):1) Any Grade 4 hematologic AEs; Grade 4 neutropenia, febrile neutropenia, Grade 3 neutropenia with infection, Grade 3 thrombocytopenia with ≥Grade 2 clinically significant bleeding, Grade 3 anemia requiring blood transfusion; 2) Any Grade ≥3 non-hematologic AEs; Grade 3 nausea/vomiting or diarrhea lasting ≥4 days after treatment, confirmed drug induced liver injury meeting Hy's law criteria; a hepatic transaminase or alkaline phosphatase level \>10 times the upper limit of normal for participants with Grade 2 hepatic transaminase or alkaline phosphatase levels at baseline as a result of liver/bone metastasis; clinically important or persistent toxicities; 3) Any toxicity causing \>2 weeks of dose delay; 4) any dose reduction due to AE during the first cycle. Grades of AEs were defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0.

Time frame: Baseline through day 29.

Part 1A: Number of Participants With Treatment-Emergent Adverse Events (TEAE)

An AE was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Grades of AEs were defined by NCI CTCAE version 5.0. Grade 3 events = unacceptable or intolerable events, significantly interrupting usual daily activity, require systemic drug therapy/other treatment. Grade 4 events = events that caused participant to be in imminent danger of death. Grade 5 events = death related to an AE.

Time frame: Baseline up to a minimum of 28 days after last dose of study treatment (maximum of 13 months)

Part 1A: Number of Participants With Laboratory Abnormalities

Laboratory assessments included hematology, chemistry and urinary tests. Participants with maximum Grade 3-4 laboratory abnormalities are reported in this OM. Grades of laboratory results were defined by NCI CTCAE version 5.0. Grade 3 events = unacceptable or intolerable events, significantly interrupting usual daily activity, require systemic drug therapy/other treatment. Grade 4 events = events that caused participant to be in imminent danger of death. Some of the Grade 4 events (activated partial thromboplastin time prolonged, anemia, hemoglobin increased, leukocytosis, lymphocyte count increased and hypoalbuminemia) could not be defined/determined based only on lab data, therefore are not reported in this OM.

Data from ClinicalTrials.gov

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Secondary Outcomes

Part 1A: PK Parameters of PF-06939999: Single Dose (SD) - Maximum Observed Plasma Concentration (Cmax)

Maximum plasma concentration of PF-06939999 after the participant received a SD on Cycle 1 Day 1. Cmax was directly observed from data.

Time frame: Pre-dose and 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours and 12 hours post the morning dose on Cycle 1 Day 1.

Part 1A: PK Parameters of PF-06939999: SD - Time to Reach Maximum Observed Plasma Concentration (Tmax)

Time to maximum plasma concentration of PF-06939999 after the participant received a SD on Cycle 1 Day 1. Tmax was observed directly from data.

Time frame: Predose, 0.5, 1, 2, 4, 6 and 12 hours post the morning dose on Cycle 1 Day 1.

Part 1A: PK Parameters of PF-06939999: SD - Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast)

Area under the plasma concentration versus time curve (AUC) from time 0 to the last measured concentration (AUClast) after the participant received a SD of PF-06939999 on Cycle 1 Day 1.

Time frame: Predose, 0.5, 1, 2, 4, 6 and 12 hours post the morning dose on Cycle 1 Day 1.

Part 1A: PK Parameters of PF-06939999: Multiple Dose (MD) - Steady State Maximum Observed Plasma Concentration (Cmax,ss)

Cmax,ss was the steady-state maximum concentration of PF-06939999 after MD. Cmax,ss was observed directly from the data.

Time frame: Predose, 0.5, 1, 2, 4, 6 and 12 hours post the morning dose on Cycle 1 Day 15.

Part 1A: PK Parameters of PF-06939999: MD - Steady State Time to Reach Maximum Observed Plasma Concentration (Tmax,ss)

Tmax,ss was the steady-state time to maximum plasma concentration of PF-06939999 after MD. Tmax,ss was observed directly from data.

Time frame: Predose, 0.5, 1, 2, 4, 6 and 12 hours post the morning dose on Cycle 1 Day 15.

Part 1A: PK Parameters of PF-06939999: MD - Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau,ss)

AUCtau,ss was the steady-state area under the concentration-time profile from time zero to time tau (τ) of PF-06939999 after MD.

Time frame: Predose, 0.5, 1, 2, 4, 6 and 12 hours post the morning dose on Cycle 1 Day 15.

Part 1A: PK Parameters of PF-06939999: MD - Apparent Oral Clearance (CL/F)

Apparent oral plasma clearance of PF-06939999 after MD. CL/F after multiple doses = Dose/AUCtau,ss. AUCtau,ss = area under the concentration-time profile from time zero to time tau after multiple doses.

Time frame: Predose, 0.5, 1, 2, 4, 6 and 12 hours post the morning dose on Cycle 1 Day 15.

Part 1A: PK Parameters of PF-06939999: MD - Accumulation Ratio (Rac)

Rac was observed accumulation ratio based on AUCtau. Rac was calculated as AUCtau (multiple dose, Cycle 1 Day 15)/ AUCtau (single dose, Cycle 1 Day 1). AUCtau was area under the concentration-time profile from time zero to time tau (τ), the dosing interval.

Time frame: Pre-dose and 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours and 12 hours post the morning dose on Cycle 1 Day 1; Pre-dose and 0.5, 1, 2, 4, 6 and 12 hours post the morning dose on Cycle 1 Day 15.

Part 2: PK Parameters of PF-06939999: SD - Cmax

Maximum plasma concentration of PF-06939999 after the participant received a SD on Cycle 1 Day 1. Cmax was directly observed from data.

Time frame: Pre-dose and 0.5 hour, 1 hour, 2 hours and 4 hours post Cycle 1 Day 1 dosing.

Part 2: PK Parameters of PF-06939999: SD - Tmax

Time to maximum plasma concentration of PF-06939999 after the participant received a SD on Cycle 1 Day 1. Tmax was observed directly from data.

Time frame: Pre-dose and 0.5 hour, 1 hour, 2 hours and 4 hours post Cycle 1 Day 1 dosing.

Part 2: PK Parameters of PF-06939999: MD - Cmax,ss

Cmax,ss was the steady-state maximum concentration of PF-06939999 after MD. Cmax,ss was observed directly from the data.

Time frame: Pre-dose and 0.5 hour, 1 hour, 2 hours and 4 hours post Cycle 1 Day 15 dosing.

Part 2: PK Parameters of PF-06939999: MD - Tmax,ss

Tmax,ss was the steady-state time to maximum plasma concentration of PF-06939999 after MD. Tmax,ss was observed directly from data.

Time frame: Pre-dose and 0.5 hour, 1 hour, 2 hours and 4 hours post Cycle 1 Day 15 dosing.

Part 2: PK Parameters of PF-06939999: MD - Trough Concentration (Ctrough).

Ctrough was trough serum concentration of PF-06939999 after MD. Ctrough = Cmin.

Time frame: Pre-dose and 0.5 hour, 1 hour, 2 hours and 4 hours post Cycle 1 Day 15 dosing.

Part 2B: PK Parameters of PF-06939999 Given With and Without Food - Cmax

Maximum concentration of PF-06939999 given with and without food. On Cycle 1 Day 15, participants enrolled in the food-effect substudy of Part 2B received an oral dose of PF-06939999 under the fasted condition (overnight fasting of at least 10 hours; water permitted). On Cycle 1 Day 16, these participants received another oral dose of PF-06939999 with a high-fat, high-calorie meal (breakfast) following 10-hour overnight fasting (water permitted).

Time frame: Predose and 0.5, 1, 2, 4, 6 and 12 hours post dose on Cycle 1 Day 15 (fasted condition); predose and 0.5, 1, 2, 4, 6 and 12 hours post dose on Cycle 1 Day 16 (with food).

Part 2B: PK Parameters of PF-06939999 Given With and Without Food - Tmax

Time to maximum plasma concentration of PF-06939999 given with and without food. On Cycle 1 Day 15, participants enrolled in the food-effect substudy of Part 2B received an oral dose of PF-06939999 under the fasted condition (overnight fasting of at least 10 hours; water permitted). On Cycle 1 Day 16, these participants received another oral dose of PF-06939999 with a high-fat, high-calorie meal (breakfast) following 10-hour overnight fasting (water permitted).

Time frame: Predose and 0.5, 1, 2, 4, 6 and 12 hours post dose on Cycle 1 Day 15 (fasted condition); predose and 0.5, 1, 2, 4, 6 and 12 hours post dose on Cycle 1 Day 16 (with food).

Part 2B: PK Parameters of PF-06939999 Given With and Without Food - AUClast

AUClast of PF-06939999 given with and without food. On Cycle 1 Day 15, participants enrolled in the food-effect substudy of Part 2B received an oral dose of PF-06939999 under the fasted condition (overnight fasting of at least 10 hours; water permitted). On Cycle 1 Day 16, these participants received another oral dose of PF-06939999 with a high-fat, high-calorie meal (breakfast) following 10-hour overnight fasting (water permitted).

Time frame: Predose and 0.5, 1, 2, 4, 6 and 12 hours post dose on Cycle 1 Day 15 (fasted condition); predose and 0.5, 1, 2, 4, 6 and 12 hours post dose on Cycle 1 Day 16 (with food).

Part 1A: Percentage of Participants With Objective Response Based on Investigator Assessment (RECIST v1.1)

Objective Response Rate (ORR) was defined as the percentage of participants who achieved CR or PR per RECIST 1.1. CR was defined as disappearance of all lesions. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Time frame: From baseline up to 28 ~ 35 days after end of treatment (maximum of 12 months).

Part 1A: Duration of Response Based on Investigator Assessment (RECIST, v1.1)

Duration of response was defined as the time from start date (which is the date of first documentation of PR or CR) to date of first documentation of objective progression or death. DOR was only applicable to those participants with an objective response (confirmed CR or PR). CR: disappearance of all lesions (with the exception of nodal disease when assessing target lesions). PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Time frame: From baseline up to 28 ~ 35 days after end of treatment (maximum of 12 months).

Part 2: Duration of Response Based on Investigator Assessment (RECIST, v1.1)

Duration of response was defined as the time from start date (which is the date of first documentation of PR or CR) to date of first documentation of objective progression or death. DoR was only applicable to those participants with an objective response (confirmed CR or PR). CR: disappearance of all lesions (with the exception of nodal disease when assessing target lesions). PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Time frame: From baseline up to 28 ~ 35 days after end of treatment (maximum of 6 months).

Part 2: Progression Free Survival Based on Investigator Assessment (RECIST, v1.1)

Progression Free Survival (PFS) was defined as the time from initiation of PF-06939999 therapy to first documentation of tumor progression or to death due to any cause, whichever occurred first.

Time frame: From baseline up to 28 ~ 35 days after end of treatment (maximum of 6 months).

Part 2: Time to Progression Based on Investigator Assessment (RECIST, v1.1)

Time to Progression (TTP) was defined as the time from the date of the first treatment to the date of the first documentation of objective tumor progression or death due to tumor progression. Disease progression is defined using RECIST v 1.1.

Time frame: From baseline up to 28 ~ 35 days after end of treatment (maximum of 6 months).

Part 2: Overall Survival

Overall Survival (OS) was defined as the time from the start date (first dose) of study treatment to the date of death due to any cause.

Time frame: From baseline up to maximum follow up (15 months).

Part 2: Probability of Survival at 6 Months and 1 Year of PF-06939999 Monotherapy

The probability of survival at select times was estimated using the Kaplan Meier method. Although an endpoint of Overall Survival at 2 years of study treatment was defined in the protocol, no data were collected/analyzed for this endpoint due to maximum follow up not reaching 2 year post study treatment.

Time frame: From baseline up to maximum follow up (15 months).