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

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.

Population: The analysis population included participants in Part 1A who had at least one dose of study treatment and either experienced DLT or did not have major treatment deviations during the DLT observation period.

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.

Time frame: Baseline up to a minimum of 28 days after last dose of study treatment (maximum of 12 months)

Population: The analysis set included all participants in Part 1A who received at least 1 dose of study treatment. Number of Participants Analyzed = number of participants evaluable for this outcome measure. Number Analyzed = number of participants evaluable for the specific laboratory test.

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)

Population: The analysis set included all participants in Part 1A who received at least 1 dose of study treatment.

Number of participants with BOR assessed using Response Evaluation Criteria in Solid Tumor (RECIST) v1.1: Complete Response (CR): disappearance of all lesions (with the exception of nodal disease when assessing target lesions). Partial Response (PR): at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered a sign of progression. Stable disease (SD): does not qualify for CR, PR or PD. Non-CR/Non-PD: Persistence of any non target lesions and/or tumor marker level above the normal limits.

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

Population: The analysis population included all participants in Part 2 who received at least one dose of study treatment and had baseline disease assessment or measurable disease at baseline, if applicable and at least one post baseline disease assessment.

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.

Time frame: Baseline up to a minimum of 28 days after last dose of study treatment (maximum of 8 months)

Population: The analysis set included all participants in Part 2 who received at least 1 dose of study treatment. Number of Participants Analyzed = number of participants evaluable for this outcome measure. Number Analyzed = number of participants evaluable for the specific laboratory test.

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 15 months)

Population: The analysis set included all participants in Part 2 who received at least 1 dose of study treatment.

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).

Population: The analysis population included all participants in Part 1A who received at least one dose of study treatment and had baseline disease assessment or measurable disease at baseline, if applicable and at least one post baseline disease assessment, with confirmed CR or PR.

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).

Population: The analysis population included all participants in Part 1A who received at least one dose of study treatment and had baseline disease assessment or measurable disease at baseline, if applicable and at least one post baseline disease assessment.

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.

Population: The analysis population included enrolled participants in Part 1A treated who did not have protocol deviations influencing PK assessment, and had sufficient information to estimate at least 1 of the PK parameters of interest, and contributed to the summary statistics of this OM.

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.

Population: The analysis population included enrolled participants in Part 1A treated who did not have protocol deviations influencing PK assessment, and had sufficient information to estimate at least 1 of the PK parameters of interest, with evaluable data that contributed to the summary statistics of this OM.

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.

Population: The analysis population included enrolled participants in Part 1A treated who did not have protocol deviations influencing PK assessment, and had sufficient information to estimate at least 1 of the PK parameters of interest, with evaluable data that contributed to the summary statistics of this OM.

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.

Population: The analysis population included enrolled participants in Part 1A treated who did not have protocol deviations influencing PK assessment, and had sufficient information to estimate at least 1 of the PK parameters of interest, with evaluable data that contributed to the summary statistics of this OM.

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.

Population: The analysis population included enrolled participants in Part 1A treated who did not had protocol deviations influencing PK assessment, and had sufficient information to estimate at least 1 of the PK parameters of interest, with evaluable data that contributed to the summary statistics of this OM.

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.

Population: The analysis population included enrolled participants in Part 1A treated who did not have protocol deviations influencing PK assessment, and had sufficient information to estimate at least 1 of the PK parameters of interest with evaluable data that contributed to the summary statistics of this outcome measure (OM).

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.

Population: The analysis population included enrolled participants in Part 1A treated who did not have protocol deviations influencing PK assessment, and had sufficient information to estimate at least 1 of the PK parameters of interest.

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.

Population: The analysis population included enrolled participants in Part 1A treated who did not have protocol deviations influencing PK assessment, and had sufficient information to estimate at least 1 of the PK parameters of interest.

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).

Population: The analysis population included participants enrolled and treated in the food-effect substudy of Part 2B who did not have protocol deviations influencing PK assessment, and had sufficient information to estimate at least 1 of the PK parameters of interest. Food-effect cohort in Part 2B was not enrolled.

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).

Population: The analysis population included participants enrolled and treated in the food-effect substudy of Part 2B who did not have protocol deviations influencing PK assessment, and had sufficient information to estimate at least 1 of the PK parameters of interest. Food-effect cohort in Part 2B was not enrolled.

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).

Population: The analysis population included participants enrolled and treated in the food-effect substudy of Part 2B who did not have protocol deviations influencing PK assessment, and had sufficient information to estimate at least 1 of the PK parameters of interest. Food-effect cohort in Part 2B was not enrolled.

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).

Population: The analysis population included all participants in Part 2 who received at least one dose of study treatment and had baseline disease assessment or measurable disease at baseline, if applicable and at least one post baseline disease assessment, with confirmed CR or PR.

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).

Population: The analysis set included all participants in Part 2 who received at least 1 dose of study treatment.

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.

Population: The analysis population included enrolled participants in Part 2 treated who did not have protocol deviations influencing PK assessment, and have sufficient information to estimate at least 1 of the PK parameters of interest, with evaluable data that contributed to the summary statistics of this OM.

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.

Population: The analysis population included enrolled participants in Part 2 treated who did not have protocol deviations influencing PK assessment, and have sufficient information to estimate at least 1 of the PK parameters of interest, with evaluable data that contributed to the summary statistics of this OM.

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.

Population: The analysis population included enrolled participants in Part 2 treated who did not have protocol deviations influencing PK assessment, and had sufficient information to estimate at least 1 of the PK parameters of interest, with evaluable data that contributed to the summary statistics of this OM.

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.

Population: The analysis population included enrolled participants in Part 2 treated who did not have protocol deviations influencing PK assessment, and had sufficient information to estimate at least 1 of the PK parameters of interest, with evaluable data that contributed to the summary statistics of this OM.

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.

Population: The analysis population included enrolled participants in Part 2 treated who did not have protocol deviations influencing PK assessment, and had sufficient information to estimate at least 1 of the PK parameters of interest, with evaluable data that contributed to the summary statistics of this OM.

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).

Population: The analysis set included all participants in Part 2 who received at least 1 dose of study treatment.

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).

Population: The analysis population included all participants in Part 2 who received at least one dose of study treatment and had baseline disease assessment or measurable disease at baseline, if applicable and at least one post baseline disease assessment.

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).

Population: The analysis population included all participants in Part 2 who received at least one dose of study treatment and had baseline disease assessment or measurable disease at baseline, if applicable and at least one post baseline disease assessment.