Outcome
| Type |
Measure |
Description |
Time frame |
Safety issue |
| Primary |
Phase 1a - Number of participants with dose limiting toxicities (DLTs) |
DLTs will be evaluated during the first cycle (21 days) as both a single agent or in combination with binimetinib. The number of DLTs will be used to determine the maximum tolerated dose (MTD)/recommended dose for further study |
Cycle 1 (approximately 21 days / 3 weeks) |
|
| Primary |
Phase 1a - Number of participants with treatment emergent adverse events (AEs) |
AEs as characterized by type, frequency, severity, timing, seriousness, and relationship to study therapy |
Baseline up to 30 days after last dose of study medication |
|
| Primary |
Phase 1a - Number of participants with clinically significant change from baseline in laboratory abnormalities |
Laboratory abnormalities as characterized by type, frequency, severity, and timing |
Baseline up to follow up visit (30 days after last dose of study treatment) |
|
| Primary |
Phase 1a - Number of dose interruptions, dose modifications, and discontinuations due to AEs |
Incidence of dose interruptions, dose modifications, and discontinuations due to AEs |
Baseline through approximately 12 months |
|
| Primary |
Phase 1b - Overall response |
Response will be evaluated via radiographical tumor assessments by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and intracranial response by modified RECIST version 1.1 (mRECIST v 1.1) or RANO for primary brain tumors |
Baseline up to approximately 12 months |
|
| Secondary |
Phase 1a: Maximum plasma concentration of PF-07284890 and binimetinib |
Single dose (Cmax) and multiple dose (assuming steady state is achieved; Css,max) pharmacokinetic (PK) parameters |
Cycle 1 Day 1 (predose, 1, 2, 4, 6, 8, and 24 hours (Day 2) post dose); Cycle 1 Day 15 (predose, 1, 2, 4, 6, and 8 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); End of Treatment (EOT) |
|
| Secondary |
Phase 1a: Time to reach maximum plasma concentration of PF-07284890 and binimetinib |
Single dose (Tmax) and multiple dose (assuming steady state is achieved; Tss,max) PK parameters |
Cycle 1 Day 1 (predose, 1, 2, 4, 6, 8, and 24 hours (Day 2) post dose); Cycle 1 Day 15 (predose, 1, 2, 4, 6, and 8 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT |
|
| Secondary |
Phase 1a: Area under the plasma concentration-time curve from time 0 to the last time point of quantifiable concentration (AUClast) of PF-07284890 and binimetinib |
Single dose PK parameter |
Cycle 1 Day 1 (predose, 1, 2, 4, 6, 8, and 24 hours (Day 2) post dose); Cycle 1 Day 15 (predose, 1, 2, 4, 6, and 8 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT |
|
| Secondary |
Phase 1a: Terminal half-life (t1/2) of PF-07284890 and binimetinib |
Single dose and multiple dose (assuming steady state is achieved and data permit) PK parameter |
Cycle 1 Day 1 (predose, 1, 2, 4, 6, 8, and 24 hours (Day 2) post dose); Cycle 1 Day 15 (predose, 1, 2, 4, 6, and 8 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT |
|
| Secondary |
Phase 1a: Area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUCinf) of PF-07284890 and binimetinib |
Single dose will be calculated as data permit PK parameter |
Cycle 1 Day 1 (predose, 1, 2, 4, 6, 8, and 24 hours (Day 2) post dose); Cycle 1 Day 15 (predose, 1, 2, 4, 6, and 8 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT |
|
| Secondary |
Phase 1a: Apparent oral clearance of PF-07284890 and binimetinib |
Single dose (CL/F) and multiple dose (assuming steady state is achieved and as data permit; CLss/F) PK parameter |
Cycle 1 Day 1 (predose, 1, 2, 4, 6, 8, and 24 hours (Day 2) post dose); Cycle 1 Day 15 (predose, 1, 2, 4, 6, and 8 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT |
|
| Secondary |
Phase 1a: Volume of distribution of PF-07284890 and binimetinib |
Single dose (Vz/F) and multiple dose (assuming steady state is achieved and as data permit; Vss/F) PK parameter |
Cycle 1 Day 1 (predose, 1, 2, 4, 6, 8, and 24 hours (Day 2) post dose); Cycle 1 Day 15 (predose, 1, 2, 4, 6, and 8 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT |
|
| Secondary |
Phase 1a: Area under the plasma concentration-time curve over the dosing interval at steady state (AUCss,T) of PF-07284890 and binimetinib |
Multiple dose (assuming steady state is achieved) PK parameter |
Cycle 1 Day 1 (predose, 1, 2, 4, 6, 8, and 24 hours (Day 2) post dose); Cycle 1 Day 15 (predose, 1, 2, 4, 6, and 8 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT |
|
| Secondary |
Phase 1a: Trough plasma concentration at steady state (Css,min) of PF-07284890 and binimetinib |
Multiple dose (assuming steady state is achieved) PK parameter |
Cycle 1 Day 1 (predose, 1, 2, 4, 6, 8, and 24 hours (Day 2) post dose); Cycle 1 Day 15 (predose, 1, 2, 4, 6, and 8 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT |
|
| Secondary |
Phase 1a: Accumulation ratio (Rac) of PF-07284890 and binimetinib |
Multiple dose (assuming steady state is achieved and as data permit) PK parameter |
Cycle 1 Day 1 (predose, 1, 2, 4, 6, 8, and 24 hours (Day 2) post dose); Cycle 1 Day 15 (predose, 1, 2, 4, 6, and 8 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT |
|
| Secondary |
Phase 1a: Overall response |
Response will be evaluated via radiographical tumor assessments by RECIST v1.1 and intracranial response by mRECIST v 1.1 or RANO for primary brain tumors |
Baseline up to approximately 12 months |
|
| Secondary |
Phase 1b - Number of patients with treatment emergent AEs |
AEs as characterized by type, frequency, severity, timing, seriousness, and relationship to study therapy |
Baseline up to 30 days after last dose of study medication |
|
| Secondary |
Phase 1b - Number of participants with clinically significant change from baseline in laboratory abnormalities |
Laboratory abnormalities as characterized by type, frequency, severity, and timing |
Baseline up to follow up visit (30 days after last dose of study treatment) |
|
| Secondary |
Phase 1b - Number of dose interruptions, dose modifications, and discontinuations due to AEs |
Incidence of dose interruptions, dose modifications, and discontinuations due to AEs |
Baseline through approximately 12 months |
|
| Secondary |
Phase 1b: Maximum plasma concentration of PF-07284890 and binimetinib |
Single dose (Cmax) and multiple dose (assuming steady state is achieved; Css,max) PK parameter |
Cycle 1 Day 1 and 15 (predose, 1, 2, and 4 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT |
|
| Secondary |
Phase 1b: Time to reach maximum plasma concentration of PF-07284890 and binimetinib |
Single dose (Tmax) and multiple dose (assuming steady state is achieved; Tss,max) PK parameter |
Cycle 1 Day 1 and 15 (predose, 1, 2, and 4 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT |
|
| Secondary |
Phase 1b: Area under the plasma concentration-time curve from time 0 to the last time point of quantifiable concentration (AUClast) of PF-07284890 and binimetinib |
Single dose PK parameter |
Cycle 1 Day 1 and 15 (predose, 1, 2, and 4 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT |
|
| Secondary |
Phase 1b: Terminal half-life (t1/2) of PF-07284890 and binimetinib |
Single dose and multiple dose (assuming steady state is achieved and data permit) PK parameter |
Cycle 1 Day 1 and 15 (predose, 1, 2, and 4 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT |
|
| Secondary |
Phase 1b: Area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUCinf) of PF-07284890 and binimetinib |
Single dose will be calculated as data permit PK parameter |
Cycle 1 Day 1 and 15 (predose, 1, 2, and 4 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT |
|
| Secondary |
Phase 1b: Apparent oral clearance of PF-07284890 and binimetinib |
Single dose (CL/F) and multiple dose (assuming steady state is achieved and as data permit; CLss/F) PK parameter |
Cycle 1 Day 1 and 15 (predose, 1, 2, and 4 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT |
|
| Secondary |
Phase 1b: Volume of distribution of PF-07284890 and binimetinib |
Single dose (Vz/F) and multiple dose (assuming steady state is achieved and as data permit; Vss/F) PK parameter |
Cycle 1 Day 1 and 15 (predose, 1, 2, and 4 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT |
|
| Secondary |
Phase 1b: Area under the plasma concentration-time curve over the dosing interval at steady state (AUCss,T) of PF-07284890 and binimetinib |
Multiple dose (assuming steady state is achieved) PK parameter |
Cycle 1 Day 1 and 15 (predose, 1, 2, and 4 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT |
|
| Secondary |
Phase 1b: Trough plasma concentration at steady state (Css,min) of PF-07284890 and binimetinib |
Multiple dose (assuming steady state is achieved) PK parameter |
Cycle 1 Day 1 and 15 (predose, 1, 2, and 4 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT |
|
| Secondary |
Phase 1b: Accumulation ration (Rac) of PF-07284890 and binimetinib |
Multiple dose (assuming steady state is achieved and as data permit) PK parameter |
Cycle 1 Day 1 and 15 (predose, 1, 2, and 4 hours post dose); Cycles 2-6 Day 1 (predose and 2 hours post dose); EOT |
|
| Secondary |
Phase 1b: Disease Control Rate (DCR) |
DCR is defined as the percent of participants with a confirmed complete response (CR), partial response (PR) or stable disease (SD) according to RECIST 1.1/RANO, at 6 weeks for both overall and intracranial |
Every 6 weeks from time of enrollment up to 1 year, then every 12 weeks thereafter |
|
| Secondary |
Phase 1b: Progression Free Survival (PFS) |
The period from study entry until disease progression, death or date of last contact for both overall and intracranial. |
Baseline to measured progressive disease (up to 12 months) |
|
| Secondary |
Phase 1b: Overall Survival (OS) |
Overall survival was the duration from enrollment to death. For participants who are alive, overall survival was censored at the last contact. |
Baseline to date of death from any cause (up to 12 months) |
|
| Secondary |
Phase 1b: Duration of Response (DoR) |
Duration of response (DR) defined as time from start of first documented objective tumor response [Complete Response (CR) or Partial Response (PR)] to first documented objective tumor progression or death due to any cause, whichever occurs first. |
Baseline, every 6 weeks until disease progression or unacceptable toxicity up to 1 year, then every 12 weeks thereafter |
|
| Secondary |
Phase 1b: Time to Tumor Response (TTR) |
TTR is defined as the time from first dose to first documentation of objective tumor response (CR or PR). For participants whose objective response (OR) proceeds from PR to CR, the onset of PR is taken as the onset of response. TTR will only be calculated for the subgroup of participants with a confirmed objective tumor response for both overall and intracranial |
Every 6 weeks from the time of enrollment up to 12 months |
|
| Secondary |
Phase 1b: Maximum plasma concentration (Cmax) of CYP34A probe substrate midazolam |
PK parameter |
Day -7 (Lead-in); Cycle 1 Day 1 and Day 15 (predose, 0.5, 1, 2, 4, and 8 hours post dose) |
|
| Secondary |
Phase 1b: Time to reach maximum plasma concentration (Tmax) of CYP3A4 probe substrate midazolam |
PK parameter |
Day -7 (Lead-in); Cycle 1 Day 1 and Day 15 (predose, 0.5, 1, 2, 4, and 8 hours post dose) |
|
| Secondary |
Phase 1b: Area under the plasma concentration-time curve from time 0 to the last time point of quantifiable concentration (AUClast) of CYP3A4 probe substrate midazolam |
PK parameter |
Day -7 (Lead-in); Cycle 1 Day 1 and Day 15 (predose, 0.5, 1, 2, 4, and 8 hours post dose) |
|
| Secondary |
Phase 1b: Terminal half-life (t1/2) of CYP3A4 probe substrate midazolam |
PK parameter as data permit |
Day -7 (Lead-in); Cycle 1 Day 1 and Day 15 (predose, 0.5, 1, 2, 4, and 8 hours post dose) |
|
| Secondary |
Phase 1b: Area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUCinf) of CYP3A4 probe substrate midazolam |
PK parameter as data permit |
Day -7 (Lead-in); Cycle 1 Day 1 and Day 15 (predose, 0.5, 1, 2, 4, and 8 hours post dose) |
|
| Secondary |
Phase 1a: Apparent oral clearance (CL/F) of CYP3A4 probe substrate midazolam |
PK parameter as data permit |
Day -7 (Lead-in); Cycle 1 Day 1 and Day 15 (predose, 0.5, 1, 2, 4, and 8 hours post dose) |
|
| Secondary |
Phase 1a: Volume of distribution (Vz/F) of CYP3A4 probe substrate midazolam |
PK parameter as data permit |
Day -7 (Lead-in); Cycle 1 Day 1 and Day 15 (predose, 0.5, 1, 2, 4, and 8 hours post dose) |
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