A Study of PF-06873600 in People With Cancer

This is a Phase 1/2a, open-label, multi-center, non-randomized, multiple dose, safety, tolerability, pharmacokinetic, and pharmacodynamic study of PF-06873600 administered as a single agent in sequential dose levels and then in combination with endocrine therapy. In Part 1A and Part 1C, successive cohorts of patients will receive escalating doses of PF-06873600 and then in dose finding (Part 1B) with PF-06873600 in combination with endocrine therapy (ET). This study contains 2 parts, dose escalation with single agent (Part 1A and 1C) and then dose finding with PF-06873600 in combination with endocrine therapy (Part 1B) followed by dose expansion arms of PF-06873600 in combination with endocrine therapy (Part 2).

• PF-06873600 (Drug): PF-06873600 tablet for oral dosing
• Endocrine Therapy 1 (Drug): Endocrine Therapy 1
• Endocrine Therapy 2 (Drug): Endocrine Therapy 2

Primary outcomes

• Number of Participants With Dose Limiting Toxicities (DLTs) - Part 1 [Cycle 1 (within 28 days after the first dose of study intervention)]: DLT was defined as any of the following adverse events (AEs) occurring in the first cycle of treatment (28 days) which were attributable to one, the other, or both agents in the combination: Hematologic - grade(G) 4 neutropenia lasting >7 days; Febrile neutropenia defined as an absolute neutrophil count (ANC) <1.0 * 10\^9/L with a single temperature of >38.3°C, or a sustained temperature of ≥38°C, for more than 1 hour; G≥3 neutropenia with associated infection; G3 thrombocytopenia with clinically significant bleeding as indicated by ≥ G2 bleeding; G4 thrombocytopenia. Nonhematologic: Confirmed case of Drug Induced Liver Injury (DILI) (Hy's Law); G≥3 AEs that were clinically significant.
• Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) - Part 1 + Part 2 [Day 1 up to 28 days after the last dose of study intervention, up to approximately 24 months]: An AE was defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s) that occurred after participants' signed informed consent has been obtained. An SAE was an AE resulting in any of the following outcomes: was fatal or life-threatening; resulted in persistent or significant disability/incapacity; constituted a congenital anomaly/birth defect; was medically significant; required inpatient hospitalization or prolongation of existing hospitalization. Treatment Related AEs were treatment emergent AEs with cause categorized by the investigator as related to study treatment.
• Number of Participants With Worst Post-Baseline Hematology Results Based on Common Terminology Criteria for Adverse Events (CTCAE) Grade: Part 1 + Part 2 [Day 1 up to 28 days after the last dose of study intervention, up to approximately 24 months]: Severity was graded as NCI CTCAE version 4.03:Grade 1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE.
• Number of Participants With Worst Post-Baseline Chemistry Results Based on Common Terminology Criteria for Adverse Events (CTCAE) Grade: Part 1 + Part 2 [Day 1 up to 28 days after the last dose of study intervention, up to approximately 24 months]: Severity was graded as NCI CTCAE version 4.03:Grade 1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE.
• Number of Participants With Post-Baseline Vital Sign Abnormalities Meeting Pre-Defined Categorization - Part 1 + Part 2 [Day 1 up to 28 days after the last dose of study intervention, up to approximately 24 months]: Pre-defined criteria included: 1) systolic blood pressure (SBP) (mm Hg) minimum (min) value <90; 2) SBP change from baseline (CFB) (mm Hg) maximum (max) decrease >=30 or max increase >=30; 3) diastolic blood pressure (DBP) (mm Hg) min <50; 4) DBP CFB (mm Hg) max decrease >=20 or max increase >=20; 5) supine heart rate (HR) beats per minute (bpm) min <40 or max >120.
• Number of Participants With Post-Baseline Electrocardiogram (ECG) Changes Meeting Pre-Defined Categorization - Part 1 + Part 2 [Day 1 up to 28 days after the last dose of study intervention, up to approximately 24 months]: ECG pre-defined categories for QTc interval adjusted according to Fridericia formula (QTcF) (msec) included: 450 <= max. <=480, 481 <= max. <=500, max >=501; QTcF CFB: 30 < max <=60, max >60; for PR and QRS: PR (msec): max >=300; PR increase from baseline: Baseline >200 and max. >=25% increase, Baseline <=200 and max. >=50% increase; QRS (msec): max >=200; QRS (msec) increase from baseline: Baseline >100 and max. >=25% increase, Baseline <=100 and max. >=50% increase. Categories, with at least 1 participant having ECG abnormality in any of the reporting arms, were reported in this outcome measure.
• Overall Response Rate (ORR): Part 2 [From the start of the treatment until disease/clinical progression or death or early study discontinuation, whichever happened earlier (approximately up to 24 months)]: ORR: percentage of participants with confirmed complete response (CR) or partial response (PR). Response evaluation criteria in solid tumors (RECIST) v1.1: a) CR = disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions that had a reduction in short axis to less than (<) 10 millimeter (mm). Disappearance of all non-target lesions. In addition, all lymph nodes assigned a non-target lesion must be non-pathological in size (<10 mm short axis) and b) PR = at least a 30 percent (%) decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. Any radiological assessments taken more than 30 days after the last dose of study therapy or after antineoplastic agents other than study treatments taken by the participants was excluded from the best overall response derivation. Confirmation of CR or PR was to be at least 4 weeks apart from the previous radiological assessment.

Secondary outcomes

• Maximum Observed Plasma Concentration (Cmax) of PF-06873600 Following a Single Oral Dose of Study Intervention on Cycle 1 Day 1 - Part 1 + Part 2 [Part 1: pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 12 hours post-dose on Cycle 1 Day 1 (C1D1); Part 2: pre-dose, 1, 2, 4, 6 hours post-dose on C1D1]: The maximum observed concentration of PF-06873600 after single dose of study intervention when given as a single agent (Part 1A and Part 1C), in combination with letrozole, and in combination with fulvestrant (Part 1B and Part 2) was reported. The Cmax value was observed directly from data.
• Time to Reach Cmax at Steady State (Tmax) of PF-06873600 Following a Single Oral Dose of Study Intervention on Cycle 1 Day 1 - Part 1 + Part 2 [Part 1: pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 12 hours post-dose on C1D1; Part 2: pre-dose, 1, 2, 4, 6 hours post-dose on C1D1]: Tmax of PF-06873600 after single dose of study intervention when given as a single agent (Part 1A and Part 1C), in combination with letrozole, and in combination with fulvestrant (Part 1B and Part 2) was reported.
• Area Under the Concentration-Time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of PF-06873600 Following a Single Oral Dose of Study Intervention on Cycle 1 Day 1 - Part 1 [Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 12 hours post-dose on C1D1]: AUClast of PF-06873600 after single dose of study intervention when given as a single agent (Part 1A and Part 1C), in combination with letrozole, and in combination with fulvestrant (Part 1B) was reported.
• Area Under the Concentration-Time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) of PF-06873600 Following a Single Oral Dose of Study Intervention on Cycle 1 Day 1 - Part 1 [Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 12 hours post-dose on C1D1]: AUCinf of PF-06873600 after single dose of study intervention when given as a single agent (Part 1A and Part 1C), in combination with letrozole, and in combination with fulvestrant (Part 1B) was reported.
• Apparent Clearance (CL/F) of PF-06873600 Following a Single Oral Dose of Study Intervention on Cycle 1 Day 1 - Part 1 [Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 12 hours post-dose on C1D1]: CL/F of PF-06873600 after single dose of study intervention when given as a single agent (Part 1A and Part 1C), in combination with letrozole, and in combination with fulvestrant (Part 1B) was reported.
• Apparent Volume of Distribution (Vz/F) of PF-06873600 Following a Single Oral Dose of Study Intervention on Cycle 1 Day 1 - Part 1 [Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 12 hours post-dose on C1D1]: Vz/F of PF-06873600 after single dose of study intervention when given as a single agent (Part 1A and Part 1C), in combination with letrozole, and in combination with fulvestrant (Part 1B) was reported.
• Terminal Half-life (t1/2) of PF-06873600 Following a Single Oral Dose of Study Intervention on Cycle 1 Day 1 - Part 1 [Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 12 hours post-dose on C1D1]: t1/2 of PF-06873600 after single dose of study intervention when given as a single agent (Part 1A and Part 1C), in combination with letrozole, and in combination with fulvestrant (Part 1B) was reported.
• Steady State Maximum Concentration (Css,Max) of PF-06873600 Following Multiple Doses of Study Intervention on Cycle 1 Day 15 - Part 1 + Part 2 [Part 1: pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 12 hours post-dose on C1D15; Part 2: pre-dose, 1, 2, 4, 6 hours post-dose on C1D15]: Css,max of PF-06873600 after multiple doses of study intervention when given as a single agent (Part 1A and Part 1C), in combination with letrozole, and in combination with fulvestrant (Part 1B and Part 2) was reported. Multiple-dose PK parameters were not calculated for the modified release selection cohort in Part 1C (ie, the group "Part 1C PF-06873600 MR 20 IR 25 mg BID").
• Time to Maximum Plasma Concentration at Steady State (Tss,Max) of PF-06873600 Following Multiple Doses of Study Intervention on Cycle 1 Day 15 - Part 1 + Part 2 [Part 1: pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 12 hours post-dose on C1D15; Part 2: pre-dose, 1, 2, 4, 6 hours post-dose on C1D15]: Tss,max of PF-06873600 after multiple doses of study intervention when given as a single agent (Part 1A and Part 1C), in combination with letrozole, and in combination with fulvestrant (Part 1B and Part 2) was reported. Multiple-dose PK parameters were not calculated for the modified release selection cohort in Part 1C (ie, the group "Part 1C PF-06873600 MR 20 IR 25 mg BID").
• Steady State Minimum Plasma Concentration (Css,Min) of PF-06873600 Following Multiple Doses of Study Intervention on Cycle 1 Day 15 - Part 1 + Part 2 [Part 1: pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 12 hours post-dose on C1D15; Part 2: pre-dose, 1, 2, 4, 6 hours post-dose on C1D15]: Css,min of PF-06873600 after multiple doses of study intervention when given as a single agent (Part 1A and Part 1C), in combination with letrozole, and in combination with fulvestrant (Part 1B and Part 2) was reported. Multiple-dose PK parameters were not calculated for the modified release selection cohort in Part 1C (ie, the group "Part 1C PF-06873600 MR 20 IR 25 mg BID").
• Steady-State Area Under the Plasma Concentration Versus Time Curve Within One Dose Interval (AUCss,Tau) of PF-06873600 Following Multiple Doses of Study Intervention on Cycle 1 Day 15 - Part 1 [Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 12 hours post-dose on C1D15]: AUCss,tau of PF-06873600 after multiple doses of study intervention when given as a single agent (Part 1A and Part 1C), in combination with letrozole, and in combination with fulvestrant (Part 1B) was reported. Multiple-dose PK parameters were not calculated for the modified release selection cohort in Part 1C (ie, the group "Part 1C PF-06873600 MR 20 IR 25 mg BID").
• Steady-State Apparent Oral Plasma Clearance (CLss/F) of PF-06873600 Following Multiple Doses of Study Intervention on Cycle 1 Day 15 - Part 1 [Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 12 hours post-dose on C1D15]: CLss/F of PF-06873600 after multiple doses of study intervention when given as a single agent (Part 1A and Part 1C), in combination with letrozole, and in combination with fulvestrant (Part 1B) was reported. Multiple-dose PK parameters were not calculated for the modified release selection cohort in Part 1C (ie, the group "Part 1C PF-06873600 MR 20 IR 25 mg BID").
• Apparent Volume of Distribution at Steady State (Vss/F) of PF-06873600 Following Multiple Doses of Study Intervention on Cycle 1 Day 15 - Part 1 [Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 12 hours post-dose on C1D15]: Vss/F of PF-06873600 after multiple doses of study intervention when given as a single agent (Part 1A and Part 1C), in combination with letrozole, and in combination with fulvestrant (Part 1B) was reported. Multiple-dose PK parameters were not calculated for the modified release selection cohort in Part 1C (ie, the group "Part 1C PF-06873600 MR 20 IR 25 mg BID").
• Accumulation Ratio Based on AUC (Rac) of PF-06873600 Following Multiple Doses of Study Intervention on Cycle 1 Day 15 - Part 1 [Pre-dose, 0.25, 0.5, 1, 2, 3, 4, 6, 12 hours post-dose on C1D15]: Rac of PF-06873600 after multiple doses of study intervention when given as a single agent (Part 1A and Part 1C), in combination with letrozole, and in combination with fulvestrant (Part 1B) was reported. Multiple-dose PK parameters were not calculated for the modified release selection cohort in Part 1C (ie, the group "Part 1C PF-06873600 MR 20 IR 25 mg BID").
• Accumulation Ratio Based on Cmax (Observed) (Rac,Cmax) of PF-06873600 Following Multiple Doses of Study Intervention on Cycle 1 Day 15 - Part 2 [Pre-dose, 1, 2, 4, 6 hours post-dose on C1D15]: Rac,cmax of PF-06873600 after multiple doses of study intervention when given as in combination with fulvestrant (Part 2) was reported.
• Pharmacodynamic (PD) Biomarker Phospho-retinoblastoma Protein (pRb) in Tumor Tissue in Participants - Part 1 + Part 2 [Screening and Cycle 2 Day 1]: Level of the PD marker, pRb, was analyzed at 2 time points, at screening and at Cycle 2 Day 1. Percentage changes of pRb at Cycle 2 Day 1 from screening (baseline) were calculated.
• PD Biomarker Ki67 in Tumor Tissue in Participants - Part 1 + Part 2 [Screening and Cycle 2 Day 1]: Level of the PD marker, Ki67, was analyzed at 2 time points, at screening and at Cycle 2 Day 1. Percent changes of pRb at Cycle 2 Day 1 from screening (baseline) were calculated.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Have a diagnosis of Hormone Receptor Positive (HR+), Human Epidermal Growth Factor Receptor 2 Negative (HER2-) breast cancer

  • Prior combined CDK 4/6 inhibitor and endocrine therapy and 1 or 2 prior lines of chemotherapy
* Have a diagnosis of metastatic triple negative breast cancer (TNBC)

  • Up to 1-2 prior lines of chemotherapy
* Have a diagnosis of advanced platinum resistant epithelial ovarian cancer (EOC)/fallopian tube cancer/primary peritoneal cancer (PPC)

  • Up to 2-3 prior lines of therapy
* Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1
* Measurable disease or non-measurable disease and refractory to or intolerant of existing therapies (Part 1)
* Measurable disease as defined by RECIST 1.1 is required (Part 1B and Part 2 only)

Exclusion Criteria:

* Known active uncontrolled or symptomatic Central Nervous System (CNS) metastases
* Other active malignancy within 3 years prior to randomization, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ
* Major surgery or radiation within 4 weeks prior to study entry
* Last anti-cancer treatment within 2 weeks prior to study entry
* Participation in other studies involving investigational drug(s) within 4 weeks prior to study entry
* Pregnant or breastfeeding female patients
* Active inflammatory gastrointestinal (GI) disease, known diverticular disease or previous gastric resection or lap band surgery including impairment of gastro intestinal function or GI disease

• Study Protocol (PDF, 2023-03-03)
• Statistical Analysis Plan (PDF, 2023-03-23)

• Pfizer CT.gov Call Center, Study director, Pfizer