Liposarcoma, Prostate Cancer, Breast Neoplasms, Adenocarcinoma of Lung
Conditions
Keywords
CDK4 inhibitor, Breast cancer, enzalutamide, fulvestrant, letrozole, endocrine therapy, Colorectal Cancer (CRC), Solid Tumors
Brief summary
This is a Phase 1/2A, open label, multicenter, nonrandomized, multiple dose, safety, tolerability, pharmacokinetic and pharmacodynamic study of PF-07220060 administered as a single agent and then in combination with endocrine therapy. The study consists of two parts and a China and Japan monotherapy cohort. Part 1 includes dose escalation cohorts evaluating PF-07220060 as single agent or in combination with endocrine therapy or enzalutamide, as well as a food effect cohort and a DDI cohort Part 2 includes dose expansion cohorts evaluating PF-07220060 in combination with endocrine therapy or enzalutamide. In Part 1A, single escalating doses of PF-07220060 alone will be administered to determine the maximum tolerated dose (MTD) and select the recommended dose for expansion In Part 1B and Part 1C, PF-07220060 will be administered in combination with 1 of 2 endocrine therapies (letrozole and fulvestrant, respectively). In Part 1D, food effect assessment of PF-07220060 at the RP2D dose level from the Part 1A will be conducted In Part 1E, the effect of PF-07220060 on the PK of midazolam will be evaluated (DDI) In Part 1F, escalating dosed of PF-07220060 will be administered in combination with enzalutamide Part 1B and Part 1C may commence at MTD or before reaching the MTD at a dose level in Part 1A. Part 2A is a dose expansion cohort with fulvestrant and will explore more than one dose of PF-07220060 in participants diagnosed with mBC. Part 2B and Part 2C are expansion for combination therapy of PF-07220060 with letrozole and fulvestrant, respectively. Part 2D is the expansion cohort for combination therapy of PF-07220060 with enzalutamide. Part 2E is an expansion cohort to evaluate PF-07220060 Monotherapy versus PF-07220060 plus fulvestrant combination therapy. The China monotherapy cohort will evaluate safety, tolerability and PK of PF-07220060 administered as single agent in Chinese participants. The Japan monotherapy cohort will evaluate safety, tolerability and PK of PF-07220060 administered as a single agent in Japanese participants.
Interventions
DRUGPF-07220060
CDK4 inhibitor
COMBINATION_PRODUCTLetrozole
Endocrine Therapy
COMBINATION_PRODUCTFulvestrant
Endocrine Therapy
DRUGMidazolam
Benzodiazepine used for DDI
COMBINATION_PRODUCTEnzalutamide
Androgen Receptor inhibitor
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Part 1: Breast Cancer (BC) * Refractory Hormone Receptor Positive (HR+), Human Epidermal Growth Factor Receptor 2 Negative (HER2-) BC * Part 1A/Part 1D/Part1E also include: Refractory HR-positive/HER2-positive BC * Part 1: Tumors other than BC (Part 1A/Part 1D/Part 1E): NSCLC, prostate, CRC, liposarcoma, or tumors with previously confirmed CDK4 or CCND1 amplification according to local standard tests * Part 1F: prostate cancer * Part 2A, 2B, 2C and 2E: * HR-positive/HER2-negative BC * Patients who are either postmenopausal women or pre/peri-menopausal (Part 2C only) * Part 1D: metastatic castration resistant prostate cancer * Lesion: * Part 1: evaluable lesion (including skin or bone lesion only) * Part 2A, 2B, 2C and 2E: measurable lesion per RECIST v1.1 * Part 2D: Participants with evaluable disease as per PCWG3; participants with bone metastases only are allowed. Participants with biochemical recurrence only are excluded. * Prior systemic Treatment * Part 1: HR-positive/HER2-negative BC * At least 1 line of SOC, including CD4/6 inhibitor therapy for advanced or metastatic disease, or if CDK4/6 inhibitors are not considered appropriate in the opinion of the investigator * At least 1 line of anti-endocrine in countries without CDK4/6 inhibitor approval or reimbursement, for advanced or metastatic disease * HR-positive/HER2-positive BC (Parts 1A/1D/1E): at least 1 prior treatment of approved HER2 targeting therapy * Tumors other than BC (Parts 1A/1D/1E/1F): tumor that is resistant to at least 2 lines of SOC for advanced or recurrent disease or for which no standard therapy is available * Part 2A and 2E: participants must have received at least 1 line of standard of care (including prior CDK4/6i) for advanced/metastatic disease; Prior chemo is allowed; Prior fulvestrant, mTOR and/or PI3K inhibitors are allowed * Part 2B: participants who have not received any prior systemic anti-cancer therapies for advanced/metastatic BC * Part 2C: * Progressed during treatment or within 12 months of completion of adjuvant therapy with an aromatase inhibitor if postmenopausal, or tamoxifen if pre or perimenopausal, or * Progressed while on or within 1 month after the endo the prior aromatase inhibitor therapy for advanced/metastatic BC if postmenopausal or prior endocrine treatment for advanced/metastatic BC if pre or perimenopausal * One previous line of chemotherapy for advanced/metastatic disease is allowed in addition to endocrine therapy * Part 2D: * Received prior abiraterone; enzalutamide and CDK4i naive * 0-1 line of chemotherapy is allowed General Inclusion Criteria * All participants must be refractory to or intolerant of existing therapies known to provide clinical benefit for their condition. * Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1 * Adequate renal, liver, and bone marrow function
Exclusion criteria
* Part 1D: participants who have had a gastrectomy or have dietary or other restrictions that preclude a 10 hour overnight fast or consumption of the high fat, high calorie meal * Part 2B: prior neoadjuvant or adjuvant treatment with a non-steroidal aromatase inhibitor with disease recurrence while on or within 12 months of completing treatment. Prior treatment with any CDK4/6 inhibitor * Part 2C: prior treatment with any CDK inhibitor, fulvestrant, everolimus, or any agent whose mechanism of action is to inhibit the PI3K-mTOR pathway * Known active uncontrolled or symptomatic Central Nervous System (CNS) metastases carcinomatous meningitis, or leptomeningeal disease * 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 intervention * Last anti-cancer treatment within 2 weeks prior to study intervention * Participation in other studies involving investigational drug(s) within 4 weeks prior to study entry * Pregnant or breastfeeding female participant * Active inflammatory gastrointestinal (GI) disease, known diverticular disease or previous gastric resection or lap band surgery including impairment of gastrointestinal function or GI disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with dose limiting toxicities in the Dose Escalation Portion | Baseline up to day 28 of Cycle 1. | First cycle (28 days) dose limiting toxicities (Parts 1A, 1B, 1C, 1F) |
| Incidence of clinically significant AEs | Weekly during Cycle 1 and 2 and then every 28 days through study completion, up to approximately 24 months; Each cycle is 28 days | Adverse Events |
| Incidence of clinically significant laboratory assessments | Weekly during Cycle 1 and 2 (each cycle is 28 days) and then every 28 days through study completion, up to approximately 24 months | safety laboratory abnormalities |
| Incidence of clinically significant abnormal vital and ECG parameters | Day 1, Day 8, Day 15 of Cycle 1 and starting from Cycle 2, and then every 28 days through study completion, up to approximately 24 months (Each cycle is 28 days) | vital signs and heart rate corrected QT interval |
| Food Effect | Day -7 through the end of Cycle 1 | Maximal Concentration, Time to Maximum Plasma Concentration, Area under the Plasma Concentration (Part 1D) |
| DDI | D1 to the end of Cycle 1 | Maximal Concentration, Time to Maximum Plasma Concentration, Area under the Plasma Concentration (Part 1E) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Multiple Dose: Steady State Maximal Concentration (Css,max) in the Dose Escalation and Dose Finding portion | Cycle 1 (each cycle is 28 days) and Day 1 of each subsequent cycle and at study completion visit, up to approximately 24 months | Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C) |
| Multiple Dose: Time to Maximum Plasma Concentration at Steady State (Tss,max) in the Dose Escalation and Dose Finding portion | Cycle 1 (each cycle is 28 days) and Day 1 of each subsequent cycle and at study completion visit, up to approximately 24 months | Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C) |
| Area Under the Plasma Concentration Versus Time Curve Within One Dose Interval (AUCss,t) in the Dose Escalation and Dose Finding portion | Cycle 1 (each cycle is 28 days) and Day 1 of each subsequent cycle and at study completion visit, up to approximately 24 months | Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C) |
| Multiple Dose: Steady State Minimum Plasma Concentration (Css,min) in the Dose Escalation and Dose Finding portion | Cycle 1 (each cycle is 28 days) and Day 1 of each subsequent cycle and at study completion visit, up to approximately 24 months | Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C) |
| Multiple Dose: Steady State Apparent Oral Plasma Clearance (CLss/F) in the Dose Escalation and Dose Finding portion | Cycle 1 (each cycle is 28 days) and Day 1 of each subsequent cycle and at study completion visit, up to approximately 24 months | Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C) |
| Multiple Dose: Apparent Volume of Distribution at Steady State (Vss/F) in the Dose Escalation and Dose Finding portion | Cycle 1 (each cycle is 28 days) and Day 1 of each subsequent cycle and at study completion visit, up to approximately 24 months | Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C) |
| Multiple Dose: Terminal Elimination Half-Life (t1/2) in the Dose Escalation and Dose Finding portion | Cycle 1 (each cycle is 28 days) and Day 1 of each subsequent cycle and at study completion visit, up to approximately 24 months | Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C) |
| Multiple Dose: Accumulation Ratio (Rac (AUCss,t /AUCsd,t)) in the Dose Escalation and Dose Finding portion | Cycle 1 (each cycle is 28 days) and Day 1 of each subsequent cycle and at study completion visit, up to approximately 24 months | Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C) |
| Tumor Response per RECIST v1.1 and per PCGW3 | baseline up to approximately 24 months | Per RECIST v1.1 (Part 1 A-E; Part 2B and 2C); per PCWG3 (Part 1F and Part 2D) |
| Single Dose: Maximal concentration (Cmax) in the Dose Escalation and Dose Finding portion | Cycle 1 (each cycle is 28 days) and Day 1 of each subsequent cycle and at study completion visit, up to approximately 24 months | Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C) |
| Progression Free Survival (PFS) | baseline up to approximately 24 months | PFS per RECIST v.1.1 |
| Time to Progression (TTP) | baseline up to approximately 24 months | TTP per RECIST v1.1 |
| Clinical Benefit Rate (CBR) | baseline up to approximately 24 months | CBR per RECIST v1.1 (Parts 2B, 2C) |
| Peak and Trough Concentration of PF-07220060 | Cycle 1 (each cycle is 28 days) and Day 1 of each subsequent cycle and at study completion visit, up to approximately 24 months | Peak and trough concentration (Parts 2B, 2C, 2D) |
| Peak and trough concentrations of enzalutamide and N-desmethyl enzalutamide | Cycle 1 (each cycle is 28 days) and Day 1 of each subsequent cycle and at study completion visit, up to approximately 24 months | Peak and trough concentrations (Part 2D) |
| Time to first skeletal events | Cycle 1 (each cycle is 28 days) to up to approximately 24 months | Time to first skeletal events (Part 2D) |
| Quality of life questionnaire | Cycle 1 (each cycle is 28 days) to up to approximately 24 months | time to functional status deterioration by FACT-P (Part 2D) |
| Radiographic Progression Free survival | Cycle 1 (each cycle is 28 days) up to approximately 24 months | Part 2D |
| PSA50 | Cycle 1 (each cycle is 28 days) to up to approximately 24 months | Part 1F and 2D |
| Duration of Response (DOR) | baseline up to approximately 24 months | Per RECIST v1.1 |
| Single Dose: Time to Maximum Plasma Concentration (Tmax) in the Dose Escalation and Dose Finding portion | Cycle 1 (each cycle is 28 days) and Day 1 of each subsequent cycle and at study completion visit, up to approximately 24 months | Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C) |
| Single Dose: Area Under the Plasma Concentration Versus Time Curve from Time Zero to the Last Sampling Time Point Within the Dose Interval (AUClast) in the Dose Escalation and Dose Finding portion | Cycle 1 (each cycle is 28 days) and Day 1 of each subsequent cycle and at study completion visit, up to approximately 24 months | Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C) |
| Single Dose: Area Under the Plasma Concentration Versus Time Curve from Time Zero Extrapolated to Infinity (AUCinf) in the Dose Escalation and Dose Finding portion | Time Frame: Cycle 1 (each cycle is 28 days) and Day 1 of each subsequent cycle and at study completion visit, up to approximately 24 months | Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C) |
| Apparent Oral Plasma Clearance (CL/F) in the Dose Escalation and Dose Finding portion | Cycle 1 (each cycle is 28 days) and Day 1 of each subsequent cycle and at study completion visit, up to approximately 24 months | Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C) |
| Single Dose: Apparent Volume of Distribution (Vz/F) in the Dose Escalation and Dose Finding portion | Cycle 1 (each cycle is 28 days) and Day 1 of each subsequent cycle and at study completion visit, up to approximately 24 months | Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C) |
Countries
Argentina, China, Czechia, Japan, Mexico, Slovakia, United Kingdom, United States
Outcome results
None listed