Liposarcoma, Prostate Cancer, Advanced Breast Cancer, NSCLC (Non-small Cell Lung Cancer), Colorectal Cancer
Conditions
Keywords
CDK4 inhibitor, Breast cancer, enzalutamide, fulvestrant, letrozole, endocrine therapy, Colorectal Cancer (CRC), Solid Tumors, giredestrant, tamoxifen
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 in combination with endocrine therapy. 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. The Giredestrant Combination Cohort will evaluate PF-07220060 in combination with giredestrant. 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 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 doses of PF-07220060 will be administered in combination with enzalutamide. In Part 1G, PF-07220060 will be administered in combination with tamoxifen to determine the RDE. Part 2A is an expansion cohort for PF-07220060 in combination with fulvestrant and will explore more than one dose of PF-07220060. Part 2B and Part 2C are expansion cohorts for PF-07220060 in combination with letrozole and fulvestrant, respectively. Part 2E is an expansion cohort to evaluate PF-07220060 Monotherapy versus PF-07220060 plus fulvestrant combination therapy. Part 2F is an expansion cohort for PF-07220060 in combination with tamoxifen. The Giredestrant Combination Cohort Group A will determine the tolerable dose of PF-07220060 in combination with giredestrant. In Group B, additional participants will be enrolled at the tolerable dose to further assess safety and PK. The China and Japan monotherapy cohorts will evaluate safety, tolerability, and PK of PF-07220060 as single agent in Chinese and Japanese participants, respectively.
Interventions
DRUGPF-07220060
CDK4 inhibitor
COMBINATION_PRODUCTLetrozole
Endocrine Therapy
COMBINATION_PRODUCTFulvestrant
Endocrine Therapy
OTHERMidazolam
Benzodiazepine
COMBINATION_PRODUCTEnzalutamide
Androgen Receptor inhibitor
COMBINATION_PRODUCTGiredestrant
Endocrine Therapy
COMBINATION_PRODUCTTamoxifen
Endocrine Therapy
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/Part 1E 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 1G: HR-positive/HER2-negative BC * Part 2A, 2B, 2C, 2E, and 2F: HR-positive/HER2-negative BC * Part 1D: metastatic castration resistant prostate cancer * Giredestrant Combination Cohort: ER-positive/HER2-negative BC * 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 * 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: 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: no 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 1G and 2F: at least 2 lines of SOC for advanced or metastatic disease, including CDK4/6 inhibitor and endocrine therapy * Giredestrant Combination Cohort: at least 1 (no more than 3) prior line(s) of SOC for advanced or metastatic disease, including CDK4/6 inhibitor and endocrine therapy 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 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; Part 1G and 2F: tamoxifen treatment within 35 days of Day -4 * Participation in other studies involving investigational drug(s) within 4 weeks prior to study entry * Part 1G and 2F: history of or current pulmonary embolism or deep vein thrombosis * Giredestrant Combination Cohort: history (within 6 months of screening) of or presence of idiopathic symptomatic bradycardia or resting heart rate \<50 bpm at screening * 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 or De-escalation Portion | At the end of Cycle 1 (each cycle is 28 days) | First cycle (28 days) dose limiting toxicities |
| Incidence of clinically significant AEs | Cycle 1 (each cycle is 28 days) through study completion, up to approximately 24 months | Adverse Events |
| Incidence of clinically significant laboratory assessments | Cycle 1 (each cycle is 28 days) through study completion, up to approximately 24 months | safety laboratory abnormalities |
| Incidence of clinically significant abnormal vital and ECG parameters | Cycle 1 (each cycle is 28 days) through study completion, up to approximately 24 months | vital signs and heart rate corrected QT interval |
| Maximal Plasma Concentration (Cmax) of PF-07220060 given with and without food | Cycle 1 (each cycle is 28 days) | Pharmacokinetic (PK) assessments for PF-07220060 (Part 1D) |
| Time to Maximum Plasma Concentration (Tmax) of PF-07220060 given with and without food | Cycle 1 (each cycle is 28 days) | Pharmacokinetic (PK) assessments for PF-07220060 (Part 1D) |
| Area Under the Plasma Concentration Versus Time Curve from Time Zero to the Last Sampling Time Point (AUClast) of PF-07220060 given with and without food | Cycle 1 (each cycle is 28 days) | Pharmacokinetic (PK) assessments for PF-07220060 (Part 1D) |
| Maximal Plasma Concentration (Cmax) of Midazolam with and without PF-07220060 | Cycle 1 (each cycle is 28 days) | Pharmacokinetic (PK) assessments for PF-07220060 (Part 1E) |
| Time to Maximum Plasma Concentration (Tmax) of Midazolam with and without PF-07220060 | Cycle 1 (each cycle is 28 days) | Pharmacokinetic (PK) assessments for PF-07220060 (Part 1E) |
| Area Under the Plasma Concentration Versus Time Curve from Time Zero to the Last Sampling Timepoint (AUClast) of Midazolam with and without PF-07220060 | Cycle 1 (each cycle is 28 days) | Pharmacokinetic (PK) assessments for PF-07220060 (Part 1E) |
| Steady State Maximal Concentration (Cmax,ss) of PF-07220060 | Cycle 1 (each cycle is 28 days) | Pharmacokinetic (PK) assessments for PF-07220060 (Giredestrant Combination Cohort) |
| Steady State Time to Maximum Plasma Concentration (Tmax,ss) of PF-07220060 | Cycle 1 (each cycle is 28 days) | Pharmacokinetic (PK) assessments for PF-07220060 (Giredestrant Combination Cohort) |
| Steady State Area Under the Plasma Concentration Versus Time Curve Within One Dose Interval (AUCτ,ss) of PF-07220060 | Cycle 1 (each cycle is 28 days) | Pharmacokinetic (PK) assessments for PF-07220060 (Giredestrant Combination Cohort) |
| Steady State Minimum Plasma Concentration (Cmin,ss) of PF-07220060 | Cycle 1 (each cycle is 28 days) | Pharmacokinetic (PK) assessments for PF-07220060 (Giredestrant Combination Cohort) |
| Steady State Maximal Concentration (Cmax,ss) of Giredestrant | Cycle 1 (each cycle is 28 days) | Pharmacokinetic (PK) assessments (Giredestrant Combination Cohort) |
| Steady State Time to Maximum Plasma Concentration (Tmax,ss) of Giredestrant | Cycle 1 (each cycle is 28 days) | Pharmacokinetic (PK) assessments (Giredestrant Combination Cohort) |
| Steady State Area Under the Plasma Concentration Versus Time Curve Within One Dose Interval (AUCτ,ss) of Giredestrant | Cycle 1 (each cycle is 28 days) | Pharmacokinetic (PK) assessments (Giredestrant Combination Cohort) |
| Steady State Minimum Plasma Concentration (Cmin,ss) of Giredestrant | Cycle 1 (each cycle is 28 days) | Pharmacokinetic (PK) assessments (Giredestrant Combination Cohort) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Single Dose: Maximal Plasma Concentration (Cmax) in the Dose Escalation and Dose Finding portion | Cycle 1 (each cycle is 28 days) | Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C, 1F) |
| Single Dose: Time to Maximum Plasma Concentration (Tmax) in the Dose Escalation and Dose Finding portion | Cycle 1 (each cycle is 28 days) | Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C, 1F) |
| 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) | Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C, 1F) |
| Multiple Dose: Steady State Maximal Concentration (Cmax,ss) in the Dose Escalation and Dose Finding portion | Cycle 1 (each cycle is 28 days) for Parts 1A/1B/1C/1E/1F; Cycle 2 (each cycle is 28 days) for Part 1G | Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C, 1E, 1F, 1G) |
| Multiple Dose: Steady State Time to Maximum Plasma Concentration (Tmax,ss) in the Dose Escalation and Dose Finding portion | Cycle 1 (each cycle is 28 days) for Parts 1A/1B/1C/1E/1F; Cycle 2 (each cycle is 28 days) for Part 1G | Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C, 1E, 1F, 1G) |
| Steady State Area Under the Plasma Concentration Versus Time Curve Within One Dose Interval (AUCt,ss) in the Dose Escalation and Dose Finding portion | Cycle 1 (each cycle is 28 days) for Parts 1A/1B/1C/1E/1F; Cycle 2 (each cycle is 28 days) for Part 1G | Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C, 1E, 1F, 1G) |
| Multiple Dose: Steady State Minimum Plasma Concentration (Cmin,ss) in the Dose Escalation and Dose Finding portion | Cycle 1 (each cycle is 28 days) for Parts 1A/1B/1C/1E/1F; Cycle 2 (each cycle is 28 days) for Part 1G | Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C, 1E, 1F, 1G) |
| Steady State Peak Concentration of Enzalutamide and N-desmethyl Enzalutamide | Cycles 1 - 12 (each cycle is 28 days) | Pharmacokinetic (PK) assessments for enzalutamide (Part 1F) |
| Steady State Trough Concentration of Enzalutamide and N-desmethyl Enzalutamide | Cycle 3 (each cycle is 28 days) | Pharmacokinetic (PK) assessments for enzalutamide (Part 1F) |
| Tumor Response per RECIST v1.1 and per PCGW3 | baseline up to approximately 24 months | Per RECIST v1.1 (all cohorts except for Part 1F); per PCWG3 (Part 1F) |
| Duration of Response (DOR) | baseline up to approximately 24 months | Per RECIST v1.1 |
| Progression Free Survival (PFS) | baseline up to approximately 24 months | PFS per RECIST v.1.1 |
| Clinical Benefit Rate (CBR) | baseline up to approximately 24 months | CBR per RECIST v1.1 |
| PSA50 | Cycle 1 (each cycle is 28 days) through study completion, up to approximately 24 months | Part 1F |
| Incidence of clinically significant AEs | Cycle 1 (each cycle is 28 days) through study completion, up to approximately 24 months | Adverse Events (Giredestrant Combination Cohort) |
| Incidence of clinically significant laboratory assessments | Cycle 1 (each cycle is 28 days) through study completion, up to approximately 24 months | Safety laboratory abnormalities (Giredestrant Combination Cohort) |
| Steady State Minimal Concentration (Cmin,ss) of Tamoxifen, 4-hydroxy-tamoxifen, N-desmethyltamoxifen, and Endoxifen | Cycle 2 (each cycle is 28 days) | Pharmacokinetic (PK) assessments for tamoxifen and metabolites (Parts 1G and 2F) |
| Metabolite to Parent Ratio of Minimal Concentration (MRCmin) of 4-hydroxy-tamoxifen, N-desmethyltamoxifen, and Endoxifen | Cycle 2 (each cycle is 28 days) | Pharmacokinetic (PK) assessments for tamoxifen and metabolites (Parts 1G and 2F) |
| Steady State Area Under the Plasma Concentration Versus Time Curve Within One Dose Interval (AUCt,ss) of Tamoxifen, 4-hydroxy-tamoxifen, N-desmethyltamoxifen, and Endoxifen | Cycle 2 (each cycle is 28 days) | Pharmacokinetic (PK) assessments for tamoxifen and metabolites (Parts 1G and 2F) |
| Steady State Peak Concentration of PF-07220060 | Cycle 1 (each cycle is 28 days) for Part 2A/2B/2C/2E; Cycle 2 (each cycle is 28 days) for Part 2F | Pharmacokinetic (PK) assessments for PF-07220060 (Part 2A, 2B, 2C, 2E, 2F) |
| Steady State Trough Concentration of PF-07220060 | Cycle 1 (each cycle is 28 days) for Parts 2A/2B/2C/2E; Cycle 2 (each cycle is 28 days) for Part 2F | Pharmacokinetic (PK) assessments for PF-07220060 (Parts 2A, 2B, 2C, 2E, 2F) |
Countries
Argentina, China, Czechia, Japan, Mexico, Slovakia, United Kingdom, United States
Contacts
CONTACTPfizer CT.gov Call Center
STUDY_DIRECTORPfizer CT.gov Call Center
Pfizer
Outcome results
None listed