Study to Test the Safety and Tolerability of PF-07220060 in Participants With Advance Solid Tumors

• PF-07220060 (Drug): CDK4 inhibitor
• Letrozole (Combination product), also known as Femara: Endocrine Therapy
• Fulvestrant (Combination product), also known as Faslodex: Endocrine Therapy
• Midazolam (Other): Benzodiazepine
• Enzalutamide (Combination product), also known as Xtandi: Androgen Receptor inhibitor
• Giredestrant (Combination product): Endocrine Therapy
• Tamoxifen (Combination product): Endocrine Therapy

Primary outcomes

• 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 outcomes

• 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)

Sex: All, ages: 18 Years to any

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

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