Study of PF-07248144 in Advanced or Metastatic Solid Tumors

Study Overview
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Brief Summary
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This is an open-label, multi center study to evaluate safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PF-07248144 and early signs of clinical efficacy of PF-07248144 as a single agent and in combination with either fulvestrant or letrozole + palbociclib or with PF-07220060 + fulvestrant

Detailed Description
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Study has two parts, Part 1 (dose escalation) and Part 2 (dose expansion). Part 1 is divided into Parts 1A, 1B, 1C and 1D and Part 2 is divided into Parts 2A, 2B and 2D. In Part 1A, single escalating doses of PF-07248144 alone will be administered to determine the maximum tolerable dose (MTD) and select the recommended dose for expansion (RDE). In Part 1B,1C and 1D, PF-07248144 will be administered in combination with either fulvestrant (Part 1B); palbociclib + letrozole (Part 1C) or PF-07220060+fulvestrant (Part 1D).. After the determination of the monotherapy RDE in Part 1A, PF-07248144 will be evaluated in a dose expansion cohort as a monotherapy in Part 2A. After determination of the combination RDE from Part 1B, PF-07248144 in combination with fulvestrant, PF-07248144 will be evaluated in a combination dose expansion with fulvestrant in Part 2B. In Part 1C, PF-07248144 in combination with letrozole + palbociclib will be evaluated for dose finding to determine the MTD and RDE for this combination. After determination of the triple combination RDE from Part 1D, PF-07248144 in combination with PF-07220060 + fulvestrant will be evaluated in a combination dose-expansion cohort, Part 2D.

Official Title
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A Phase 1 Dose Escalation and Expansion Study to Evaluate Safety, Tolerability, Pharmacokinetic, Pharmacodynamic, and Anti-tumor Activity of PF-07248144 in Participants With Advanced or Metastatic Solid Tumors.

Conditions
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Locally Advanced or Metastatic ER+ HER2- Breast Cancer, Locally Advanced or Metastatic Castration-resistant Prostate Cancer, Locally Advanced or Metastatic Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: PF-07248144
* Drug: Fulvestrant
* Drug: Letrozole
* Drug: Palbociclib
* Drug: PF-07220060


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Disease Characteristics - Breast, Prostate, and Lung Cancer Part 1A (Monotherapy Dose Escalation) Histological or cytological diagnosis of locally advanced or metastatic ER+HER2- breast cancer, CRPC, or NSCLC that is intolerant or resistant to standard therapy or for which no standard therapy is available. Part 1B, Part 1C and Part 1D (Combination Dose Escalation) Histological or cytological diagnosis of locally advanced or metastatic ER+HER2- breast cancer. Participants must have progressed after at least 1 prior line of treatment with an endocrine therapy and CDK4/6 inhibitor in the advanced or metastatic setting. Part 2A (ER+HER2- breast cancer 2L+, monotherapy) Histological or cytological diagnosis of locally advanced or metastatic ER+HER2- breast cancer. Participants must have progressed after at least 1 prior line of CDK4/6 inhibitor and 1 line of endocrine therapy. Part 2B (ER+HER2- breast cancer 2-4L, combination with fulvestrant) Histological or cytological diagnosis of advanced or metastatic ER+HER2- breast cancer. Participants must have progressive disease after at least 1 prior line of a CDK4/6 inhibitor and at least 1 prior line of endocrine therapy.. Participants must not have received more than 3 prior lines of systemic therapies including up to 1 line of cytotoxic chemotherapy for visceral disease in advanced or metastatic setting; Participants may have but are not required to have prior treatment with fulvestrant. Part 2D (ER+HER2- breast cancer 2-4L, combination with PF-07220060 (CDK4i) and fulvestrant): Histological or cytological diagnosis of advanced or metastatic ER+HER2- breast cancer. Participants must have progressive disease after at least 1 prior line of a CDK4/6 inhibitor and at least 1 prior line of endocrine therapy. Participants must have not received more than 3 lines of systemic therapies including up to 1 line of cytotoxic chemotherapy for visceral disease in advanced or metastatic setting; Participants may have but are not required to have prior treatment with fulvestrant. Participants with ER+HER2- advanced or metastatic breast cancer must have documentation of ER-positive tumor (≥1% positive stained cells) based on most recent tumor biopsy utilizing an assay consistent with local standards. Participants with ER+HER2- advanced or metastatic breast cancer must have documentation of HER2-negative tumor: HER2-negative tumor is determined as immunohistochemistry score 0/1+ or negative by in situ hybridization (FISH/CISH/SISH/DISH) defined as a HER2/CEP17 ratio <2 or for single probe assessment a HER2 copy number <4. Female participants with ER+HER2- advanced or metastatic breast cancer considered to be of childbearing potential (or have tubal ligations only) must be willing to undergo medically induced menopause by treatment with the approved LHRH agonist such as goserelin, leuprolide or equivalent agents to induce chemical menopause. Female participants with ER+HER2- advanced or metastatic breast cancer of nonchildbearing potential must meet at least 1 criteria of achieving postmenopausal status. Participants must have at least 1 measurable lesion as defined by RECIST version 1.1 that has not been previously irradiated. Eastern Cooperative Oncology Group (ECOG) Performance Status PS 0 or 1 Female or male patients aged ≥ 18 years (Japan ≥ 20 years) (South Korea ≥ 19 years). Adequate renal, liver, and bone marrow function. Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade 1 except for adverse events (AEs) not constituting a safety risk by investigator judgment. Exclusion Criteria: Unmanageable ascites (limited medical treatment to control ascites is permitted, but all participants with ascites require review by sponsor's medical monitor). Participants with any other active malignancy within 3 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ. Major surgery, radiation therapy, or systemic anti-cancer therapy within 3 weeks prior to study entry. Prior irradiation to >25% of the bone marrow. ECG clinically relevant abnormalities (eg, QTc >470 msec, complete LBBB, second/third degree AV block, ST elevation or EKG changes suggesting myocardial infarction or active myocardia ischemia). Therapeutic anticoagulation. However, low molecular weight heparin is allowed. Vitamin K antagonists or factor Xa inhibitors may be allowed following discussion with the Sponsor. Known or suspected hypersensitivity or severe allergy to active ingredient/excipients of PF-07248144. Active inflammatory GI disease, refractory and unresolved chronic diarrhea or previous gastric resection, lap band surgery or other GI conditions and surgeries that may significantly alter the absorption of PF-07248144 tablets. Gastroesophageal reflux disease under treatment is allowed. Pregnant or breastfeeding female participants.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: The dose escalation parts and the dose finding parts of the study will be guided by a Bayesian analysis of Cycle 1 dose-limiting toxicity (DLT) data for PF-07248144 as monotherapy or in combination (Part 1B, Part 1C and Part 1D). A traditional 2-parameter Bayesian Logistic Regression Model (BLRM) will be used to model the DLT relationship of PF-07248144 monotherapy and a more complex BLRM model specifically designed for combinations will be used to model the dose/DLT relationship of PF-07248144 given in combination with fulvestrant, with letrozole + palbociclib or with PF-07220060 + fulvestrant.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1A Monotherapy Dose Escalation<br>PF-07248144 Monotherapy Escalation | Drug: PF-07248144<br>* KAT6 Inhibitor<br>|
| Experimental: 1B Combination Dose Escalation<br>PF-07248144 with Fulvestrant Combination Dose Escalation | Drug: PF-07248144<br>* KAT6 Inhibitor<br>Drug: Fulvestrant<br>* Endocrine Therapy<br>* Other names: Faslodex;|
| Experimental: 1C Combination Dose Escalation<br>PF-07248144 with Letrozole + Palbociclib Combination Dose Escalation | Drug: PF-07248144<br>* KAT6 Inhibitor<br>Drug: Letrozole<br>* Endocrine Therapy<br>* Other names: Femara;Drug: Palbociclib<br>* CDK4/6 Inhibitor<br>* Other names: Ibrance;|
| Experimental: 2A Monotherapy Dose Expansion Arm<br>PF-07248144 Monotherapy Dose Expansion | Drug: PF-07248144<br>* KAT6 Inhibitor<br>|
| Experimental: 2B Combination Dose Expansion Arm<br>PF-07248144 with Fulvestrant Dose Expansion | Drug: PF-07248144<br>* KAT6 Inhibitor<br>Drug: Fulvestrant<br>* Endocrine Therapy<br>* Other names: Faslodex;|
| Experimental: 1D Combination Dose Escalation<br>PF-07248144 with PF-07220060 +Fulvestrant | Drug: PF-07248144<br>* KAT6 Inhibitor<br>Drug: Fulvestrant<br>* Endocrine Therapy<br>* Other names: Faslodex;Drug: PF-07220060<br>* CDK4 inhibitor<br>|
| Experimental: 2D Combination Dose Expansion Arm<br>PF-07248144 with PF-07220060 +Fulvestrant Dose Expansion | Drug: PF-07248144<br>* KAT6 Inhibitor<br>Drug: Fulvestrant<br>* Endocrine Therapy<br>* Other names: Faslodex;Drug: PF-07220060<br>* CDK4 inhibitor<br>|
| Experimental: China Monotherapy Dose Expansion<br>PF-07248144 Monotherapy Dose Expansion | Drug: PF-07248144<br>* KAT6 Inhibitor<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with dose-limiting toxicities in the Dose Escalation Arms. | Dose-limiting toxicities (DLTs) | Up to 29 days | 
| Safety and Tolerability as assessed by adverse event monitoring for participants enrolled in the Dose Escalation Arms. | Adverse Events as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), timing, seriousness, and relationship to study therapy. | Up to 24 months | 
| Safety and Tolerability through monitoring of laboratory assessments for participants enrolled in the Dose Escalation Arms. | Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), and timing. | Up to 24 months | 
| Safety and Tolerability as assessed by adverse event monitoring for participants enrolled in the Dose Expansion Arms | Adverse Events as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), timing, seriousness, and relationship to study therapy. | Up to 24 months | 
| Safety and Tolerability through monitoring of laboratory assessments for participants enroled in the Dose Expansion Arms | Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), and timing. | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Single Dose: Maximum Observed Concentration (Cmax) in the Dose Escalation and Dose Finding Arms | Pharmacokinetic (PK) assessments for PF-07248144 and PF-07220060 (Part 1D) | Up to 24 months | 
| Single Dose: Time to Maximum concentration (Tmax) in the Dose Escalation and Dose Finding Arms | Pharmacokinetic (PK) assessments for PF-07248144 and PF-07220060 (Part 1D) | Up to 24 months | 
| Single Dose: AUC from time zero to time of last measurable concentration (AUClast) in the Dose Escalation and Dose Finding Arms | Pharmacokinetic (PK) assessments for PF-07248144 and PF-07220060 (Part 1D) | Up to 24 months | 
| Single and Multiple Dose: Terminal Elimination half-life (t1/2) in the Dose Escalation and Dose Finding Arms | Pharmacokinetic (PK) assessments for PF-07248144 and PF-07220060 (Part 1D) | Up to 24 months | 
| Multiple Dose: Steady-State Cmax (Cmax,ss) in the Dose Escalation and Dose Finding Arms | Pharmacokinetic (PK) assessments for PF-07248144 and PF-07220060 (Part 1D) | Up to 24 months | 
| Multiple Dose: Steady-state Tmax (Tmax,ss) in the Dose Escalation and Dose Finding Arms | Pharmacokinetic (PK) assessments for PF-07248144 and PF-07220060 (Part 1D) | Up to 24 months | 
| Multiple Dose: Steady state AUC during a dosage interval (τ) (AUCτ,ss) in the Dose Escalation and Dose Finding Arms | Pharmacokinetic (PK) assessments for PF-07248144 and PF-07220060 (Part 1D) | Up to 24 months | 
| Multiple Dose: Steady-state Cmin (Cmin,ss) in the Dose Escalation and Dose Finding Arms. | Pharmacokinetic (PK) assessments for PF-07248144 and PF-07220060 (Part 1D) | Up to 24 months | 
| Multiple Dose: Steady-state apparent total clearance (CLss/F) in the Dose Escalation and Dose Finding Arms. | Pharmacokinetic (PK) assessments for PF-07248144 and PF-07220060 (Part 1D) | Up to 24 months | 
| Palbociclib trough concentrations at steady instate (Cmin,ss) in the 1C combination dose finding arm. | Pharmacokinetic (PK) assessment for palbociclib exposure. | Up to 24 months | 
| Best Overall Response (BOR) in participants in the Dose Expansion Arms |  | Up to 24 months | 
| Duration of Response (DOR) in participants enrolled in the Dose Expansion Arms |  | Up to 24 months | 
| Peak concentrations of PF-07248144 and PF-07220060 (Part 2D) for selected cycles in the Dose Expansion Arms | Pharmacokinetic (PK) assessment for PF-07248144 and PF-07220060 (Part 2D) | Up to 24 months | 
| Trough concentrations of PF-07248144 for selected cycles in the Dose Expansion Arms | Pharmacokinetic (PK) assessment for PF-07248144 and PF-07220060 (Part 2D) | Up to 24 months | 
| Maximum Observed Concentration (Cmax) in the participants in the food effect subset in monotherapy dose expansion arm | The effect of food on the PK of PF-07248144. | Cycle 1 Day -7 and Cycle 1 Day 1 (each cycle is 28 days) | 
| Time to Maximum concentration (Tmax) in the participants in the food effect subset in monotherapy dose expansion arm | The effect of food on the PK of PF-07248144. | Cycle 1 Day -7 and Cycle 1 Day 1 (each cycle is 28 days) | 
| AUC from time zero to time of last measurable concentration (AUClast) in the participants in the food effect subset in monotherapy dose expansion arm | The effect of food on the PK of PF 07248144. | Cycle 1 Day -7 and Cycle 1 Day 1 (each cycle is 28 days) | 
| Amount of PF-07248144 excreted in urine relative to dose administered (%) in a sub-set of participants in monotherapy dose expansion arm. | Evaluate urine pharmacokinetic (PK) of PF-07248144. | Up to 24 months | 
| Renal clearance (CLr) in a sub-set of participants in monotherapy dose expansion arm | Evaluate urine pharmacokinetic (PK) of PF-07248144. | Up to 24 months | 
| Progression Free Survival (PFS) observed in participants in the Dose Expansion Arms |  | Up to 24 months | 
| Time to Progression (TTP) observed in participants enrolled in the Dose Expansion Arms |  | Up to 24 months | 
| Overall survival (OS) observed in participants enrolled in Dose Expansion Arms |  | Up to 24 months | 
| Best Overall Response (BOR) observed in participants in the dose expansion arms |  | Up to 24 months | 
| Duration of Response (DOR) observed in participants in the dose expansion arms |  | up to 24 months | 
| Clinical Benefit Rate (CBR) observed in participants in the Dose Expansion Arms |  | up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Solid tumors