A PHASE 1/2A 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
Summary
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 other agents
Detailed description
Study has two parts, Part 1 (dose escalation) and Part 2 (dose expansion). Part 1 is divided into Parts 1A, 1B, 1C, 1D and 1E and Part 2 is divided into Parts 2A, 2B, 2D and 2E. 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, 1D and 1E PF-07248144 will be administered in combination with either fulvestrant (Part 1B); palbociclib + letrozole (Part 1C) or PF-07220060+fulvestrant (Part 1D) or vepdegestrant (Part 1E). 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. After determination of the combination RDE from Part 1E, PF-07248144 in combination with vepdegestrant will be evaluated in a combination dose-expansion cohort, Part 2E.
Arms & interventions
- DrugPF-07248144
KAT6 Inhibitor
- DrugFulvestrant
Endocrine Therapy
- DrugLetrozole
Endocrine Therapy
- DrugPalbociclib
CDK4/6 Inhibitor
- DrugPF-07220060
CDK4 inhibitor
- DrugPF-07850327, ARV-471, vepdegestrant
PROTAC (PROteolysis Targeting Chimera) ER degrader
Outcome measures
Primary
Number of participants with dose-limiting toxicities in the Dose Escalation Arms.
Dose-limiting toxicities (DLTs)
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Up to 24 months
Secondary
Single Dose: Maximum Observed Concentration (Cmax) in the Dose Escalation and Dose Finding Arms
Time frame: Up to 24 months
Single Dose: Time to Maximum concentration (Tmax) in the Dose Escalation and Dose Finding Arms
Time frame: 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
Time frame: Up to 24 months
Single and Multiple Dose: Terminal Elimination half-life (t1/2) in the Dose Escalation and Dose Finding Arms
Time frame: Up to 24 months
Multiple Dose: Steady-State Cmax (Cmax,ss) in the Dose Escalation and Dose Finding Arms
Time frame: Up to 24 months
Multiple Dose: Steady-state Tmax (Tmax,ss) in the Dose Escalation and Dose Finding Arms
Time frame: Up to 24 months
Multiple Dose: Steady state AUC during a dosage interval (τ) (AUCτ,ss) in the Dose Escalation and Dose Finding Arms
Time frame: Up to 24 months
Multiple Dose: Steady-state Cmin (Cmin,ss) in the Dose Escalation and Dose Finding Arms.
Time frame: Up to 24 months
Multiple Dose: Steady-state apparent total clearance (CLss/F) in the Dose Escalation and Dose Finding Arms.
Time frame: Up to 24 months
Palbociclib trough concentrations at steady instate (Cmin,ss) in the 1C combination dose finding arm.
Time frame: Up to 24 months
Peak concentrations of PF-07248144, PF-07220060 (Part 2D) and vepdegestrant and ARV-473 (Part 2E) for selected cycles in the Dose Expansion Arms
Time frame: Up to 24 months
Trough concentrations of PF-07248144 for selected cycles in the Dose Expansion Arms
Time frame: Up to 24 months
Maximum Observed Concentration (Cmax) in the participants in the food effect subset in monotherapy dose expansion arm
Time frame: 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
Time frame: 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
Time frame: 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.
Time frame: Up to 24 months
Renal clearance (CLr) in a sub-set of participants in monotherapy dose expansion arm
Time frame: Up to 24 months
Progression Free Survival (PFS) observed in participants in the Dose Expansion Arms
Time frame: Up to 24 months
Time to Progression (TTP) observed in participants enrolled in the Dose Expansion Arms
Time frame: Up to 24 months
Overall survival (OS) observed in participants enrolled in Dose Expansion Arms
Time frame: Up to 24 months
Best Overall Response (BOR) observed in participants in the dose expansion arms
Time frame: Up to 24 months
Duration of Response (DOR) observed in participants in the dose expansion arms
Time frame: up to 24 months
Clinical Benefit Rate (CBR) observed in participants in the Dose Expansion Arms
Time frame: up to 24 months
Eligibility criteria
Study locations (23)
HonorHealth
Scottsdale, Arizona, 85258
Cedars Sinai Medical Center
Los Angeles, California, 90048
Cedars-Sinai Cancer at Cedars-Sinai Medical Center
Los Angeles, California, 90048
UCSF Medical Center at Mission Bay
San Francisco, California, 94158
Smilow Cancer Hospital at Yale - New Haven
New Haven, Connecticut, 06510
Yale-New Haven Hospital- Yale Cancer Center
New Haven, Connecticut, 06510
Smilow Cancer Hospital Phase 1 Unit
New Haven, Connecticut, 06511
Yale University
New Haven, Connecticut, 06511
Holy Cross Hospital
Fort Lauderdale, Florida, 33308
St. Elizabeth Healthcare
Edgewood, Kentucky, 41017
University Medical Center, lnc.:DBA University of Louisville Hospital
Louisville, Kentucky, 40202
University of Louisville
Louisville, Kentucky, 40202
UofL Health Brown Cancer Center
Louisville, Kentucky, 40202
SCRI Oncology Partners
Nashville, Tennessee, 37203
MD Anderson The Woodlands
Conroe, Texas, 77384
The University of Texas M. D. Anderson Cancer Center
Houston, Texas, 77030
U.T. MD Anderson Cancer Center
Houston, Texas, 77030
MD Anderson West Houston
Houston, Texas, 77079
MD Anderson League City
League City, Texas, 77573
NEXT Oncology
San Antonio, Texas, 78229
MD Anderson
Sugar Land, Texas, 77478
Swedish Cancer Institute
Seattle, Washington, 98104
Swedish Medical Center
Seattle, Washington, 98122
References
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