KAT6: Study of PF-07248144 in Advanced or Metastatic Solid Tumors

Sponsor

Pfizer (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04606446

Collaborator

(none)

108

Enrollment

Locations

Arms

Anticipated Duration (Months)

2.5

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief 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 either fulvestrant or letrozole + palbociclib.

Condition or Disease	Intervention/Treatment	Phase
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	Drug: PF-07248144 Drug: Fulvestrant Drug: Letrozole Drug: Palbociclib	Phase 1

Detailed Description

Study has two parts, Part 1 (dose escalation) and Part 2 (dose expansion). Part 1 is divided into Parts 1A, 1B, and 1C and Part 2 is divided into Parts 2A and 2B. 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 and 1C, PF-07248144 will be administered in combination with either fulvestrant or letrozole + palbociclib. 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

108 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Intervention 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 with fulvestrant or with letrozole + palbociclib. 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 toxicity relationship of PF-07248144 given in combination with fulvestrant or with letrozole + palbociclib.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 with fulvestrant or with letrozole + palbociclib. 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 toxicity relationship of PF-07248144 given in combination with fulvestrant or with letrozole + palbociclib.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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.

Actual Study Start Date :

Nov 16, 2020

Anticipated Primary Completion Date :

Nov 15, 2023

Anticipated Study Completion Date :

Apr 18, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1A Monotherapy Escalation Dose Level 1 PF-07248144 Monotherapy Escalation	Drug: PF-07248144 KAT6 Inhibitor
Experimental: 1A Monotherapy Escalation Dose Level 2 PF-07248144 Monotherapy Escalation	Drug: PF-07248144 KAT6 Inhibitor
Experimental: 1A Monotherapy Escalation Dose Level 3 PF-07248144 Monotherapy Escalation	Drug: PF-07248144 KAT6 Inhibitor
Experimental: 1A Monotherapy Escalation Dose Level 4 PF-07248144 Monotherapy Escalation	Drug: PF-07248144 KAT6 Inhibitor
Experimental: 1B Combination Dose Finding Arm level 1 PF-07248144 with Fulvestrant Combination Dose Finding	Drug: PF-07248144 KAT6 Inhibitor Drug: Fulvestrant Endocrine Therapy Other Names: Faslodex
Experimental: 1B Combination Dose Finding Arm Level 2 PF-07248144 with Fulvestrant Combination Dose Finding	Drug: PF-07248144 KAT6 Inhibitor Drug: Fulvestrant Endocrine Therapy Other Names: Faslodex
Experimental: 1C Combination Dose Finding Arm Level 1 PF-07248144 with Letrozole + Palbociclib Combination Dose Finding	Drug: PF-07248144 KAT6 Inhibitor Drug: Letrozole Endocrine Therapy Other Names: Femara Drug: Palbociclib CDK4/6 Inhibitor Other Names: Ibrance
Experimental: 1C Combination Dose FInding Arm Level 2 PF-07248144 with Letrozole + Palbociclib Combination Dose Finding	Drug: PF-07248144 KAT6 Inhibitor Drug: Letrozole Endocrine Therapy Other Names: Femara Drug: Palbociclib CDK4/6 Inhibitor Other Names: Ibrance
Experimental: 2A Monotherapy Dose Expansion Arm PF-07248144 Monotherapy Dose Expansion	Drug: PF-07248144 KAT6 Inhibitor
Experimental: 2B Combination Dose Expansion Arm PF-07248144 with Fulvestrant Dose Expansion	Drug: PF-07248144 KAT6 Inhibitor Drug: Fulvestrant Endocrine Therapy Other Names: Faslodex
Experimental: 1A Monotherapy Escalation Dose Level 5 PF-07248144 Monotherapy Escalation	Drug: PF-07248144 KAT6 Inhibitor

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

Single Dose: Maximum Observed Concentration (Cmax) in the Dose Escalation and Dose Finding Arms [Up to 24 months]
Pharmacokinetic (PK) assessments for PF-07248144
Single Dose: Time to Maximum concentration (Tmax) in the Dose Escalation and Dose Finding Arms [Up to 24 months]
Pharmacokinetic (PK) assessments for PF-07248144
Single Dose: AUC from time zero to time of last measurable concentration (AUClast) in the Dose Escalation and Dose Finding Arms [Up to 24 months]
Pharmacokinetic (PK) assessments for PF-07248144
Single and Multiple Dose: Terminal Elimination half-life (t1/2) in the Dose Escalation and Dose Finding Arms [Up to 24 months]
Pharmacokinetic (PK) assessments for PF-07248144
Multiple Dose: Steady-State Cmax (Cmax,ss) in the Dose Escalation and Dose Finding Arms [Up to 24 months]
Pharmacokinetic (PK) assessments for PF-07248144
Multiple Dose: Steady-state Tmax (Tmax,ss) in the Dose Escalation and Dose Finding Arms [Up to 24 months]
Pharmacokinetic (PK) assessments for PF-07248144
Multiple Dose: Steady state AUC during a dosage interval (τ) (AUCτ,ss) in the Dose Escalation and Dose Finding Arms [Up to 24 months]
Pharmacokinetic (PK) assessments for PF-07248144
Multiple Dose: Steady-state Cmin (Cmin,ss) in the Dose Escalation and Dose Finding Arms. [Up to 24 months]
Pharmacokinetic (PK) assessments for PF-07248144
Multiple Dose: Steady-state apparent total clearance (CLss/F) in the Dose Escalation and Dose Finding Arms. [Up to 24 months]
Pharmacokinetic (PK) assessments for PF-07248144
Palbociclib trough concentrations at steady instate (Cmin,ss) in the 1C combination dose finding arm. [Up to 24 months]
Pharmacokinetic (PK) assessment for palbociclib exposure.
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 for selected cycles in the Dose Expansion Arms [Up to 24 months]
Pharmacokinetic (PK) assessment for PF-07248144
Trough concentrations of PF-07248144 for selected cycles in the Dose Expansion Arms [Up to 24 months]
Pharmacokinetic (PK) assessment for PF-07248144
Maximum Observed Concentration (Cmax) in the participants in the food effect subset in monotherapy dose expansion arm [Cycle 1 Day -7 and Cycle 1 Day 1 (each cycle is 28 days)]
The effect of food on the PK of PF-07248144.
Time to Maximum concentration (Tmax) in the participants in the food effect subset in monotherapy dose expansion arm [Cycle 1 Day -7 and Cycle 1 Day 1 (each cycle is 28 days)]
The effect of food on the PK of PF-07248144.
AUC from time zero to time of last measurable concentration (AUClast) in the participants in the food effect subset in monotherapy dose expansion arm [Cycle 1 Day -7 and Cycle 1 Day 1 (each cycle is 28 days)]
The effect of food on the PK of PF 07248144.
Amount of PF-07248144 excreted in urine relative to dose administered (%) in a sub-set of participants in monotherapy dose expansion arm. [Up to 24 months]
Evaluate urine pharmacokinetic (PK) of PF-07248144.
Renal clearance (CLr) in a sub-set of participants in monotherapy dose expansion arm [Up to 24 months]
Evaluate urine pharmacokinetic (PK) of PF-07248144.
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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 and Part 1C (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, fulvestrant-naive, combination with fulvestrant) Histological or cytological diagnosis of advanced or metastatic ER+HER2- breast cancer. Participants must have progressed after 1 line of a CDK4/6 inhibitor and 1 line of endocrine therapy.
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 4 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	HonorHealth	Scottsdale	Arizona	United States	85258
2	Cedars Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute	Los Angeles	California	United States	90048
3	Cedars-Sinai Medical Center; SOCCI Pharmacy	Los Angeles	California	United States	90048
4	UCSF Medical Center at Mission Bay	San Francisco	California	United States	94158
5	Smilow Cancer Hospital at Yale - New Haven	New Haven	Connecticut	United States	06510
6	Smilow Cancer Hospital Phase 1 Unit	New Haven	Connecticut	United States	06511
7	Yale New Haven Hospital	New Haven	Connecticut	United States	06520-8064
8	Holy Cross Hospital	Fort Lauderdale	Florida	United States	33308
9	James Graham Brown Cancer Center	Louisville	Kentucky	United States	40202
10	University Medical Center, lnc.:DBA University of Louisville Hospital	Louisville	Kentucky	United States	40202
11	Michigan Health Professionals	Farmington Hills	Michigan	United States	48334
12	Revive Research Institute	Farmington Hills	Michigan	United States	48334
13	Thomas Jefferson University, Bodine Center for Radiation Therapy	Philadelphia	Pennsylvania	United States	19107
14	Thomas Jefferson University, Clinical Research Unit	Philadelphia	Pennsylvania	United States	19107
15	Thomas Jefferson University, Gibbon Building	Philadelphia	Pennsylvania	United States	19107
16	Thomas Jefferson University, Investigational Drug Service	Philadelphia	Pennsylvania	United States	19107
17	Thomas Jefferson University, Main Office Building	Philadelphia	Pennsylvania	United States	19107
18	Thomas Jefferson University, Sidney Kimmel Cancer Center, Clinical Research Organization	Philadelphia	Pennsylvania	United States	19107
19	Thomas Jefferson University, Sidney Kimmel Cancer Center	Philadelphia	Pennsylvania	United States	19107
20	Thomas Jefferson University	Philadelphia	Pennsylvania	United States	19107
21	TJU Research PK/PD Lab	Philadelphia	Pennsylvania	United States	19107
22	Tennessee Oncology PLLC	Franklin	Tennessee	United States	37067
23	Sarah Cannon Research Institute	Nashville	Tennessee	United States	37203
24	Tennessee Oncology PLLC	Nashville	Tennessee	United States	37203
25	The Sarah Cannon Research Institute / Tennessee Oncology, PLLC	Nashville	Tennessee	United States	37203
26	The University of Texas M. D. Anderson Cancer Center	Houston	Texas	United States	77030
27	U.T. MD Anderson Cancer Center	Houston	Texas	United States	77030
28	NEXT Oncology	San Antonio	Texas	United States	78229
29	Chris O'Brien Lifehouse	Camperdown	New South Wales	Australia	2050
30	Peter MacCallum Cancer Centre	Melbourne	Victoria	Australia	3000
31	Royal Melbourne Hospital	Melbourne	Victoria	Australia	3000
32	Western Health-Sunshine & Footscray Hospitals	St Albans	Victoria	Australia	3021
33	St. John of God Subiaco Hospital	Subiaco	Western Australia	Australia	6008
34	Aichi Cancer Center Hospital	Nagoya	Aichi	Japan	464-8681
35	National Cancer Center Hospital East	Kashiwa	Chiba	Japan	277-8577
36	Kanagawa cancer center	Yokohama	Kanagawa	Japan	2418515
37	National Cancer Center Hospital	Chuo-ku	Tokyo	Japan	104-0045
38	Seoul National University Bundang Hospital	Seongnam	Ky?nggi-do	Korea, Republic of	13620
39	Seoul National University Hospital	Seoul	Seoul-teukbyeolsi [seoul]	Korea, Republic of	03080
40	Severance Hospital, Yonsei University Health System	Seoul	Seoul-teukbyeolsi [seoul]	Korea, Republic of	03722
41	Samsung Medical Center	Seoul	Seoul-teukbyeolsi [seoul]	Korea, Republic of	06351
42	Kyungpook National University Chilgok Hospital	Daegu	Taegu-kwangyǒkshi	Korea, Republic of	41404
43	Asan Medical Center	Seoul		Korea, Republic of	05505