CDK4: Study to Test the Safety and Tolerability of PF-07220060 in Participants With Advance Solid Tumors

Sponsor

Pfizer (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04557449

Collaborator

(none)

118

Enrollment

Locations

Arms

54.6

Anticipated Duration (Months)

13.1

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a Phase 1, open label, multicenter, nonrandomized, multiple dose, safety, tolerability, pharmacokinetic and pharmacodynamic study of PF-07220060 administered as a single agent and then in combination with endocrine therapy.

In Part 1A, single escalating doses of PF-07220060 alone will be administered to determine the maximum tolerated dose (MTD) and select the recommended phase 2 dose (RP2D).

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 the Part 1A will be conducted.

Part 1B and Part 1C may commence at MTD or before reaching the MTD at a dose level in Part 1A.

Part 2B and Part 2C are expansion for combination therapy of PF-07220060 with letrozole and fulvestrant, respectively.

Condition or Disease	Intervention/Treatment	Phase
Liposarcoma CRC Prostate Cancer Breast Neoplasms Adenocarcinoma of Lung Solid Tumors	Drug: PF-07220060 Combination Product: Letrozole Combination Product: Fulvestrant	Phase 1

Study Design

Study Type:

Interventional

Anticipated Enrollment :

118 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Intervention Model Description:

Part 1A: dose escalation of PF-07220060 Part 1B: dose finding of PF-07220060 in combination with letrozole Part 1C:dose finding of PF-07220060 in combination with fulvestrant Part 1D: food effect assessment of PF-07220060 at RP2D in Part 1A Part 2A: dose expansion of PF-07220060 in combination with letrozole Part 2B: dose expansion of PF-07220060 in combination with fulvestrantPart 1A: dose escalation of PF-07220060 Part 1B: dose finding of PF-07220060 in combination with letrozole Part 1C:dose finding of PF-07220060 in combination with fulvestrant Part 1D: food effect assessment of PF-07220060 at RP2D in Part 1A Part 2A: dose expansion of PF-07220060 in combination with letrozole Part 2B: dose expansion of PF-07220060 in combination with fulvestrant

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A PHASE 1/1B STUDY EVALUATING THE SAFETY, TOLERABILITY, PHARMACOKINETICS, PHARMACODYNAMICS, AND ANTI-TUMOR ACTIVITY OF PF-07220060 AS A SINGLE AGENT AND AS PART OF COMBINATION THERAPY IN PARTICIPANTS WITH ADVANCED SOLID TUMORS

Actual Study Start Date :

Sep 23, 2020

Anticipated Primary Completion Date :

Apr 11, 2025

Anticipated Study Completion Date :

Apr 11, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1A Monotherapy Escalation Arm 1 PF-07220060 Monotherapy Escalation	Drug: PF-07220060 CDK4 inhibitor
Experimental: 1A Monotherapy Escalation Arm 2 PF-07220060 Monotherapy Escalation	Drug: PF-07220060 CDK4 inhibitor
Experimental: 1A Monotherapy Escalation Arm 3 PF-07220060 Monotherapy Escalation	Drug: PF-07220060 CDK4 inhibitor
Experimental: 1A Monotherapy Escalation Arm 4 PF-07220060 Monotherapy Escalation	Drug: PF-07220060 CDK4 inhibitor
Experimental: 1B Combination Dose Finding Arm 1 PF-07220060 with Letrozole combination Escalation	Drug: PF-07220060 CDK4 inhibitor Combination Product: Letrozole Endocrine Therapy Other Names: Femara
Experimental: 1B Combination Dose Finding Arm 2 PF-07220060 with Letrozole Combination Escalation	Drug: PF-07220060 CDK4 inhibitor Combination Product: Letrozole Endocrine Therapy Other Names: Femara
Experimental: 1C Combination Dose Finding Arm 1 PF-07220060 with Fulvestrant Combination Escalation	Drug: PF-07220060 CDK4 inhibitor Combination Product: Fulvestrant Endocrine Therapy Other Names: Faslodex
Experimental: 1C Combination Dose Finding Arm 2 PF-07220060 with Fulvestrant Combination Escalation	Drug: PF-07220060 CDK4 inhibitor Combination Product: Fulvestrant Endocrine Therapy Other Names: Faslodex
Experimental: 2B Combination Dose Expansion PF-07220060 with Letrozole Combination Expansion	Drug: PF-07220060 CDK4 inhibitor Combination Product: Letrozole Endocrine Therapy Other Names: Femara
Experimental: 2C Combination Dose Expansion PF-07220060 with fulvestrant Combination Expansion	Drug: PF-07220060 CDK4 inhibitor Combination Product: Fulvestrant Endocrine Therapy Other Names: Faslodex
Experimental: 1D Monotherapy Food Effect PF-07220060 Monotherapy Food Effect	Drug: PF-07220060 CDK4 inhibitor
Experimental: 1A Monotherapy Escalation Arm 5 PF-07220060 Monotherapy Escalation	Drug: PF-07220060 CDK4 inhibitor

Outcome Measures

Primary Outcome Measures

Number of participants with dose limiting toxicities in the Dose Escalation Portion [Baseline up to day 28 of Cycle 1.]
First cycle (28 days) dose limiting toxicities (Parts 1A, 1B, 1C)
Incidence of clinically significant AEs [Weekly during Cycle 1 and 2 and then every 28 days through study completion, up to approximately 24 months; Each cycle is 28 days]
Adverse Events
Incidence of clinically significant laboratory assessments [Weekly during Cycle 1 and 2 (each cycle is 28 days) and then every 28 days through study completion, up to approximately 24 months]
safety laboratory abnormalities
Incidence of clinically significant abnormal vital and ECG parameters [Day 1, Day 8, Day 15 of Cycle 1 and starting from Cycle 2, and then every 28 days through study completion, up to approximately 24 months (Each cycle is 28 days)]
vital signs and heart rate corrected QT interval (Parts 1A, 1B, 1C, 1D)
Food Effect [Day -7 through the end of Cycle 1]
Maximal Concentration, Time to Maximum Plasma Concentration, Area under the Plasma Concentration (Part 1D)

Secondary Outcome Measures

Single Dose: Maximal concentration (Cmax) in the Dose Escalation and Dose Finding portion [Cycle 1 (each cycle is 28 days) and Day 1 of each subsequent cycle and at study completion visit, up to approximately 24 months]
Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C)
Single Dose: Time to Maximum Plasma Concentration (Tmax) in the Dose Escalation and Dose Finding portion [Cycle 1 (each cycle is 28 days) and Day 1 of each subsequent cycle and at study completion visit, up to approximately 24 months]
Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C)
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) and Day 1 of each subsequent cycle and at study completion visit, up to approximately 24 months]
Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C)
Single Dose: Area Under the Plasma Concentration Versus Time Curve from Time Zero Extrapolated to Infinity (AUCinf) in the Dose Escalation and Dose Finding portion [Time Frame: Cycle 1 (each cycle is 28 days) and Day 1 of each subsequent cycle and at study completion visit, up to approximately 24 months]
Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C)
Apparent Oral Plasma Clearance (CL/F) in the Dose Escalation and Dose Finding portion [Cycle 1 (each cycle is 28 days) and Day 1 of each subsequent cycle and at study completion visit, up to approximately 24 months]
Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C)
Single Dose: Apparent Volume of Distribution (Vz/F) in the Dose Escalation and Dose Finding portion [Cycle 1 (each cycle is 28 days) and Day 1 of each subsequent cycle and at study completion visit, up to approximately 24 months]
Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C)
Multiple Dose: Steady State Maximal Concentration (Css,max) in the Dose Escalation and Dose Finding portion [Cycle 1 (each cycle is 28 days) and Day 1 of each subsequent cycle and at study completion visit, up to approximately 24 months]
Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C)
Multiple Dose: Time to Maximum Plasma Concentration at Steady State (Tss,max) in the Dose Escalation and Dose Finding portion [Cycle 1 (each cycle is 28 days) and Day 1 of each subsequent cycle and at study completion visit, up to approximately 24 months]
Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C)
Area Under the Plasma Concentration Versus Time Curve Within One Dose Interval (AUCss,t) in the Dose Escalation and Dose Finding portion [Cycle 1 (each cycle is 28 days) and Day 1 of each subsequent cycle and at study completion visit, up to approximately 24 months]
Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C)
Multiple Dose: Steady State Minimum Plasma Concentration (Css,min) in the Dose Escalation and Dose Finding portion [Cycle 1 (each cycle is 28 days) and Day 1 of each subsequent cycle and at study completion visit, up to approximately 24 months]
Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C)
Multiple Dose: Steady State Apparent Oral Plasma Clearance (CLss/F) in the Dose Escalation and Dose Finding portion [Cycle 1 (each cycle is 28 days) and Day 1 of each subsequent cycle and at study completion visit, up to approximately 24 months]
Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C)
Multiple Dose: Apparent Volume of Distribution at Steady State (Vss/F) in the Dose Escalation and Dose Finding portion [Cycle 1 (each cycle is 28 days) and Day 1 of each subsequent cycle and at study completion visit, up to approximately 24 months]
Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C)
Multiple Dose: Terminal Elimination Half-Life (t1/2) in the Dose Escalation and Dose Finding portion [Cycle 1 (each cycle is 28 days) and Day 1 of each subsequent cycle and at study completion visit, up to approximately 24 months]
Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C)
Multiple Dose: Accumulation Ratio (Rac (AUCss,t /AUCsd,t)) in the Dose Escalation and Dose Finding portion [Cycle 1 (each cycle is 28 days) and Day 1 of each subsequent cycle and at study completion visit, up to approximately 24 months]
Pharmacokinetic (PK) assessments for PF-07220060 (Parts 1A, 1B, 1C)
Tumor Response per RECIST v1.1 [baseline up to approximately 24 months]
Per RECIST v1.1
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
Time to Progression (TTP) [baseline up to approximately 24 months]
TTP per RECIST v1.1
Clinical Benefit Rate (CBR) [baseline up to approximately 24 months]
CBR per RECIST v1.1 (Parts 2B, 2C)
Peak and Trough Concentration of PF-07220060 [Cycle 1 (each cycle is 28 days) and Day 1 of each subsequent cycle and at study completion visit, up to approximately 24 months]
Peak and trough concentration (Parts 2B, 2C)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 also include: Refractory HR-positive/HER2-positive BC
Part 1: Tumors other than BC (Part 1A/Part 1D): NSCLC, prostate, CRC, liposarcoma, or tumors with previously confirmed CDK4 or CCND1 amplification according to local standard tests
Part 2:
HR-positive/HER2-negative BC
Patients who are either postmenopausal women or pre/peri-menopausal (Part 2C only)
Lesion:
Part 1: evaluable lesion (including skin or bone lesion only)
Part 2: measurable lesion per RECIST v1.1
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
At least 1 line of anti-endocrine in countries without CDK4/6 inhibitor approval or reimbursement, for advanced or metastatic disease
HR-positive/HER2-positive BC (Parts 1A/1D): at least 1 prior treatment of approved HER2 targeting therapy
Tumors other than BC (Parts 1A/1D): 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 2B: participants who have not received any 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

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 1D: participants who have had a gastrectomy or have dietary or other restrictions that preclude a 10 hour overnight fast or consumption of the high fat, high calorie meal
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
Participation in other studies involving investigational drug(s) within 4 weeks prior to study entry
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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Smilow Cancer Hospital at Yale - New Haven	New Haven	Connecticut	United States	06510
2	Smilow Cancer Hospital Phase 1 Unit	New Haven	Connecticut	United States	06511
3	Brigham & Women's Hospital	Boston	Massachusetts	United States	02115
4	Dana-Farber Cancer Institute (DFCI)	Boston	Massachusetts	United States	02215
5	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
6	START Midwest	Grand Rapids	Michigan	United States	49546
7	Sarah Cannon Research Institute	Nashville	Tennessee	United States	37203
8	Tennessee Oncology, PLLC	Nashville	Tennessee	United States	37203
9	The University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030