Clinical trial NCT04606446: Study of PF-07248144 in Advanced or Metastatic Solid Tumors
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: 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
Keywords: Solid tumors
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2020-10-28
Enrollment: 320
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
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 (Part 1B, Part 1C, Part 1D and Part 1E).

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, with PF-07220060 + fulvestrant or with vepdegestrant.
Primary purpose: TREATMENT

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 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.

Eligibility criteria: 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, Part 1D and Part 1E (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.
* Part 2E (ER+HER2- breast cancer 2-4L, combination with vepdegestrant): 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 received 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.

Primary outcomes:
measure: Number of participants with dose-limiting toxicities in the Dose Escalation Arms.
timeFrame: Up to 29 days
measure: Safety and Tolerability as assessed by adverse event monitoring for participants enrolled in the Dose Escalation Arms.
timeFrame: Up to 24 months
measure: Safety and Tolerability through monitoring of laboratory assessments for participants enrolled in the Dose Escalation Arms.
timeFrame: Up to 24 months
measure: Safety and Tolerability as assessed by adverse event monitoring for participants enrolled in the Dose Expansion Arms
timeFrame: Up to 24 months
measure: Safety and Tolerability through monitoring of laboratory assessments for participants enroled in the Dose Expansion Arms
timeFrame: Up to 24 months
Secondary outcomes:
measure: Single Dose: Maximum Observed Concentration (Cmax) in the Dose Escalation and Dose Finding Arms
timeFrame: Up to 24 months
measure: Single Dose: Time to Maximum concentration (Tmax) in the Dose Escalation and Dose Finding Arms
timeFrame: Up to 24 months
measure: Single Dose: AUC from time zero to time of last measurable concentration (AUClast) in the Dose Escalation and Dose Finding Arms
timeFrame: Up to 24 months
measure: Single and Multiple Dose: Terminal Elimination half-life (t1/2) in the Dose Escalation and Dose Finding Arms
timeFrame: Up to 24 months
measure: Multiple Dose: Steady-State Cmax (Cmax,ss) in the Dose Escalation and Dose Finding Arms
timeFrame: Up to 24 months
measure: Multiple Dose: Steady-state Tmax (Tmax,ss) in the Dose Escalation and Dose Finding Arms
timeFrame: Up to 24 months
measure: Multiple Dose: Steady state AUC during a dosage interval (τ) (AUCτ,ss) in the Dose Escalation and Dose Finding Arms
timeFrame: Up to 24 months
measure: Multiple Dose: Steady-state Cmin (Cmin,ss) in the Dose Escalation and Dose Finding Arms.
timeFrame: Up to 24 months
measure: Multiple Dose: Steady-state apparent total clearance (CLss/F) in the Dose Escalation and Dose Finding Arms.
timeFrame: Up to 24 months
measure: Palbociclib trough concentrations at steady instate (Cmin,ss) in the 1C combination dose finding arm.
timeFrame: Up to 24 months
measure: Peak concentrations of PF-07248144, PF-07220060 (Part 2D) and vepdegestrant and ARV-473 (Part 2E) for selected cycles in the Dose Expansion Arms
timeFrame: Up to 24 months
measure: Trough concentrations of PF-07248144 for selected cycles in the Dose Expansion Arms
timeFrame: Up to 24 months
measure: Maximum Observed Concentration (Cmax) in the participants in the food effect subset in monotherapy dose expansion arm
timeFrame: Cycle 1 Day -7 and Cycle 1 Day 1 (each cycle is 28 days)
measure: Time to Maximum concentration (Tmax) in the participants in the food effect subset in monotherapy dose expansion arm
timeFrame: Cycle 1 Day -7 and Cycle 1 Day 1 (each cycle is 28 days)
measure: AUC from time zero to time of last measurable concentration (AUClast) in the participants in the food effect subset in monotherapy dose expansion arm
timeFrame: Cycle 1 Day -7 and Cycle 1 Day 1 (each cycle is 28 days)
measure: Amount of PF-07248144 excreted in urine relative to dose administered (%) in a sub-set of participants in monotherapy dose expansion arm.
timeFrame: Up to 24 months
measure: Renal clearance (CLr) in a sub-set of participants in monotherapy dose expansion arm
timeFrame: Up to 24 months
measure: Progression Free Survival (PFS) observed in participants in the Dose Expansion Arms
timeFrame: Up to 24 months
measure: Time to Progression (TTP) observed in participants enrolled in the Dose Expansion Arms
timeFrame: Up to 24 months
measure: Overall survival (OS) observed in participants enrolled in Dose Expansion Arms
timeFrame: Up to 24 months
measure: Best Overall Response (BOR) observed in participants in the dose expansion arms
timeFrame: Up to 24 months
measure: Duration of Response (DOR) observed in participants in the dose expansion arms
timeFrame: up to 24 months
measure: Clinical Benefit Rate (CBR) observed in participants in the Dose Expansion Arms
timeFrame: up to 24 months
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: HonorHealth
state: Arizona
city: Los Angeles
country: United States
facility: Cedars Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center; SOCCI Pharmacy
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center at Mission Bay
state: California
city: New Haven
country: United States
facility: Smilow Cancer Hospital at Yale - New Haven
state: Connecticut
city: New Haven
country: United States
facility: Yale-New Haven Hospital- Yale Cancer Center
state: Connecticut
city: New Haven
country: United States
facility: Smilow Cancer Hospital Phase 1 Unit
state: Connecticut
city: Fort Lauderdale
country: United States
facility: Holy Cross Hospital
state: Florida
city: Edgewood
country: United States
facility: St. Elizabeth Healthcare
state: Kentucky
city: Louisville
country: United States
facility: James Graham Brown Cancer Center
state: Kentucky
city: Louisville
country: United States
facility: University Medical Center, lnc.:DBA University of Louisville Hospital
state: Kentucky
city: Franklin
country: United States
facility: Tennessee Oncology PLLC
state: Tennessee
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Oncology PLLC
state: Tennessee
city: Nashville
country: United States
facility: The Sarah Cannon Research Institute / Tennessee Oncology, PLLC
state: Tennessee
city: Houston
country: United States
facility: The University of Texas M. D. Anderson Cancer Center
state: Texas
city: Houston
country: United States
facility: U.T. MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: NEXT Oncology
state: Texas
city: Seattle
country: United States
facility: Swedish Cancer Institute
state: Washington
city: Seattle
country: United States
facility: Swedish Medical Center
state: Washington
city: Camperdown
country: Australia
facility: Chris O'Brien Lifehouse
state: New South Wales
city: Adelaide
country: Australia
facility: Cancer Research South Australia
state: South Australia
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: St Albans
country: Australia
facility: Western Health-Sunshine & Footscray Hospitals
state: Victoria
city: Subiaco
country: Australia
facility: St. John of God Subiaco Hospital
state: Western Australia
city: Beijing
country: China
facility: Beijing Cancer hospital
state: Beijing
city: Guangzhou
country: China
facility: SUN Yat-Sen University Cancer Center
state: Guangdong
city: Wuhan
country: China
facility: Hubei Cancer Hospital
state: Hubei
city: Changchun
country: China
facility: Jilin Province Tumor Hospital
state: Jilin
city: Xi'an
country: China
facility: The First Affiliated Hospital of Xi'an Jiaotong University
state: Shaanxi
city: Nagoya
country: Japan
facility: Aichi Cancer Center Hospital
state: Aichi
city: Kashiwa
country: Japan
facility: National Cancer Center Hospital East
state: Chiba
city: Yokohama
country: Japan
facility: Kanagawa cancer center
state: Kanagawa
city: Chuo-ku
country: Japan
facility: National Cancer Center Hospital
state: Tokyo
city: Seongnam
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
state: Ky?nggi-do
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
state: Seoul-teukbyeolsi [seoul]
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
state: Seoul-teukbyeolsi [seoul]
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
state: Seoul-teukbyeolsi [seoul]
city: Daegu
country: Korea, Republic of
facility: Kyungpook National University Chilgok Hospital
state: Taegu-kwangyǒkshi
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References: