A Dose Escalation Study of PF-06650808 in Patients With Advanced Solid Tumors

A PHASE 1 DOSE ESCALATION STUDY EVALUATING THE SAFETY AND TOLERABILITY OF PF-06650808 IN PATIENTS WITH ADVANCED SOLID TUMORS

To assess the safety and tolerability at increasing dose levels of PF-06650808 in patients with advanced solid tumors in order to determine the maximum tolerated dose and select the recommended Phase 2 dose.

Study Overview

• Status: Terminated
• Conditions: Neoplasms; Breast Cancer
• Intervention / Treatment: Drug: PF-06650808; Drug: PF-06650808

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • Ronald Reagan UCLA Medical Center
    • Los Angeles, California, United States, 90095
      • UCLA Hematology/Oncology
    • Los Angeles, California, United States, 90095
      • Ronald Reagan UCLA Medical Center, Drug Information Center
    • Los Angeles, California, United States, 90095
      • Westwood Bowyer Clinic
    • Santa Monica, California, United States, 90404
      • UCLA Hematology/Oncology - Santa Monica
    • Santa Monica, California, United States, 90404
      • Santa Monica - UCLA Medical Center & Orthopaedic Hospital
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University James Cancer Hospital
    • Columbus, Ohio, United States, 43221
      • The Ohio State University Martha Morehouse Medical Plaza
    • Columbus, Ohio, United States, 43210
      • The OSU Investigational Drug Services
    • Columbus, Ohio, United States, 43212
      • The OSU Stephanie Spielman Comprehensive Breast Center
  • Texas
    • San Antonio, Texas, United States, 78229
      • South Texas Accelerated Research Therapeutics, LLC (START)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of advanced/metastatic solid tumor that is resistant to standard therapy or for which no standard therapy is available
• Previously treated metastatic triple negative breast cancer that expresses Notch3 with at least one measurable lesion
• Adequate bone marrow, renal and liver function

Exclusion Criteria:

• Major surgery, radiation therapy or systemic anti-cancer therapy within 4 weeks of starting study treatment
• Patients with known symptomatic brain metastases requiring steroids
• Prior treatment with a compound of the same mechanism

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PF-06650808	Drug: PF-06650808; Dose Escalation Phase [Part 1] - PF-06650808 will be administered at doses starting at 0.2 mg/kg. Increases in dose will continue until MTD is determined.; Drug: PF-06650808; Dose Expansion Phase [Part 2] - Patients will be treated at the MTD or Recommended Phase 2 dose selected in Part 1.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Dose-limiting Toxicities (DLT) (Part 1)	Severity of AEs (adverse events ) was graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. For the purpose of dose escalation, any of the following AEs which were not considered related to disease progression occurring in the first cycle of treatment (21 days) were classified as DLTs: 1) Hematologic: Grade 4 neutropenia lasting >7 days; Febrile neutropenia; Grade>=3 neutropenia with infection; Any grade thrombocytopenia associated with clinically significant or life threatening bleeding; Grade 4 thrombocytopenia >=72 hours or platelets<=10,000/mm3 regardless of duration. 2) Non hematologic: Grade>=3 toxicities except those that had not been maximally treated; Delayed by more than 2 weeks in receiving the next scheduled cycle due to persisting toxicities not attributable to disease progression. 3) clinically important or persistent toxicities may have been considered a DLT following review by the Sponsor and the investigators.	Day 1 up to Day 21
Percentage of Participants With Objective Response (Part 1 and Part 2)	Assessment of response was made using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. A participant achieved complete response (CR) if both target and non-target lesions achieved CR, no new lesions; achieved partial response (PR) if target lesions achieved CR or PR, non-target lesions were assessed as non-CR/non-PD (progressive disease), indeterminate or missing, and no new lesions. For target lesions, CR: complete disappearance of all target lesions except nodal disease (target nodes must decrease to normal size); PR: >= 30% decrease under baseline of the sum of diameters of all target measurable lesions. For non-target lesions, CR: disappearance of all non-target lesions and normalization of tumor marker levels and all lymph nodes must be normal in size; non-CR/non-PD: persistence of any non-target lesions and/or tumor marker level above the normal limits. The overall objective response was defined as confirmed CR and PR.	Day 1 and every 6 weeks until disease progression, unacceptable toxicity, or up to 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Part 1 and Part 2)	AE was defined as any untoward medical occurrence in a clinical investigation participant administered a product or medical device, regardless of the causal relationship to study treatment. Treatment-emergent AEs (TEAEs) were defined as AEs which occurred for the first time during the effective duration of treatment or AEs that increased in severity during treatment. Serious AEs (SAEs) were defined as any untoward medical occurrence at any dose that resulted in death; was life-threatening (immediate risk of death); required inpatient hospitalization or caused prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduction normal life functions). AEs included SAEs and non-serious AEs. Causality to study treatment was determined by the investigator. Severity was graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.	3 years
Number of Participants With Laboratory Abnormalities Without Regard to Baseline (Hematology) (Part 1 and Part 2)	Hematology evaluation included hemoglobin, platelets, white blood cell, absolute neutrophils, absolute lymphocytes, absolute monocytes, absolute eosinophils and absolute basophils. The participants who experienced laboratory test abnormalities were determined by investigators.	3 years
Number of Participants With Laboratory Abnormalities Without Regard to Baseline (Chemistries) (Part 1 and Part 2)	Chemistry evaluation included alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, sodium, potassium, magnesium, chloride, calcium, total bilirubin, blood urea nitrogen (BUN) or urea, creatinine, uric acid, glucose (non-fasted), albumin, phosphorus, bicarbonate or carbon dioxide, total protein and lactate dehydrogenase. The participants who experienced laboratory test abnormalities were determined by investigators.	3 years
Number of Participants With Laboratory Abnormalities Without Regard to Baseline (Urinalysis) (Part 1 and Part 2)	Urinalysis included urine protein. Microscopic analyses were performed if dipstick was abnormal. The participants who experienced laboratory test abnormalities were determined by investigators.	3 years
Number of Participants With Vital Signs Meeting Categorical Summarization Criteria (Part 1 and Part 2)	Vital Signs tests included systolic and diastolic blood pressure (BP) and pulse rate of seated supine and standing . Vital signs categorical summarization criteria were 1), supine and standing BP: systolic (SBP) greater than or equal to (>=) 30 millimeters of mercury (mm Hg) change from baseline, systolic less than (<) 90 mm Hg; diastolic BP (DBP) >=20 mm Hg change from baseline, diastolic <50 mm Hg; 2), supine and standing pulse rate <40 or greater than (>) 120 beats per minute (bpm).	3 years
Maximum Observed Serum Concentration (Cmax) (Part 1 and Part 2)	Maximum observed serum concentration (Cmax) of ADC (PF-06650808), total antibody (PF-06460005) and unconjugated payload (PF-06380101) were observed directly from data. PF-06650808 is comprised of an antibody (PF-06460005) and a cytotoxic agent (PF-06380101).	Pre-dose, 1, 4 and 24 hours post-dose, Days 4, 8 and 15 in Cycle 1 and Cycle 4
Time to Reach Maximum Observed Serum Concentration (Tmax) (Part 1 and Part 2)	Tmax of ADC (PF-06650808), total antibody (PF-06460005) and unconjugated payload (PF-06380101) were observed directly from data as time of first occurrence.	Pre-dose, 1, 4 and 24 hours post-dose, Days 4, 8 and 15 in Cycle 1 and Cycle 4
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) (Part 1 and Part 2)	Tau refers to the dosing interval, and it equals to 504 hours (3 weeks) of ADC (PF-06650808), total antibody (PF-06460005) and unconjugated payload (PF-06380101) were determined using linear/log trapezoidal method.	Pre-dose, 1, 4 and 24 hours post-dose, Days 4, 8 and 15 in Cycle 1 and Cycle 4
Clearance (CL) (Part 1 and Part 2)	Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL was calculated as dose/AUCinf, where AUCinf was the area under the serum concentration-time profile from time 0 extrapolated to infinite time. CL was only for PF-06650808 (ADC) and Cycle 1.	Pre-dose, 1, 4 and 24 hours post-dose, Days 4, 8 and 15 in Cycle 1
Volume of Distribution at Steady State (Vss) (Part 1 and Part 2)	Vss was calculated as dose/(AUCinf × kel), where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Vss was only for PF-06650808 (ADC) and Cycle 1.	Pre-dose, 1, 4 and 24 hours post-dose, Days 4, 8 and 15 in Cycle 1
Terminal Elimination Half-Life (t1/2) (Part 1 and Part 2)	Terminal elimination half-life was defined as the time measured for the serum concentration to decrease by one half, and calculated as loge(2)/kel.	Pre-dose, 1, 4 and 24 hours post-dose, Days 4, 8 and 15 in Cycle 1 and Cycle 4
Number of Participants With the Presence of Anti-PF-06650808 Antibodies (Part 1 and Part 2)	Assays to assess for anti drug (anti PF-06650808) antibodies (ADA) were performed. Positive ADA: titer>=1.88.	3 years
Progression Free Survival and Overall Survival (Part 2)	Progression Free Survival was defined as the time from Cycle 1 Day 1 (C1D1) to first documentation of disease progression or to death due to any cause, whichever occurs first. Overall survival was defined as the time from initial dose until death from any cause, and is measured in the intent to treat population.	3 years

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

General Publications

• Rosen LS, Wesolowski R, Baffa R, Liao KH, Hua SY, Gibson BL, Pirie-Shepherd S, Tolcher AW. A phase I, dose-escalation study of PF-06650808, an anti-Notch3 antibody-drug conjugate, in patients with breast cancer and other advanced solid tumors. Invest New Drugs. 2020 Feb;38(1):120-130. doi: 10.1007/s10637-019-00754-y. Epub 2019 Mar 18.

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2014
• Primary Completion (Actual): July 1, 2017
• Study Completion (Actual): July 1, 2017

Study Registration Dates

• First Submitted: April 30, 2014
• First Submitted That Met QC Criteria: April 30, 2014
• First Posted (Estimate): May 2, 2014

Study Record Updates

• Last Update Posted (Actual): March 29, 2019
• Last Update Submitted That Met QC Criteria: December 21, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Keywords: Phase 1; solid tumors; triple negative breast cancer; PF-06650808
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms
• Other Study ID Numbers: B7501001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.