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

Study Overview
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Brief Summary
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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.

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

Conditions
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Neoplasms, Breast Cancer

Intervention / Treatment
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* Drug: PF-06650808
* Drug: PF-06650808


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-06650808<br> | Drug: PF-06650808<br>* 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.<br>Drug: PF-06650808<br>* Dose Expansion Phase [Part 2] - Patients will be treated at the MTD or Recommended Phase 2 dose selected in Part 1.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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solid tumors, triple negative breast cancer, PF-06650808, Phase 1