A Study Of PF-06647263 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-06647263 in patients with advanced solid tumors in order to determine the maximum tolerated dose and select the recommended Phase 2 dose.

Detailed Description
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The clinical study will include 2 parts. Part 1 will estimate the MTD in dose escalation cohorts in patients with advanced solid tumors for whom no standard therapy is available in order to establish the RP2D. Part 2 will include patients with previously treated metastatic triple negative breast cancer (TNBC).

Official Title
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A FIRST-IN-HUMAN PHASE 1, DOSE ESCALATION, SAFETY AND PHARMACOKINETIC STUDY OF PF-06647263 IN ADULT PATIENTS WITH ADVANCED SOLID TUMORS

Conditions
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Neoplasms, Triple-Negative Breast Cancer

Intervention / Treatment
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* Drug: PF-06647263
* Drug: PF-06647263


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of solid tumor that is advanced/metastatic and resistant to standard therapy or for whom no standard therapy is available Performance Status of 0 or 1 Adequate bone marrow, kidney, and liver function Part 2 includes advanced triple negative breast cancer patients. Exclusion Criteria: Brain metastases requiring steroids Major surgery, radiation therapy, or systemic anti-cancer therapy within 4 weeks of study treatment start Active and clinically significant bacterial, fungal or viral infection

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1<br> | Drug: PF-06647263<br>* Part 1- PF-06647263 will be administered intravenously in either a 21 day cycle or weekly in cohorts of 2 or more patients starting at a dose of 0.015 mg/kg. Increases in dose will continue until MTD is determined.<br>Drug: PF-06647263<br>* Part 2- Patients with triple negative breast cancer 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 (DLTs) (Part 1) | DLTs were defined as any of the following adverse events (AEs) which were not considered related to disease progression occurring in the first cycle of treatment:(1)Hematologic: grade 4 neutropenia lasting >7 days; febrile neutropenia (defined as neutropenia >=Grade 3 and a single body temperature >38.3°C or a sustained temperature of >=38°C for more than 1 hour); 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/mm^3 regardless of duration. (2)Non- hematologic: bilirubin increase >=2 × upper limit of normal (ULN) and not related to disease progression or other known cause; all other Grade >=3 toxicities, except those that had not been maximally treated (eg, nausea, vomiting, diarrhea); delay by more than 2 weeks in receiving the next scheduled cycle due to persisting toxicities not attributable to disease progression. | Baseline up to Cycle 2 Day 1 (22 days) | 
| Percentage of Participants With Objective Response (Part 2) | Objective response rate (ORR) refers to percentage of participants who achieved complete response (CR) or partial response (PR) determined by Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1. A participant achieved CR if both target and non-target lesions achieved CR, no new lesions; achieved 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. | Baseline, every 6 weeks until disease progression or unacceptable toxicity up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (AEs) (All Causality, All Cycles) | An AE was any untoward medical occurrence in a clinical investigation patient administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. Any events occurring following start of treatment or increasing in severity were counted as treatment-emergent. | Baseline up to 28 days after the last treatment administration (Approximately 13 months) | 
| Number of Participants With Treatment-Emergent AEs (Treatment-related, All Cycles) | An AE was any untoward medical occurrence in a clinical investigation patient administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. Any events occurring following start of treatment or increasing in severity were counted as treatment-emergent. | Baseline up to 28 days after the last treatment administration (Approximately 13 months) | 
| Number of Participants With Treatment-Emergent Serious Adverse Events (SAEs) (All Causality, All Cycles) | A SAE was any untoward medical occurrence at any dose that: resulted in death; was life-threatening (immediate risk of death); required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); resulted in congenital anomaly/birth defect. Any events occurring following start of treatment or increasing in severity were counted as treatment-emergent. | Baseline up to 28 days after the last treatment administration (Approximately 13 months) | 
| Number of Participants With Treatment-Emergent SAEs (Treatment-related, All Cycles) | A SAE was any untoward medical occurrence at any dose that: resulted in death; was life-threatening (immediate risk of death); required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); resulted in congenital anomaly/birth defect. Any events occurring following start of treatment or increasing in severity were counted as treatment-emergent. | Baseline up to 28 days after the last treatment administration (Approximately 13 months) | 
| Number of Participants With Vital Signs Abnormalities | Following parameters were analyzed for examination of vital signs: sitting systolic and diastolic blood pressure (SBP & DBP), and sitting pulse rate. The abnormal criteria were: (1) minimum SBP <90mmHg; (2) SBP change from baseline, maximum decrease >=30mmHg or maximum increase >=30mmHg; (3) minimum DBP <50mmHg; (4) DBP change from baseline, maximum decrease >=20mmHg or maximum increase >=20mmHg; (5) minimum supine pulse rate <40 BPM or maximum supine pulse rate >120 BPM. | Baseline, Days 1, 8, 15 of each cycle, and post treatment period. (Approximately 13 months) | 
| Area Under the Serum Concentration-time Profile From Time 0 to the 504-hour Time Point (AUC504) of PF-06647263 | AUC504 was determined by linear/log trapezoidal method. AUC504 analysis only applied to QW groups. | Cycle 1 Day 1: predose, 1, 4, 24, 72 hrs postdose, Cycle 1 Days 8 and 15: predose, 1 and 72 hrs postdose, up to Cycle 2 Day 1 predose (504 hr). | 
| Area Under the Concentration-Time Profile From Time 0 to Time Tau (AUCtau) of PF-06647263 | Tau is dosing interval, where tau=168 hours for the QW dosing and 504-hour for the Q3W dosing. AUC tau was determined by linear/log trapezoidal method. In time frame, C=cycle, D=day. | QW: C1D1: predose, 1,4,24,72 hrs postdose, C1D8 & 15: predose, 1 & 72 hrs postdose, up to C2D1 predose. Q3W: C1D1: predose,1,4 and 24 hrs postdose, C1D4,8,15 up to C2D1 predose; C4D1: pre-dose,1,4 and 24 hrs postdose, C4D4,8,15 up to C5D1 predose. | 
| Maximum Observed Serum Concentration (Cmax) of PF-06647263 | Maximum observed serum concentration Cmax was determined directly from data. In time frame, C=cycle, D=day. | QW: C1D1: predose, 1,4,24,72 hrs postdose, C1D8 & 15: predose, 1 & 72 hrs postdose, up to C2D1 predose. Q3W: C1D1: predose,1,4 and 24 hrs postdose, C1D4,8,15 up to C2D1 predose; C4D1: pre-dose,1,4 and 24 hrs postdose, C4D4,8,15 up to C5D1 predose. | 
| Time for Cmax (Tmax) of PF-06647963 | Tmax was determined directly from data as time of first occurrence. In time frame, C=cycle, D=day. | QW: C1D1: predose, 1,4,24,72 hrs postdose, C1D8 & 15: predose, 1 & 72 hrs postdose, up to C2D1 predose. Q3W: C1D1: predose,1,4 and 24 hrs postdose, C1D4,8,15 up to C2D1 predose; C4D1: pre-dose,1,4 and 24 hrs postdose, C4D4,8,15 up to C5D1 predose. | 
| Clearance (CL) of PF-06647263 | For single dose, CL was determined by Dose/AUCinf while for multiple dose, CL was determined by Dose/AUCtau. AUCinf was the area under the serum concentration-time profile from time 0 extrapolated to infinite time. In time frame, C=cycle, D=day. | QW: C1D15: predose, 1 & 72 hrs postdose, up to C2D1 predose. Q3W: C1D1: predose,1,4 and 24 hrs postdose, C1D4,8,15 up to C2D1 predose; C4D1: pre-dose,1,4 and 24 hrs postdose, C4D4,8,15 up to C5D1 predose. | 
| Volume of Distribution at Steady State (Vss) of PF-06647263 | Vss was determined by CL × MRT (mean residence time). MRT=[AUMCtau +tau(AUCinf-AUCtau)]/AUCtau. AUMCtau was the area under the first moment curve derived using the linear/log trapezoidal method. In time frame, C=cycle, D=day. | QW: C1D15: predose, 1 & 72 hrs postdose, up to C2D1 predose. Q3W: C1D1: predose,1,4 and 24 hrs postdose, C1D4,8,15 up to C2D1 predose; C4D1: pre-dose,1,4 and 24 hrs postdose, C4D4,8,15 up to C5D1 predose. | 
| Terminal Serum Half-life (t1/2) of PF-06647263 | T1/2 was determined by loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log linear concentration-time curve. The t1/2 analysis only applied to Q3W group. In time frame, C=cycle, D=day. | Q3W: C1D1: predose,1,4 and 24 hrs postdose, C1D4,8,15 up to C2D1 predose; C4D1: pre-dose,1,4 and 24 hrs postdose, C4D4,8,15 up to C5D1 predose. | 
| AUC504 of Total Antibody | AUC504 was determined by linear/log trapezoidal method. AUC504 analysis only applied to QW groups. PF-06647263 is an antibody-drug conjugate (ADC) which comprises total antibody (PF-06523432) and unconjugated payload ( CL-184538). | Cycle 1 Day 1: predose, 1, 4, 24, 72 hrs postdose, Cycle 1 Days 8 and 15: predose, 1 and 72 hrs postdose, up to Cycle 2 Day 1 predose (504 hr). | 
| AUCtau of Total Antibody | Tau is dosing interval, where tau=168 hours for the QW dosing and 504-hour for the Q3W dosing. AUC tau was determined by linear/log trapezoidal method. PF-06647263 is an antibody-drug conjugate (ADC) which comprises total antibody (PF-06523432) and unconjugated payload ( CL-184538). In time frame, C=cycle, D=day. | QW: C1D1: predose, 1,4,24,72 hrs postdose, C1D8 & 15: predose, 1 & 72 hrs postdose, up to C2D1 predose. Q3W: C1D1: predose,1,4 and 24 hrs postdose, C1D4,8,15 up to C2D1 predose; C4D1: pre-dose,1,4 and 24 hrs postdose, C4D4,8,15 up to C5D1 predose. | 
| Cmax of Total Antibody | Cmax was determined directly from data. PF-06647263 is an antibody-drug conjugate (ADC) which comprises total antibody (PF-06523432) and unconjugated payload ( CL-184538). In time frame, C=cycle, D=day. | QW: C1D1: predose, 1,4,24,72 hrs postdose, C1D8 & 15: predose, 1 & 72 hrs postdose, up to C2D1 predose. Q3W: C1D1: predose,1,4 and 24 hrs postdose, C1D4,8,15 up to C2D1 predose; C4D1: pre-dose,1,4 and 24 hrs postdose, C4D4,8,15 up to C5D1 predose. | 
| Tmax of Total Antibody | Tmax was determined directly from data as time of first occurrence. PF-06647263 is an antibody-drug conjugate (ADC) which comprises total antibody (PF-06523432) and unconjugated payload ( CL-184538). In time frame, C=cycle, D=day. | QW: C1D1: predose, 1,4,24,72 hrs postdose, C1D8 & 15: predose, 1 & 72 hrs postdose, up to C2D1 predose. Q3W: C1D1: predose,1,4 and 24 hrs postdose, C1D4,8,15 up to C2D1 predose; C4D1: pre-dose,1,4 and 24 hrs postdose, C4D4,8,15 up to C5D1 predose. | 
| CL of Total Antibody | For single dose, CL was determined by Dose/AUCinf while for multiple dose, CL was determined by Dose/AUCtau. PF-06647263 is an antibody-drug conjugate (ADC) which comprises total antibody (PF-06523432) and unconjugated payload ( CL-184538). In time frame, C=cycle, D=day. | QW: C1D15: predose, 1 & 72 hrs postdose, up to C2D1 predose. Q3W: C1D1: predose,1,4 and 24 hrs postdose, C1D4,8,15 up to C2D1 predose; C4D1: pre-dose,1,4 and 24 hrs postdose, C4D4,8,15 up to C5D1 predose. | 
| Vss of Total Antibody | Vss was determined by CL × MRT (mean residence time). MRT=[AUMCtau +tau(AUCinf-AUCtau)]/AUCtau. AUMCtau was the area under the first moment curve derived using the linear/log trapezoidal method. PF-06647263 is an antibody-drug conjugate (ADC) which comprises total antibody (PF-06523432) and unconjugated payload ( CL-184538). In time frame, C=cycle, D=day. | QW: C1D15: predose, 1 & 72 hrs postdose, up to C2D1 predose. Q3W: C1D1: predose,1,4 and 24 hrs postdose, C1D4,8,15 up to C2D1 predose; C4D1: pre-dose,1,4 and 24 hrs postdose, C4D4,8,15 up to C5D1 predose. | 
| t1/2 of Total Antibody | T1/2 was determined by loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log linear concentration-time curve. The t1/2 analysis only applied to Q3W group. PF-06647263 is an antibody-drug conjugate (ADC) which comprises total antibody (PF-06523432) and unconjugated payload ( CL-184538). In time frame, C=cycle, D=day. | Q3W: C1D1: predose,1,4 and 24 hrs postdose, C1D4,8,15 up to C2D1 predose; C4D1: pre-dose,1,4 and 24 hrs postdose, C4D4,8,15 up to C5D1 predose. | 
| Cmax of Unconjugated Payload CL-184538 | Cmax was determined directly from data. PF-06647263 is an antibody-drug conjugate (ADC) which comprises total antibody (PF-06523432) and unconjugated payload ( CL-184538). | Every Cycle: Days 1, 8, 15. up to end of treatment (Approximately 13 months) | 
| Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | Following parameters were analyzed for laboratory examination: hematology, blood chemistry, coagulation panel, urinalysis and pregnancy test. | Baseline up to 7 days post end of treatment (Approximately 13 months) | 
| Number of Participants With Positive Antibodies for PF-06647263, Total Antibody (PF-06523432), and Unconjugated Payload (CL-184538) | Positive was defined as: anti-drug antibody (ADA) titer >=1.88. In time frame, C=cycle, D=day. | QW: C1:D1&D15; every other cycle: D1; end of treatment. Q3W:C1: D1&D15; Cycles 2 through 4: D1; every other cycle: D1; end of treatment. | 
| Number of Participants With Positive Neutralizing Anti PF-06647263 Antibody | Positive was defined as: neutralizing antibody titer >=1.30. In time frame, C=cycle, D=day. | QW: C1:D1&D15; every other cycle: D1; end of treatment. Q3W:C1: D1&D15; Cycles 2 through 4: D1; every other cycle: D1; end of treatment. | 
| Number of Participants With Treatment-Emergent and Treatment-Boosted Anti PF-06647263 Antibody | Treatment-Emergent=Baseline negative with at least one positive ADA sample post-treatment. Treatment-Boosted=Baseline positive but endpoint titer (log10-scale titer) increases by at least 0.5 (representing 3-fold titer increase). In time frame, C=cycle, D=day. | QW: C1:D1&D15; every other cycle: D1; end of treatment. Q3W:C1: D1&D15; Cycles 2 through 4: D1; every other cycle: D1; end of treatment. | 
| Percentage of Participants With Objective Response (Part 1) | Objective response rate (ORR) refers to percentage of participants who achieved complete response (CR) or partial response (PR) determined by Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1. A participant achieved CR if both target and non-target lesions achieved CR, no new lesions; achieved 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. | Baseline, every 6 weeks until disease progression or unacceptable toxicity up to 24 months | 
| Percentage of Participants With Clinical Benefit Response | Clinical Benefit Response (CBR) was defined as a CR, PR or stable disease (SD) ≥6 cycles. CR was defined as disappearance of all target lesions. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as the reference of baseline sum diameters. Stable disease was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD (progressive disease: >=20% increase in the sum of diameters of target lesions and an absolute increase of >=5mm or appearance of >=1 new lesion), taking as reference the smallest sum diameters while on study. | Baseline, every 6 weeks until disease progression or unacceptable toxicity up to 24 months | 
| Progression Free Survival | The progression free survival (PFS) was defined as the time from Cycle 1 Day 1 to first documentation of disease progression or to death due to any cause, whichever occurred first. PFS was characterized by the estimate median time to event which was derived using Kaplan-Meier method. | Baseline, every 6 weeks until disease progression or unacceptable toxicity up to 24 months | 
| Overall Survival (OS)-Stratifying for EFNA4 Expression (Part 2) |  | Baseline up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TNBC, Triple negative breast cancer, ADC, PF-06647263, solid tumors, tumors, neoplasm metastasis