Description:
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.
Title
- Brief Title: A Study Of PF-06647263 In Patients With Advanced Solid Tumors
- Official Title: A FIRST-IN-HUMAN PHASE 1, DOSE ESCALATION, SAFETY AND PHARMACOKINETIC STUDY OF PF-06647263 IN ADULT PATIENTS WITH ADVANCED SOLID TUMORS
Clinical Trial IDs
- ORG STUDY ID:
B7521001
- NCT ID:
NCT02078752
Conditions
- Neoplasms
- Triple-Negative Breast Cancer
Interventions
| Drug | Synonyms | Arms |
|---|
| PF-06647263 | | Part 1 |
| PF-06647263 | | Part 1 |
Purpose
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
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).
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Part 1 | Experimental | | |
Eligibility Criteria
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
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Number of Participants With Dose Limiting Toxicities (DLTs) (Part 1) |
| Time Frame: | Baseline up to Cycle 2 Day 1 (22 days) |
| Safety Issue: | |
| Description: | 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. |
Secondary Outcome Measures
| Measure: | Number of Participants With Treatment-Emergent Adverse Events (AEs) (All Causality, All Cycles) |
| Time Frame: | Baseline up to 28 days after the last treatment administration (Approximately 13 months) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Number of Participants With Treatment-Emergent AEs (Treatment-related, All Cycles) |
| Time Frame: | Baseline up to 28 days after the last treatment administration (Approximately 13 months) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Number of Participants With Treatment-Emergent Serious Adverse Events (SAEs) (All Causality, All Cycles) |
| Time Frame: | Baseline up to 28 days after the last treatment administration (Approximately 13 months) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Number of Participants With Treatment-Emergent SAEs (Treatment-related, All Cycles) |
| Time Frame: | Baseline up to 28 days after the last treatment administration (Approximately 13 months) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Number of Participants With Vital Signs Abnormalities |
| Time Frame: | Baseline, Days 1, 8, 15 of each cycle, and post treatment period. (Approximately 13 months) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Area Under the Serum Concentration-time Profile From Time 0 to the 504-hour Time Point (AUC504) of PF-06647263 |
| Time Frame: | 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). |
| Safety Issue: | |
| Description: | AUC504 was determined by linear/log trapezoidal method. AUC504 analysis only applied to QW groups. |
| Measure: | Area Under the Concentration-Time Profile From Time 0 to Time Tau (AUCtau) of PF-06647263 |
| Time Frame: | 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. |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Maximum Observed Serum Concentration (Cmax) of PF-06647263 |
| Time Frame: | 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. |
| Safety Issue: | |
| Description: | Maximum observed serum concentration Cmax was determined directly from data. In time frame, C=cycle, D=day. |
| Measure: | Time for Cmax (Tmax) of PF-06647963 |
| Time Frame: | 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. |
| Safety Issue: | |
| Description: | Tmax was determined directly from data as time of first occurrence. In time frame, C=cycle, D=day. |
| Measure: | Clearance (CL) of PF-06647263 |
| Time Frame: | 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. |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Volume of Distribution at Steady State (Vss) of PF-06647263 |
| Time Frame: | 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. |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Terminal Serum Half-life (t1/2) of PF-06647263 |
| Time Frame: | 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. |
| Safety Issue: | |
| Description: | 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. |
| Measure: | AUC504 of Total Antibody |
| Time Frame: | 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). |
| Safety Issue: | |
| Description: | 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). |
| Measure: | AUCtau of Total Antibody |
| Time Frame: | 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. |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Cmax of Total Antibody |
| Time Frame: | 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. |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Tmax of Total Antibody |
| Time Frame: | 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. |
| Safety Issue: | |
| Description: | 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. |
| Measure: | CL of Total Antibody |
| Time Frame: | 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. |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Vss of Total Antibody |
| Time Frame: | 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. |
| Safety Issue: | |
| Description: | 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. |
| Measure: | t1/2 of Total Antibody |
| Time Frame: | 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. |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Cmax of Unconjugated Payload CL-184538 |
| Time Frame: | Every Cycle: Days 1, 8, 15. up to end of treatment (Approximately 13 months) |
| Safety Issue: | |
| Description: | 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). |
| Measure: | Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) |
| Time Frame: | Baseline up to 7 days post end of treatment (Approximately 13 months) |
| Safety Issue: | |
| Description: | Following parameters were analyzed for laboratory examination: hematology, blood chemistry, coagulation panel, urinalysis and pregnancy test. |
| Measure: | Number of Participants With Positive Antibodies for PF-06647263, Total Antibody (PF-06523432), and Unconjugated Payload (CL-184538) |
| Time Frame: | 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. |
| Safety Issue: | |
| Description: | Positive was defined as: anti-drug antibody (ADA) titer >=1.88. In time frame, C=cycle, D=day. |
| Measure: | Number of Participants With Positive Neutralizing Anti PF-06647263 Antibody |
| Time Frame: | 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. |
| Safety Issue: | |
| Description: | Positive was defined as: neutralizing antibody titer >=1.30. In time frame, C=cycle, D=day. |
| Measure: | Number of Participants With Treatment-Emergent and Treatment-Boosted Anti PF-06647263 Antibody |
| Time Frame: | 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. |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Percentage of Participants With Objective Response (Part 1) |
| Time Frame: | Baseline, every 6 weeks until disease progression or unacceptable toxicity up to 24 months |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Percentage of Participants With Clinical Benefit Response |
| Time Frame: | Baseline, every 6 weeks until disease progression or unacceptable toxicity up to 24 months |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Progression Free Survival |
| Time Frame: | Baseline, every 6 weeks until disease progression or unacceptable toxicity up to 24 months |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Overall Survival (OS)-Stratifying for EFNA4 Expression (Part 2) |
| Time Frame: | Baseline up to 24 months |
| Safety Issue: | |
| Description: | |
Details
| Phase: | Phase 1 |
| Primary Purpose: | Interventional |
| Overall Status: | Terminated |
| Lead Sponsor: | Pfizer |
Trial Keywords
- ADC
- PF-06647263
- solid tumors
- tumors
- neoplasm metastasis
- TNBC
- Triple negative breast cancer
Last Updated
April 29, 2019
