A Study Of PF-06647263 In Patients With Advanced Solid Tumors

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.

Time frame: Baseline up to Cycle 2 Day 1 (22 days)

Population: The analysis set included all enrolled participants who received at least 1 dose of PF-06647263.

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.

Time frame: Baseline, every 6 weeks until disease progression or unacceptable toxicity up to 24 months

Population: The analysis set included all treated participants in Part 2 with measurable disease at baseline.

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.

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.

Population: Number of Participants Analyzed represents the number of participants who were enrolled and received at least 1 dose of PF-06647263. Number Analyzed represents the number of participants contributing to the PK parameter summary statistics at that time point.

AUC504 was determined by linear/log trapezoidal method. AUC504 analysis only applied to QW groups.

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).

Population: The analysis population was defined as all enrolled patients treated who had sufficient information to estimate AUC504.

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).

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).

Population: The analysis population was defined as all enrolled patients treated who had sufficient information to estimate AUC504.

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.

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.

Population: Number of Participants Analyzed represents the number of participants who were enrolled and received at least 1 dose of PF-06647263. Number Analyzed represents the number of participants contributing to the PK parameter summary statistics at that time point.

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.

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.

Population: Number of Participants Analyzed represents the number of participants who were enrolled and received at least 1 dose of PF-06647263. Number Analyzed represents the number of participants contributing to the PK parameter summary statistics at that time point.

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.

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.

Population: Number of Participants Analyzed represents the number of participants who were enrolled and received at least 1 dose of PF-06647263. Number Analyzed represents the number of participants contributing to the PK parameter summary statistics at that time point.

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.

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.

Population: Number of Participants Analyzed represents the number of participants who were enrolled and received at least 1 dose of PF-06647263. Number Analyzed represents the number of participants contributing to the PK parameter summary statistics at that time point.

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).

Time frame: Every Cycle: Days 1, 8, 15. up to end of treatment (Approximately 13 months)

Population: The analysis set was defined as enrolled patients who were analyzed for pharmacokinetics.

Maximum observed serum concentration Cmax was determined directly from data. In time frame, C=cycle, D=day.

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.

Population: Number of Participants Analyzed represents the number of participants who were enrolled and received at least 1 dose of PF-06647263. Number Analyzed represents the number of participants contributing to the PK parameter summary statistics at that time point.

Following parameters were analyzed for laboratory examination: hematology, blood chemistry, coagulation panel, urinalysis and pregnancy test.

Time frame: Baseline up to 7 days post end of treatment (Approximately 13 months)

Population: The safety analysis set included all enrolled participants who received at least 1 dose of PF-06647263.

Positive was defined as: anti-drug antibody (ADA) titer \>=1.88. In time frame, C=cycle, D=day.

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.

Population: Number of Participants Analyzed represents the number of participants who were enrolled and received at least 1 dose of PF-06647263. Number Analyzed represents the number of participants tested for that parameter.

Positive was defined as: neutralizing antibody titer \>=1.30. In time frame, C=cycle, D=day.

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.

Population: The analysis set included all participants who were treated and tested for that parameter.

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.

Time frame: Baseline up to 28 days after the last treatment administration (Approximately 13 months)

Population: The safety analysis set included all enrolled participants who received at least 1 dose of PF-06647263.

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.

Time frame: Baseline up to 28 days after the last treatment administration (Approximately 13 months)

Population: The safety analysis set included all enrolled participants who received at least 1 dose of PF-06647263.

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.

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.

Population: Number of Participants Analyzed represents the number of participants who were enrolled and received at least 1 dose of PF-06647263. Number Analyzed represents the number of participants tested for that parameter.

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.

Time frame: Baseline up to 28 days after the last treatment administration (Approximately 13 months)

Population: The safety analysis set included all enrolled participants who received at least 1 dose of PF-06647263.

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.

Time frame: Baseline up to 28 days after the last treatment administration (Approximately 13 months)

Population: The safety analysis set included all enrolled participants who received at least 1 dose of PF-06647263.

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.

Time frame: Baseline, Days 1, 8, 15 of each cycle, and post treatment period. (Approximately 13 months)

Population: The safety analysis set included all enrolled participants who received at least 1 dose of PF-06647263.

Time frame: Baseline up to 24 months

Population: OS was not estimable since there were fewer number of participants with event.

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.

Time frame: Baseline, every 6 weeks until disease progression or unacceptable toxicity up to 24 months

Population: The analysis set included the number of participants with measurable disease at baseline.

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.

Time frame: Baseline, every 6 weeks until disease progression or unacceptable toxicity up to 24 months

Population: The analysis set included treated participants with measurable disease at baseline.

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.

Time frame: Baseline, every 6 weeks until disease progression or unacceptable toxicity up to 24 months

Population: The analysis set included the number of participants with event.

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.

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.

Population: Number of Participants Analyzed represents the number of participants who were enrolled and received at least 1 dose of PF-06647263. Number Analyzed represents the number of participants contributing to the PK parameter summary statistics at that time point.

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.

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.

Population: Number of Participants Analyzed represents the number of participants who were enrolled and received at least 1 dose of PF-06647263. Number Analyzed represents the number of participants contributing to the PK parameter summary statistics at that time point.

Tmax was determined directly from data as time of first occurrence. In time frame, C=cycle, D=day.

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.

Population: Number of Participants Analyzed represents the number of participants who were enrolled and received at least 1 dose of PF-06647263. Number Analyzed represents the number of participants contributing to the PK parameter summary statistics at that time point.

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.

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.

Population: Number of Participants Analyzed represents the number of participants who were enrolled and received at least 1 dose of PF-06647263. Number Analyzed represents the number of participants contributing to the PK parameter summary statistics at that time point.

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.

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.

Population: Number of Participants Analyzed represents the number of participants who were enrolled and received at least 1 dose of PF-06647263. Number Analyzed represents the number of participants contributing to the PK parameter summary statistics at that time point.

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.

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.

Population: Number of Participants Analyzed represents the number of participants who were enrolled and received at least 1 dose of PF-06647263. Number Analyzed represents the number of participants contributing to the PK parameter summary statistics at that time point.