First-in-human study to assess safety, tolerability, PK, and preliminary activity of PF-07284890 as a single agent and in combination with binimetinib in participants with BRAF V600-mutated advanced solid tumor malignancies with and without brain involvement.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
65
PF-07284890 will be administered orally, daily for 21 consecutive days (21-day cycle)
Binimetinib will be administered together with PF-07284890 orally, 45mg twice daily
Midazolam will be administered 7 days before start of study drug, on Cycle 1 Day 1, and on Cycle 1 Day 15
Number of Participants With Dose Limiting Toxicities (DLTs): Phase 1a
DLT was defined as any adverse event (AE) or abnormal laboratory value which were related to study treatment and assessed as unrelated to disease (disease progression), occurring during the first 21 days of treatment that met at least 1 of the study specified criteria. DLTs were graded according to the National Cancer Institute- Common Terminology Criteria for Adverse Events (NCI-CTCAE), version (v) 5.0.
Time frame: Cycle 1 (21 Days)
Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a
An adverse event (AE) was any untoward medical occurrence in participant/ clinical study participant temporally associated with use of study intervention, whether/ not considered related to study intervention. TEAEs were defined as any AE that occurs during on-treatment period. The on-treatment period was defined as period that starts with first dose of study treatment and ends at last dose of study treatment +30 days, or start of new anti-cancer therapy \[- 1 day\], whichever occurred first. Serious TEAEs were any untoward medical occurrence at any dose that: suspected to cause death; life-threatening; required hospitalization; persistent/significant disability/incapacity and might caused congenital anomaly/birth defect. Serious treatment related TEAEs were related to study treatment and relatedness was judged by investigator. TEAEs were graded according to NCI-CTCAE v 5.0 (grade 3= severe, grade 4= life-threatening and grade 5= death related to AE). AEs included SAEs and all non-SAE.
Time frame: From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment or start of new anti-cancer therapy (-1 Day) whichever occurred first (maximum treatment exposure: 542 days; maximum follow-up: 572 days)
Number of Participants With Hematology Laboratory Abnormalities of Any CTCAE Grade: Phase 1a
The following hematology laboratory parameters were assessed: activated partial thromboplastin time prolonged, anemia, hemoglobin increased, international normalized ratio (INR) increased, leukocytosis, lymphocyte count decreased, lymphocyte count increased, neutrophil count decreased, platelet count decreased and white blood cell decreased. Laboratory abnormality events were graded according to NCI CTCAE v5.0; grade 1=mild, grade 2=moderate, grade 3=severe, grade 4=life-threatening consequences and grade 5=death. In this outcome measure, those number of participants are reported who had hematology laboratory abnormality in any parameter of any CTCAE Grades.
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City of Hope (City of Hope National Medical Center, City of Hope Medical Center)
Duarte, California, United States
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, California, United States
Orlando Health Cancer Institute
Orlando, Florida, United States
Moffitt Cancer Center
Tampa, Florida, United States
Richard M Schulze Family Foundation Outpatient Center at McKinley Campus
Tampa, Florida, United States
Northwestern Medical Group
Chicago, Illinois, United States
Northwestern Memorial Hospital
Chicago, Illinois, United States
University of Iowa Hospitals and Clinics
Iowa City, Iowa, United States
Johns Hopkins University / Johns Hopkins Hospital
Baltimore, Maryland, United States
Massachusetts General Hospital
Boston, Massachusetts, United States
...and 35 more locations
Time frame: From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment (maximum treatment exposure: 542 days; maximum follow-up: 572 days)
Number of Participants With Chemistry Laboratory Abnormalities of Any CTCAE Grade: Phase 1a
The following chemistry laboratory parameters were assessed: alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, creatine phosphokinase (CPK) increased, creatinine increased, hypercalcemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia and hyponatremia. Laboratory abnormality events were graded according to NCI CTCAE v5.0; grade 1=mild, grade 2=moderate, grade 3=severe, grade 4=life-threatening consequences and grade 5=death. In this outcome measure, those number of participants are reported who had chemistry laboratory abnormality in any parameter of any CTCAE Grades.
Time frame: From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment (maximum treatment exposure: 542 days; maximum follow-up: 572 days)
Number of Participants With Dose Interruptions Due to TEAEs: Phase 1a
Dose interruption was defined as a planned dosing day with 0 mg total dose administered. Dose interruptions were applicable to unexpected dose interruptions. In this outcome measure, dose interruptions for any drug were considered.
Time frame: During study treatment (from first dose of study treatment [Day 1] up to last dose of study treatment [maximum treatment exposure: 542 days])
Number of Participants With Dose Reduction Due to TEAEs: Phase 1a
A dose reduction was defined as the day when the actual dose was less than the planned dose at enrollment and the actual dose was greater than 0 mg (ie, missed doses were not counted as a reduction). In this outcome measure, dose reductions for any drug were considered.
Time frame: During study treatment (from first dose of study treatment [Day 1] up to last dose of study treatment [maximum treatment exposure: 542 days])
Number of Participants With Dose Discontinuations Due to TEAEs: Phase 1a
In this outcome measure, dose discontinuations for any drug due to TEAEs were considered.
Time frame: During study treatment (from first dose of study treatment [Day 1] up to last dose of study treatment [maximum treatment exposure: 542 days])
Extracranial Response Rate by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1: Phase 1b
Extracranial response rate was defined as the percentage of participants with a best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR) in extracranial lesions by Investigator assessment per RECIST v1.1. CR: disappearance of all target and non-target lesions. Any pathological lymph nodes (non-target) must have reduction in short axis to less than (\<) 10 millimeter (mm). PR: at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From date of first dose until CR or PR (maximum treatment exposure: 400 days)
Intracranial Response Rate by mRECISTv1.1: Phase 1b
Intracranial response rate as assessed using modified RECIST (mRECIST) v 1.1., was defined as the percentage of participants with brain or central nervous system (CNS) involvement who achieved a CR or PR. CR: disappearance of all target and non-target lesions. For target lesions: Any pathological lymph nodes must be \<10 mm in the short axis. For non-target lesions: All lymph nodes identified as a site of disease at baseline must be non-pathological (eg, \<10 mm short axis). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From date of first dose until CR or PR (maximum treatment exposure: 400 days)
Overall Response Rate (ORR): Phase 1b
ORR: percentage of participants with BOR of confirmed CR/PR by investigator assessment in intracranial metastasis (mRECISTv1.1) and extracranial lesions (RECISTv1.1). RECIST v1.1- CR: disappearance of all target and non-target lesions. Any pathological lymph node (non-target) must have reduction in short axis to \<10mm. PR: at least 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. mRECIST- CR: disappearance of all target and non-target lesion. For target lesion: Any pathological lymph nodes must be \<10 mm in short axis. For non-target lesion: All lymph nodes identified as site of disease at baseline must be non-pathological (eg, \<10 mm short axis). PR: at least 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters.
Time frame: From date of first dose until CR or PR (maximum treatment exposure: 400 days)
Response Rate Using Response Assessment in Neuro-Oncology (RANO) for Primary Brain Tumors: Phase 1b
RANO response rate was defined as the percentage of glioblastoma participants who achieved a CR or PR per RANO. CR was defined as complete disappearance of all enhancing measurable and non-measurable disease sustained for more than or equal to (\>=) 4 weeks; no new lesions; stable or improved non-enhancing (T2/ \[fluid attenuated inversion recovery\] FLAIR) lesions; off steroids and neurological condition stable or improved. PR was defined as \>=50% decrease compared to baseline in the sum of the perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks; no progression of non-measurable disease; no new lesions; stable or improved non enhancing (T2/FLAIR) lesions on the same or lower dose of corticosteroids compared with baseline scan; the corticosteroid dose at the time of the scan evaluation should be no greater than the dose at the time of the baseline scan and neurological condition stable or improved.
Time frame: From date of first dose until CR or PR (maximum treatment exposure: 400 days)
Maximum Observed Concentration (Cmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a
Time frame: Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1 (C1D1); 24 hours was only for arms where study drug was administered as QD.
Time for Cmax (Tmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a
Time frame: Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on C1D1; 24 hours was only for arms where study drug was administered as QD.
Area Under the Plasma Concentration Time Curve From Time Zero to the Last Time Point of Quantifiable Concentration (AUClast) of PF-07284890 and Binimetinib for Single Dose: Phase 1a
AUClast was determined using the linear/log trapezoidal method.
Time frame: Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on C1D1; 24 hours was only for arms where study drug was administered as QD.
Terminal Elimination Half Life (t½) of PF-07284890 and Binimetinib for Single Dose: Phase 1a
T1/2 was calculated as loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.
Time frame: Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on C1D1; 24 hours was only for arms where study drug was administered as QD.
Area Under the Plasma Concentration Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of PF-07284890 and Binimetinib for Single Dose: Phase 1a
AUCinf was calculated as AUClast + (Clast/kel), where Clast is the predicted plasma concentration at the last quantifiable time point from the log-linear regression analysis. Those outcome measures are either due to either patient(s) has insufficient sample(s) (e.g., sampling only through Tmax or 1 sample after) for analyses or t1/2 could not be determined
Time frame: Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on C1D1; 24 hours was only for arms where study drug was administered as QD.
Apparent Oral Clearance (CL/F) of PF-07284890 and Binimetinib for Single Dose: Phase 1a
CL/F was calculated as Dose/AUCinf.
Time frame: Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on C1D1; 24 hours was only for arms where study drug was administered as QD.
Apparent Volume of Distribution (Vz/F) of PF-07284890 and Binimetinib for Single Dose: Phase 1a
Vz/F was calculated as Dose/(AUCinf \* kel) where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.
Time frame: Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on C1D1; 24 hours was only for arms where study drug was administered as QD.
Cmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a
Time frame: Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15
Tmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a
Time frame: Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15
Area Under the Plasma Concentration Time Curve Over the Dosing Interval (AUCtau) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a
Time frame: Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15
Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a
Time frame: Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15
CL/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a
CL/F was calculated as Dose/AUCinf.
Time frame: Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15
Vz/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a
Vz/F was calculated as Dose/(AUCinf \* kel) where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.
Time frame: Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15
t½ of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a
T1/2 was calculated as loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. In the determination of the t1/2, steady-state was assumed and the pre-dose value was used for the 24-hour post-dose value, which could have enabled the reporting of the t1/2 value higher than 8 hours.
Time frame: Pre-dose (24 hours post-dose concentration), 1, 2, 4, 6 and 8 hours post dose on C1D15
Accumulation Ratio (Rac) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a
Rac was defined as area under the plasma concentration-time curve over the dosing interval at steady state (AUCss,τ) divided by area under the plasma concentration-time curve over the dosing interval from a single dose (AUCsd,τ).
Time frame: Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D1 and C1D15
Extracranial Response Rate by RECISTv1.1: Phase 1a
Extracranial response rate was defined as the percentage of participants with a BOR of CR or confirmed PR in extracranial lesions by Investigator assessment per RECIST v1.1. CR: disappearance of all target and non-target lesions. Any pathological lymph nodes (non-target) must have reduction in short axis to \< 10 mm. PR: at least a 30 % decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From date of first dose until CR or PR (maximum treatment exposure: 542 days)
Intracranial Response Rate by mRECISTv1.1: Phase 1a
Intracranial response rate as assessed using modified mRECIST v 1.1., was defined as the percentage of participants with brain or CNS involvement who achieved a CR or PR. CR: disappearance of all target and non-target lesions. For target lesions: Any pathological lymph nodes must be \<10 mm in the short axis. For non-target lesions: All lymph nodes identified as a site of disease at baseline must be non-pathological (eg, \<10 mm short axis). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From date of first dose until CR or PR (maximum treatment exposure: 542 days)
ORR by RECISTv1.1: Phase 1a
ORR: percentage of participants with BOR of confirmed CR/PR by investigator assessment in intracranial metastasis (mRECISTv1.1) and extracranial lesions (RECISTv1.1). RECIST v1.1- CR: disappearance of all target and non-target lesions. Any pathological lymph node (non-target) must have reduction in short axis to \<10mm. PR: at least 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. mRECIST- CR: disappearance of all target and non-target lesion. For target lesion: Any pathological lymph nodes must be \<10 mm in short axis. For non-target lesion: All lymph nodes identified as site of disease at baseline must be non-pathological (eg, \<10 mm short axis). PR: at least 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters.
Time frame: From date of first dose until CR or PR (maximum treatment exposure: 542 days)
Overall Response Rate as Per RANO for Brain Tumours: Phase 1a
RANO response rate was defined as the percentage of glioblastoma participants who achieved a CR or PR per RANO. CR was defined as complete disappearance of all enhancing measurable and non-measurable disease sustained for \>= 4 weeks; no new lesions; stable or improved non-enhancing (T2/FLAIR) lesions; off steroids and neurological condition stable or improved. PR was defined as \>=50% decrease compared to baseline in the sum of the perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks; no progression of non-measurable disease; stable or improved non enhancing (T2/FLAIR) lesions on the same or lower dose of corticosteroids compared with baseline scan; the corticosteroid dose at the time of the scan evaluation should be no greater than the dose at the time of the baseline scan and neurological condition stable or improved.
Time frame: From date of first dose until CR or PR (maximum treatment exposure: 542 days)
Number of Participants With TEAEs, Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1b
An AE was any untoward medical occurrence in participant/ clinical study participant temporally associated with use of study intervention, whether/ not considered related to study intervention. TEAEs were defined as any AE that occurs during on-treatment period. The on-treatment period was defined as period that starts with first dose of study treatment and ends at last dose of study treatment +30 days, or start of new anti-cancer therapy \[- 1 day\], whichever occurred first. Serious TEAEs were any untoward medical occurrence at any dose that: suspected to cause death; life-threatening; required hospitalization; persistent/significant disability/incapacity and might caused congenital anomaly/birth defect. Serious treatment related TEAEs were related to study treatment and relatedness was judged by investigator. TEAEs were graded according to NCI-CTCAE v 5.0 (grade 3= severe, grade 4= life-threatening and grade 5= death related to AE). AEs included SAEs and all non-SAE.
Time frame: From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment/start of new anti-cancer therapy (-1 Day) whichever occurred first (maximum treatment exposure: 400 days, maximum follow up: 430 days)
Number of Participants With Hematology Laboratory Abnormalities: Phase 1b
The following hematology laboratory parameters were assessed: activated partial thromboplastin time prolonged, anemia, hemoglobin increased, INR increased, leukocytosis, lymphocyte count decreased, lymphocyte count increased, neutrophil count decreased, platelet count decreased and white blood cell decreased. Laboratory abnormality events were graded according to NCI CTCAE v5.0; grade 1=mild, grade 2=moderate, grade 3=severe, grade 4=life-threatening consequences and grade 5=death. In this outcome measure, those number of participants are reported who had hematology laboratory abnormality in any parameter of any CTCAE Grades.
Time frame: From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment (maximum treatment exposure: 400 days, maximum follow up: 430 days)
Number of Participants With Chemistry Laboratory Abnormalities: Phase 1b
The following chemistry laboratory parameters were assessed: alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, CPK increased, creatinine increased, hypercalcemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia and hyponatremia. Laboratory abnormality events were graded according to NCI CTCAE v5.0; grade 1=mild, grade 2=moderate, grade 3=severe, grade 4=life-threatening consequences and grade 5=death. In this outcome measure, those number of participants are reported who had chemistry laboratory abnormality in any parameter of any CTCAE Grades.
Time frame: From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment (maximum treatment exposure: 400 days, maximum follow up: 430 days)
Number of Participants With Dose Interruptions Due to TEAEs: Phase 1b
Dose interruption was defined as a planned dosing day with 0 mg total dose administered. Dose interruptions were applicable to unexpected dose interruptions. In this outcome measure, dose interruptions for any drug were considered.
Time frame: During study treatment (from first dose of study treatment [Day 1] up to last dose of study treatment [maximum treatment exposure: 400 days])
Number of Participants With Dose Reduction Due to TEAEs: Phase 1b
A dose reduction was defined as the day when the actual dose was less than the planned dose at enrollment and the actual dose was greater than 0 mg (ie, missed doses were not counted as a reduction). In this outcome measure, dose reductions for any drug were considered.
Time frame: During study treatment (from first dose of study treatment [Day 1] up to last dose of study treatment [maximum treatment exposure: 400 days])
Number of Participants With Dose Discontinuations Due to TEAEs: Phase 1b
In this outcome measure, dose discontinuations for any drug due to TEAEs were considered.
Time frame: During study treatment (from first dose of study treatment [Day 1] up to last dose of study treatment [maximum treatment exposure: 400 days])
Cmax of PF-07284890 and Binimetinib for Single Dose: Phase 1b
Time frame: Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on C1D1
Tmax of PF-07284890 and Binimetinib for Single Dose: Phase 1b
Time frame: Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on C1D1
AUClast of PF-07284890 and Binimetinib for Single Dose: Phase 1b
AUClast was determined using the linear/log trapezoidal method.
Time frame: Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on C1D1
Cmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b
Time frame: Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15
Tmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b
Time frame: Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15
AUCtau of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b
Time frame: Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15
Cmin of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b
Time frame: Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15
CL/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b
CL/F was calculated as Dose/AUCinf.
Time frame: Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15
Intracranial Disease Control Rate (DCR) Per mRECIST v1.1: Phase1b
DCR: percentage of participants with BOR of CR, PR/ SD, Non-CR/Non-PD by Investigator assessment. CR: disappearance of all target and non-target lesions. For target lesions: Any pathological lymph nodes must be \<10 mm in short axis. For non-target lesions: All lymph nodes identified as site of disease at baseline must be non-pathological. PR: At least 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive disease (PD). PD: for target lesions- At least 20% increase in sum of diameters of target lesions, taking as reference smallest sum of diameters recorded since treatment started. In addition, sum must have an absolute increase of at least 5 mm. PD for non-target lesions- unequivocal progression of existing non-target lesions. Non-CR/Non-PD: persistence of 1/ more non-target lesion(s) identified as site of disease.
Time frame: From date of first dose until CR or PR or SD (maximum treatment exposure: 400 days)
Overall Disease Control Rate (DCR) Per RECIST v1.1: Phase1b
DCR: percentage of participants with BOR of CR, PR or SD, Non-CR/Non-PD by Investigator assessment. CR: disappearance of all target \& non-target lesions. For target lesions: Any pathological lymph nodes must be \<10 mm in short axis. For non-target lesions: All lymph nodes identified as site of disease at baseline must be non-pathological. PR: At least 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD: for target lesions- At least 20% increase in sum of diameters of target lesions, taking as reference smallest sum of diameters recorded since treatment started. In addition, sum must have an absolute increase of at least 5 mm. PD for non-target lesions- unequivocal progression of existing non-target lesions. Non-CR/Non-PD: persistence of 1/ more non-target lesion(s) identified as site of disease.
Time frame: From date of first dose until CR or PR or SD (maximum treatment exposure: 400 days)
Intracranial Progression Free Survival (PFS) by mRECISTv1.1: Phase1b
PFS was defined as the time from date of the first dose of study treatment to the earliest documented disease progression by Investigator assessment, or death due to any cause, whichever occurred first. PD: for target lesions- At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters recorded since the treatment started . In addition, the sum must have an absolute increase of at least 5 mm. PD for non-target lesions- unequivocal progression of existing non-target lesions. If a participant had not had a PFS event at the time of the analysis cutoff or at the start of any new anticancer therapy, PFS was censored at the date of last adequate tumor assessment. Analysis was performed using Kaplan-Meier method.
Time frame: From date of first dose of study treatment until first documentation of PD or death due to any cause or censoring date whichever occurred first (maximum treatment exposure: 400 days)
Overall Progression Free Survival (PFS): Phase1b
PFS was defined as the time from date of the first dose of study treatment to the earliest documented disease progression by Investigator assessment, or death due to any cause, whichever occurred first. PD: for target lesions- at least 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study (this includes baseline sum if that is smallest on study). In addition to the relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered a sign of progression. PD for non-target lesions- unequivocal progression of existing non-target lesion. If a participant had not had a PFS event at the time of the analysis cutoff or at the start of any new anticancer therapy, PFS was censored at the date of last adequate tumor assessment. Overall PFS included evaluation for brain metastasis and extracranial lesions. Analysis was performed using Kaplan-Meier method.
Time frame: From start of study treatment until first documentation of PD or death due to any cause or censoring date (maximum treatment exposure: 400 days)
Overall Survival (OS): Phase1b
Overall survival was defined as the time from the date of first study treatment to the date of death due to any cause. Participants who were still alive at the end of the study or lost to follow-up were censored at the last date they were known to be alive. Analysis was performed using Kaplan-Meier method.
Time frame: From start of study treatment until death due to any cause or censoring date (maximum treatment exposure: 400 days)
Intracranial Duration of Response (DOR) by mRECIST v1.1: Phase1b
DOR was defined as the time from date of the first radiographic response (CR or PR) to the earliest documented PD or death due to any cause. CR: disappearance of all target and non-target lesions. For target lesions: Any pathological lymph nodes must be \<10 mm in the short axis. For non-target lesions: All lymph nodes identified as a site of disease at baseline must be non-pathological (eg, \<10 mm short axis). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: for target lesions- At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters recorded since the treatment started. In addition, the sum must have an absolute increase of at least 5 mm. PD for non-target lesions- unequivocal progression of existing non target lesions.
Time frame: From CR or PR until first documented PD or death due to any cause (maximum treatment exposure: 400 days)
Overall DOR by RECIST v1.1: Phase1b
DOR: time from date of first radiographic response (CR/PR) to earliest documented PD/ death due to any cause.CR: disappearance of all target and non-target lesions. Any pathological lymph nodes (non-target) must have reduction in short axis to \< 10 mm. PR: at least a 30 % decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: for target lesions- At least 20% increase in sum of diameters of target lesions, taking as reference smallest sum of diameters recorded since treatment started. PD for non-target lesions- unequivocal progression of existing non-target lesions.
Time frame: From CR or PR until first documented PD or death due to any cause (maximum treatment exposure: 400 days)
Intracranial Time to Response (TTR) by mRECIST v1.1: Phase1b
Time to response is the time from treatment start to date of first documentation of objective response (PR or CR). CR: disappearance of all target and non-target lesions. For target lesions: Any pathological lymph nodes must be \<10 mm in the short axis. For non-target lesions: All lymph nodes identified as a site of disease at baseline must be non-pathological (eg, \<10 mm short axis). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From date of first dose until CR or PR (maximum treatment exposure: 400 days)
Overall TTR by RECIST v1.1: Phase1b
Time to response is the time from treatment start to date of first documentation of objective response (PR or CR). CR: disappearance of all target and non-target lesions. Any pathological lymph nodes (non-target) must have reduction in short axis to \< 10 mm. PR: at least a 30 % decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Response evaluable population.
Time frame: From date of first dose until CR or PR (maximum treatment exposure: 400 days)