The purpose of this first-in-human (FIH) study of BLZ945 given as a single agent or in combination with PDR001 was to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and anti-tumor activity of BLZ945, administered orally, as a single agent or in combination with PDR001, administered intravenously (i.v.) in adult patients with advanced solid tumors.
This study was a first in human, open-label, multi-center phase I/II study which consisted of a phase I dose escalation part of BLZ945 as single agent, and of BLZ945 in combination with PDR001, where alternative dosing regimens of BLZ945 were evaluated. The escalation was guided by a Bayesian logistic regression model with overdose control. Once the maximum tolerated dose (MTD) / recommended phase 2 dose (RP2D) for BLZ945 as single agent was established, a phase II part could commence, should signs of antitumor activity had been seen during the phase I. Once the MTD/RP2D for BLZ945 in combination with PDR001 was established, a phase II part could commence. Phase I part of the study involved patients with advanced solid tumors, including patients with recurrent glioblastoma and patients with Hodgkin's lymphoma, and phase II part patients with relapsed or refractory glioblastoma. A separate Japanese single agent dose escalation was performed in order to ensure that the safety and pharmacokinetic profiles of BLZ945 single agent were adequately characterized in Japanese patients. The Japanese dose escalation for BLZ945 single agent run separately from the ongoing global dose escalation. No Japanese patients were enrolled in phase II part according to protocol. The enrollment of the Japanese cohort was halted per investigator letter, dated 18-Jun-2021.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
192
BLZ945 administered orally as a capsule. Up to five alternative dosing schedules were evaluated: once per day (QD) 7 days on/7 days off (i.e., administer BLZ945 for 7 days and suspend for 7 days), QD 4 days on/10 days off, twice per day (BID) 4 days on/10 days off, once weekly (Q1W) QD and Q1W BID. Each cycle consisted of 28 days.
PDR001 400 mg administered via intravenous (i.v.) infusion every 4 weeks (Q4W)
Dana Farber Cancer Institute Dana Farber Cancer Institute
Boston, Massachusetts, United States
Sarah Cannon Research Institute Sarah Cannon Research
Nashville, Tennessee, United States
UT M.D Anderson Cancer Center
Houston, Texas, United States
Phase I: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period
Number of participants with AEs (any AE regardless of seriousness) and SAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs. The on-treatment period is defined from the day of first administration of study treatment up to 30 days after the date of its last administration.
Time frame: From first dose of study medication up to 30 days after last dose, with a maximum duration of 3.1 years for BLZ945 single agent and 4.1 years for BLZ945 in combination with PDR001
Phase I: Number of Participants With Dose Reductions and Dose Interruptions of BLZ945
Number of participants with at least one dose reduction of BLZ945 and number of participants with at least one dose interruption of BLZ945.
Time frame: From first dose of study medication up to last dose, with a maximum duration of 3 years for BLZ945 single agent and 4 years for BLZ945 in combination with PDR001
Phase I: Number of Participants With Dose Reductions and Dose Interruptions of PDR001
Number of participants with at least one dose reduction of PDR001 and number of participants with at least one dose interruption of PDR001. Dose reductions were not permitted for PDR001.
Time frame: From first dose of study medication up to last dose, with a maximum duration of 4 years
Phase I: Dose Intensity of BLZ945
Dose intensity of BLZ945 was calculated as cumulative actual dose in milligrams divided by the number of dose days scheduled per protocol during the treatment period. The denominator was calculated considering that patients received doses 7 days out of every 14 in the 7 days on/7 days off regimen, 4 days out of every 14 in the 4 days on/10 days off regimen and 1 day out of every 7 in the Q1W regimen.
Time frame: From first dose of study medication up to last dose, with a maximum duration of 3 years for BLZ945 single agent and 4 years for BLZ945 in combination with PDR001
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Mays Cancer Ctr Uthsa Mdacc
San Antonio, Texas, United States
Novartis Investigative Site
Tel Aviv, Israel
Novartis Investigative Site
Rozzano, MI, Italy
Novartis Investigative Site
Nagoya, Aichi-ken, Japan
Novartis Investigative Site
Koto Ku, Tokyo, Japan
Novartis Investigative Site
Singapore, Singapore
Novartis Investigative Site
Barcelona, Catalonia, Spain
...and 4 more locations
Phase I: Dose Intensity of PDR001
Dose intensity of PDR001 was calculated as cumulative actual dose in milligrams divided by the number of dose days scheduled per protocol during the treatment period. The denominator was calculated considering that patients received doses 1 day out of every 28 in the Q4W regimen.
Time frame: From first dose of study medication up to last dose, with a maximum duration of 4 years
Phase I: Number of Participants With Dose-Limiting Toxicities (DLTs) (Non-Japanese Cohort)
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 assessed as unrelated to disease, disease progression, inter-current illness or concomitant medications, which occurs within the first 28 days of treatment with BLZ945 as single agent or in combination with PDR001 during the dose escalation part of the study. Other clinically significant toxicities may be considered to be DLTs, even if not CTCAE grade 3 or higher.
Time frame: 28 days
Phase I: Number of Participants With Dose-Limiting Toxicities (DLTs) (Japanese Cohort)
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 assessed as unrelated to disease, disease progression, inter-current illness or concomitant medications, which occurs within the first 28 days of treatment with BLZ945 as single agent or in combination with PDR001 during the dose escalation part of the study. Other clinically significant toxicities may be considered to be DLTs, even if not CTCAE grade 3 or higher.
Time frame: 28 days
Phase II: Progression-Free Survival Rate at 6 Months (PFS6) Per RANO Criteria for Glioblastoma
PFS rate represents the percentage of participants without a first documented progression or death due to any cause after the start of study treatment. Tumor response was based on local investigator assessment per Response Assessment in Neuro Oncology (RANO) criteria. PFS was analyzed using Kaplan-Meier estimates.
Time frame: 6 months
Phase I: Progression-Free Survival (PFS) Per RECIST v1.1
PFS is defined as the time from the date of start of treatment to the date of the first documented progression or death due to any cause. If a patient did not have an event, PFS was censored at the date of the last adequate tumor assessment. Tumor response was based on local investigator assessment per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. PFS was analyzed using Kaplan-Meier estimates.
Time frame: From start of treatment until first documented progression or death due to any cause, assessed up to 3.1 years for BLZ945 single agent and 4.4 years for BLZ945 in combination with PDR001
Phase I: Progression-Free Survival (PFS) Per irRC
PFS is defined as the time from the date of start of treatment to the date of the first documented progression or death due to any cause. If a patient did not have an event, PFS was censored at the date of the last adequate tumor assessment. Tumor response was based on local investigator assessment per immune-related Response Criteria (irRC). PFS was analyzed using Kaplan-Meier estimates.
Time frame: From start of treatment until first documented progression or death due to any cause, assessed up to 3.1 years for BLZ945 single agent and 4.4 years for BLZ945 in combination with PDR001
Phase I: Progression-Free Survival (PFS) Per RANO
PFS is defined as the time from the date of start of treatment to the date of the first documented progression or death due to any cause. If a patient did not have an event, PFS was censored at the date of the last adequate tumor assessment. Tumor response was based on local investigator assessment per response assessment in neuro-oncology (RANO) criteria. PFS was analyzed using Kaplan-Meier estimates.
Time frame: From start of treatment until first documented progression or death due to any cause, assessed up to 3.1 years for BLZ945 single agent and 4.4 years for BLZ945 in combination with PDR001
Phase I and II: Progression-Free Survival (PFS) Per iRANO
PFS is defined as the time from the date of start of treatment to the date of the first documented progression or death due to any cause. If a patient did not have an event, PFS was censored at the date of the last adequate tumor assessment. Tumor response was based on local investigator assessment per immune response assessment in neuro-oncology (iRANO) criteria. PFS was analyzed using Kaplan-Meier estimates.
Time frame: From start of treatment until first documented progression or death due to any cause, assessed up to 3.1 years for BLZ945 single agent and 4.4 years for BLZ945 in combination with PDR001
Phase I: Progression-Free Survival (PFS) Per Guidelines for Efficacy Evaluation in Lymphoma Studies
PFS is defined as the time from the date of start of treatment to the date of the first documented progression or death due to any cause. If a patient did not have an event, PFS was censored at the date of the last adequate tumor assessment. Tumor response was based on local investigator assessment per guidelines for efficacy evaluation in lymphoma studies. PFS was analyzed using Kaplan-Meier estimates.
Time frame: From start of treatment until first documented progression or death due to any cause, assessed up to 3.1 years for BLZ945 single agent and 4.4 years for BLZ945 in combination with PDR001
Phase I: Best Overall Response (BOR) With Confirmation Per RECIST v1.1
BOR is defined as the best response recorded from the start of the study treatment until disease progression/recurrence, based on local investigator assessment per RECIST v1.1. However, any assessments taken more than 30 days after the last dose of study therapy were not included in the best overall response derivation. Complete Response (CR) and Partial response (PR) had to be confirmed by a new assessment after at least 4 weeks.
Time frame: From start of treatment until disease progression, assessed up to 3.1 years for BLZ945 single agent and 4.1 years for BLZ945 in combination with PDR001
Phase I: Best Overall Response (BOR) With Confirmation Per irRC
BOR is defined as the best response recorded from the start of the study treatment until disease progression/recurrence, based on local investigator assessment per irRC. However, any assessments taken more than 30 days after the last dose of study therapy were not included in the best overall response derivation. Complete Response (CR) and Partial response (PR) had to be confirmed by a new assessment after at least 4 weeks. Additionally, for irRC, progressive disease had to be confirmed.
Time frame: From start of treatment until disease progression, assessed up to 3.1 years for BLZ945 single agent and 4.1 years for BLZ945 in combination with PDR001
Phase I and II: Best Overall Response (BOR) (Sustained) Per RANO
BOR is defined as the best response recorded from the start of the study treatment until disease progression (taking as reference for progressive disease the smallest measurements recorded since the treatment started), based on local investigator assessment per RANO criteria. However, any assessments taken more than 30 days after the last dose of study therapy were not included in the best overall response derivation. If a response recorded at one scheduled magnetic resonance imaging (MRI) did not persist at the next regular scheduled MRI, the response was recorded based on the prior scan, but was designated as a non-sustained response. If the response was sustained, i.e. still present on the subsequent MRI, it was recorded as a sustained response, lasting until the time of tumor progression. CR and PR had to be confirmed by repeat assessments performed not less than 4 weeks after the criteria for response were first met.
Time frame: From start of treatment until disease progression, assessed up to 4.1 years in Phase I and 1.4 years in Phase II
Phase I and II: Best Overall Response (BOR) (Sustained) Per iRANO
BOR is defined as the best response recorded from the start of the study treatment until disease progression (taking as reference for progressive disease the smallest measurements recorded since the treatment started), based on local investigator assessment per iRANO. However, any assessments taken more than 30 days after the last dose of study therapy were not included in the best overall response derivation. If a response recorded at one scheduled magnetic resonance imaging (MRI) did not persist at the next regular scheduled MRI, the response was recorded based on the prior scan, but was designated as a non-sustained response. If the response was sustained, i.e. still present on the subsequent MRI, it was recorded as a sustained response, lasting until the time of tumor progression. CR and PR had to be confirmed by repeat assessments performed not less than 4 weeks after the criteria for response were first met. Additionally, for iRANO, progressive disease had to be confirmed.
Time frame: From start of treatment until disease progression, assessed up to 4.1 years in Phase I and 1.4 years in Phase II
Phase I: Best Overall Response (BOR) Per Guidelines for Efficacy Evaluation in Lymphoma Studies
BOR is defined as the best response recorded from the start of the study treatment until disease progression/recurrence, based on local investigator assessment per guidelines for efficacy evaluation in lymphoma studies. However, any assessments taken more than 30 days after the last dose of study therapy were not included in the best overall response derivation.
Time frame: From start of treatment until disease progression, assessed up to 3.1 years for BLZ945 single agent and 4.1 years for BLZ945 in combination with PDR001
Phase I: Overall Response Rate (ORR) Per RECIST v1.1
ORR is the percentage of patients with a best overall response of complete response (CR) or partial response (PR), based on local investigator assessment per RECIST v1.1.
Time frame: Up to 3.1 years for BLZ945 single agent and 4.1 years for BLZ945 in combination with PDR001
Phase I: Overall Response Rate (ORR) Per irRC
ORR is the percentage of patients with a best overall response of complete response (irCR) or partial response (irPR), based on local investigator assessment per irRC.
Time frame: Up to 3.1 years for BLZ945 single agent and 4.1 years for BLZ945 in combination with PDR001
Phase I: Overall Response Rate (ORR) Per Guidelines for Efficacy Evaluation in Lymphoma Studies
ORR is the percentage of patients with a best overall response of complete response (CR) or partial response (PR), based on local investigator assessment per guidelines for efficacy evaluation in lymphoma studies.
Time frame: Up to 3.1 years for BLZ945 single agent and 4.1 years for BLZ945 in combination with PDR001
Phase I: Disease Control Rate (DCR) Per RECIST v1.1
DCR is the percentage of patients with a best overall response of complete response (CR), partial response (PR) or stable disease (SD), based on local investigator assessment per RECIST v1.1.
Time frame: Up to 3.1 years for BLZ945 single agent and 4.1 years for BLZ945 in combination with PDR001
Phase I: Disease Control Rate (DCR) Per irRC
DCR is the percentage of patients with a best overall response of complete response (irCR), partial response (irPR) or stable disease (irSD), based on local investigator assessment per irRC.
Time frame: Up to 3.1 years for BLZ945 single agent and 4.1 years for BLZ945 in combination with PDR001
Phase I and II: Disease Control Rate (DCR) Per RANO
DCR is the percentage of patients with a best overall response of complete response (CR), partial response (PR) or stable disease (SD), based on local investigator assessment per RANO criteria.
Time frame: Up to 4.1 years in Phase I and 1.4 years in Phase II
Phase I and II: Disease Control Rate (DCR) Per iRANO
DCR is the percentage of patients with a best overall response of complete response (CR), partial response (PR) or stable disease (SD), based on local investigator assessment per iRANO criteria.
Time frame: Up to 4.1 years in Phase I and 1.4 years in Phase II
Phase I: Disease Control Rate (DCR) Per Guidelines for Efficacy Evaluation in Lymphoma Studies
DCR is the percentage of patients with a best overall response of complete response (CR), partial response (PR) or stable disease (SD), based on local investigator assessment per guidelines for efficacy evaluation in lymphoma studies.
Time frame: Up to 3.1 years for BLZ945 single agent and 4.1 years for BLZ945 in combination with PDR001
Phase II: Duration of Response (DOR) Per RANO
DOR only applies to patients for whom best overall response is complete response (CR) or partial response (PR) based on local investigator assessment per RANO. DOR is defined as the time from the date of first documented response to the date of first documented progression or death due to underlying cancer. If a patient did not have an event, DOR was censored at the date of last adequate tumor assessment.
Time frame: Up to 1.4 years for BLZ945 single agent and 0.6 years for BLZ945 in combination with PDR001
Phase II: Duration of Response (DOR) Per iRANO
DOR only applies to patients for whom best overall response is complete response (CR) or partial response (PR) based on local investigator assessment per iRANO. DOR is defined as the time from the date of first documented response to the date of first documented progression or death due to underlying cancer. If a patient did not have an event, DOR was censored at the date of last adequate tumor assessment.
Time frame: Up to 1.4 years for BLZ945 single agent and 0.6 years for BLZ945 in combination with PDR001
Phase II: Overall Survival (OS)
OS is defined as the time from date of start of treatment to date of death due to any cause. If a patient was not known to have died, OS time was censored at the date of last contact. OS was estimated using Kaplan-Meier estimates.
Time frame: From start of treatment until death due to any cause, assessed up to 1.9 years for BLZ945 single agent and 1.3 years for BLZ945 in combination with PDR001
Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period
Number of participants with AEs (any AE regardless of seriousness) and SAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs. The on-treatment period is defined from the day of first administration of study treatment up to 30 days after the date of its last administration.
Time frame: From first dose of study medication up to 30 days after last dose, with a maximum duration of 1.4 years for BLZ945 single agent and 0.6 years for BLZ945 in combination with PDR001
Phase II: Number of Participants With Dose Reductions and Dose Interruptions of BLZ945
Number of participants with at least one dose reduction of BLZ945 and number of participants with at least one dose interruption of BLZ945.
Time frame: From first dose of study medication up to last dose, with a maximum duration of 1.3 years for BLZ945 single agent and 0.5 years for BLZ945 in combination with PDR001
Phase II: Number of Participants With Dose Reductions and Dose Interruptions of PDR001
Number of participants with at least one dose reduction of PDR001 and number of participants with at least one dose interruption of PDR001. Dose reductions were not permitted for PDR001.
Time frame: From first dose of study medication up to last dose, with a maximum duration of 0.5 years
Phase II: Dose Intensity of BLZ945
Dose intensity of BLZ945 was calculated as cumulative actual dose in milligrams divided by the number of dose days scheduled per protocol during the treatment period. The denominator was calculated considering that patients received doses 4 days out of every 14 in the 4 days on/10 days off regimen.
Time frame: From first dose of study medication up to last dose, with a maximum duration of 1.3 years for BLZ945 single agent and 0.5 years for BLZ945 in combination with PDR001
Phase II: Dose Intensity of PDR001
Dose intensity of PDR001 was calculated as cumulative actual dose in milligrams divided by the number of dose days scheduled per protocol during the treatment period. The denominator was calculated considering that patients received doses 1 day out of every 28 in the Q4W regimen.
Time frame: From first dose of study medication up to last dose, with a maximum duration of 0.5 years
Phase I and II: Maximum Observed Serum Concentration (Cmax) of BLZ945 (7d on/7d Off Regimen)
Pharmacokinetic (PK) parameters were calculated based on BLZ945 serum concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed serum concentration following a dose.
Time frame: Cycle 1 Day 1 and Cycle 1 Day 7 (1 cycle=28 days): pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose
Phase I and II: Maximum Observed Serum Concentration (Cmax) of BLZ945 (Q1W Regimen)
Pharmacokinetic (PK) parameters were calculated based on BLZ945 serum concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed serum concentration following a dose.
Time frame: Cycle 1 Day 1 and Cycle 1 Day 8 (1 cycle=28 days): pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose (QD dosing); pre-dose, 0.5, 1, 2, 4, 6, 8 and 12 hours post morning dose (and pre evening dose) and 12 hours post evening dose (BID dosing)
Phase I and II: Maximum Observed Serum Concentration (Cmax) of BLZ945 (4d on/10d Off Regimen)
Pharmacokinetic (PK) parameters were calculated based on BLZ945 serum concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed serum concentration following a dose.
Time frame: Cycle 1 Day 1 and Cycle 1 Day 4 (1 cycle=28 days): pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose (QD dosing); pre-dose, 0.5, 1, 2, 4, 6, 8 and 12 hours post morning dose (and pre evening dose) and 12 hours post evening dose (BID dosing)
Phase I and II: Time to Reach Maximum Serum Concentration (Tmax) of BLZ945 (7d on/7d Off Regimen)
Pharmacokinetic (PK) parameters were calculated based on BLZ945 serum concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) serum concentration following a dose. Actual recorded sampling times were considered for the calculations.
Time frame: Cycle 1 Day 1 and Cycle 1 Day 7 (1 cycle=28 days): pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose
Phase I and II: Time to Reach Maximum Serum Concentration (Tmax) of BLZ945 (Q1W Regimen)
Pharmacokinetic (PK) parameters were calculated based on BLZ945 serum concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) serum concentration following a dose. Actual recorded sampling times were considered for the calculations.
Time frame: Cycle 1 Day 1 and Cycle 1 Day 8 (1 cycle=28 days): pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose (QD dosing); pre-dose, 0.5, 1, 2, 4, 6, 8 and 12 hours post morning dose (and pre evening dose) and 12 hours post evening dose (BID dosing)
Phase I and II: Time to Reach Maximum Serum Concentration (Tmax) of BLZ945 (4d on/10d Off Regimen)
Pharmacokinetic (PK) parameters were calculated based on BLZ945 serum concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) serum concentration following a dose. Actual recorded sampling times were considered for the calculations.
Time frame: Cycle 1 Day 1 and Cycle 1 Day 4 (1 cycle=28 days): pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose (QD dosing); pre-dose, 0.5, 1, 2, 4, 6, 8 and 12 hours post morning dose (and pre evening dose) and 12 hours post evening dose (BID dosing)
Phase I and II: Area Under the Serum Concentration-time Curve From Time Zero to 24 Hours Post Dose (AUC0-24hr) of BLZ945 (7d on/7d Off Regimen)
PK parameters were calculated based on BLZ945 serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC0-24hr calculation.
Time frame: Cycle 1 Day 1 and Cycle 1 Day 7 (1 cycle=28 days): pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose
Phase I and II: Area Under the Serum Concentration-time Curve From Time Zero to 24 Hours Post Dose (AUC0-24hr) of BLZ945 (Q1W Regimen, QD Dosing)
PK parameters were calculated based on BLZ945 serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC0-24hr calculation.
Time frame: Cycle 1 Day 1 and Cycle 1 Day 8 (1 cycle=28 days): pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose
Phase I and II: Area Under the Serum Concentration-time Curve From Time Zero to 12 Hours Post Dose (AUC0-12hr) of BLZ945 (Q1W Regimen, BID Dosing)
PK parameters were calculated based on BLZ945 serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC0-12hr calculation.
Time frame: Cycle 1 Day 1 and Cycle 1 Day 8 (1 cycle=28 days): pre-dose, 0.5, 1, 2, 4, 6, 8 and 12 hours post morning dose (and pre evening dose) and 12 hours post evening dose
Phase I and II: Area Under the Serum Concentration-time Curve From Time Zero to 24 Hours Post Dose (AUC0-24hr) of BLZ945 (4d on/10d Off Regimen, QD Dosing)
PK parameters were calculated based on BLZ945 serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC0-24hr calculation.
Time frame: Cycle 1 Day 1 and Cycle 1 Day 4 (1 cycle=28 days): pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours post dose
Phase I and II: Area Under the Serum Concentration-time Curve From Time Zero to 12 Hours Post Dose (AUC0-12hr) of BLZ945 (4d on/10d Off Regimen, BID Dosing)
PK parameters were calculated based on BLZ945 serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC0-12hr calculation.
Time frame: Cycle 1 Day 1 and Cycle 1 Day 4 (1 cycle=28 days): pre-dose, 0.5, 1, 2, 4, 6, 8 and 12 hours post morning dose (and pre evening dose) and 12 hours post evening dose
Phase I and II: Maximum Observed Serum Concentration (Cmax) of PDR001
Pharmacokinetic (PK) parameters were calculated based on PDR001 serum concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed serum concentration following a dose.
Time frame: pre-infusion and 1, 24, 168, 336 and 672 hours after completion of the infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The average duration of the infusion was 30 minutes. The duration of one cycle was 28 days
Phase I and II: Time to Reach Maximum Serum Concentration (Tmax) of PDR001
Pharmacokinetic (PK) parameters were calculated based on PDR001 serum concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) serum concentration following a dose. Actual recorded sampling times were considered for the calculations.
Time frame: pre-infusion and 1, 24, 168, 336 and 672 hours after completion of the infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The average duration of the infusion was 30 minutes. The duration of one cycle was 28 days
Phase I and II: Area Under the Serum Concentration-time Curve From Time Zero to 28 Days Post Dose (AUC0-28day) of PDR001
PK parameters were calculated based on PDR001 serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC0-28day calculation.
Time frame: pre-infusion and 1, 24, 168, 336 and 672 hours after completion of the infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The average duration of the infusion was 30 minutes. The duration of one cycle was 28 days
Phase I and II: Number of Participants With Anti-PDR001 Antibodies
Immunogenicity was evaluated in serum in a validated three-tiered assay approach. Samples were screened for potential anti-PDR001 antibodies and positive screen results were confirmed using a confirmatory assay. For confirmed anti-drug antibodies (ADA) positive samples, titers were determined. Patient ADA status was defined as follows: * ADA-negative at baseline: ADA-negative sample at baseline * ADA-positive at baseline: ADA-positive sample at baseline * ADA-negative post-baseline: patient with ADA-negative sample at baseline and at least 1 post baseline determinant sample, all of which are ADA-negative samples * Treatment-induced ADA-positive = ADA-negative sample at baseline and at least 1 treatment-induced ADA-positive sample * Treatment-boosted ADA-positive = ADA-positive sample at baseline and at least 1 treatment-boosted ADA-positive sample
Time frame: Baseline (before first dose) and post-baseline (assessed throughout the treatment and safety follow-up, up to 4.4 years in phase I and 0.9 years in phase II).