A Study of BLZ945 Single Agent or BLZ945 in Combination With PDR001 in Advanced Solid Tumors

• ClinicalTrials.gov Identifier: NCT02829723
• Recruitment Status: Terminated
• First Posted: July 12, 2016
• Results First Posted: January 18, 2024
• Last Update Posted: January 18, 2024
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Advanced Solid Tumors	Drug: BLZ945; Drug: PDR001	Phase 1; Phase 2

Detailed Description:

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 192 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II, Open-label, Multi-center Study of the Safety and Efficacy of BLZ945 as Single Agent and in Combination With PDR001 in Adults Patients With Advanced Solid Tumors
• Actual Study Start Date: October 21, 2016
• Actual Primary Completion Date: December 1, 2022
• Actual Study Completion Date: December 1, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: BLZ945 single agent; BLZ945 administered as single agent	Drug: BLZ945; 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.
Experimental: BLZ945 + PDR001; BLZ945 administered in combination with PDR001	Drug: BLZ945; 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.; Drug: PDR001; PDR001 400 mg administered via intravenous (i.v.) infusion every 4 weeks (Q4W); Other Name: spartalizumab

Outcome Measures

Primary Outcome Measures :

1. Phase I: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period [ 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 ]

   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.

2. Phase I: Number of Participants With Dose Reductions and Dose Interruptions 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 ]
   Number of participants with at least one dose reduction of BLZ945 and number of participants with at least one dose interruption of BLZ945.
3. Phase I: Number of Participants With Dose Reductions and Dose Interruptions of PDR001 [ Time Frame: From first dose of study medication up to last dose, with a maximum duration of 4 years ]
   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.
4. Phase I: Dose Intensity 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 ]
   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.
5. Phase I: Dose Intensity of PDR001 [ Time Frame: From first dose of study medication up to last dose, with a maximum duration of 4 years ]
   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.
6. Phase I: Number of Participants With Dose-Limiting Toxicities (DLTs) (Non-Japanese Cohort) [ Time Frame: 28 days ]
   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.
7. Phase I: Number of Participants With Dose-Limiting Toxicities (DLTs) (Japanese Cohort) [ Time Frame: 28 days ]
   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.
8. Phase II: Progression-Free Survival Rate at 6 Months (PFS6) Per RANO Criteria for Glioblastoma [ Time Frame: 6 months ]

   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.

Secondary Outcome Measures :

1. Phase I: Progression-Free Survival (PFS) Per RECIST v1.1 [ 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 ]

   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.

2. Phase I: Progression-Free Survival (PFS) Per irRC [ 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 ]

   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.

3. Phase I: Progression-Free Survival (PFS) Per RANO [ 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 ]

   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.

4. Phase I and II: Progression-Free Survival (PFS) Per iRANO [ 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 ]

   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.

5. Phase I: Progression-Free Survival (PFS) Per Guidelines for Efficacy Evaluation in Lymphoma Studies [ 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 ]

   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.

6. Phase I: Best Overall Response (BOR) With Confirmation Per RECIST v1.1 [ 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 ]

   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.

7. Phase I: Best Overall Response (BOR) With Confirmation Per irRC [ 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 ]

   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.

8. Phase I and II: Best Overall Response (BOR) (Sustained) Per RANO [ 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 ]

   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.

9. Phase I and II: Best Overall Response (BOR) (Sustained) Per iRANO [ 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 ]

   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.

10. Phase I: Best Overall Response (BOR) Per Guidelines for Efficacy Evaluation in Lymphoma Studies [ 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 ]
    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.
11. Phase I: Overall Response Rate (ORR) 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 ]
    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.
12. Phase I: Overall Response Rate (ORR) Per irRC [ Time Frame: Up to 3.1 years for BLZ945 single agent and 4.1 years for BLZ945 in combination with PDR001 ]
    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.
13. Phase I: Overall Response Rate (ORR) 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 ]
    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.
14. Phase I: Disease Control Rate (DCR) 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 ]
    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.
15. Phase I: Disease Control Rate (DCR) Per irRC [ Time Frame: Up to 3.1 years for BLZ945 single agent and 4.1 years for BLZ945 in combination with PDR001 ]
    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.
16. Phase I and II: Disease Control Rate (DCR) Per RANO [ Time Frame: Up to 4.1 years in Phase I and 1.4 years in Phase II ]
    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.
17. Phase I and II: Disease Control Rate (DCR) Per iRANO [ Time Frame: Up to 4.1 years in Phase I and 1.4 years in Phase II ]
    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.
18. Phase I: Disease Control Rate (DCR) 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 ]
    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.
19. Phase II: Duration of Response (DOR) Per RANO [ Time Frame: Up to 1.4 years for BLZ945 single agent and 0.6 years for BLZ945 in combination with PDR001 ]
    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.
20. Phase II: Duration of Response (DOR) Per iRANO [ Time Frame: Up to 1.4 years for BLZ945 single agent and 0.6 years for BLZ945 in combination with PDR001 ]
    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.
21. Phase II: Overall Survival (OS) [ 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 ]

    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.

22. Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period [ 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 ]

    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.

23. Phase II: Number of Participants With Dose Reductions and Dose Interruptions 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 ]
    Number of participants with at least one dose reduction of BLZ945 and number of participants with at least one dose interruption of BLZ945.
24. Phase II: Number of Participants With Dose Reductions and Dose Interruptions of PDR001 [ Time Frame: From first dose of study medication up to last dose, with a maximum duration of 0.5 years ]
    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.
25. Phase II: Dose Intensity 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 ]
    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.
26. Phase II: Dose Intensity of PDR001 [ Time Frame: From first dose of study medication up to last dose, with a maximum duration of 0.5 years ]
    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.
27. Phase I and II: Maximum Observed Serum Concentration (Cmax) of BLZ945 (7d on/7d Off Regimen) [ 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 ]
    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.
28. Phase I and II: Maximum Observed Serum Concentration (Cmax) of BLZ945 (Q1W Regimen) [ 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) ]
    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.
29. Phase I and II: Maximum Observed Serum Concentration (Cmax) of BLZ945 (4d on/10d Off Regimen) [ 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) ]
    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.
30. Phase I and II: Time to Reach Maximum Serum Concentration (Tmax) of BLZ945 (7d on/7d Off Regimen) [ 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 ]
    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.
31. Phase I and II: Time to Reach Maximum Serum Concentration (Tmax) of BLZ945 (Q1W Regimen) [ 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) ]
    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.
32. Phase I and II: Time to Reach Maximum Serum Concentration (Tmax) of BLZ945 (4d on/10d Off Regimen) [ 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) ]
    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.
33. 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) [ 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 ]
    PK parameters were calculated based on BLZ945 serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC0-24hr calculation.
34. 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) [ 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 ]
    PK parameters were calculated based on BLZ945 serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC0-24hr calculation.
35. 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) [ 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 ]
    PK parameters were calculated based on BLZ945 serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC0-12hr calculation.
36. 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) [ 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 ]
    PK parameters were calculated based on BLZ945 serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC0-24hr calculation.
37. 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) [ 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 ]
    PK parameters were calculated based on BLZ945 serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC0-12hr calculation.
38. Phase I and II: Maximum Observed Serum Concentration (Cmax) of PDR001 [ 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 ]
    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.
39. Phase I and II: Time to Reach Maximum Serum Concentration (Tmax) of PDR001 [ 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 ]
    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.
40. Phase I and II: Area Under the Serum Concentration-time Curve From Time Zero to 28 Days Post Dose (AUC0-28day) of PDR001 [ 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 ]
    PK parameters were calculated based on PDR001 serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC0-28day calculation.
41. Phase I and II: Number of Participants With Anti-PDR001 Antibodies [ 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). ]

    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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Phase I: Patients with advanced/metastatic solid tumors including relapsed or refractory (r/r) glioblastoma and r/r lymphoma, with measurable or unmeasurable disease as determined by the respective response evaluation criteria.
2. Phase I: Patients with a site of disease amenable to biopsy, and willing to undergo a new tumor biopsy at screening, and during treatment.
3. Phase II: Patients with advanced/metastatic/recurrent isocitrate dehydrogenase (IDH) wild-type glioblastoma, with at least one measurable lesion as determined by RANO

Exclusion Criteria:

1. History of severe hypersensitivity reactions to monoclonal antibodies.
2. Impaired cardiac function or clinically significant cardiac disease.
3. Active autoimmune disease or a documented history of autoimmune disease.
4. Systemic steroid therapy or any immunosuppressive therapy
5. Use of any vaccines against infectious diseases within 4 weeks of initiation of study treatment.
6. Patient receiving treatment with medications that either strong inducers or inhibitors of CYP2C8 or CYP3A4/5, or patients receiving medication that prohibits proton pump inhibitors and that cannot be discontinued at least 1 week prior to start of treatment and for the duration of the study.
7. Presence of symptomatic central nervous system (CNS) metastases, or CNS metastases that require local CNS-directed therapy (such as radiotherapy or surgery), or increasing doses of corticosteroids within the prior 2 weeks before start of study treatment (not applicable for glioblastoma).

Contacts and Locations

Locations

United States, Massachusetts

Dana Farber Cancer Institute Dana Farber Cancer Institute

Boston, Massachusetts, United States, 02215

United States, Tennessee

Sarah Cannon Research Institute Sarah Cannon Research

Nashville, Tennessee, United States, 37203

United States, Texas

UT M.D Anderson Cancer Center

Houston, Texas, United States, 77030

Mays Cancer Ctr Uthsa Mdacc

San Antonio, Texas, United States, 78229

Israel

Novartis Investigative Site

Tel Aviv, Israel, 6423906

Italy

Novartis Investigative Site

Rozzano, MI, Italy, 20089

Japan

Novartis Investigative Site

Nagoya, Aichi, Japan, 466 8560

Novartis Investigative Site

Koto ku, Tokyo, Japan, 135 8550

Singapore

Novartis Investigative Site

Singapore, Singapore, 168583

Spain

Novartis Investigative Site

Barcelona, Catalunya, Spain, 08035

Novartis Investigative Site

Hospitalet de LLobregat, Catalunya, Spain, 08907

Novartis Investigative Site

Madrid, Spain, 28041

Switzerland

Novartis Investigative Site

Zurich, Switzerland, 8091

Taiwan

Novartis Investigative Site

Taipei, Taiwan, 10002

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

  Study Documents (Full-Text)

Documents provided by Novartis ( Novartis Pharmaceuticals ):

Study Protocol  [PDF] May 5, 2022

Statistical Analysis Plan  [PDF] July 17, 2023

More Information

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02829723
• Other Study ID Numbers: CBLZ945X2101; 2015-005806-12 ( EudraCT Number )
• First Posted: July 12, 2016
• Results First Posted: January 18, 2024
• Last Update Posted: January 18, 2024
• Last Verified: December 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

Phase I/II; BLZ945; PDR001; CSF-1R; PD-1; advanced solid tumors; glioblastoma

Additional relevant MeSH terms:

Neoplasms; Spartalizumab; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Immunological; Antineoplastic Agents