Clinical trial NCT02829723: A Study of BLZ945 Single Agent or BLZ945 in Combination With PDR001 in Advanced Solid Tumors
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Advanced Solid Tumors
Keywords: Phase I/II
BLZ945
PDR001
CSF-1R
PD-1
advanced solid tumors
glioblastoma
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2016-07-12
Enrollment: 192
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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).

Primary outcomes:
measure: Phase I: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period
timeFrame: 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
measure: Phase I: Number of Participants With Dose Reductions and Dose Interruptions of BLZ945
timeFrame: 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
measure: Phase I: Number of Participants With Dose Reductions and Dose Interruptions of PDR001
timeFrame: From first dose of study medication up to last dose, with a maximum duration of 4 years
measure: Phase I: Dose Intensity of BLZ945
timeFrame: 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
measure: Phase I: Dose Intensity of PDR001
timeFrame: From first dose of study medication up to last dose, with a maximum duration of 4 years
measure: Phase I: Number of Participants With Dose-Limiting Toxicities (DLTs) (Non-Japanese Cohort)
timeFrame: 28 days
measure: Phase I: Number of Participants With Dose-Limiting Toxicities (DLTs) (Japanese Cohort)
timeFrame: 28 days
measure: Phase II: Progression-Free Survival Rate at 6 Months (PFS6) Per RANO Criteria for Glioblastoma
timeFrame: 6 months
Secondary outcomes:
measure: Phase I: Progression-Free Survival (PFS) Per RECIST v1.1
timeFrame: 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
measure: Phase I: Progression-Free Survival (PFS) Per irRC
timeFrame: 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
measure: Phase I: Progression-Free Survival (PFS) Per RANO
timeFrame: 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
measure: Phase I and II: Progression-Free Survival (PFS) Per iRANO
timeFrame: 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
measure: Phase I: Progression-Free Survival (PFS) Per Guidelines for Efficacy Evaluation in Lymphoma Studies
timeFrame: 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
measure: Phase I: Best Overall Response (BOR) With Confirmation Per RECIST v1.1
timeFrame: 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
measure: Phase I: Best Overall Response (BOR) With Confirmation Per irRC
timeFrame: 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
measure: Phase I and II: Best Overall Response (BOR) (Sustained) Per RANO
timeFrame: From start of treatment until disease progression, assessed up to 4.1 years in Phase I and 1.4 years in Phase II
measure: Phase I and II: Best Overall Response (BOR) (Sustained) Per iRANO
timeFrame: From start of treatment until disease progression, assessed up to 4.1 years in Phase I and 1.4 years in Phase II
measure: Phase I: Best Overall Response (BOR) Per Guidelines for Efficacy Evaluation in Lymphoma Studies
timeFrame: 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
measure: Phase I: Overall Response Rate (ORR) Per RECIST v1.1
timeFrame: Up to 3.1 years for BLZ945 single agent and 4.1 years for BLZ945 in combination with PDR001
measure: Phase I: Overall Response Rate (ORR) Per irRC
timeFrame: Up to 3.1 years for BLZ945 single agent and 4.1 years for BLZ945 in combination with PDR001
measure: Phase I: Overall Response Rate (ORR) Per Guidelines for Efficacy Evaluation in Lymphoma Studies
timeFrame: Up to 3.1 years for BLZ945 single agent and 4.1 years for BLZ945 in combination with PDR001
measure: Phase I: Disease Control Rate (DCR) Per RECIST v1.1
timeFrame: Up to 3.1 years for BLZ945 single agent and 4.1 years for BLZ945 in combination with PDR001
measure: Phase I: Disease Control Rate (DCR) Per irRC
timeFrame: Up to 3.1 years for BLZ945 single agent and 4.1 years for BLZ945 in combination with PDR001
measure: Phase I and II: Disease Control Rate (DCR) Per RANO
timeFrame: Up to 4.1 years in Phase I and 1.4 years in Phase II
measure: Phase I and II: Disease Control Rate (DCR) Per iRANO
timeFrame: Up to 4.1 years in Phase I and 1.4 years in Phase II
measure: Phase I: Disease Control Rate (DCR) Per Guidelines for Efficacy Evaluation in Lymphoma Studies
timeFrame: Up to 3.1 years for BLZ945 single agent and 4.1 years for BLZ945 in combination with PDR001
measure: Phase II: Duration of Response (DOR) Per RANO
timeFrame: Up to 1.4 years for BLZ945 single agent and 0.6 years for BLZ945 in combination with PDR001
measure: Phase II: Duration of Response (DOR) Per iRANO
timeFrame: Up to 1.4 years for BLZ945 single agent and 0.6 years for BLZ945 in combination with PDR001
measure: Phase II: Overall Survival (OS)
timeFrame: 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
measure: Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period
timeFrame: 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
measure: Phase II: Number of Participants With Dose Reductions and Dose Interruptions of BLZ945
timeFrame: 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
measure: Phase II: Number of Participants With Dose Reductions and Dose Interruptions of PDR001
timeFrame: From first dose of study medication up to last dose, with a maximum duration of 0.5 years
measure: Phase II: Dose Intensity of BLZ945
timeFrame: 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
measure: Phase II: Dose Intensity of PDR001
timeFrame: From first dose of study medication up to last dose, with a maximum duration of 0.5 years
measure: Phase I and II: Maximum Observed Serum Concentration (Cmax) of BLZ945 (7d on/7d Off Regimen)
timeFrame: 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
measure: Phase I and II: Maximum Observed Serum Concentration (Cmax) of BLZ945 (Q1W Regimen)
timeFrame: 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)
measure: Phase I and II: Maximum Observed Serum Concentration (Cmax) of BLZ945 (4d on/10d Off Regimen)
timeFrame: 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)
measure: Phase I and II: Time to Reach Maximum Serum Concentration (Tmax) of BLZ945 (7d on/7d Off Regimen)
timeFrame: 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
measure: Phase I and II: Time to Reach Maximum Serum Concentration (Tmax) of BLZ945 (Q1W Regimen)
timeFrame: 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)
measure: Phase I and II: Time to Reach Maximum Serum Concentration (Tmax) of BLZ945 (4d on/10d Off Regimen)
timeFrame: 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)
measure: 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)
timeFrame: 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
measure: 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)
timeFrame: 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
measure: 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)
timeFrame: 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
measure: 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)
timeFrame: 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
measure: 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)
timeFrame: 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
measure: Phase I and II: Maximum Observed Serum Concentration (Cmax) of PDR001
timeFrame: 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
measure: Phase I and II: Time to Reach Maximum Serum Concentration (Tmax) of PDR001
timeFrame: 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
measure: Phase I and II: Area Under the Serum Concentration-time Curve From Time Zero to 28 Days Post Dose (AUC0-28day) of PDR001
timeFrame: 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
measure: Phase I and II: Number of Participants With Anti-PDR001 Antibodies
timeFrame: 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).
Other outcomes:
Locations:
city: Boston
country: United States
facility: Dana Farber Cancer Institute Dana Farber Cancer Institute
state: Massachusetts
city: Nashville
country: United States
facility: Sarah Cannon Research Institute Sarah Cannon Research
state: Tennessee
city: Houston
country: United States
facility: UT M.D Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: Mays Cancer Ctr Uthsa Mdacc
state: Texas
city: Tel Aviv
country: Israel
facility: Novartis Investigative Site
city: Rozzano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Nagoya
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Koto ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Hospitalet de LLobregat
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Zurich
country: Switzerland
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: