Phase II Study Evaluating the Efficacy and Safety of Ociperlimab in Combination With Tislelizumab and Chemotherapy as First-line Treatment for Participants With Advanced Triple Negative Breast Cancer

Phase 2

Withdrawn

• Conditions: Triple Negative Breast Cancer
• Interventions: Drug: Ociperlimab; Drug: Tislelizumab; Drug: Nab-paclitaxel; Drug: Paclitaxel; Drug: Placebo; Drug: Carboplatin; Drug: Pembrolizumab; Drug: Gemcitabine

• Registration Number: NCT05809895
• Lead Sponsor: Novartis Pharmaceuticals

Brief Summary

The primary scientific question of interest of this study is whether the combination of ociperlimab, tislelizumab and chemotherapy improves progression-free survival (PFS) compared to the combination of placebo, pembrolizumab and chemotherapy as first-line therapy for adult men and women with advanced triple negative breast cancer (TNBC) whose tumors express programmed death ligand 1 (PD - L1) \[combined positive score (CPS) ≥10\], regardless of study treatment discontinuation or start of new anti-neoplastic therapy.

Detailed Description

This is a randomized, double-blind, placebo-controlled, multicenter, Phase II study evaluating the efficacy and safety of ociperlimab in combination with tislelizumab and chemotherapy as first-line treatment for participants with advanced TNBC whose tumors express PD-L1 (CPS ≥ 10).

Additionally, the efficacy and safety of the triple combination (ociperlimab + tislelizumab + chemotherapy) will be assessed in Arm D (a separate single-arm, open-label cohort) in 30 participants with advanced TNBC whose tumors express PD-L1 (CPS ≥ 1 to \< 10).

Study treatment will continue until the participant experiences one of the following: disease progression per investigator's assessment by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1, unacceptable toxicity, pregnancy, treatment is discontinued at the discretion of the investigator or participant, start of a new antineoplastic therapy, withdrawal of consent, lost to follow-up, death, or study is terminated by the sponsor.

Study Timeline

• Study First Submitted: 2023-03-30
• Study First Submitted QC: 2023-03-30
• Study First Posted: 2023-04-12
• Status Verified: 2023-07
• Last Update Submitted: 2023-07-21
• Last Update Posted: 2023-07-24
• Study Start: 2023-09-15
• Primary Completion: 2029-07-17
• Study Completion: 2029-07-18

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

Inclusion Criteria

• Participant has histologically confirmed diagnosis of advanced (loco-regionally recurrent and not amenable to curative therapy, or metastatic (stage IV)) TNBC
• Participant has completed systemic treatment for Stage I-III breast cancer, if indicated, and ≥ 6 months have elapsed between the completion of systemic treatment with curative intent and disease recurrence
• A recently or newly obtained tumor biopsy from a metastatic site must be provided for determination of PD-L1 expression using the PD-L1 IHC 22C3 assay by a Novartis designated central laboratory, prior to study randomization. If a result of PD-L1 expression assessed by a PD-L1 IHC 22C3 pharmDx test in a local laboratory is available, this can serve as PD-L1 status confirmation. For Arms A, B and C participants must have PD-L1 positive tumors with CPS≥ 10. For Arm D, participants must have PD-L1 positive tumors with CPS ≥ 1 to < 10.
• Participant has measurable disease, i.e., at least one measurable lesion per RECIST 1.1 criteria (a lesion at a previously irradiated site may only be counted as a target lesion if there is clear sign of progression since the irradiation)
• Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Participant has life expectancy ≥ 12 weeks from the start of study treatment

Key

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Exclusion Criteria

• Participant has received prior treatment with immunotherapy in the metastatic setting, or anti-T cell immunoreceptor with Ig and ITIM domains (TIGIT) therapy in any setting

• History of severe hypersensitivity to any of the study drugs (i.e. monoclonal antibodies, gemcitabine, carboplatin, nab-paclitaxel, paclitaxel) or its excipients or to drugs of similar chemical classes

• Participant with inflammatory breast cancer at screening

• Participant has central nervous system (CNS) involvement which was not previously treated and/or was newly detected at screening. Previously treated CNS involvement must fulfill the following criteria to be eligible for the trial:

  1. Completed prior therapy (including radiation and/or surgery) for CNS metastases ≥ 28 days prior to the start of the study and
  2. CNS tumor is clinically stable at the time of screening, and
  3. Participant is not receiving steroids and/or enzyme inducing anti-epileptic medications for brain metastases

• Participant has an active autoimmune diseases or history of autoimmune diseases that may relapse

• Participant has not recovered from all toxicities related to prior anticancer therapies to National Cancer Institute (NCI) CTCAE version 5.0 Grade ≤1. Exception to this criterion: participants with any grade of alopecia are allowed to enter the study

Other inclusion/exclusion criteria may apply

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm D: ociperlimab + tislelizumab + chemotherapy (PD-L1 CPS score ≥ 1 to < 10)	Ociperlimab	Exploratory arm: Participants with a PD-L1 CPS ≥ 1 to \< 10 will receive ociperlimab + tislelizumab + chemotherapy. The choice of one of three chemotherapy options is at the discretion of the investigator provided that it is either: (1) paclitaxel, (2) nab-paclitaxel, or (3) gemcitabine plus carboplatin.
Arm A: ociperlimab+tislelizumab+chemotherapy (PD-L1 CPS ≥ 10)	Tislelizumab	Participants with a PD-L1 CPS ≥ 10 will receive after randomization ociperlimab + tislelizumab + chemotherapy. The choice of one of three chemotherapy options is at the discretion of the investigator provided that it is either: (1) paclitaxel, (2) nab-paclitaxel, or (3) gemcitabine plus carboplatin.
Arm A: ociperlimab+tislelizumab+chemotherapy (PD-L1 CPS ≥ 10)	Gemcitabine	Participants with a PD-L1 CPS ≥ 10 will receive after randomization ociperlimab + tislelizumab + chemotherapy. The choice of one of three chemotherapy options is at the discretion of the investigator provided that it is either: (1) paclitaxel, (2) nab-paclitaxel, or (3) gemcitabine plus carboplatin.
Arm B: placebo + pembrolizumab + chemotherapy (PD-L1 CPS ≥ 10)	Nab-paclitaxel	Participants with a PD-L1 CPS ≥ 10 will receive after randomization placebo + pembrolizumab + chemotherapy. The choice of one of three chemotherapy options is at the discretion of the investigator provided that it is either: (1) paclitaxel, (2) nab-paclitaxel, or (3) gemcitabine plus carboplatin.
Arm C: placebo + tislelizumab + chemotherapy (PD-L1 CPS ≥ 10)	Placebo	Participants with a PD-L1 CPS ≥ 10 will receive after randomization placebo + tislelizumab + chemotherapy. The choice of one of three chemotherapy options is at the discretion of the investigator provided that it is either: (1) paclitaxel, (2) nab-paclitaxel, or (3) gemcitabine plus carboplatin.
Arm A: ociperlimab+tislelizumab+chemotherapy (PD-L1 CPS ≥ 10)	Nab-paclitaxel	Participants with a PD-L1 CPS ≥ 10 will receive after randomization ociperlimab + tislelizumab + chemotherapy. The choice of one of three chemotherapy options is at the discretion of the investigator provided that it is either: (1) paclitaxel, (2) nab-paclitaxel, or (3) gemcitabine plus carboplatin.
Arm D: ociperlimab + tislelizumab + chemotherapy (PD-L1 CPS score ≥ 1 to < 10)	Nab-paclitaxel	Exploratory arm: Participants with a PD-L1 CPS ≥ 1 to \< 10 will receive ociperlimab + tislelizumab + chemotherapy. The choice of one of three chemotherapy options is at the discretion of the investigator provided that it is either: (1) paclitaxel, (2) nab-paclitaxel, or (3) gemcitabine plus carboplatin.
Arm A: ociperlimab+tislelizumab+chemotherapy (PD-L1 CPS ≥ 10)	Ociperlimab	Participants with a PD-L1 CPS ≥ 10 will receive after randomization ociperlimab + tislelizumab + chemotherapy. The choice of one of three chemotherapy options is at the discretion of the investigator provided that it is either: (1) paclitaxel, (2) nab-paclitaxel, or (3) gemcitabine plus carboplatin.
Arm B: placebo + pembrolizumab + chemotherapy (PD-L1 CPS ≥ 10)	Placebo	Participants with a PD-L1 CPS ≥ 10 will receive after randomization placebo + pembrolizumab + chemotherapy. The choice of one of three chemotherapy options is at the discretion of the investigator provided that it is either: (1) paclitaxel, (2) nab-paclitaxel, or (3) gemcitabine plus carboplatin.
Arm C: placebo + tislelizumab + chemotherapy (PD-L1 CPS ≥ 10)	Nab-paclitaxel	Participants with a PD-L1 CPS ≥ 10 will receive after randomization placebo + tislelizumab + chemotherapy. The choice of one of three chemotherapy options is at the discretion of the investigator provided that it is either: (1) paclitaxel, (2) nab-paclitaxel, or (3) gemcitabine plus carboplatin.
Arm A: ociperlimab+tislelizumab+chemotherapy (PD-L1 CPS ≥ 10)	Paclitaxel	Participants with a PD-L1 CPS ≥ 10 will receive after randomization ociperlimab + tislelizumab + chemotherapy. The choice of one of three chemotherapy options is at the discretion of the investigator provided that it is either: (1) paclitaxel, (2) nab-paclitaxel, or (3) gemcitabine plus carboplatin.
Arm A: ociperlimab+tislelizumab+chemotherapy (PD-L1 CPS ≥ 10)	Carboplatin	Participants with a PD-L1 CPS ≥ 10 will receive after randomization ociperlimab + tislelizumab + chemotherapy. The choice of one of three chemotherapy options is at the discretion of the investigator provided that it is either: (1) paclitaxel, (2) nab-paclitaxel, or (3) gemcitabine plus carboplatin.
Arm B: placebo + pembrolizumab + chemotherapy (PD-L1 CPS ≥ 10)	Paclitaxel	Participants with a PD-L1 CPS ≥ 10 will receive after randomization placebo + pembrolizumab + chemotherapy. The choice of one of three chemotherapy options is at the discretion of the investigator provided that it is either: (1) paclitaxel, (2) nab-paclitaxel, or (3) gemcitabine plus carboplatin.
Arm B: placebo + pembrolizumab + chemotherapy (PD-L1 CPS ≥ 10)	Carboplatin	Participants with a PD-L1 CPS ≥ 10 will receive after randomization placebo + pembrolizumab + chemotherapy. The choice of one of three chemotherapy options is at the discretion of the investigator provided that it is either: (1) paclitaxel, (2) nab-paclitaxel, or (3) gemcitabine plus carboplatin.
Arm B: placebo + pembrolizumab + chemotherapy (PD-L1 CPS ≥ 10)	Pembrolizumab	Participants with a PD-L1 CPS ≥ 10 will receive after randomization placebo + pembrolizumab + chemotherapy. The choice of one of three chemotherapy options is at the discretion of the investigator provided that it is either: (1) paclitaxel, (2) nab-paclitaxel, or (3) gemcitabine plus carboplatin.
Arm C: placebo + tislelizumab + chemotherapy (PD-L1 CPS ≥ 10)	Carboplatin	Participants with a PD-L1 CPS ≥ 10 will receive after randomization placebo + tislelizumab + chemotherapy. The choice of one of three chemotherapy options is at the discretion of the investigator provided that it is either: (1) paclitaxel, (2) nab-paclitaxel, or (3) gemcitabine plus carboplatin.
Arm B: placebo + pembrolizumab + chemotherapy (PD-L1 CPS ≥ 10)	Gemcitabine	Participants with a PD-L1 CPS ≥ 10 will receive after randomization placebo + pembrolizumab + chemotherapy. The choice of one of three chemotherapy options is at the discretion of the investigator provided that it is either: (1) paclitaxel, (2) nab-paclitaxel, or (3) gemcitabine plus carboplatin.
Arm C: placebo + tislelizumab + chemotherapy (PD-L1 CPS ≥ 10)	Tislelizumab	Participants with a PD-L1 CPS ≥ 10 will receive after randomization placebo + tislelizumab + chemotherapy. The choice of one of three chemotherapy options is at the discretion of the investigator provided that it is either: (1) paclitaxel, (2) nab-paclitaxel, or (3) gemcitabine plus carboplatin.
Arm C: placebo + tislelizumab + chemotherapy (PD-L1 CPS ≥ 10)	Paclitaxel	Participants with a PD-L1 CPS ≥ 10 will receive after randomization placebo + tislelizumab + chemotherapy. The choice of one of three chemotherapy options is at the discretion of the investigator provided that it is either: (1) paclitaxel, (2) nab-paclitaxel, or (3) gemcitabine plus carboplatin.
Arm C: placebo + tislelizumab + chemotherapy (PD-L1 CPS ≥ 10)	Gemcitabine	Participants with a PD-L1 CPS ≥ 10 will receive after randomization placebo + tislelizumab + chemotherapy. The choice of one of three chemotherapy options is at the discretion of the investigator provided that it is either: (1) paclitaxel, (2) nab-paclitaxel, or (3) gemcitabine plus carboplatin.
Arm D: ociperlimab + tislelizumab + chemotherapy (PD-L1 CPS score ≥ 1 to < 10)	Tislelizumab	Exploratory arm: Participants with a PD-L1 CPS ≥ 1 to \< 10 will receive ociperlimab + tislelizumab + chemotherapy. The choice of one of three chemotherapy options is at the discretion of the investigator provided that it is either: (1) paclitaxel, (2) nab-paclitaxel, or (3) gemcitabine plus carboplatin.
Arm D: ociperlimab + tislelizumab + chemotherapy (PD-L1 CPS score ≥ 1 to < 10)	Paclitaxel	Exploratory arm: Participants with a PD-L1 CPS ≥ 1 to \< 10 will receive ociperlimab + tislelizumab + chemotherapy. The choice of one of three chemotherapy options is at the discretion of the investigator provided that it is either: (1) paclitaxel, (2) nab-paclitaxel, or (3) gemcitabine plus carboplatin.
Arm D: ociperlimab + tislelizumab + chemotherapy (PD-L1 CPS score ≥ 1 to < 10)	Carboplatin	Exploratory arm: Participants with a PD-L1 CPS ≥ 1 to \< 10 will receive ociperlimab + tislelizumab + chemotherapy. The choice of one of three chemotherapy options is at the discretion of the investigator provided that it is either: (1) paclitaxel, (2) nab-paclitaxel, or (3) gemcitabine plus carboplatin.
Arm D: ociperlimab + tislelizumab + chemotherapy (PD-L1 CPS score ≥ 1 to < 10)	Gemcitabine	Exploratory arm: Participants with a PD-L1 CPS ≥ 1 to \< 10 will receive ociperlimab + tislelizumab + chemotherapy. The choice of one of three chemotherapy options is at the discretion of the investigator provided that it is either: (1) paclitaxel, (2) nab-paclitaxel, or (3) gemcitabine plus carboplatin.

Primary Outcome Measures

Name	Time	Method
Progression-free Survival (PFS) based on investigator assessment using RECIST 1.1 criteria in Arm A and B	From randomization to date of disease progression or death, assessed up to approximately 32 months after first randomization	PFS is defined as the time from the date of randomization to the date of first documented progression or death due to any cause. The comparison of PFS between Arm A and Arm B will be provided

Secondary Outcome Measures

Name	Time	Method
Time to response (TTR) based on investigator assessment using RECIST 1.1 criteria in Arm A, B and C	From randomization to first documented response, assessed up to approximately 32 months after first randomization	TTR is defined as the time from date of randomization to the first documented response of either CR or PR, as per local investigator assessment according to RECIST 1.1
Anti-drug Antibodies (ADA) prevalence at Baseline for tislelizumab	Baseline	prevalence at baseline is calculated as the percentage of participants who had an ADA positive result at baseline for tislelizumab
Time to 5-point definitive deterioration in FACT-B TOI score	Up to approximately 32 months after first dose	Time to 5-point definitive deterioration in the FACT-B TOI in Arms A, B and C. The FACT-B is a questionnaire that consists of 37 items with items from FACT-General (FACT-G) questionnaire (27 items) and from the Breast Cancer Subscale (BCS, 10 items). FACT-B consists of five subscales that address different aspects of the participant's quality of life: physical well-being (PWB), social/family well-being (SWB), emotional well-being (EWB), functional well-being (FWB), and BCS. The FACT-B TOI is a composite of PWB, FWB and BCS, and ranges from 0 to 96, with higher scores indicating better quality of life. Definitive deterioration is defined as the time from the date of randomization to the date of event defined at least 5-point worsening from baseline with no later improvement above this threshold during the course of treatment or until death due to any cause, in the FACT-B TOI score.
Overall Response Rate (ORR) based on investigator assessment using RECIST 1.1 criteria in Arm A, B and C	Up to approximately 32 months after first randomization	ORR is defined as the percentage of participants with best overall response (BOR) of complete response (CR) or partial response (PR) as per local assessment according to RECIST 1.1.
Progression-free Survival (PFS) based on investigator assessment using RECIST 1.1 criteria in Arm A, B and C	From randomization to date of disease progression or death, assessed up to approximately 32 months after first randomization	PFS is defined as the time from the date of randomization to the date of first documented progression or death due to any cause. PFS for participants in Arm C will be compared to PFS for participants in Arm A and B.
Duration of Response (DOR) based on investigator assessment using RECIST 1.1 criteria in Arm A, B and C	From first documented response to disease progression or death, assessed up to approximately 32 months after first randomization	DOR is defined as the duration of time between the date of first documented response (CR or PR as per local investigator assessment according to RECIST 1.1) and the date of first documented progression or death due to any cause.
Number of participants with dose modifications	Approximately 32 months after first dose	Number of participants with dose interruption and reductions for each drug component as a measure of tolerability
Anti-drug Antibodies (ADA) incidence on treatment for tislelizumab	From Cycle 1 to Cycle 16, end of treatment and 30 day safety follow-up. Each cycle is 21 days	ADA incidence on treatment will be calculated as the percentage of participants who are treatment-induced ADA positive for tislelizumab
Change from baseline in the Functional Assessment of Cancer Therapy-Breast (FACT-B) Trial Outcomes Index (TOI) score	Up to approximately 32 months after first dose	Change from baseline in the FACT-B TOI score for participants in Arms A, B and C. The FACT-B is a questionnaire that consists of 37 items with items from FACT-General (FACT-G) questionnaire (27 items) and from the Breast Cancer Subscale (BCS, 10 items). FACT-B consists of five subscales that address different aspects of the participant's quality of life: physical well-being (PWB), social/family well-being (SWB), emotional well-being (EWB), functional well-being (FWB), and BCS. The FACT-B TOI is a composite of PWB, FWB and BCS, and ranges from 0 to 96, with higher scores indicating better quality of life.
Serum concentrations of tislelizumab	Cycle (C) 1 Day (D) 1, C1D2, C1D4, C1D8, C1D15, D1 of C2, C3, C4 and C5, C5D8, D1 of C6, C8, C12 and C16, end of treatment and 30 day post-treatment. Each cycle is 21 days.	Summary statistics of serum tislelizumab concentrations by time point
Clinical benefit rate (CBR) with confirmed response in Arm A, B and C	Approximately 32 months after first randomization	CBR is defined as the percentage of participants with a BOR of confirmed CR, PR or stable disease (SD) lasting for a duration of 24 weeks. CR, PR and SD are defined as per local investigator assessment according to RECIST 1.1
Anti-drug Antibodies (ADA) prevalence at Baseline for ociperlimab	Baseline	prevalence at baseline is calculated as the percentage of participants who had an ADA positive result at baseline for ociperlimab
Anti-drug Antibodies (ADA) incidence on treatment for ociperlimab	From Cycle 1 to Cycle 16, end of treatment and 30 day safety follow-up. Each cycle is 21 days	ADA incidence on treatment will be calculated as the percentage of participants who are treatment-induced ADA positive for ociperlimab
Serum concentrations of ociperlimab	Cycle (C) 1 Day (D) 1, C1D2, C1D4, C1D8, C1D15, D1 of C2, C3, C4 and C5, C5D8, D1 of C6, C8, C12 and C16, end of treatment and 30 day post-treatment. Each cycle is 21 days.	Summary statistics of serum ociperlimab concentrations by time point
Overall Survival (OS) based on investigator assessment using RECIST 1.1 criteria in Arm A, B and C	From randomization to death, assessed up to approximately 32 months after first randomization	OS is defined as the time from date of randomization to date of death due to any cause. The comparison of OS between Arm A and Arm B, Arm B and Arm C, and Arm A and Arm C will be provided.