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

Novartis Pharmaceuticals

Overview

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.

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Conditions

Triple Negative Breast Cancer

Interventions

OciperlimabDRUG

900 mg intravenously (IV) every 3 weeks (Q3W)

TislelizumabDRUG

200 mg intravenously (IV) Q3W

PaclitaxelDRUG

90 mg/m2 intravenously (IV) on Days 1, 8 and 15 every 28 days

Nab-paclitaxel

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Key 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 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

Outcomes

Primary Outcomes

Progression-free Survival (PFS) based on investigator assessment using RECIST 1.1 criteria in Arm A and B

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

Time frame: From randomization to date of disease progression or death, assessed up to approximately 32 months after first randomization

Secondary Outcomes

Overall Survival (OS) based on investigator assessment using RECIST 1.1 criteria in Arm A, B and C

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.

Time frame: From randomization to death, assessed up to approximately 32 months after first randomization

Overall Response Rate (ORR) based on investigator assessment using RECIST 1.1 criteria in Arm A, B and C

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.

Time frame: Up to approximately 32 months after first randomization

Clinical benefit rate (CBR) with confirmed response in Arm A, B and C

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

Time frame: Approximately 32 months after first randomization

Time to response (TTR) based on investigator assessment using RECIST 1.1 criteria in Arm A, B and C

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

Data from ClinicalTrials.gov

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100 mg/m2 intravenously (IV) on Days 1, 8 and 15 every 28 days

CarboplatinDRUG

AUC 2 intravenously (IV) on Days 1 and 8 every 21 days

PlaceboDRUG

normal saline intravenously (IV) Q3W

PembrolizumabDRUG

200 mg intravenously (IV) Q3W

GemcitabineDRUG

1000 mg/m2 intravenously (IV) on Days 1 and 8 every 21 days

Time frame: From randomization to first documented response, assessed up to approximately 32 months after first randomization

Duration of Response (DOR) based on investigator assessment using RECIST 1.1 criteria in Arm A, B and C

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.

Time frame: From first documented response to disease progression or death, assessed up to approximately 32 months after first randomization

Progression-free Survival (PFS) based on investigator assessment using RECIST 1.1 criteria in Arm A, B and C

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.

Time frame: From randomization to date of disease progression or death, assessed up to approximately 32 months after first randomization

Number of participants with dose modifications

Number of participants with dose interruption and reductions for each drug component as a measure of tolerability

Time frame: Approximately 32 months after first dose

Anti-drug Antibodies (ADA) prevalence at Baseline for ociperlimab

prevalence at baseline is calculated as the percentage of participants who had an ADA positive result at baseline for ociperlimab

Time frame: Baseline

Anti-drug Antibodies (ADA) prevalence at Baseline for tislelizumab

prevalence at baseline is calculated as the percentage of participants who had an ADA positive result at baseline for tislelizumab

Time frame: Baseline

Anti-drug Antibodies (ADA) incidence on treatment for ociperlimab

ADA incidence on treatment will be calculated as the percentage of participants who are treatment-induced ADA positive for ociperlimab

Time frame: From Cycle 1 to Cycle 16, end of treatment and 30 day safety follow-up. Each cycle is 21 days

Anti-drug Antibodies (ADA) incidence on treatment for tislelizumab

ADA incidence on treatment will be calculated as the percentage of participants who are treatment-induced ADA positive for tislelizumab

Time frame: From Cycle 1 to Cycle 16, end of treatment and 30 day safety follow-up. Each cycle is 21 days

Change from baseline in the Functional Assessment of Cancer Therapy-Breast (FACT-B) Trial Outcomes Index (TOI) score

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.

Time frame: Up to approximately 32 months after first dose

Time to 5-point definitive deterioration in FACT-B TOI score

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.

Time frame: Up to approximately 32 months after first dose

Serum concentrations of ociperlimab

Summary statistics of serum ociperlimab concentrations by time point

Time frame: 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.

Serum concentrations of tislelizumab

Summary statistics of serum tislelizumab concentrations by time point

Time frame: 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.