Trilaciclib, a CDK 4/6 Inhibitor, in Patients Receiving Gemcitabine and Carboplatin for Metastatic Triple-Negative Breast Cancer (TNBC)

Study Overview
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Brief Summary
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This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of trilaciclib versus placebo administered prior to gemcitabine and carboplatin in patients receiving first- or second-line treatment for locally advanced unresectable/metastatic TNBC.

Detailed Description
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This study will have two separate cohorts (Cohort 1 and Cohort 2). Both cohorts will follow the same general study conduct/design with similar primary and key secondary endpoints and identical treatment arms. Cohort 1 will evaluate patients receiving first-line therapy, regardless of programmed death-ligand 1 (PD-L1) status, who are programmed cell death protein 1 (PD-1)/PD-L1 inhibitor therapy naïve. Cohort 2 will evaluate PD-L1 positive patients receiving second-line therapy following prior PD-1/PD-L1 inhibitor therapy in the locally advanced unresectable/metastatic setting.

Official Title
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A Phase 3, Randomized, Double-Blind Study of Trilaciclib or Placebo in Patients Receiving First- or Second-Line Gemcitabine and Carboplatin Chemotherapy for Locally Advanced Unresectable or Metastatic Triple-Negative Breast Cancer (PRESERVE 2)

Conditions
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TNBC - Triple-Negative Breast Cancer, Breast Cancer

Intervention / Treatment
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* Drug: Trilaciclib
* Drug: Placebo
* Drug: Gemcitabine
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >/= 18 years of age with evaluable locally advanced unresectable or metastatic TNBC. Documentation of triple negative breast cancer (estrogen and progesterone receptor <1% and HER2-negative) Prior systemic therapies (Cohort 1 only): No prior systemic therapy in the locally advanced unresectable/metastatic setting including chemotherapy, targeted therapy, immunotherapy, or investigational agents. Prior PD-1/PD-L1 inhibitor treatment is not permitted in any setting, including in the neoadjuvant setting. Time between completion of last treatment with curative intent and first metastatic recurrence must be ≥ 6 months. Prior systemic therapies (Cohort 2 only): Documentation of PD-L1 positive status Treated with a PD-1/PD-L1 inhibitor for a minimum duration of 4 months in the locally advanced unresectable/metastatic setting and as the most recent therapy. Radiation therapy for metastatic disease is permitted. There is no required minimum washout period for radiation therapy. Patients should be recovered from the effects of radiation. Archival tumor tissue must be available or a fresh biopsy must be obtained, unless approved by the Medical Monitor. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Adequate organ function as demonstrated by normal laboratory values Exclusion Criteria: Prior treatment with gemcitabine in any setting. Prior treatment with carboplatin in the locally advanced unresectable/metastatic setting. Prior carboplatin in the (neo)adjuvant/curative setting is permitted as long as it was completed ≥ 6 months prior to the first metastatic recurrence. Presence of central nervous system (CNS) metastases and/or leptomeningeal disease requiring immediate treatment with radiation therapy or steroids. Receipt of any cytotoxic chemotherapy within 14 days prior to the first dose of study drugs. QTcF interval >480 msec at Screening (confirmed in triplicate). For patients with ventricular pacemakers, QTcF >500 msec. Known hypersensitivity to carboplatin or other platinum-containing compounds, or mannitol Pregnant or lactating women Prior hematopoietic stem cell or bone marrow transplantation

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trilaciclib + gemcitabine + carboplatin<br>Trilaciclib (240mg/m2) + gemcitabine (1000 mg/m2) and carboplatin (AUC 2) | Drug: Trilaciclib<br>* Trilaciclib administered IV over 30mins prior to chemotherapy on Day 1 and Day 8 of each 21-day cycle.<br>* Other names: COSELA;Drug: Gemcitabine<br>* Gemcitabine administered IV on Day 1 and Day 8 of each 21-day cycle.<br>Drug: Carboplatin<br>* Carboplatin administered IV on Day 1 and Day 8 of each 21-day cycle.<br>|
| Placebo Comparator: Placebo + gemcitabine + carboplatin<br>The subjects in the placebo arm will follow the same schedule as the trilaciclib arm, but will receive placebo instead of trilaciclib. | Drug: Placebo<br>* Placebo administered IV over 30mins prior to chemotherapy on Day 1 and Day 8 of each 21-day cycle.<br>* Other names: 5 % Dextrose in water (D5W);Drug: Gemcitabine<br>* Gemcitabine administered IV on Day 1 and Day 8 of each 21-day cycle.<br>Drug: Carboplatin<br>* Carboplatin administered IV on Day 1 and Day 8 of each 21-day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect on Overall Survival (OS) | (Cohort 1):To evaluate the effect of trilaciclib on overall survival (OS) compared with placebo in patients receiving first-line gemcitabine and carboplatin. | Cohort 1:From date of randomization up to 39 months | 
| Effect on Overall Survival (OS) | (Cohort 2): To evaluate the effect of trilaciclib on OS compared with placebo in patients receiving gemcitabine and carboplatin as second-line therapy after treatment with a PD-1/PD-L1 inhibitor in the locally advanced unresectable/metastatic setting | Cohort 2: From date of randomization up to 28 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of life/Effects On Chemotherapy-Induced Fatigue | To assess the effect of trilaciclib on patients' quality of life as measured by time to first confirmed deterioration of fatigue compared with placebo in patients receiving gemcitabine and carboplatin | Cycle 1 Day 1 (each cycle is 21 days) up to 14 months | 
| Myeloprotective Effects | Occurrence of cytopenias, febrile neutropenia, hospitalization due to chemotherapy-induced myelosuppression, RBC and platelet transfusions, growth factor administration, and dose reductions and delays | Cycle 1 Day 1 (each cycle is 21 days) up to 14 months | 
| Progression Free Survival | To evaluate the effect of trilaciclib on progression-free survival (PFS) compared with placebo in patients receiving gemcitabine and carboplatin. | From date of randomization up to 14 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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breast cancer, gemcitabine, carboplatin, solid tumors, breast, chemotherapy, TNBC, trilaciclib, cyclin-dependent kinase 4/6 inhibitor, CDK 4/6 Inhibitor, triple-negative breast cancer, metastatic, chemotherapy-induced fatigue, HER2-negative, immunotherapy, immune checkpoint inhibitor therapy, chemotherapy-induced myelosuppression, myeloprotection, myeloprotective, PD-1/PD-L1 inhibitor therapy, advanced, stage 4, preserve, PRESERVE 2