Trilaciclib, a CDK 4/6 Inhibitor, in Patients With Advanced/Metastatic Bladder Cancer Receiving Chemotherapy Then Avelumab

Study Overview
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Brief Summary
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This is a Phase 2, multicenter, randomized, open-label study evaluating the safety and efficacy of trilaciclib administered with platinum-based chemotherapy followed by trilaciclib administered with avelumab maintenance therapy compared with platinum-based chemotherapy followed by avelumab maintenance therapy in patients receiving first-line treatment for advanced/metastatic bladder cancer.

Detailed Description
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Patients will be randomly assigned (1:1) to receive standard of care platinum-based chemotherapy (with or without the addition of trilaciclib) administered intravenously (IV) in 21-day cycles followed by standard of care avelumab maintenance therapy (with or without the addition of trilaciclib) administered IV in 14-day cycles. Patients enrolled in the study will be eligible to receive 4-6 cycles of platinum-based chemotherapy, and patients without progressive disease (PD) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 guidelines (i.e., with an ongoing complete response [CR], partial response [PR], or stable disease) after platinum-based chemotherapy will be eligible to receive avelumab maintenance therapy until disease progression, unacceptable toxicity, withdrawal of consent, Investigator decision, or the end of the trial, whichever comes first. Patients will be followed for survival approximately every 3 months after receiving the last dose of study medication.

Official Title
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A Phase 2, Randomized, Open-Label Study of Trilaciclib Administered With First-Line Platinum-Based Chemotherapy and Avelumab Maintenance Therapy in Patients With Untreated, Locally Advanced or Metastatic Urothelial Carcinoma (PRESERVE 3)

Conditions
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Urothelial Carcinoma, Bladder Cancer, Myelosuppression Adult, Chemotherapy-induced Neutropenia, Metastatic Bladder Cancer

Intervention / Treatment
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* Drug: Trilaciclib
* Drug: Gemcitabine
* Drug: Cisplatin
* Drug: Carboplatin
* Drug: Avelumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years Histologically documented, locally advanced (T4b, any N; or any T, N 2-3) or metastatic urothelial carcinoma (M1, Stage IV) Measurable disease as defined by RECIST v1.1 No prior systemic therapy in the inoperable, locally advanced, or metastatic setting including chemotherapy, immune checkpoint inhibitor therapy, targeted therapy, or investigational agents 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 0-2 Adequate organ function as demonstrated by normal laboratory values Exclusion Criteria: Prior treatment with IL-2, IFN-α, or an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 or CD137 agonists, or cytotoxic T-lymphocyte associated protein 4 (CTLA-4) antibody (including ipilimumab), or any other therapeutic antibody or drug specifically targeting T cell co-stimulation or immune checkpoint pathways in any setting Malignancies other than urothelial carcinoma within 3 years prior to randomization, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or of the cervix, or low-grade (Gleason ≤6) prostate cancer on surveillance without any plans for treatment intervention (e.g., surgery, radiation, or castration) Presence of central nervous system (CNS) metastases/leptomeningeal disease requiring immediate treatment with radiation therapy or steroids. QTcF interval > 480 msec. For patients with ventricular pacemakers, QTcF > 500 msec Known hypersensitivity or allergy to avelumab, gemcitabine, cisplatin or carboplatin Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥3), any history of anaphylaxis, or uncontrolled asthma Prior hematopoietic stem cell or bone marrow transplantation, or solid organ transplantation Pregnant or lactating women Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent Current use of immunosuppressive medication, EXCEPT for the following: Intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection) Systemic corticosteroids at physiological doses ≤10 mg/day of prednisone or equivalent Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)

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
Interventional Model Description: Random assignment (1:1) to one of two treatment arms
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Platinum-based chemotherapy followed by avelumab maintenance therapy<br>Gemcitabine (1000 mg/m2) + Cisplatin (70 mg/m2) or Carboplatin (AUC 4.5) followed by Avelumab (800 mg) | Drug: Gemcitabine<br>* Gemcitabine administered IV on Day 1 and Day 8 of each 21-day cycle<br>Drug: Cisplatin<br>* Cisplatin administered IV on Day 1 of each 21-day cycle<br>Drug: Carboplatin<br>* Carboplatin administered IV on Day 1 of each 21-day cycle<br>Drug: Avelumab<br>* Avelumab will be dosed on Day 1 of each 14-day maintenance cycle<br>* Other names: Bavencio;|
| Experimental: Trilaciclib plus platinum-based chemotherapy followed by avelumab maintenance therapy<br>Trilaciclib (240 mg/m2) + Gemcitabine (1000 mg/m2) + Cisplatin (70 mg/m2) or Carboplatin (AUC 4.5) followed by Trilaciclib (240 mg/m2) + Avelumab (800 mg) | Drug: Trilaciclib<br>* Trilaciclib administered IV prior to chemotherapy and avelumab maintenance therapy on each day chemotherapy and avelumab maintenance therapy is administered.<br>* Other names: G1T28;Drug: Gemcitabine<br>* Gemcitabine administered IV on Day 1 and Day 8 of each 21-day cycle<br>Drug: Cisplatin<br>* Cisplatin administered IV on Day 1 of each 21-day cycle<br>Drug: Carboplatin<br>* Carboplatin administered IV on Day 1 of each 21-day cycle<br>Drug: Avelumab<br>* Avelumab will be dosed on Day 1 of each 14-day maintenance cycle<br>* Other names: Bavencio;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival | To evaluate the effect of trilaciclib on progression-free survival (PFS) when administered with platinum-based chemotherapy followed by trilaciclib administered with avelumab maintenance therapy compared with platinum-based chemotherapy followed by avelumab maintenance therapy alone. | From date of randomization until date of documented radiologic disease progression per RECIST v1.1 or death due to any cause, whichever comes first (on average 7 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-tumor Effects | To assess objective response rates as measured by RECIST 1.1 | From date of randomization until date of documented radiologic disease progression per RECIST v1.1 or death due to any cause, whichever comes first (on average 7 months) | 
| Anti-tumor Effects | To evaluate the effect of trilaciclib on overall survival (OS) when administered with platinum-based chemotherapy followed by trilaciclib administered with avelumab maintenance therapy compared with platinum-based chemotherapy followed by avelumab maintenance therapy alone. | From date of randomization until date of death due to any cause (on average 25 months) | 
| Myeloprotective Effects | To assess the effects of trilaciclib on the neutrophil lineage as measured by the occurrence of severe neutropenia during platinum-based chemotherapy treatment | Cycle 1 Day 1 (each cycle is 21 days) through treatment with platinum-based chemotherapy (up to 4 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Trilaciclib dihydrochloride/Cosela, Metastatic Urothelial Carcinoma, Cyclin-dependent kinase 4/6 inhibitor, Immuno-oncology, Solid tumor, Chemotherapy-induced myelosuppression, Myeloprotective