Trilaciclib, a CDK 4/6 Inhibitor, in Patients With Advanced/Metastatic Bladder Cancer Receiving Chemotherapy Then Avelumab (PRESERVE3)

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)

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.

Study Overview

• Status: Terminated
• Conditions: Bladder Cancer; Urothelial Carcinoma; Chemotherapy-induced Neutropenia; Myelosuppression Adult; Metastatic Bladder Cancer
• Intervention / Treatment: Drug: Gemcitabine; Drug: Cisplatin; Drug: Carboplatin; Drug: Avelumab; Drug: Trilaciclib

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 92
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Lyon, France, 69373
    • Centre Leon Berard - departement d'oncologie medicale
  • Paris, France, 75015
    • Hôpital Européen Georges Pompidou - Service d'Oncologie Médicale
  • Vandœuvre-lès-Nancy, France, 54519
    • Institut de Cancérologie de Lorraine
  • Bas-Rhin
    • Strasbourg, Bas-Rhin, France, 67091
      • Hopitaux Universitaires de Strasbourg - Service Oncologie et Hématologie
  • Gironde
    • Bordeaux cedex, Gironde, France, 33076
      • Institut Bergonié - Oncologie Médicale et Pédiatrique
• Georgia
  • Tbilisi, Georgia, 0144
    • National Center of Urology Named after Laur Managadze
  • Tbilisi, Georgia, 186
    • LTD "Multiprofile Clinic Consilium Medulla"
  • Ajaria
    • Batumi, Ajaria, Georgia, 6010
      • High Technology Hospital MedCenter Ltd
• Hungary
  • Budapest, Hungary, 1122
    • Országos Onkológiai Intézet
  • Budapest, Hungary, H-1145
    • Uzsoki Utcai Kórház
  • Jász-Nagykun-Szolnok
    • Szolnok, Jász-Nagykun-Szolnok, Hungary, H-5000
      • Jasz-Nagykun-Szolnok Megyei Hetenyi Geza Korhaz - Rendeloint
• Spain
  • Barcelona, Spain, 08041
    • Hospital de la Santa Creu i Sant Pau
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d´Hebrón
  • Barcelona, Spain, 08036
    • Hospital Clinic de Barcelona - Servicio de Oncología Médica
  • Granada, Spain, 18014
    • H.U. V. de las Nieves
  • Lugo, Spain, 27003
    • Hospital Universitario Lucus Augusti
  • Valencia, Spain, 46009
    • Fundación Instituto Valenciano de Oncología
  • Valencia, Spain, 46026
    • Hospital Politecnic Universitari La Fe
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Institut Català d'Oncologia-Hospital Universitari Germans Trias i Pujol
    • Manresa, Barcelona, Spain, 08243
      • ALTHAIA, Xarxa Assistencial Universitiria de Manresa
  • Madrid
    • Majadahonda, Madrid, Spain, 28222
      • Hospital Universitario Puerta de Hierro Majadahonda
• United States
  • California
    • Los Angeles, California, United States, 90067
      • Valkyrie Clinical Trial
    • Whittier, California, United States, 90603
      • The Oncology Institute of Hope and Innovation
  • Colorado
    • Littleton, Colorado, United States, 80120
      • Rocky Mountain Cancer Centers
  • Florida
    • Fort Myers, Florida, United States, 33901
      • Florida Cancer Specialists - South
    • Pensacola, Florida, United States, 32503
      • Woodlands Medical Specialists
    • Saint Petersburg, Florida, United States, 33705
      • Florida Cancer Specialists - North
  • Idaho
    • Coeur d'Alene, Idaho, United States, 83814
      • Beacon Cancer Center PLLC
  • Maryland
    • Baltimore, Maryland, United States, 21237
      • The Harry and Jeanette Weinberg Cancer Institute
  • New York
    • Albany, New York, United States, 12206
      • New York Oncology Hematology, P.C.
    • Bronx, New York, United States, 10461
      • Montefiore Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina at Chapel Hill
  • Oregon
    • Tigard, Oregon, United States, 46241
      • Northwest Cancer Specialists, P.C.
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology, PLLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥18 years
2. Histologically documented, locally advanced (T4b, any N; or any T, N 2-3) or metastatic urothelial carcinoma (M1, Stage IV)
3. Measurable disease as defined by RECIST v1.1
4. No prior systemic therapy in the inoperable, locally advanced, or metastatic setting including chemotherapy, immune checkpoint inhibitor therapy, targeted therapy, or investigational agents
5. Archival tumor tissue must be available or a fresh biopsy must be obtained, unless approved by the Medical Monitor
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
7. Adequate organ function as demonstrated by normal laboratory values

Exclusion Criteria:

1. 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
2. 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)
3. Presence of central nervous system (CNS) metastases/leptomeningeal disease requiring immediate treatment with radiation therapy or steroids.
4. QTcF interval > 480 msec. For patients with ventricular pacemakers, QTcF > 500 msec
5. Known hypersensitivity or allergy to avelumab, gemcitabine, cisplatin or carboplatin
6. Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥3), any history of anaphylaxis, or uncontrolled asthma
7. Prior hematopoietic stem cell or bone marrow transplantation, or solid organ transplantation
8. Pregnant or lactating women
9. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent

10. Current use of immunosuppressive medication, EXCEPT for the following:

    1. Intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection)
    2. Systemic corticosteroids at physiological doses ≤10 mg/day of prednisone or equivalent
    3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: G1 Therapeutics, Inc.
• Investigators: Study Director: Clinical Contact, G1 Therapeutics, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): June 4, 2021
• Primary Completion (Actual): April 7, 2023
• Study Completion (Actual): March 1, 2024

Study Registration Dates

• First Submitted: May 5, 2021
• First Submitted That Met QC Criteria: May 13, 2021
• First Posted (Actual): May 14, 2021

Study Record Updates

• Last Update Posted (Actual): March 22, 2024
• Last Update Submitted That Met QC Criteria: March 21, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Solid tumor; Immuno-oncology; Metastatic Urothelial Carcinoma; Trilaciclib dihydrochloride/Cosela; Cyclin-dependent kinase 4/6 inhibitor; Chemotherapy-induced myelosuppression; Myeloprotective
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Neoplasms, Glandular and Epithelial; Urinary Bladder Diseases; Hematologic Diseases; Agranulocytosis; Leukopenia; Leukocyte Disorders; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Cytopenia; Carcinoma; Neutropenia; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Antineoplastic Agents, Immunological; Carboplatin; Avelumab; Gemcitabine
• Other Study ID Numbers: G1T28-209

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No