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

Phase 2

Terminated

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

Interventions: Drug: Gemcitabine
Drug: Trilaciclib
Drug: Cisplatin
Drug: Carboplatin
Drug: Avelumab

Registration Number: NCT04887831

Lead Sponsor: G1 Therapeutics, Inc.

Brief Summary: 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 participants receiving first-line treatment for advanced/metastatic urothelial carcinoma.

Detailed Description: Participants 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.

Participants enrolled in the study will be eligible to receive 4-6 cycles of platinum-based chemotherapy, and participants 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 \[SD\]) 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.

Participants will be followed for survival approximately every 3 months after receiving the last dose of study medication.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 92

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) (also termed Transitional cell carcinoma [TCC] or Urothelial cell carcinoma [UCC] of the urinary tract; including renal pelvis, ureters, urinary bladder, and urethra)
1. Participants with mixed histologies are required to have a dominant transitional cell pattern (small cell carcinoma of any proportion is not allowed)
2. Locally advanced bladder cancer must be inoperable on the basis of involvement of pelvic sidewall or adjacent viscera (clinical Stage T4b) or bulky nodal metastasis (N2-N3)
Measurable disease as defined by RECIST v1.1

a. Previously irradiated lesions should not be counted as target lesions unless there has been demonstrated progression in the lesion since radiotherapy and no other lesions are available for selection as target lesions.
Considered to be eligible to receive platinum-based chemotherapy and avelumab maintenance therapy, in the Investigator's judgment
No prior systemic therapy in the inoperable, locally advanced, or metastatic setting including chemotherapy, immune checkpoint inhibitor therapy, targeted therapy, or investigational agents
1. For participants who received prior adjuvant/neoadjuvant chemotherapy for urothelial carcinoma, a treatment-free interval > 12 months between the last treatment administration and the date of recurrence is required in order to be considered treatment-naïve in the metastatic setting. If a participant received adjuvant/neoadjuvant chemoradiation for urothelial carcinoma, a treatment-free interval >12 months between last platinum dose and the date of recurrence is required.
2. For participants who received prior Immune checkpoint inhibitors (ICI) therapy in the adjuvant/neoadjuvant setting, a treatment-free interval > 3 months between the last dose of ICI and date of recurrence is required.
3. Prior local intravesical chemotherapy or immunotherapy is allowed if completed ≥4 weeks prior to the initiation of study treatment
A formalin-fixed paraffin-embedded (FFPE) tumor tissue block (75-micron) or at least 15 (5-micron) unstained slides from archival or fresh tumor biopsy or resection; the most recent biopsy tissue preferred. Participants who have fewer than 15 unstained slides available at baseline (but no fewer than 10) may be eligible following discussion with the Medical Monitor.
1. Tumor tissue should be of good quality based on total and viable tumor content. For core-needle biopsy specimens, at least three cores should be submitted for evaluation.
2. Transurethral resection of bladder tumor (TURBT) specimens must contain a muscle -invasive component (i.e., T2 or greater) of the bladder tumor as verified by local pathology review. If the TURBT specimens do not contain a muscle-invasive component, then specimens obtained at the time of cystectomy/nephroureterectomy (i.e., pT2 or greater) or metastatic spread (i.e., a sample from a metastatic lesion) will be required prior to randomization. An archival specimen, if available, should also be submitted.
3. Participants who do not have tissue specimens that meet eligibility requirements may undergo a biopsy during the screening period. Acceptable samples include core needle biopsies for deep tumor tissue (minimum three cores) or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions.
4. Tumor tissue from bone metastases is not evaluable for programmed death-ligand 1 (PD-L1) expression and is therefore not acceptable.
Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
Adequate organ function as demonstrated by the following laboratory values:
1. Hemoglobin ≥9.0 gram per deciliter (g/dL) in the absence of RBC transfusion or ESA administration within 14 days prior to first dose of study drug
2. Absolute neutrophil count (ANC) ≥1.5 × 10^9/L
3. Platelet count ≥100 × 10^9/L
4. Estimated glomerular filtration rate ≥ 30 mL/minute/1.73 m^2
5. Total bilirubin ≤1.5 × upper limit of normal (ULN) (<3 ULN if Gilbert's disease)
6. ALT and AST ≤2.5 × ULN in the absence of liver metastasis or <5 × ULN in the presence of liver metastasis
Resolution of nonhematologic toxicities from prior systemic therapy, radiation therapy, or surgical procedures to ≤ Grade 1

a. Alopecia and sensory neuropathy ≤ Grade 2, as well as any electrolyte laboratory abnormalities not constituting a safety risk based on investigator's judgment are acceptable
Predicted life expectancy of ≥3 months
Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form and in this protocol

Exclusion Criteria

Prior treatment with IL-2, IFN-α, 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 within 12 months prior to randomization
Malignancies other than urothelial carcinoma within 2 years prior to randomization, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ, or low-grade (Gleason ≤6) prostate cancer on surveillance without any plans for treatment intervention (e.g., surgery, radiation, or castration), or other non-clinically significant cancers, which may be considered after discussion with the medical monitor
Presence of central nervous system (CNS) metastases/leptomeningeal disease requiring immediate treatment with radiation therapy or steroids. Participant must be off steroids administered for brain metastases for at least 2 weeks prior to the first dose of study drugs. No stereotactic radiation within 1 week or whole-brain radiation within 14 days prior to first dose of study drugs
Uncontrolled ischemic heart disease or uncontrolled symptomatic congestive heart failure (≥ Class II New York Heart Association functional classification system), myocardial infarction within 6 months prior to first dose of study drugs, unstable angina, or serious cardiac arrhythmia requiring medication
QTcF interval > 480 msec. For participants with ventricular pacemakers, QTcF > 500 msec
Known history of stroke or cerebrovascular accident within 6 months prior to first dose of study drugs
Known history of serious, chronic active infection (e.g., human immunodeficiency virus, hepatitis B or C, tuberculosis, etc.)

a. Viral load indicative of HIV, HIV 1/2 antibodies, positive hepatitis B virus surface antigen or hepatitis C virus ribonucleic acid (RNA) if anti-hepatitis C virus antibody screening test positive
Severe infections within 4 weeks prior to randomization, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
1. Therapeutic oral or IV antibiotic use within 2 weeks prior to randomization
2. Participants receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease or for dental extraction) are eligible
Other uncontrolled serious chronic disease or psychiatric condition that in the Investigator's opinion could affect participant safety, compliance, or follow-up in the protocol
Receipt of any investigational medication within 4 weeks, or at least 5 half-lives, whichever is greater, prior to the first dose of study drugs
Known hypersensitivity or allergy to study drugs or any component in their formulations
Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥3), any history of anaphylaxis, or uncontrolled asthma (i.e., 3 or more features of asthma symptom control per Global Initiative for Asthma [GINA] 2020)
Prior hematopoietic stem cell or bone marrow transplantation, or solid organ transplantation
Radiotherapy to any non-Central nervous system (CNS) site within 1 week prior to the first dose of study drugs, or within 2 weeks to any CNS sites
Pregnant or lactating women

a. Women of childbearing potential must have negative serum pregnancy test result within 7 days prior to initiating study treatment
Major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks prior to study treatment start, or anticipation of the need for major surgical procedure during the course of the study
Received a live, attenuated vaccine within 4 weeks prior to the first dose of study drugs
1. Inactive vaccines, including but not limited to influenza vaccine, pneumococcal vaccine, shingles vaccine, and regionally approved Covid-19 vaccines are allowed
2. Participants must agree not to receive a live, attenuated influenza vaccine during study treatment
History of immune colitis, inflammatory bowel disease, idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest computed tomography (CT) scan

a. History of radiation pneumonitis in the radiation field (fibrosis) is permitted
Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Participants with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible
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)
Participants who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the Investigator, or participants who are employees of G1 Therapeutics, Inc. directly involved in the conduct of the study.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Platinum-based chemotherapy followed by avelumab maintenance therapy	Gemcitabine	Gemcitabine 1000 milligram per square meter (mg/m\^2) + Cisplatin (70 mg/m\^2) or Carboplatin (Area under the concentration-time curve \[AUC\] 4.5) followed by Avelumab (800 mg)
Platinum-based chemotherapy followed by avelumab maintenance therapy	Cisplatin	Gemcitabine 1000 milligram per square meter (mg/m\^2) + Cisplatin (70 mg/m\^2) or Carboplatin (Area under the concentration-time curve \[AUC\] 4.5) followed by Avelumab (800 mg)
Trilaciclib plus platinum-based chemotherapy followed by avelumab maintenance therapy	Cisplatin	Trilaciclib (240 mg/m\^2) + Gemcitabine (1000 mg/m\^2) + Cisplatin (70 mg/m\^2) or Carboplatin (AUC 4.5) followed by Trilaciclib (240 mg/m\^2) + Avelumab (800 mg)
Trilaciclib plus platinum-based chemotherapy followed by avelumab maintenance therapy	Avelumab	Trilaciclib (240 mg/m\^2) + Gemcitabine (1000 mg/m\^2) + Cisplatin (70 mg/m\^2) or Carboplatin (AUC 4.5) followed by Trilaciclib (240 mg/m\^2) + Avelumab (800 mg)
Platinum-based chemotherapy followed by avelumab maintenance therapy	Carboplatin	Gemcitabine 1000 milligram per square meter (mg/m\^2) + Cisplatin (70 mg/m\^2) or Carboplatin (Area under the concentration-time curve \[AUC\] 4.5) followed by Avelumab (800 mg)
Platinum-based chemotherapy followed by avelumab maintenance therapy	Avelumab	Gemcitabine 1000 milligram per square meter (mg/m\^2) + Cisplatin (70 mg/m\^2) or Carboplatin (Area under the concentration-time curve \[AUC\] 4.5) followed by Avelumab (800 mg)
Trilaciclib plus platinum-based chemotherapy followed by avelumab maintenance therapy	Trilaciclib	Trilaciclib (240 mg/m\^2) + Gemcitabine (1000 mg/m\^2) + Cisplatin (70 mg/m\^2) or Carboplatin (AUC 4.5) followed by Trilaciclib (240 mg/m\^2) + Avelumab (800 mg)
Trilaciclib plus platinum-based chemotherapy followed by avelumab maintenance therapy	Gemcitabine	Trilaciclib (240 mg/m\^2) + Gemcitabine (1000 mg/m\^2) + Cisplatin (70 mg/m\^2) or Carboplatin (AUC 4.5) followed by Trilaciclib (240 mg/m\^2) + Avelumab (800 mg)
Trilaciclib plus platinum-based chemotherapy followed by avelumab maintenance therapy	Carboplatin	Trilaciclib (240 mg/m\^2) + Gemcitabine (1000 mg/m\^2) + Cisplatin (70 mg/m\^2) or Carboplatin (AUC 4.5) followed by Trilaciclib (240 mg/m\^2) + Avelumab (800 mg)

Primary Outcome Measures

Name	Time	Method
Number of Participants With Progression-Free Survival (PFS) During Overall Study	From date of randomization until date of documented radiologic disease progression per RECIST v1.1 or death due to any cause, whichever comes first. Approximately 96 weeks	The PFS was defined as the time from date of randomization to the date of the first documented disease progression, or death in the absence of PD for those who had a PFS event, and the time from randomization to the censoring date for those who did not have a PFS event.

Secondary Outcome Measures

Name	Time	Method
Disease Control Rate (DCR) During Maintenance Period	From date of randomization, up to 12 cycles (21-day each) of Maintenance therapy until disease progression, unacceptable toxicity or discontinuation by the participant or investigator, assessed up to 34 weeks.	The DCR was defined as the percentage of participants with best overall response (BOR) of confirmed CR, confirmed PR, or SD.
Overall Survival During Maintenance Period	From date of randomization, up to 12 cycles (21-day each) of Maintenance therapy until disease progression, unacceptable toxicity or discontinuation by the participant or investigator, assessed up to 34 weeks.	The OS was calculated as the time (months) from date of randomization to the date of death due to any cause.
Overall Survival During Overall Study	From first administration of study treatment (Day 1) until 30 days after the last dose of study treatment, approximately 96 weeks.	The OS was calculated as the time (months) from date of randomization to the date of death due to any cause.
Number of Participants With Objective Response Rate (ORR) During Chemotherapy Period	From date of randomization until date of documented radiologic disease progression per RECIST v1.1 or death due to any cause, whichever comes first. Approximately 96 weeks	The ORR defined as the percentage of participants who had an objective response (unconfirmed or confirmed) per RECIST v1.1
Number of Participants With Objective Response Rate During Overall Treatment Period	From date of randomization until date of documented radiologic disease progression per RECIST v1.1 or death due to any cause, whichever comes first. Approximately 96 weeks	The ORR defined as the percentage of participants who had an objective response (unconfirmed or confirmed) per RECIST v1.1
Percentage of Participants Survived at 12 Months [Overall Survival (OS) Rate]	From date of randomization (Day 1) up to Month 12	The OS during the study was defined as the time from the date of randomization to the date of death for participants who died in the study regardless of cause, or to the last contact date known to be alive for those who survived as of the date of data snapshot for intermediate planned analysis or final database lock for final analyses (censored cases).
Disease Control Rate During Overall Study	From date of randomization until date of documented radiologic disease progression per RECIST v1.1 or death due to any cause, whichever comes first. Approximately 96 weeks	The DCR was defined as the percentage of participants with BOR of confirmed CR, confirmed PR, or SD.
Percentage of Participants With Probability of Survival at 16 Months.	16 months	The OS was defined as the time from the date of randomization to the date of death for participants who died in the study regardless of cause, or to the last contact date known to be alive for those who survived as of the date for final database lock (censored cases).
Number of Participants With Adverse Events (AE)	From first administration of study treatment (Day 1) until 30 days after the last dose of study treatment, approximately 96 weeks.	An AE was defined as any untoward or unfavourable medical occurrence in a clinical research study participant, including any abnormal sign (e.g. abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the participants' involvement in the research, whether or not considered related to participation in the research.
Myeloprotective Effects	Cycle 1 Day 1 (each cycle is 21 days) through treatment with platinum-based chemotherapy, approximately up to 4 months	To assess the effects of trilaciclib on the neutrophil lineage as measured by the occurrence of severe neutropenia during platinum-based chemotherapy treatment. Myeloprotective effects protect the blood-forming cells in the bone marrow from the side effects of chemotherapy such as bone marrow suppression.
Number of Participants With Progression-Free Survival During Maintenance Period	From date of randomization, up to 12 cycles (21-day each) of Maintenance therapy until disease progression, unacceptable toxicity or discontinuation by the participant or investigator, assessed up to 34 weeks.	The PFS was defined as the time from date of randomization to the date of the first documented disease progression, or death in the absence of PD for those who had a PFS event, and the time from randomization to the censoring date for those who did not have a PFS event.
Duration of Response (DoR), Overall Study	From date of randomization until date of documented radiologic disease progression per RECIST v1.1 or death due to any cause, whichever comes first. Approximately 96 weeks	The DoR was defined as the time from the date of first documented response (CR or PR) to date of first occurrence of disease progression as determined by the investigator, or death from any cause, whichever occurs first.
Number of Participants With Serious Adverse Events (SAE)	From first administration of study treatment (Day 1) until 30 days after the last dose of study treatment, approximately 96 weeks.	SAEs were defined as any untoward medical occurrence that at any dose resulted in death, was life threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity or was a congenital anomaly/birth defect.

Trial Locations

Locations (34): Valkyrie Clinical Trial
🇺🇸
Los Angeles, California, United States
The Oncology Institute of Hope and Innovation
🇺🇸
Whittier, California, United States
Rocky Mountain Cancer Centers
🇺🇸
Littleton, Colorado, United States
Florida Cancer Specialists - South
🇺🇸
Fort Myers, Florida, United States
Woodlands Medical Specialists
🇺🇸
Pensacola, Florida, United States
Florida Cancer Specialists - North
🇺🇸
St. Petersburg, Florida, United States
Beacon Cancer Center PLLC
🇺🇸
Coeur d'Alene, Idaho, United States
The Harry and Jeanette Weinberg Cancer Institute
🇺🇸
Baltimore, Maryland, United States
New York Oncology Hematology, P.C.
🇺🇸
Albany, New York, United States
Montefiore Medical Center
🇺🇸
The Bronx, New York, United States
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Valkyrie Clinical Trial
🇺🇸Los Angeles, California, United States