Untreated, Locally Advanced or Metastatic Urothelial Carcinoma MedDRA version: 20.0 Level: LLT Classification code 10046714 Term: Urothelial carcinoma bladder System Organ Class: 100000004864 MedDRA version: 20.0 Level: LLT Classification code 10064467 Term: Urothelial carcinoma System Organ Class: 100000004864
Conditions
Interventions
Trade Name: COSELA
Pharmaceutical Form: Powder for concentrate for solution for infusion
INN or Proposed INN: Trilaciclib dihydrochloride
CAS Number: 1977495-97-8
Current Sponsor code: G1T28
Other des
Sponsors
G1 Therapeutics, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
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) (also termed TCC or UCC of the urinary tract; including renal pelvis, ureters, urinary bladder, and urethra). a. Patients with mixed histologies are required to have a dominant transitional cell pattern (small cell carcinoma of any proportion is not allowed). b. 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) 3. 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. 4. Considered to be eligible to receive platinum-based chemotherapy and avelumab maintenance therapy, in the Investigator’s judgment 5. No prior systemic therapy in the inoperable, locally advanced, or metastatic setting including chemotherapy, immune checkpoint inhibitor therapy, targeted therapy, or investigational agents. a. For patients who received prior adjuvant/neoadjuvant chemotherapy or chemoradiation 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. b. Prior local intravesical chemotherapy or immunotherapy is allowed if completed =4 weeks prior to the initiation of study treatment. 6. Provision of a recent formalin-fixed, paraffin-embedded (FFPE) tumor tissue block (75-micron) or at least 15 (5-micron) unstained slides from the most recent primary or metastatic tumor biopsy or resection obtained prior to treatment with first-line chemotherapy but within one year of randomization, with no intervening systemic anti-cancer therapy. If a suitable tissue sample is not otherwise available, then an FFPE tissue block from a de novo biopsy (core needle or excisional) must have been obtained for research purposes prior to randomization in this study. Patients who have fewer than 15 unstained slides available at baseline (but no fewer than 10) may be eligible following discussion with the Medical Monitor. a. 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. b. 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. c. Patients 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. d. Tumor tissue from bone metastases is not evaluable for PD-L1 expression and is therefore not acceptable. 7. ECOG performance status of 0-2 8. Adeq
Exclusion criteria
Exclusion criteria: 1. Prior treatment with IL-2, IFN-a, 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. Patient 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 4. 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 5. QTcF interval > 480 msec. For patients with ventricular pacemakers, QTcF > 500 msec 6. Known history of stroke or cerebrovascular accident within 6 months prior to first dose of study drugs 7. Known serious active infection (e.g., human immunodeficiency virus, hepatitis B or C, tuberculosis, etc.). a. Positive hepatitis B virus surface antigen or hepatitis C virus ribonucleic acid (RNA) if anti-hepatitis C virus antibody screening test positive 8. Any active infection requiring systemic therapy or any severe infections within 4 weeks prior to randomization, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia. a. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease or for dental extraction) are eligible 9. Other uncontrolled serious chronic disease or psychiatric condition that in the Investigator’s opinion could affect patient safety, compliance, or follow-up in the protocol 10. 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 11. Known hypersensitivity or allergy to study drugs or any component in their formulations 12. 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) (GINA, 2020) 13. Prior hematopoietic stem cell or bone marrow transplantation, or solid organ transplantation 14. Radiotherapy to any non-CNS site within 1 week prior to the first dose of study drugs, or within 2 weeks to any CNS sites 15. Pregnant or lactating women. a. Women of childbearing potential must have negative serum pregnancy test result within 7 days prior to initiating study treatment 16. 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 17. Recei
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the anti-tumor efficacy of trilaciclib compared to a control group (as measured by PFS in the overall study);Secondary Objective: -To evaluate the anti-tumor efficacy of trilaciclib compared to a control group (as measured by ORR, DCR, DOR, PFS in the maintenance period, and OS). -To evaluate the myeloprotective effects of trilaciclib when combined with platinum-based chemotherapy compared with chemotherapy alone -To assess the effects of trilaciclib on the neutrophil lineage compared to a control group. -To assess the effects of trilaciclib on the RBC lineage compared to a control group. -To assess the effects of trilaciclib on the platelet lineage compared to a control group. -To assess the effects of trilaciclib on hospitalizations due to chemotherapyinduced myelosuppression compared to a control group. -To assess the effects of trilaciclib on chemotherapy dosing compared to a control group. -To assess the safety and tolerability of trilaciclib compared to a control group;Primary end point(s): The primary efficacy endpoint, PFS (months) during the overall study, is defined as the time from the date of randomization to the date of documented radiologic disease progression per RECIST v1.1 or death due to any cause, whichever comes first regardless of in which treatment period the event occurs.;Timepoint(s) of evaluation of this end point: The primary analysis for PFS will be conducted at the time when 63 patients have radiographic-determined disease progression or died. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • ORR defined as the proportion of patients who had an objective response (unconfirmed or confirmed) per RECIST v1.1 (chemotherapy period, maintenance period, during the overall study) • DCR, defined as the proportion of patients with best overall response of confirmed CR or PR, or SD lasting at least 24 weeks per RECIST v1.1 (maintenance period, during the overall study) • DOR per RECIST v1.1 (during the overall study) • PFS (maintenance period). • OS defined as the time (months) from the date of randomization to the date of death (maintenance period, during the overall study) • Probability of survival at Month 16 • Duration of severe (Grade 4) neutropenia in Cycle 1 • Occurrence of severe (Grade 4) neutropenia • Occurrence of febrile neutropenia AEs • Occurrence of G-CSF administration • Occurrence of Grade 3 or 4 decreased hemoglobin laboratory values • RBC transfusions on or after Week 5 (occurrence and number of transfusions) • Occurrence of ESA administration • Occurrence of Grade 3 or 4 decreased platelet count laboratory values • Platelet transfusions (occurrence and number of transfusions) • Occurrence and number of hospitalizations due to chemotherapy-induced myelosuppression • All-cause dose reductions (occurrence and number of reductions) • All-cause cycle delays (occurrence and number of delays) • Occurrence and severity of AEs by NCI-CTCAE v5.0 • Trilaciclib AESIs • Avelumab AESIs • Changes in laboratory parameters (hematology and serum chemistry), vital signs and ECG parameters • Grade 3 or 4 abnormalities in serum chemistry laboratory parameters • Occurrence of trilaciclib dose delays and infusion interruptions • Occurrence of chemotherapy dose reductions • Occurrence of chemotherapy dose delays and infusion interruptions • Occurrence of avelumab dose delays and infusion interruptions;Timepoint(s) of evaluation of this end point: 1. After all randomized patients have either completed chemotherapy or discontinued during the c | — |
Countries
France, Georgia, Hungary, Romania, Spain, United States
Contacts
Public ContactClinical Trial Information
G1 Therapeutics, Inc.
Outcome results
None listed