Sponsor no longer pursuing trilaciclib for the indication.

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.

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.

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 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)

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

   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

6. 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.

7. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

8. 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

9. 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

10. Predicted life expectancy of ≥3 months

11. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

12. 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:

1. 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

2. 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

3. 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

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 participants 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 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

8. 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

9. 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

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)

13. Prior hematopoietic stem cell or bone marrow transplantation, or solid organ transplantation

14. 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

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. 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

18. 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

19. 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

20. 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)

21. 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.

Investigator agrees to submit any disclosure to Sponsor for review at least thirty (30) days prior to submission. Within sixty (60) days of its receipt, Sponsor can provide feedback on any disclosure Sponsor may require Investigator to remove, Confidential Information (other than study data), and/or to delay the proposed publication or presentation for an additional sixty (60) days to enable Sponsor to seek patent protection for inventions.