Bladder Cancer, Chemotherapy-induced Neutropenia, Metastatic Bladder Cancer, Myelosuppression Adult, Urothelial Carcinoma
Conditions
Keywords
Trilaciclib dihydrochloride/Cosela, Metastatic Urothelial Carcinoma, Cyclin-dependent kinase 4/6 inhibitor, Immuno-oncology, Solid tumor, Chemotherapy-induced myelosuppression, Myeloprotective
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.
Interventions
DRUGTrilaciclib
Trilaciclib administered IV prior to chemotherapy and avelumab maintenance therapy on each day chemotherapy and avelumab maintenance therapy is administered.
DRUGGemcitabine
Gemcitabine administered IV on Day 1 and Day 8 of each 21-day cycle
DRUGCisplatin
Cisplatin administered IV on Day 1 of each 21-day cycle
DRUGCarboplatin
Carboplatin administered IV on Day 1 of each 21-day cycle
DRUGAvelumab
Avelumab administered IV on Day 1 of each 14-day maintenance cycle
Sponsors
G1 Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Random assignment (1:1) to one of two treatment arms
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| 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. |
| 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. |
| 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. |
| 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. |
| 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 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. |
| 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). |
| 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 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. |
| 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. |
Countries
France, Georgia, Hungary, Spain, United States
Participant flow
Recruitment details
This study was conducted at 55 sites in the United States (US), Hungary, Georgia, France, and Spain from 4 June 2021 (first participant enrolled) to 1 March 2024 (last participant last visit).
Pre-assignment details
Of the 116 participants enrolled, 24 were screen failures and 92 participants were randomized to treatment.
Participants by arm
| Arm | Count |
|---|---|
| Platinum-based Chemotherapy Followed by Avelumab Maintenance Therapy Gemcitabine (1000 mg/m\^2) + Cisplatin (70 mg/m\^2) or Carboplatin (AUC 4.5) followed by Avelumab (800 mg)
Gemcitabine: Gemcitabine administered IV on Day 1 and Day 8 of each 21-day cycle
Cisplatin: Cisplatin administered IV on Day 1 of each 21-day cycle
Carboplatin: Carboplatin administered IV on Day 1 of each 21-day cycle
Avelumab: Avelumab administered IV on Day 1 of each 14-day maintenance cycle | 47 |
| Trilaciclib Plus Platinum-based Chemotherapy Followed by Avelumab Maintenance Therapy 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: Trilaciclib administered IV prior to chemotherapy and avelumab maintenance therapy on each day chemotherapy and avelumab maintenance therapy is administered.
Gemcitabine: Gemcitabine administered IV on Day 1 and Day 8 of each 21-day cycle
Cisplatin: Cisplatin administered IV on Day 1 of each 21-day cycle
Carboplatin: Carboplatin administered IV on Day 1 of each 21-day cycle
Avelumab: Avelumab administered IV on Day 1 of each 14-day maintenance cycle | 45 |
| Total | 92 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 26 | 26 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Other | 1 | 0 |
| Overall Study | Study Terminated by Sponsor | 18 | 17 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | Platinum-based Chemotherapy Followed by Avelumab Maintenance Therapy | Trilaciclib Plus Platinum-based Chemotherapy Followed by Avelumab Maintenance Therapy | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 34 Participants | 28 Participants | 62 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants | 17 Participants | 30 Participants |
| Age, Continuous | 67.8 years STANDARD_DEVIATION 10.34 | 67.3 years STANDARD_DEVIATION 8.4 | 67.6 years STANDARD_DEVIATION 9.39 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 38 Participants | 34 Participants | 72 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 8 Participants | 9 Participants | 17 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 9 Participants | 11 Participants | 20 Participants |
| Race (NIH/OMB) White | 37 Participants | 34 Participants | 71 Participants |
| Sex: Female, Male Female | 8 Participants | 11 Participants | 19 Participants |
| Sex: Female, Male Male | 39 Participants | 34 Participants | 73 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 26 / 47 | 26 / 45 |
| other Total, other adverse events | 45 / 47 | 44 / 45 |
| serious Total, serious adverse events | 13 / 47 | 18 / 45 |
Outcome results
Primary
Number of Participants With Progression-Free Survival (PFS) During Overall Study
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.
Time frame: 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
Population: The Intent-to-treat (ITT) analysis set included all randomized participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Platinum-based Chemotherapy Followed by Avelumab Maintenance Therapy | Number of Participants With Progression-Free Survival (PFS) During Overall Study | 36 Participants |
| Trilaciclib Plus Platinum-based Chemotherapy Followed by Avelumab Maintenance Therapy | Number of Participants With Progression-Free Survival (PFS) During Overall Study | 34 Participants |
Secondary
Disease Control Rate (DCR) During Maintenance Period
The DCR was defined as the percentage of participants with best overall response (BOR) of confirmed CR, confirmed PR, or SD.
Time frame: 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.
Population: The maintenance population included all the randomized participants who received at least 1 dose of any study drug during the maintenance period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Platinum-based Chemotherapy Followed by Avelumab Maintenance Therapy | Disease Control Rate (DCR) During Maintenance Period | 44.8 Percentage of participants |
| Trilaciclib Plus Platinum-based Chemotherapy Followed by Avelumab Maintenance Therapy | Disease Control Rate (DCR) During Maintenance Period | 26.7 Percentage of participants |
Secondary
Disease Control Rate During Overall Study
The DCR was defined as the percentage of participants with BOR of confirmed CR, confirmed PR, or SD.
Time frame: 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
Population: The RE analysis set included those participants who were in the ITT population and received at least 1 dose of any study drug, have measurable (target) tumor lesion(s) at baseline tumor assessment, and have at least 1 of the following: (1) at least 1 post-baseline tumor assessment; (2) discontinued treatment because of clinical progression prior to their first post-baseline tumor scan; (3) died due to disease progression prior to their first post-baseline tumor scan.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Platinum-based Chemotherapy Followed by Avelumab Maintenance Therapy | Disease Control Rate During Overall Study | 89.1 percentage of participants |
| Trilaciclib Plus Platinum-based Chemotherapy Followed by Avelumab Maintenance Therapy | Disease Control Rate During Overall Study | 82.2 percentage of participants |
Secondary
Duration of Response (DoR), Overall Study
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.
Time frame: 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
Population: The RE analysis set included those participants who were in the ITT population and received at least 1 dose of any study drug, have measurable (target) tumor lesion(s) at baseline tumor assessment, and have at least 1 of the following: (1) at least 1 post-baseline tumor assessment; (2) discontinued treatment because of clinical progression prior to their first post-baseline tumor scan; (3) died due to disease progression prior to their first post-baseline tumor scan.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Platinum-based Chemotherapy Followed by Avelumab Maintenance Therapy | Duration of Response (DoR), Overall Study | 6.6 Months |
| Trilaciclib Plus Platinum-based Chemotherapy Followed by Avelumab Maintenance Therapy | Duration of Response (DoR), Overall Study | 7.0 Months |
Secondary
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. Myeloprotective effects protect the blood-forming cells in the bone marrow from the side effects of chemotherapy such as bone marrow suppression.
Time frame: Cycle 1 Day 1 (each cycle is 21 days) through treatment with platinum-based chemotherapy, approximately up to 4 months
Population: The ITT analysis set included all randomized participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Platinum-based Chemotherapy Followed by Avelumab Maintenance Therapy | Myeloprotective Effects | 0.8 Duration of severe neutropenia (days) | Standard Deviation 2.88 |
| Trilaciclib Plus Platinum-based Chemotherapy Followed by Avelumab Maintenance Therapy | Myeloprotective Effects | 0.5 Duration of severe neutropenia (days) | Standard Deviation 2 |
Secondary
Number of Participants With Adverse Events (AE)
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.
Time frame: From first administration of study treatment (Day 1) until 30 days after the last dose of study treatment, approximately 96 weeks.
Population: The Safety Population included all randomized participants who received at least 1 dose of any study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Platinum-based Chemotherapy Followed by Avelumab Maintenance Therapy | Number of Participants With Adverse Events (AE) | 45 Participants |
| Trilaciclib Plus Platinum-based Chemotherapy Followed by Avelumab Maintenance Therapy | Number of Participants With Adverse Events (AE) | 44 Participants |
Secondary
Number of Participants With Objective Response Rate During Overall Treatment Period
The ORR defined as the percentage of participants who had an objective response (unconfirmed or confirmed) per RECIST v1.1
Time frame: 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
Population: The RE analysis set included those participants who were in the ITT population and received at least 1 dose of any study drug, have measurable (target) tumor lesion(s) at baseline tumor assessment, and have at least 1 of the following: (1) at least 1 post-baseline tumor assessment; (2) discontinued treatment because of clinical progression prior to their first post-baseline tumor scan; (3) died due to disease progression prior to their first post-baseline tumor scan.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Platinum-based Chemotherapy Followed by Avelumab Maintenance Therapy | Number of Participants With Objective Response Rate During Overall Treatment Period | 24 Participants |
| Trilaciclib Plus Platinum-based Chemotherapy Followed by Avelumab Maintenance Therapy | Number of Participants With Objective Response Rate During Overall Treatment Period | 23 Participants |
p-value: 0.93895% CI: [-0.22, 0.203]Cochran-Mantel-Haenszel
Secondary
Number of Participants With Objective Response Rate (ORR) During Chemotherapy Period
The ORR defined as the percentage of participants who had an objective response (unconfirmed or confirmed) per RECIST v1.1
Time frame: 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
Population: The Response Evaluable (RE) analysis set included those participants who were in the ITT population and received at least 1 dose of any study drug, have measurable (target) tumor lesion(s) at baseline tumor assessment, and have at least 1 of the following: (1) at least 1 post-baseline tumor assessment; (2) discontinued treatment because of clinical progression prior to their first post-baseline tumor scan; (3) died due to disease progression prior to their first post-baseline tumor scan.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Platinum-based Chemotherapy Followed by Avelumab Maintenance Therapy | Number of Participants With Objective Response Rate (ORR) During Chemotherapy Period | 24 Participants |
| Trilaciclib Plus Platinum-based Chemotherapy Followed by Avelumab Maintenance Therapy | Number of Participants With Objective Response Rate (ORR) During Chemotherapy Period | 19 Participants |
p-value: 0.3495% CI: [-0.308, 0.105]Cochran-Mantel-Haenszel
Secondary
Number of Participants With Progression-Free Survival During Maintenance Period
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.
Time frame: 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.
Population: The maintenance population included all the randomized participants who received at least 1 dose of any study drug during the maintenance period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Platinum-based Chemotherapy Followed by Avelumab Maintenance Therapy | Number of Participants With Progression-Free Survival During Maintenance Period | 22 Participants |
| Trilaciclib Plus Platinum-based Chemotherapy Followed by Avelumab Maintenance Therapy | Number of Participants With Progression-Free Survival During Maintenance Period | 20 Participants |
Secondary
Number of Participants With Serious Adverse Events (SAE)
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.
Time frame: From first administration of study treatment (Day 1) until 30 days after the last dose of study treatment, approximately 96 weeks.
Population: The Safety Population included all randomized participants who received at least 1 dose of any study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Platinum-based Chemotherapy Followed by Avelumab Maintenance Therapy | Number of Participants With Serious Adverse Events (SAE) | 13 Participants |
| Trilaciclib Plus Platinum-based Chemotherapy Followed by Avelumab Maintenance Therapy | Number of Participants With Serious Adverse Events (SAE) | 18 Participants |
Secondary
Overall Survival During Maintenance Period
The OS was calculated as the time (months) from date of randomization to the date of death due to any cause.
Time frame: 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.
Population: The maintenance population included all the randomized participants who received at least 1 dose of any study drug during the maintenance period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Platinum-based Chemotherapy Followed by Avelumab Maintenance Therapy | Overall Survival During Maintenance Period | 13 Participants |
| Trilaciclib Plus Platinum-based Chemotherapy Followed by Avelumab Maintenance Therapy | Overall Survival During Maintenance Period | 17 Participants |
Secondary
Overall Survival During Overall Study
The OS was calculated as the time (months) from date of randomization to the date of death due to any cause.
Time frame: From first administration of study treatment (Day 1) until 30 days after the last dose of study treatment, approximately 96 weeks.
Population: The ITT analysis set included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Platinum-based Chemotherapy Followed by Avelumab Maintenance Therapy | Overall Survival During Overall Study | 14.6 months |
| Trilaciclib Plus Platinum-based Chemotherapy Followed by Avelumab Maintenance Therapy | Overall Survival During Overall Study | 15.4 months |
Secondary
Percentage of Participants Survived at 12 Months [Overall Survival (OS) Rate]
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).
Time frame: From date of randomization (Day 1) up to Month 12
Population: The ITT analysis set included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Platinum-based Chemotherapy Followed by Avelumab Maintenance Therapy | Percentage of Participants Survived at 12 Months [Overall Survival (OS) Rate] | 64.6 Percentage Of - Participants |
| Trilaciclib Plus Platinum-based Chemotherapy Followed by Avelumab Maintenance Therapy | Percentage of Participants Survived at 12 Months [Overall Survival (OS) Rate] | 54.0 Percentage Of - Participants |
Secondary
Percentage of Participants With Probability of Survival at 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).
Time frame: 16 months
Population: The ITT analysis set included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Platinum-based Chemotherapy Followed by Avelumab Maintenance Therapy | Percentage of Participants With Probability of Survival at 16 Months. | 44.5 percentage of participants |
| Trilaciclib Plus Platinum-based Chemotherapy Followed by Avelumab Maintenance Therapy | Percentage of Participants With Probability of Survival at 16 Months. | 46.9 percentage of participants |