Chemotherapeutic Toxicity, Colorectal Cancer Metastatic, Myelosuppression-Adult
Conditions
Keywords
Colorectal Cancer, mCRC, colon, chemotherapy-induced myelosuppression, chemotherapy-induced neutropenia, chemotherapy-induced anemia, CDK 4/6 inhibitor, trilaciclib, FOLFOXIRI, bevacizumab, myelosuppression, cyclin-dependent kinase 4/6 inhibitor, myelopreservation, rectum, Preserve, PRESERVE 1
Brief summary
This was a randomized, double-blind, placebo-controlled, global, multicenter, Phase 3 trial evaluating the impact of trilaciclib on myelopreservation and anti-tumor efficacy when administered prior to FOLFOXIRI/bevacizumab in patients with pMMR/MSS mCRC who have not received systemic therapy for metastatic disease.
Detailed description
Patients were randomly assigned (1:1) to receive placebo or trilaciclib on Days 1 and 2 administered intravenously (IV) prior to FOLFOXIRI/bevacizumab in 14-day cycles for up to 12 cycles (Induction). Following completion of Induction, patients continued in Maintenance, where they received trilaciclib or placebo per randomization allocation at study entry. Trilaciclib/placebo will be administered prior to infusional-5FU/leucovorin/bevacizumab at the same dose and schedule used during Induction. The patient continued to receive treatment on study until disease progression, unacceptable toxicity, withdrawal of consent, discontinuation by Investigator, or the end of the trial, whichever occurs first. Treatment cycles occurred consecutively without interruption, except when necessary to manage toxicities or for administrative reasons.
Interventions
DRUGTrilaciclib
Trilaciclib diluted in dextrose 5% in water or normal saline (sodium chloride solution 0.9%) administered by IV infusion over approximately 30 (±10) minutes no more than 4 hours prior to each Day 1 chemotherapy administration. Second dose of trilaciclib was administered on Day 2.
DRUGPlacebo
Dextrose 5% in water or normal saline (sodium chloride solution 0.9%) administered by IV infusion over 30 (±10) minutes no more than 4 hours prior to each Day 1 chemotherapy administration. Second dose of placebo was administered on Day 2.
Sponsors
G1 Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Double-Blinded Trial
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥ 18 years of age at the time of signing the informed consent. Patients \> 70 years of age must have a G8 Health State Screening Tool (geriatric screening tool) score \> 14. 2. Proficient mismatch repair/microsatellite stable (pMMR/MSS), histologically or cytologically-confirmed adenocarcinoma of the colon or rectum. Patients with any BRAF or KRAS mutation status (wild type or mutant) are eligible. If historical pMMR/MSS and/or BRAF V600E mutational status are not known, a tumor specimen (archival or fresh biopsy) must be sent for testing and results must be available at the time of randomization in interactive web response system (IWRS). If testing cannot be completed using a standard clinical assay performed institutionally/locally, the tumor specimen may be sent to the Sponsor's designated central laboratory for analysis; only historical KRAS mutational status will be collected (ie, no testing required prior to study entry). Note: Any sample sent for MSS/BRAF analysis will be in addition to that required per Inclusion Criterion 5. 3. Unresectable and measurable or metastatic colorectal cancer per RECIST v1.1 4. ECOG performance status of 0 to 1 5. A formalin-fixed paraffin-embedded (FFPE) tumor specimen (from archival or fresh biopsy) with an associated pathology report documenting pMMR/MSS mCRC must be confirmed to be available to send to the Sponsor for planned retrospective biomarker analyses (tissue requirements are provided in the associated laboratory manual). 6. Hemoglobin ≥ 9.0 g/dL in the absence of RBC transfusion or ESA administration within 14 days prior to first dose of trilaciclib/placebo 7. Absolute neutrophil count (ANC) ≥ 1.5 × 10\^9 /L 8. Platelet count ≥ 100 × 10\^9 /L 9. Estimated glomerular filtration rate (eGFR) ≥ 30 mL/minute/1.73m\^2 10. Total bilirubin ≤ 1.5 × upper limit of normal (ULN) 11. AST, ALT, and alkaline phosphatase ≤ 3 × ULN for patients without liver or bone metastases; AST, ALT and alkaline phosphatase ≤ 5 × ULN in the presence of liver metastases; AST and ALT ≤ 3 x ULN and alkaline phosphatase ≤ 5 × ULN in the presence of bone metastases 12. Resolution of nonhematologic toxicities from prior therapy or surgical procedures to ≤ Grade 1 or baseline (except alopecia) 13. Urine dipstick protein \< 2+. If ≥ 2+ at Screening, then a 24-hour urine collection must be done to demonstrate ≤ 1 g of protein/24 hours 14. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Please see Section 17.4 for detailed instructions on methods of contraception requirements. 15. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
Exclusion criteria
1. Prior systemic therapy for mCRC. Patients who received adjuvant/neoadjuvant therapy (ie, treatment with curative intent) for colorectal cancer are eligible if it has been ≥ 6 months between the last dose of systemic chemotherapy and the date of informed consent. 2. Any radiotherapy, chemotherapy, immunotherapy, biologic, investigational, or hormonal therapy for cancer treatment (except for adjuvant hormonal therapy for breast cancer or prostate cancer defined as M0 disease or PSA persistence/recurrence without metastatic disease) within 3 weeks prior to the first dose of trilaciclib/placebo. 3. Receipt of any low-dose systemic chemotherapeutic agent (e.g., low-dose methotrexate for rheumatoid arthritis) administered for a nononcologic purpose within 3 weeks prior to the first dose of trilaciclib/placebo. 4. Presence of central nervous system (CNS) metastases/leptomeningeal disease requiring immediate treatment with radiation therapy or steroids (i.e., patient must be off steroids administered for brain metastases for at least 14 days prior to the first dose of trilaciclib/placebo). 5. QTcF interval \> 450 msec (males) or \> 470 msec (females) at screening. For patients with ventricular pacemakers, QTcF \> 500 msec. 6. Personal or family history of long QT syndrome 7. Symptomatic peripheral neuropathy 8. History of interstitial lung disease (ILD) 9. Uncontrolled hypertension (blood pressure ≥ 150/90mm Hg) 10. Clinically significant (i.e., active) cardiovascular disease at the time of signing the informed consent; for example cerebrovascular accidents (≤ 6 months before the first dose of trilaciclib/placebo), myocardial infarction (≤ 6 months before the first dose of trilaciclib/placebo), unstable angina, serious cardiac arrhythmia requiring medication, or uncontrolled symptomatic congestive heart failure \[Class II or higher as defined by the New York Heart Association \[NYHA\] functional classification system\]) 11. Serious, non-healing wound, ulcer, or bone fracture 12. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study treatment start, or anticipation of the need for major surgical procedure during the course of the study. 13. Known serious active infection (e.g., human immunodeficiency virus \[HIV\], hepatitis B or C, tuberculosis, etc.) 14. Known Gilbert's Syndrome or homozygous for the UGT1A1\*28 allele. UGT1A1 genotyping is not required for this study. 15. Chronic inflammatory bowel disease and/or active intestinal obstruction. Patients should not be treated until the intestinal obstruction has resolved. 16. Previous history of significant/severe hemorrhage, within 1 month before randomization. History of previous abdominal fistula or gastrointestinal perforation within 6 months before randomization 17. Known history of bleeding diathesis or coagulopathy 18. INR \> 1.5 within 14 days prior to starting study treatment. EXEMPTION: patients on full anticoagulation must have an in-range INR (usually between 2 to 3) if INR is used for monitoring. Any anticoagulation therapy must be at stable dosing prior to enrollment. 19. Ongoing or anticipated treatment with potent cytochrome inhibitors CYP450 3A4 (such as ketoconazole) or inducers (such as rifampicin, carbamazepine, phenobarbital, phenytoin or St. John's wort). Irinotecan should not be delivered concurrently. 20. Patients with ongoing or anticipated treatment with sorivudine or its chemically related analogues, such as brivudine. 21. Chronic, daily treatment with high-dose aspirin (\> 325 mg/day) 22. Prior allogeneic or autologous hematopoietic stem cell or bone marrow transplantation 23. Receipt of any live attenuated vaccines within 4 weeks prior to first dose of study treatment 24. Known hypersensitivity to any of the drugs used in this study 25. Pregnant or lactating women 26. Legal incapacity or limited legal capacity 27. 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 28. Any contraindications to the administration of FOLFOXIRI and bevacizumab at the discretion of the investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Severe Neutropenia (DSN) | Cycles 1 to 4 (14-day cycles up to 56 days) | The DSN was defined as the number of days for the first severe neutropenia (SN) event in Cycles 1, 2, 3, or 4 for participants who had at least one SN event in the first 4 cycles of Induction. It was calculated as the days from the date of the first absolute neutrophil count (ANC) value of \< 0.5 × 10\^9/L to the date of the first ANC value ≥ 0.5 × 10\^9/L where no additional ANC values \< 0.5 × 10\^9/L were observed for the remainder of that cycle. |
| Occurrence of Severe Neutropenia (SN) During Induction | Induction Period, cycles 1-12 (14-day cycles up to 168 days) | Severe neutropenia was defined as the absolute neutrophil count (ANC) laboratory value that met the Common Terminology Criteria for Adverse vents (CTCAE) criteria for ≥ Grade 4 toxicity (ie, ANC \< 0.5 × 10\^9/L in SI Unit) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Red Blood Cell Lineage | Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab | To assess the effects of trilaciclib on the red blood cell (RBC) lineage compared with placebo in patients receiving FOLFOXIRI/bevacizumab for pMMR/MSS mCRC by measure of Grade 3 or 4 decreased hemoglobin laboratory values, RBC transfusions on or after Week 5, and erythropoiesis-stimulating agents (ESA) administration |
| Platelet Lineage | Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab | To assess the effects of trilaciclib on the platelet lineage compared with placebo in patients receiving FOLFOXIRI/bevacizumab for pMMR/MSS mCR by measure of Grade 3 or 4 decreased platelet count laboratory values and Platelet transfusions. |
| Multiple Lineage | Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab | To assess the effects of trilaciclib on multiple lineages compared with placebo in patients receiving FOLFOXIRI/bevacizumab for pMMR/MSS mCRC by measure of Grade 3 or 4 hematologic lab values. |
| Standard of Care Dosing | Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab | To assess the effects of trilaciclib on standard of care dosing compared with placebo in patients receiving FOLFOXIRI/ bevacizumab for pMMR/MSS mCRC by measure of all-cause dose reductions or cycle delays and relative dose intensity for FOLFOXIRI/bevacizumab |
| Healthcare Utilization | Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab | To assess the effects of trilaciclib on healthcare utilization compared with placebo in patients receiving FOLFOXIRI/ bevacizumab for pMMR/MSS mCRC by measure of hospitalizations and antibiotic use. |
| Overall Survival (OS) | Up to 52 months | Overall survival is defined as the time from the date of the first dose of study treatment to the date of death from any cause. |
| Objective Response Rate (ORR) | Assessed from the day of the first dose of the study drug, through 30 days after the last dose of the study drug, up to 115 weeks | ORR was defined as the percentage of participants in the analysis population who had a Complete Response (CR) defined as a disappearance of all target lesions with pathological lymph nodes having a reduction in short axis to \<10 mm or Partial Response (PR) defined as at least a 30% decrease in the sum of diameters of target lesions, using the baseline sum diameters as a reference based on RECIST v1.1. |
| Duration of Objective Response (DOR) | Assessed from the day of the first dose of the study drug, through 30 days after the last dose of the study drug, up to 115 weeks | DOR is the time between first objective response of CR or PR and the first date that progressive disease is objectively documented or death, whichever comes first. |
| Progression Free Survival (PFS) | Assessed from the day of the first dose of the study drug, through 30 days after the last dose of the study drug, up to 115 weeks | PFS is defined as the time from the date of randomization until the date of documented radiologic disease progression per RECIST v1.1 or death due to any cause, whichever comes first. |
| Quality of Life/ Effects on Chemotherapy-Induced Fatigue | Through Induction Period- on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab | To assess the effects of trilaciclib on chemotherapy-induced fatigue compared with placebo in patients receiving FOLFOXIRI/bevacizumab for pMMR/MSS mCRC, as measured by Time To First Confirmed Deterioration of Fatigue (TTCD-fatigue) during Induction, as measured by the FACIT-F (Functional Assessment of Chronic Illness Therapy-Fatigue). |
| Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Safety was assessed from the day of the first dose of the study drug, through 30 days after the last dose of the study drug, up to 115 weeks | To assess the safety and tolerability of trilaciclib compared with placebo in patients receiving FOLFOXIRI/ bevacizumab for pMMR/MSS mCRC by measure of occurrence and severity of AEs by National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0, changes in laboratory parameters, vital signs and electrocardiogram (ECG) parameters, grade 3 or 4 abnormalities in chemistry laboratory parameters, and study treatment discontinuation due to AEs. |
| Best Overall Response (BOR) | Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab | Best overall response (BOR) will be determined using all visit responses prior to or on the date of (i) radiographic disease progression; (ii) withdrawal of consent to obtain scans; (iii) death; (iv) lost to follow-up; or (v) initiation of subsequent anti-cancer therapy other than the study drugs, whichever is earlier will be based on RECIST v1.1. |
| Additional Myelopreservation Measures | Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab | To assess the effects of trilaciclib on additional measures of the neutrophil lineage compared with placebo in patients receiving FOLFOXIRI/bevacizumab for pMMR/MSS mCRC as measured by the number of SN events, granulocyte-colony stimulating factor (G-CSF) administration and febrile neutropenia (FN) adverse events (AE) |
Countries
China, Hungary, Italy, Poland, Spain, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
89 study centers in 8 countries consented at least 1 participant. The first participant was enrolled on January 6, 2021 and the last visit of the last participant occurred on March 31, 2023.
Pre-assignment details
A total of 458 participants were screened in this study. 326 participants were randomized in a double-blind manner to receive either trilaciclib or placebo, administered on Days 1 and 2 of each cycle of FOLFOXIRI and bevacizumab therapy. A total of 319 participants received at least 1 dose of study drug.
Participants by arm
| Arm | Count |
|---|---|
| Trilaciclib + FOLFOXIRI/Bevacizumab During Induction the following study drugs were administered on Day 1:
Trilaciclib - IV infusion prior to chemotherapy Irinotecan- IV, Oxaliplatin - IV, Leucovorin- IV, Fluorouracil (5-FU) - continuous infusion (CI) over 46-48 hours beginning on Day 1, Bevacizumab - IV
The Induction Day 1 administration of trilaciclib was repeated on Induction Day 2.
Following completion of Induction, patients continued in Maintenance, where they continued to receive trilaciclib per randomization allocation. Trilaciclib was administered prior to infusional-5FU/leucovorin/bevacizumab at the same dose and schedule used during Induction. | 164 |
| Placebo + FOLFOXIRI/Bevacizumab The subjects in the placebo arm followed the same schedule as the trilaciclib arm, but received placebo instead of trilaciclib
Placebo: dextrose 5% in water or normal saline (sodium chloride solution 0.9%) | 162 |
| Total | 326 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 49 | 26 |
| Overall Study | Lost to Follow-up | 3 | 4 |
| Overall Study | Other, unspecified | 8 | 7 |
| Overall Study | Study terminated by Sponsor | 92 | 114 |
| Overall Study | Withdrawal by Subject | 12 | 11 |
Baseline characteristics
| Characteristic | Trilaciclib + FOLFOXIRI/Bevacizumab | Placebo + FOLFOXIRI/Bevacizumab | Total |
|---|---|---|---|
| Age, Continuous | 56.2 Years STANDARD_DEVIATION 11.8 | 55.5 Years STANDARD_DEVIATION 10.6 | 55.8 Years STANDARD_DEVIATION 11.21 |
| Race/Ethnicity, Customized Asian | 32 Participants | 33 Participants | 65 Participants |
| Race/Ethnicity, Customized Black or African American | 4 Participants | 9 Participants | 13 Participants |
| Race/Ethnicity, Customized Not Reported | 3 Participants | 3 Participants | 6 Participants |
| Race/Ethnicity, Customized Other | 3 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Unknown | 3 Participants | 5 Participants | 8 Participants |
| Race/Ethnicity, Customized White | 119 Participants | 112 Participants | 231 Participants |
| Sex: Female, Male Female | 58 Participants | 61 Participants | 119 Participants |
| Sex: Female, Male Male | 106 Participants | 101 Participants | 207 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 49 / 159 | 26 / 160 |
| other Total, other adverse events | 155 / 159 | 159 / 160 |
| serious Total, serious adverse events | 47 / 159 | 47 / 160 |
Outcome results
Primary
Duration of Severe Neutropenia (DSN)
The DSN was defined as the number of days for the first severe neutropenia (SN) event in Cycles 1, 2, 3, or 4 for participants who had at least one SN event in the first 4 cycles of Induction. It was calculated as the days from the date of the first absolute neutrophil count (ANC) value of \< 0.5 × 10\^9/L to the date of the first ANC value ≥ 0.5 × 10\^9/L where no additional ANC values \< 0.5 × 10\^9/L were observed for the remainder of that cycle.
Time frame: Cycles 1 to 4 (14-day cycles up to 56 days)
Population: A Modified Intent-to-Treat (mITT) population was utilized in order to account for potential data integrity issues resulting from the war in Ukraine. The criteria for patients to be included in the mITT population consisted of all patients being randomized in countries other than Ukraine and all patients in Ukraine being randomized prior to 09 September 2021.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trilaciclib + FOLFOXIRI/Bevacizumab | Duration of Severe Neutropenia (DSN) | 0.1 days | Standard Deviation 0.84 |
| Placebo + FOLFOXIRI/Bevacizumab | Duration of Severe Neutropenia (DSN) | 1.3 days | Standard Deviation 3.14 |
p-value: <0.00195% CI: [-1.7, -0.6]ANCOVA
Primary
Occurrence of Severe Neutropenia (SN) During Induction
Severe neutropenia was defined as the absolute neutrophil count (ANC) laboratory value that met the Common Terminology Criteria for Adverse vents (CTCAE) criteria for ≥ Grade 4 toxicity (ie, ANC \< 0.5 × 10\^9/L in SI Unit)
Time frame: Induction Period, cycles 1-12 (14-day cycles up to 168 days)
Population: A Modified Intent-to-Treat (mITT) population was utilized in order to account for potential data integrity issues resulting from the war in Ukraine. The criteria for patients to be included in the mITT population consisted of all patients being randomized in countries other than Ukraine and all patients in Ukraine being randomized prior to 09 September 2021.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trilaciclib + FOLFOXIRI/Bevacizumab | Occurrence of Severe Neutropenia (SN) During Induction | 0.1 event per 100 cycles |
| Placebo + FOLFOXIRI/Bevacizumab | Occurrence of Severe Neutropenia (SN) During Induction | 3 event per 100 cycles |
p-value: <0.00195% CI: [0.01, 0.19]modified Poisson model
Secondary
Additional Myelopreservation Measures
To assess the effects of trilaciclib on additional measures of the neutrophil lineage compared with placebo in patients receiving FOLFOXIRI/bevacizumab for pMMR/MSS mCRC as measured by the number of SN events, granulocyte-colony stimulating factor (G-CSF) administration and febrile neutropenia (FN) adverse events (AE)
Time frame: Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab
Population: Due to early study termination, data were not collected for this outcome measure.
Secondary
Best Overall Response (BOR)
Best overall response (BOR) will be determined using all visit responses prior to or on the date of (i) radiographic disease progression; (ii) withdrawal of consent to obtain scans; (iii) death; (iv) lost to follow-up; or (v) initiation of subsequent anti-cancer therapy other than the study drugs, whichever is earlier will be based on RECIST v1.1.
Time frame: Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab
Population: The Response Evaluable (RE) population included those patients in the mITT population who received at least 1 dose of any study drug and had measurable (target) tumor lesion(s) at the baseline tumor assessment. The patients also had at least 1 post-baseline tumor assessment, discontinued treatment because of clinical progression prior to their first post-baseline tumor scan, or died due to disease progression prior to their first post-baseline tumor scan.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trilaciclib + FOLFOXIRI/Bevacizumab | Best Overall Response (BOR) | Partial response | 75 percentage of participants |
| Trilaciclib + FOLFOXIRI/Bevacizumab | Best Overall Response (BOR) | Progressive disease | 5 percentage of participants |
| Trilaciclib + FOLFOXIRI/Bevacizumab | Best Overall Response (BOR) | Stable disease | 50 percentage of participants |
| Trilaciclib + FOLFOXIRI/Bevacizumab | Best Overall Response (BOR) | Not evaluable | 7 percentage of participants |
| Trilaciclib + FOLFOXIRI/Bevacizumab | Best Overall Response (BOR) | Complete response | 0 percentage of participants |
| Placebo + FOLFOXIRI/Bevacizumab | Best Overall Response (BOR) | Not evaluable | 3 percentage of participants |
| Placebo + FOLFOXIRI/Bevacizumab | Best Overall Response (BOR) | Complete response | 3 percentage of participants |
| Placebo + FOLFOXIRI/Bevacizumab | Best Overall Response (BOR) | Partial response | 91 percentage of participants |
| Placebo + FOLFOXIRI/Bevacizumab | Best Overall Response (BOR) | Stable disease | 36 percentage of participants |
| Placebo + FOLFOXIRI/Bevacizumab | Best Overall Response (BOR) | Progressive disease | 7 percentage of participants |
Secondary
Duration of Objective Response (DOR)
DOR is the time between first objective response of CR or PR and the first date that progressive disease is objectively documented or death, whichever comes first.
Time frame: Assessed from the day of the first dose of the study drug, through 30 days after the last dose of the study drug, up to 115 weeks
Population: The Response Evaluable (RE) population included those patients in the mITT population who received at least 1 dose of any study drug and had measurable (target) tumor lesion(s) at the baseline tumor assessment. The patients also had at least 1 post-baseline tumor assessment, discontinued treatment because of clinical progression prior to their first post-baseline tumor scan, or died due to disease progression prior to their first post-baseline tumor scan.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trilaciclib + FOLFOXIRI/Bevacizumab | Duration of Objective Response (DOR) | 9.1 months |
| Placebo + FOLFOXIRI/Bevacizumab | Duration of Objective Response (DOR) | 12.7 months |
Secondary
Healthcare Utilization
To assess the effects of trilaciclib on healthcare utilization compared with placebo in patients receiving FOLFOXIRI/ bevacizumab for pMMR/MSS mCRC by measure of hospitalizations and antibiotic use.
Time frame: Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab
Population: Due to early study termination, data were not collected for this outcome measure.
Secondary
Multiple Lineage
To assess the effects of trilaciclib on multiple lineages compared with placebo in patients receiving FOLFOXIRI/bevacizumab for pMMR/MSS mCRC by measure of Grade 3 or 4 hematologic lab values.
Time frame: Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab
Population: Due to early study termination, data were not collected for this outcome measure.
Secondary
Number of Participants With Reported Adverse Events to Measure Safety and Tolerability
To assess the safety and tolerability of trilaciclib compared with placebo in patients receiving FOLFOXIRI/ bevacizumab for pMMR/MSS mCRC by measure of occurrence and severity of AEs by National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0, changes in laboratory parameters, vital signs and electrocardiogram (ECG) parameters, grade 3 or 4 abnormalities in chemistry laboratory parameters, and study treatment discontinuation due to AEs.
Time frame: Safety was assessed from the day of the first dose of the study drug, through 30 days after the last dose of the study drug, up to 115 weeks
Population: The Safety population included all randomized patients who received at least 1 dose of any study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Trilaciclib + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Number of patients with any AE | 157 Participants |
| Trilaciclib + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Number of patients with any AE of CTCAE Grade ≥ 3 | 106 Participants |
| Trilaciclib + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Number of patients with any AE of CTCAE Grade ≥ 4 | 18 Participants |
| Trilaciclib + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Number of patients with any study drug-related AE | 154 Participants |
| Trilaciclib + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Trilaciclib/Placebo-Related AE | 109 Participants |
| Trilaciclib + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Fluorouracil-related AE | 139 Participants |
| Trilaciclib + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Leucovorin-related AE | 103 Participants |
| Trilaciclib + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Oxaliplatin-related AE | 143 Participants |
| Trilaciclib + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Irinotecan-related AE | 143 Participants |
| Trilaciclib + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Bevacizumab-related AE | 127 Participants |
| Trilaciclib + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Patients with any serious AE | 47 Participants |
| Trilaciclib + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Patients with AE leading to discontinuation of any study drug | 50 Participants |
| Trilaciclib + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Leading to trilaciclib/placebo discontinuation | 19 Participants |
| Trilaciclib + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Leading to fluorouracil discontinuation | 19 Participants |
| Trilaciclib + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Leading to leucovorin discontinuation | 20 Participants |
| Trilaciclib + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Leading to oxaliplatin discontinuation | 38 Participants |
| Trilaciclib + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Leading to irinotecan discontinuation | 20 Participants |
| Trilaciclib + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Leading to bevacizumab discontinuation | 31 Participants |
| Trilaciclib + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Patients with trilaciclib/placebo-related AE leading to discontinuation of any study drug | 10 Participants |
| Trilaciclib + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Patients with AE leading to death | 8 Participants |
| Trilaciclib + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Patients with AESI for trilaciclib | 33 Participants |
| Placebo + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Patients with any serious AE | 47 Participants |
| Placebo + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Number of patients with any AE | 159 Participants |
| Placebo + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Patients with trilaciclib/placebo-related AE leading to discontinuation of any study drug | 9 Participants |
| Placebo + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Number of patients with any AE of CTCAE Grade ≥ 3 | 117 Participants |
| Placebo + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Patients with AE leading to discontinuation of any study drug | 47 Participants |
| Placebo + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Number of patients with any AE of CTCAE Grade ≥ 4 | 35 Participants |
| Placebo + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Leading to irinotecan discontinuation | 20 Participants |
| Placebo + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Number of patients with any study drug-related AE | 155 Participants |
| Placebo + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Leading to trilaciclib/placebo discontinuation | 13 Participants |
| Placebo + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Trilaciclib/Placebo-Related AE | 103 Participants |
| Placebo + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Patients with AESI for trilaciclib | 28 Participants |
| Placebo + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Fluorouracil-related AE | 151 Participants |
| Placebo + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Leading to fluorouracil discontinuation | 14 Participants |
| Placebo + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Leucovorin-related AE | 122 Participants |
| Placebo + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Leading to bevacizumab discontinuation | 26 Participants |
| Placebo + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Oxaliplatin-related AE | 151 Participants |
| Placebo + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Leading to leucovorin discontinuation | 13 Participants |
| Placebo + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Irinotecan-related AE | 151 Participants |
| Placebo + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Patients with AE leading to death | 3 Participants |
| Placebo + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Bevacizumab-related AE | 128 Participants |
| Placebo + FOLFOXIRI/Bevacizumab | Number of Participants With Reported Adverse Events to Measure Safety and Tolerability | Leading to oxaliplatin discontinuation | 30 Participants |
Secondary
Objective Response Rate (ORR)
ORR was defined as the percentage of participants in the analysis population who had a Complete Response (CR) defined as a disappearance of all target lesions with pathological lymph nodes having a reduction in short axis to \<10 mm or Partial Response (PR) defined as at least a 30% decrease in the sum of diameters of target lesions, using the baseline sum diameters as a reference based on RECIST v1.1.
Time frame: Assessed from the day of the first dose of the study drug, through 30 days after the last dose of the study drug, up to 115 weeks
Population: The Response Evaluable (RE) population included those patients in the mITT population who received at least 1 dose of any study drug and had measurable (target) tumor lesion(s) at the baseline tumor assessment. The patients also had at least 1 post-baseline tumor assessment, discontinued treatment because of clinical progression prior to their first post-baseline tumor scan, or died due to disease progression prior to their first post-baseline tumor scan.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trilaciclib + FOLFOXIRI/Bevacizumab | Objective Response Rate (ORR) | 41.6 percentage of participants |
| Placebo + FOLFOXIRI/Bevacizumab | Objective Response Rate (ORR) | 57.1 percentage of participants |
Secondary
Overall Survival (OS)
Overall survival is defined as the time from the date of the first dose of study treatment to the date of death from any cause.
Time frame: Up to 52 months
Population: Due to early study termination, data were not collected for this outcome measure.
Secondary
Platelet Lineage
To assess the effects of trilaciclib on the platelet lineage compared with placebo in patients receiving FOLFOXIRI/bevacizumab for pMMR/MSS mCR by measure of Grade 3 or 4 decreased platelet count laboratory values and Platelet transfusions.
Time frame: Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab
Population: Due to early study termination, data were not collected for this outcome measure.
Secondary
Progression Free Survival (PFS)
PFS is defined as the time from the date of randomization until the date of documented radiologic disease progression per RECIST v1.1 or death due to any cause, whichever comes first.
Time frame: Assessed from the day of the first dose of the study drug, through 30 days after the last dose of the study drug, up to 115 weeks
Population: Modified Intent-to-Treat (mITT) population was utilized in order to account for potential data integrity issues resulting from the war in Ukraine. The criteria for patients to be included in the mITT population consisted of all patients being randomized in countries other than Ukraine and all patients in Ukraine being randomized prior to 09 September 2021.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Trilaciclib + FOLFOXIRI/Bevacizumab | Progression Free Survival (PFS) | 10.3 months |
| Placebo + FOLFOXIRI/Bevacizumab | Progression Free Survival (PFS) | 13.1 months |
Secondary
Quality of Life/ Effects on Chemotherapy-Induced Fatigue
To assess the effects of trilaciclib on chemotherapy-induced fatigue compared with placebo in patients receiving FOLFOXIRI/bevacizumab for pMMR/MSS mCRC, as measured by Time To First Confirmed Deterioration of Fatigue (TTCD-fatigue) during Induction, as measured by the FACIT-F (Functional Assessment of Chronic Illness Therapy-Fatigue).
Time frame: Through Induction Period- on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab
Population: Due to early study termination, data were not collected for this outcome measure.
Secondary
Red Blood Cell Lineage
To assess the effects of trilaciclib on the red blood cell (RBC) lineage compared with placebo in patients receiving FOLFOXIRI/bevacizumab for pMMR/MSS mCRC by measure of Grade 3 or 4 decreased hemoglobin laboratory values, RBC transfusions on or after Week 5, and erythropoiesis-stimulating agents (ESA) administration
Time frame: Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab
Population: Due to early study termination, data were not collected for this outcome measure.
Secondary
Standard of Care Dosing
To assess the effects of trilaciclib on standard of care dosing compared with placebo in patients receiving FOLFOXIRI/ bevacizumab for pMMR/MSS mCRC by measure of all-cause dose reductions or cycle delays and relative dose intensity for FOLFOXIRI/bevacizumab
Time frame: Through Induction Period - on average 24 weeks (up to 12 cycles) of FOLFOXIRI/bevacizumab
Population: Due to early study termination, data were not collected for this outcome measure.