Unresectable or Metastatic Microsatellite Stable/Mismatch Repair Proficient Colorectal Cancer
Conditions
Keywords
Colorectal Cancer, Microsatellite Stable, Mismatch Repair Proficient, Maintenance Therapy
Brief summary
This is a Phase 1b/2 study to investigate the efficacy and safety of alcestobart (LBL-007) plus tislelizumab when administered in combination with bevacizumab plus fluoropyrimidine, and alcestobart in combination with bevacizumab plus fluoropyrimidine versus bevacizumab plus fluoropyrimidine to participants with colorectal cancer.
Interventions
DRUGAlcestobart
Administered intravenously (IV) at one of the following doses * Low dose: 150 mg once every 3 weeks * Medium dose: 300 mg once every 3 weeks or 200 mg once every 2 weeks * High dose: 600 mg once every 3 weeks or 400 mg once every 2 weeks
DRUGTislelizumab
Administered intravenously at a dose of either 200 mg once every 3 weeks or 300 mg once every 4 weeks.
DRUGBevacizumab or Bevacizumab biosimilar
Administered intravenously at a dose of either 7.5 mg/kg once every 3 weeks or 5 mg/kg once every 2 weeks.
DRUGFluoropyrimidine (FP)
Fluoropyrimidine treatment included one of the following: \- Capecitabine 850 mg/m\^2 administered orally twice daily for the first 2 weeks of each 3-week cycle, OR \- 5-fluorouracil (5-FU) 1600 to 2400 mg/m\^2 continuous infusion over 46 to 48 hours in combination with leucovorin or levoleucovorin (LV) IV administered per local guidelines and/or prescribing information once every 2 weeks.
Sponsors
BeiGene
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participant must have measurable disease as defined per RECIST((Response Evaluation Criteria in Solid Tumors) version 1.1 * Has a histologically confirmed colorectal adenocarcinoma with metastatic or unresectable disease (Stage IV as defined by American Joint Committee on Cancer \[AJCC\] 8th edition) * No prior systemic therapy for colorectal cancer (CRC) in the metastatic setting except for the induction treatment of first-line therapy. Note: Local regional treatment performed during induction systemic treatment is allowed * Participants who have completed the first-line induction treatment, with an overall response of stable disease or better. The duration of induction treatment should be completed within approximately 6 months. The first dose of study treatment needs to occur within 2 weeks (for 2-week regimen) or 3 weeks (for 3-week regimen) to 6 weeks after Day 1 of the last cycle of induction therapy
Exclusion criteria
* Participants whose disease has become resectable at the investigator's discretion during or after induction treatment are not eligible * Progressive disease occurred less than 6 months from completion of any prior neoadjuvant therapy (ie, chemotherapy with or without radiotherapy) or adjuvant therapy (ie, chemotherapy with or without radiotherapy), whichever occurred later * Participants who have been treated with anti-epidermal growth factor receptor (EGFR) antibody in the induction treatment * Any prior therapy targeting T-cell stimulation or checkpoint pathways * Participants with B-raf proto-oncogene, serine/threonine kinase (BRAF)V600E mutations * Have locally or centrally confirmed microsatellite instability-high (MSI-H) by polymerase chain reaction (PCR) method or dMMR by immunohistochemistry (IHC) method Note: Other protocol defined criteria may apply.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b: Number of Participants With Treatment-emergent Adverse Events (AEs) and Serious AEs (SAEs) | From first dose of study drug up to 30 days after last dose; maximum time on treatment was 16.2 months. | An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatments, whether considered related to study treatments or not. A serious AE (SAE) was any untoward medical occurrence that, at any dose- * resulted in death, * was life threatening, * required hospitalization or prolongation of existing hospitalization, * resulted in disability/incapacity, * was a congenital anomaly/birth defect. |
| Phase 2: Progression Free Survival (PFS) as Assessed by The Investigator in PD-L1 Positive Arms A and C | From randomization until disease progression, death, study discontinuation, or data cutoff, whichever occurred first (maximum follow-up time: Arm A, 11.0 months, Arm C, 8.0 months) | PFS, as assessed by the investigator per RECIST v1.1 is defined as the time from the date of randomization to the date of first documentation of disease progression or death, whichever occured first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2: Progression Free Survival (PFS) as Assessed by The Investigator in PD-L1 Negative Arms D and E | From randomization until disease progression, death, study discontinuation, or data cutoff, whichever occurred first (maximum follow-up time: Arm D, 10.6 months, Arm E, 10.5 months) | PFS, as assessed by the investigator per RECIST v1.1 is defined as the time from the date of randomization to the date of first documentation of disease progression or death, whichever occurs first. |
| Phase 2: Objective Response Rate (ORR) as Assessed by The Investigator in PD-L1 Negative Arms D and E | From randomization until disease progression, death, study discontinuation, or data cutoff, whichever occurred first (maximum follow-up time: Arm D, 10.6 months, Arm E, 10.5 months)) | ORR is defined as the proportion of participants with a confirmed complete response (CR) or partial response (PR) from the time of randomization. CR and PR were confirmed per RECIST v1.1. * CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to \< 10 mm. * PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| Phase 2: Objective Response Rate (ORR) as Assessed by The Investigator in PD-L1 Positive Arms A and C | From randomization until disease progression, death, study discontinuation, or data cutoff, whichever occurred first (maximum follow-up time: Arm A, 11.0 months, Arm C, 8.0 months) | ORR is defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) from the time of randomization. CR and PR were confirmed per RECIST v1.1. * CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to \< 10 mm. * PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| Phase 2: Number of Participants With Treatment-emergent AEs and SAEs | From first dose of study drug up to 30 days after last dose; maximum time on treatment in Phase 2 was 10.9 months | An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatments, whether considered related to study treatments or not. A serious AE (SAE) was any untoward medical occurrence that, at any dose- * resulted in death, * was life threatening, * required hospitalization or prolongation of existing hospitalization, * resulted in disability/incapacity, * was a congenital anomaly/birth defect. |
| Phase 2: Duration of Response (DOR) as Assessed by The Investigator in PD-L1 Negative Arms D and E | From first documented response until disease progression or death (maximum follow-up time for DOR was 2.8 months) | DOR, defined as the time from the first confirmed objective response after randomization until the first documentation of disease progression or death, whichever comes first. |
| Phase 2: Duration of Response (DOR) as Assessed by The Investigator in PD-L1 Positive Arms A and C | From first documented response until disease progression or death (maximum follow-up time for DOR was 4.2 months) | DOR is defined as the time from the first determination of an objective confirmed response after randomization until the first documentation of disease progression or death, whichever comes first. |
Countries
Australia, China, Puerto Rico, United States
Contacts
STUDY_DIRECTORStudy Director
BeiGene
Participant flow
Recruitment details
The study began in January 2023 and was conducted in 3 countries. The study consisted of Phase 1b and Phase 2. Phase 1b was completed as planned. On 20 December 2024, the sponsor decided to close enrollment in Phase 2 before achieving the planned sample size. Participants who continued to benefit from the study drugs were permitted to continue treatment in an Extended treatment Period which is currently ongoing.
Pre-assignment details
Participants in Phase 1b were assigned to cohorts of increasing dose levels of alcestobart sequentially. In Phase 2, PD-L1-positive participants were randomized in a 2:1:2 ratio to 1 of 3 treatment arms stratified by liver metastases (absent vs. present) and PD-L1-negative participants were randomized in a 1:1 ratio to 1 of 2 treatment arms.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 53.7 years STANDARD_DEVIATION 11.62 |
| Liver Metastases: Yes/No No | 1 Participants |
| Liver Metastases: Yes/No Yes | 5 Participants |
| Race/Ethnicity, Customized Asian | 69 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 4 Participants |
| Race/Ethnicity, Customized Multiple | 5 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 22 Participants |
| Race/Ethnicity, Customized Not reported | 1 Participants |
| Race/Ethnicity, Customized Other | 2 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants |
| Race/Ethnicity, Customized White | 1 Participants |
| Region of Enrollment Australia | 1 Participants |
| Region of Enrollment China | 66 Participants |
| Region of Enrollment United States | 1 Participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 6 | 3 / 13 | 1 / 6 | 0 / 18 | 0 / 9 | 0 / 16 | 2 / 22 | 2 / 23 |
| other Total, other adverse events | 6 / 6 | 13 / 13 | 6 / 6 | 17 / 18 | 9 / 9 | 12 / 14 | 21 / 22 | 22 / 22 |
| serious Total, serious adverse events | 3 / 6 | 8 / 13 | 3 / 6 | 3 / 18 | 1 / 9 | 3 / 14 | 7 / 22 | 4 / 22 |
Outcome results
None listed