Advanced Colorectal Cancer, Advanced Esophageal Adenocarcinoma, Advanced Gastric Cancer, Advanced Gastroesophageal Junction Cancer, Advanced Non-squamous Non-small-cell Lung Cancer, Advanced Pancreatic Ductal Adenocarcinoma, Metastatic Solid Tumors
Conditions
Keywords
KRAS wild type amplification, Metastatic Solid Tumors, Advanced Non-squamous Non-small-cell Lung Cancer, Advanced Colorectal Cancer, Advanced Pancreatic Ductal Adenocarcinoma, Advanced Gastric Cancer, Advanced Gastroesophageal Junction Cancer, Advanced Esophageal Adenocarcinoma
Brief summary
This is a first-in-human (FIH), open-label, multicenter, dose escalation and dose expansion study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity of BGB-53038 as monotherapy in participants with advanced or metastatic solid tumors harboring KRAS mutations or amplification, as well as when used in combination with tislelizumab (also known as BGB-A317) in participants with nonsquamous non-small cell lung cancer (NSCLC) and used in combination with cetuximab in participants with colorectal cancer (CRC). The study consists of 2 phases: Phase 1a Dose Escalation and Safety Expansion and Phase 1b Dose Expansion.
Interventions
DRUGBGB-53038
Administered orally
DRUGTislelizumab
administered by intravenous infusion
DRUGCetuximab
administered by intravenous infusion
Sponsors
BeOne Medicines
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. Must sign a written ICF; and understand and agree to comply with the requirements of the study and the schedule of activities. 2. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1. 3. Participants must have evidence of a KRAS mutation or wild-type amplification (copy number ≥ 8) based on testing of either tumor tissue or liquid biopsy (blood or plasma) as determined by local laboratory 4. Able to provide an archived tumor tissue sample or fresh biopsy sample. 5. ≥ 1 measurable lesion per RECIST v1.1. 6. Adequate organ function. 7. Females of childbearing potential must be willing to use a highly effective method of birth control for the duration of the study, for \> 7 days after the last dose of BGB-53038, \> 120 days after the last dose of tislelizumab, or \> 2 months after the last dose of cetuximab, whichever is later 8. Nonsterile males must be willing to use a highly effective method of birth control for the duration of the study treatment period and for ≥ 4 months after the last dose of study drug(s).
Exclusion criteria
1. Participants with tumors harboring KRAS G12R mutation. 2. Participants who have prior therapy with other anti-RAS treatment, including, but not limited to, therapy targeting specific KRAS allele mutation inhibitors, pan-KRAS inhibitors, and other pan-RAS inhibitors 3. Participants with active leptomeningeal disease or uncontrolled, untreated brain metastasis. Participants with a history of treated and, at the time of screening, stable CNS metastases are eligible, provided they meet select criteria. 4. Any malignancy ≤ 2 years before the first dose of study treatment(s) except for the specific cancer under investigation in this study and any locally recurring cancer that has been treated with curative intent (eg, resected basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast). 5. Participants with untreated chronic hepatitis B or chronic HBV carriers with HBV DNA ≥ 500 IU/mL (or ≥ 2500 copies/mL) at screening. Participants with active hepatitis C. 6. Participants with clinically significant infections (including tuberculosis infection) requiring systemic (oral or intravenous) antibacterial, antifungal, or antiviral therapy ≤ 14 days before the first dose of study treatment. Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1a: Number of Participants Experiencing Adverse Events (AEs) | Up to approximately 2 years | Number of participants with treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) characterized by type, frequency, severity (as graded by the National Cancer Institute-Common Terminology Criteria for Adverse Events \[NCICTCAE\] Version \[v\] 5.0), timing, seriousness, and relationship to study drug(s); and adverse events meeting protocol-defined dose-limiting toxicity (DLT) criteria |
| Phase 1a: Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of BGB-53038 | Up to approximately 2 years | defined as the highest dose at which 30% of the participants experienced a DLT or the highest dose administered, respectively. |
| Phase 1a: Recommended Dose for Expansion (RDFE) of BGB-53038 | Up to approximately 2 years | The potential RDFE(s) of BGB-53038 as monotherapy or in combination with other antitumor therapies (tislelizumab or cetuximab) will be determined based on the totality of safety, tolerability, pharmacokinetics (PK), pharmacodynamics, preliminary antitumor activity, and any other relevant data, as available. |
| Phase 1b: Overall Response Rate (ORR) | Up to approximately 2 years | ORR is defined as the percentage of participants with best overall response (BOR) of complete response (CR) or partial response (PR) assessed by the investigator using RECIST v1.1 |
| Phase 1b: Recommended Phase 2 Dose (RP2D) of BGB-53038 | Up to approximately 2 years | The RP2D of BGB-53038 as monotherapy or in combination with other antitumor therapies (tislelizumab or cetuximab) will be determined based on safety, long-term tolerability, PK, preliminary antitumor activity, and any other relevant data, as available |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1a: Single-dose and steady-state area under the concentration-time curve (AUC) of BGB-53038 | Up to approximately 2 years | — |
| Phase 1a: Single-dose and steady-state Half-life (t1/2) of BGB-53038 | Up to approximately 2 years | — |
| Phase 1a: Single-dose and steady-state maximum observed plasma concentration (Cmax) of BGB-53038 | Up to approximately 2 years | — |
| Phase 1a: Single-dose and steady-state trough concentration (Ctrough) of BGB-53038 | Up to approximately 2 years | — |
| Phase 1b: ORR | Up to approximately 2 years | ORR is defined as the percentage of participants with best overall response (BOR) of complete response (CR) or partial response (PR) assessed by the investigator using RECIST v1.1. |
| Duration of Response (DOR) | Up to approximately 2 years | DOR is defined as the time from the first determination of an objective response per RECIST v1.1 until the first documentation of disease progression or death, whichever occurs first as assessed by the investigator. |
| Time to Response (TRR) | Up to approximately 2 years | defined as the time from the date of first dose of study drug to first documentation of response as assessed by the investigator per RECIST v1.1 |
| Disease Control Rate (DCR) | Up to approximately 2 years | DCR is defined as the percentage of participants who achieve CR, PR, or stable disease (SD) lasting ≥ 24 weeks as assessed by the investigator per RECIST v1.1 |
| Progression Free Survival (PFS) | Up to approximately 2 years | PFS is defined as the time from the date of the first dose of study drug(s) to the date of the first documentation of progressive disease assessed by the investigator using RECIST v1.1 or death, whichever occurs first. |
| Phase 1b: Overall Survival (OS) | Up to approximately 2 years | defined as the time from the date of first dose of study drug until the date of death from any cause |
| Phase 1b: Number of Participants Experiencing Adverse Events (AEs) | Up to approximately 2 years | Number of participants with treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) characterized by type, frequency, severity (as graded by the NCI-CTCAE v5.0), timing, seriousness, and relationship to study drug(s) |
| Plasma concentrations of BGB-53038 | Up to approximately 2 years | — |
Countries
Australia, China, New Zealand, South Korea, United States
Contacts
STUDY_DIRECTORStudy Director
BeOne Medicines
Outcome results
None listed