Advanced Solid Tumor, Metastatic Solid Tumor, RAS Mutation
Conditions
Brief summary
The purpose of this study is to test if the BG-85738 is safe and if it works in patients with advanced solid tumors with RAS mutations when it is given on its own and in combination.
Detailed description
A solid tumor is an abnormal mass of tissue caused by the uncontrolled growth of cells which can develop in organs, bones, or soft tissues. An advanced or metastatic solid tumor is a cancer that has either grown into nearby tissues ("advanced") or spread to distant parts of the body ("metastatic"). Many types of solid cancers have a change (mutation) in a gene called RAS gene. In normal cells, RAS proteins work by controlling when cells grow and divide. RAS mutations in cancer cells might lead to hyperactivation of the RAS proteins, which can result in continuous and uncontrolled growth of cancer cells. BG-85738 is a new experimental medicine that has been designed to block RAS proteins that are hyperactive. The purpose of this study is to test whether BG-85738 is safe and if it can help to treat adults with advanced or metastatic solid tumors with a RAS mutation. This study has two parts, one called dose escalation, and one called safety expansion. During the dose escalation part, the study doctors will test different doses of the study drug\[s\] to find the recommended dose that people can take without having serious side effects. During the dose expansion part, the study doctors will test the study drug in a larger number of people using the dose\[s\] identified from dose escalation. The study will enroll patients at multiple centers worldwide who have been diagnosed with an advanced solid tumor that has a RAS gene mutation. The overall time to participate in this study is approximately 13 to 24 months. Participants will make regular visits to the clinic for treatment, health checks, blood tests, and for tumor and imaging tests.
Interventions
DRUGBG-85738
Administered orally
DRUGTislelizumab
Administered intravenously
DRUGCetuximab
Administered intravenously
Sponsors
BeOne Medicines
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Participants are eligible to be included in the study only if they meet all the following criteria: * Participants must sign the informed consent form and be capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. * Participants must be ≥ 18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place, whichever is older), at the time of signing the ICF. * Participants with histologically or cytologically confirmed advanced, metastatic, and unresectable solid tumors and meet study part and cohort-specific criteria * Participants must have evidence of a RAS mutation defined as a nonsynonymous mutation in Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma RAS viral oncogene homolog (NRAS), or Harvey rat sarcoma viral oncogene homolog (HRAS) at codons 12, 13, or 61 (G12, G13, or Q61), based on testing of either tumor tissue or liquid biopsy (blood or plasma) as determined by the local laboratory
Exclusion criteria
Participants are excluded from the study if they meet any of the following criteria: * Participants who have prior RAS-targeted therapy, including, but not limited to, KRAS mutation-specific inhibitors (with the exception of participants with NSCLC and colorectal cancer who received a G12C inhibitor), pan-KRAS inhibitors, and pan-RAS inhibitors. * Participants who have a history of severe allergic reactions or hypersensitivity to the active ingredient and excipients of study treatment. * Participants who are unable to comply with the requirements of the protocol. * Participants with active leptomeningeal disease or uncontrolled, untreated brain metastases * Participants with any malignancy ≤ 3 years before the first dose of study treatment except for the specific cancer under investigation in this study and any locally recurring cancer that has been treated curatively (e.g., resected basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast). * Participants with active hepatitis C. * Participants with medical history of untreated Human Immunodeficiency Virus infection. Note: Other protocol defined criteria may apply.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1a (Part A and Part B): Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) | From first dose to 30 days after last dose or initiation of a new anticancer therapy, whichever occurs first, up to approximately 24 months | An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporarily associated with the use of study treatment, whether considered related to study treatment or not. An SAE is any untoward medical occurrence that, at any dose, * Results in death * Is life-threatening * Requires hospitalization or prolongation of existing hospitalization * Results in disability/incapacity * Is congenital anomaly/birth defect * Is considered a significant medical AE by the investigator based on medical judgement |
| Phase 1a (Parts A and B): Number of Participants with Dose Limiting Toxicity (DLT) | Up to approximately 1 month | — |
| Phase 1a (Parts A and B): Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of BG-85738 as monotherapy or in combination with other antitumor agents | Up to approximately 1 month | MTD is defined as the highest dose level with the target DLT closest but not exceeding 0.33. MAD is defined as the maximum administered dose and it is used when MTD is not reached. |
| Phase 1a: Recommended Dose for Expansion (RDFE) of BG-85738 | Up to approximately 1 month | — |
| Part 1b (Parts C and D): Overall Response Rate (ORR) | Up to approximately 24 months | ORR is defined as the percentage of participants who achieve complete response (CR) or partial response (PR). * CR: Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \< 10 mm. * PR: A ≥ 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| Phase 1b Dose Expansion: Recommended Phase 2 dose (RP2D) of BG-85738 | Up to approximately 24 months | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1a (Part A and Part B): Terminal Half Life (t1/2) of BG-85738 | Up to approximately 2 months | — |
| Phase 1a (Part A and Part B): Area Under the Plasma Concentration-Time Curve (AUC) of BG-85738 | Up to approximately 2 months | — |
| Phase 1a (Part A and Part B): Minimum Observed Serum Concentration (Ctrough) of BG-85738 | Up to approximately 2 months | — |
| Phase 1a (Part A and Part B): Maximum Observed Plasma Concentration (Cmax) of BG-85738 | Up to approximately 2 months | — |
| Phase 1a (Part A and Part B): Overall Response Rate (ORR) | Up to approximately 24 months | ORR is defined as the percentage of participants who achieve complete response (CR) or partial response (PR). * CR: Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \< 10 mm. * PR: A ≥ 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| Phase 1b (Parts C and D): Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) | From first dose to 30 days after last dose or initiation of a new anticancer therapy, whichever occurs first, up to approximately 24 months | An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporarily associated with the use of study treatment, whether considered related to study treatment or not. An SAE is any untoward medical occurrence that, at any dose, * Results in death * Is life-threatening * Requires hospitalization or prolongation of existing hospitalization * Results in disability/incapacity * Is congenital anomaly/birth defect * Is considered a significant medical AE by the investigator based on medical judgement |
| Phase 1b (Part C and D): Duration of response (DOR) | Up to approximately 24 months | DOR is defined as the time from the first determination of an overall response until the first documentation of progression or death, whichever comes first. |
| Phase 1b (Part C and D): Disease control rate (DCR) | Up to approximately 24 months | DCR is defined as the percentage of participants with best of response of a CR, PR, and stable disease. |
| Phase 1b (Part C and D): Time to response (TTR) | Up to approximately 24 months | TTR is defined as the time from date of the first dose of study treatment to the first overall response. |
| Phase 1b (Part C and D): Progression-free survival (PFS) as assessed by the investigator | Up to approximately 24 months | PFS is defined as the time from the date of the first dose of study treatment to the date of the first documentation of progressive disease or death, whichever occurs first, as assessed by the investigator per RECIST v1.1 |
| Phase 1b (Part C): Intracranial Objective Response Rate (iORR) | Up to approximately 24 months | Intracranial objective response rate is defined as the percentage of patients with a best overall Intracranial response of CR or PR according to modified (m)RECIST v1.1 per Investigator assessment. |
| Phase 1b (Part C): Intracranial Duration of Response (iDOR) | Up to approximately 24 months | iDOR is defined as the time from the first determination of an overall intracranial response until the first documentation of progression or death, whichever comes first, with intracranial assessments by the investigator via modified RECIST v1.1 adapted for brain metastases. |
| Phase 1b (Part C): Intracranial Progression-free survival (iPFS) as determined from tumor assessments by the investigator | Up to approximately 24 months | iPFS is defined as the time from the date of the first dose of study treatment to the date of the first documentation of progressive disease or death, whichever occurs first. PFS is determined from tumor assessments by the investigator per a modified RECIST v1.1 adapted for brain metastases |
Countries
Australia
Contacts
CONTACTStudy Director
STUDY_DIRECTORStudy Director
BeOne Medicine
Outcome results
None listed