Advanced Solid Tumor, Bladder Cancer, Breast Cancer, Endometrial Cancer, Gastric Cancer, GastroEsophageal Cancer, Hormone-receptor-positive Breast Cancer, Hormone Receptor Positive HER-2 Negative Breast Cancer, Ovarian Cancer, Prostate Cancer, Small Cell Lung Cancer, TNBC - Triple-Negative Breast Cancer
Conditions
Keywords
breast cancer, small cell lung cancer, ovarian cancer, gastric cancer, cdk2 inhibitor, BG-68501, HR+ HER2- breast cancer, endometrial cancer, prostate cancer, BGB-43395, bladder cancer, urothelial cancer, gastroesophageal cancer, cdk4 inhibitor, fulvestrant
Brief summary
This study is a first-in-human (FIH), Phase 1a/1b study of BG-68501, a cyclin-dependent kinase-2 inhibitor (CDK2i), to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity of BG-68501 in participants with advanced, nonresectable, or metastatic solid tumors as monotherapy and in combination with fulvestrant with or without BGB-43395, a selective CDK4 inhibitor, in adults with hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer (BC). The study will also identify a recommended dose for expansion (RDFE) for BG-68501 as monotherapy and in combination for subsequent disease directed studies. The study will be conducted in 2 parts: Part 1 (dose escalation and safety expansion, including evaluation of food effect) and Part 2 (dose expansion).
Interventions
DRUGBG-68501
Planned doses administered orally.
DRUGFulvestrant
Standard dose administered via intramuscular injection.
DRUGBGB-43395
Planned doses administered orally.
Sponsors
BeiGene
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
Part 1 (Dose Escalation) Inclusion Criteria: * Monotherapy Cohorts: Participants with histologically or cytologically confirmed advanced or metastatic solid tumors potentially associated with CDK2 dependency including HR+/HER2- breast cancer, platinum refractory or resistant serous ovarian cancer (PROC), endometrial cancer, and others. Prior available standard-of-care systemic therapies for advanced or metastatic disease are required. The requirements for enrollment into a food effect evaluation cohort are the same as the monotherapy cohorts with the exception that participants with gastric cancer and gastroesophageal adenocarcinoma are excluded. * Combination Cohorts (BG-68501 with fulvestrant with or without BGB-43395): Enrollment is restricted to only participants with HR+/HER2- BC. In regions where approved and available, participants must have received one or more lines of treatment for advanced/metastatic disease as well as prior endocrine therapy and a CDK4/6 inhibitor in either the adjuvant or advanced/metastatic setting. If applicable, the requirements for enrollment into a food effect evaluation cohort are the same as the combination cohorts. Part 1 (Safety Expansion) and Part 2 (Dose Expansion) Inclusion Criteria: * Participants with advanced, non-resectable, or metastatic HR+/HER2- BC or PROC, including fallopian tube or primary peritoneal cancer. * PROC participants must have received: * ≥ 1 line of platinum-containing chemotherapy for advanced disease. * ≤ 4 prior therapeutic regimens in the advanced/metastatic setting. * HR+/HER2- BC: * Participants enrolled in regions where CDK4/6 inhibitors are approved and available must have received ≥ 1 line of therapy including endocrine therapy and a CDK4/6 inhibitor. Participants can have received up to 2 lines of prior cytotoxic chemotherapy or ADC treatments for advanced disease. General Inclusion Criteria: * Female participants with advanced or metastatic HR+/HER2- BC will be required to have ovarian function suppression using gonadotropin hormone-releasing hormone (GnRH) agonists (such as goserelin) or be postmenopausal. * Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1. * Adequate organ function. * For dose escalation, participants with advanced solid tumors other than HR+/HER2- BC must have measurable disease per RECIST 1.1. Participants with HR+/HER2- BC with bone-only disease are eligible for dose escalation only. For safety expansion and dose expansion, all participants must have ≥1 measurable lesion per RECIST v 1.1. General
Exclusion criteria
* For all cohorts: Prior therapy selectively targeting CDK2 inhibition. * For triple combination cohorts: Prior therapy targeting CDK2 or selectively targeting CDK4. Prior CDK4/6 inhibitor therapy is permitted and required in local regions where it is approved and available. * Known leptomeningeal disease or uncontrolled, untreated brain metastasis. Participants with a history of treated central nervous system (CNS) metastases may be eligible if they meet additional criteria. * Any malignancy ≤ 3 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, treated papillary thyroid carcinoma, or carcinoma in situ of the cervix or breast). * Uncontrolled diabetes. * Infection requiring systemic antibacterial, antifungal, or antiviral therapy antiviral therapy ≤ 28 days before the first dose of study drug(s), or symptomatic COVID-19 infection. * Active hepatitis B infection or active hepatitis C infection. * Any major surgical procedure ≤ 28 days before the first dose of study treatment(s). * Prior allogeneic stem cell transplantation, or organ transplantation. Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) | From the first dose of study drug(s) to 30 days after the last dose; approximately 6-12 months | Number of participants with treatment-emergent AEs and SAEs. |
| Part 1: Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of BG-68501 | Up to approximately 24 months | MTD is defined as the highest dose evaluated for which estimated toxicity rate is the closest to the target toxicity rate. MAD is defined as the highest dose administered if MTD is not reached. |
| Part 1: Recommended dose(s) for Expansion (RDFE) of BG-68501 monotherapy in participants with solid tumors | Up to approximately 24 months | RDFE of BG-68501 alone will be determined based upon the MTD or MAD. |
| Part 1: RDFE of BG-68501 in combination with fulvestrant and BGB-43395 in participants with HR+/HER2- BC | Up to approximately 24 months | RDFE of BG-68501 in combination with fulvestrant and BGB-43395 will be determined based upon the MTD or MAD. |
| Part 2: Objective Response Rate (ORR) | Up to approximately 20 months | ORR is defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR). CR and PR that is confirmed by repeat assessments, as assessed by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: ORR | Up to approximately 20 months | ORR is defined as the percentage of participants with best overall response of CR or PR. CR and PR that is confirmed by repeat assessments, as assessed by the investigator using RECIST v1.1. |
| Part 2: Number of participants with AEs and SAEs | From the first dose of study drug(s) to 30 days after the last dose; approximately 6-12 months | Number of participants with AEs and SAEs, including findings from physical examinations, electrocardiograms (ECGs), and laboratory assessments. |
| Parts 1 and 2: Duration of Response (DOR) | Up to approximately 20 months | DOR is defined as the time from the first confirmed objective response by the investigator using RECIST v1.1 until the first documentation of disease progression after treatment initiation or death, whichever comes first. |
| Parts 1 and 2: Time to Response (TTR) | Up to approximately 20 months | TTR is defined as the time from the treatment initiation to the first determination of overall response by the investigator using RECIST v1.1. |
| Parts 1 and 2: Disease Control Rate (DCR) | Up to approximately 20 months | DCR is defined as the percentage of participants with the best overall response, of a CR, PR, and stable disease assessed by the investigator using RECIST v1.1. |
| Parts 1 and 2: Clinical Benefit Rate (CBR) | Up to approximately 20 months | CBR is defined as the percentage of participants with best overall response of confirmed CR, PR, or stable disease lasting ≥ 24 weeks assessed by the investigator using RECIST v1.1. |
| Part 1: Maximum observed plasma concentration (Cmax) for BG-68501 and BGB-43395 | 2 times in the first 2 months | — |
| Part 1: Observed plasma trough concentration (Ctrough) for BG-68501 and BGB-43395 | 5 times in the first 2 months | — |
| Part 1: Area under the concentration-time curve (AUC) for BG-68501 and BGB-43395 | 2 times in the first 2 months | — |
| Part 1: Half-life (t1/2) for BG-68501 and BGB-43395 | 2 times in the first 2 months | — |
| Part 2: Plasma concentrations for BG-68501 and BGB-43395 | 5 times in approximately 3 months | — |
Countries
Australia, China, Israel, Moldova, New Zealand, United States
Contacts
STUDY_DIRECTORStudy Director
BeiGene
Outcome results
None listed