BMS-986463 for Advanced Cancer
Recruiting in Palo Alto (17 mi)
+9 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Bristol-Myers Squibb
Disqualifiers: Leptomeningeal metastases, Concurrent malignancy, others
No Placebo Group
Trial Summary
What is the purpose of this trial?The purpose of this study is to evaluate the safety, tolerability, and efficacy of escalating doses of BMS-986463 in participants with select advanced malignant tumors.
Do I need to stop my current medications for the trial?
The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.
What makes the drug BMS-986463 unique for treating advanced cancer?
BMS-986463 is unique because it is a Bcl-2 inhibitor, which targets proteins that help cancer cells survive, potentially making it effective in combination with other treatments to enhance their effects. This approach is different from standard treatments that may not specifically target these survival proteins.
12345Eligibility Criteria
This trial is for individuals with certain advanced cancers, including uterine, ovarian, non-small cell lung cancer, and serous cystadenocarcinoma. Participants should be able to receive escalating doses of the study drug.Inclusion Criteria
I am fully active or restricted in physically strenuous activity but can do light work.
I have a tumor that can be biopsied in addition to the main one.
My cancer cannot be removed by surgery and has spread.
Exclusion Criteria
I do not have cancer spread to the lining of my brain and spinal cord.
I have no other cancers needing treatment or active cancers in the last 2 years.
I have not had radiation therapy in the last 2 weeks.
+1 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Dose Escalation
Participants receive escalating doses of BMS-986463 to evaluate safety and tolerability
8-12 weeks
Dose Expansion
Participants receive expanded doses of BMS-986463 to further evaluate efficacy
8-12 weeks
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The focus of this study is on BMS-986463. It's given in increasing amounts to see how safe it is and how well it works against specific advanced cancers.
2Treatment groups
Experimental Treatment
Group I: Arm 2: Dose ExpansionExperimental Treatment1 Intervention
Group II: Arm 1: Dose EscalationExperimental Treatment1 Intervention
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
USC/Norris Comprehensive Cancer CenterLos Angeles, CA
Valkyrie Clinical TrialsLos Angeles, CA
Local Institution - 0027Toronto, Canada
Local Institution - 0006Los Angeles, CA
More Trial Locations
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Who Is Running the Clinical Trial?
Bristol-Myers SquibbLead Sponsor
References
Phase I trial of BCL-2 antisense oligonucleotide (G3139) administered by continuous intravenous infusion in patients with advanced cancer. [2012]To evaluate the safety and pharmacokinetics of BCL-2 antisense oligonucleotide (G3139) administered by prolonged i.v. infusion in patients with advanced cancer.
Safety, efficacy, and pharmacokinetics of navitoclax (ABT-263) in combination with erlotinib in patients with advanced solid tumors. [2018]Navitoclax (ABT-263), a novel, oral Bcl-2 inhibitor, enhances the antitumor effects of chemotherapy in vitro by lowering the apoptotic threshold. This phase I study (NCT01009073) evaluated the safety, pharmacokinetics, and preliminary antitumor activity of navitoclax combined with erlotinib in patients with advanced solid tumors.
BH3 Inhibitor Sensitivity and Bcl-2 Dependence in Primary Acute Lymphoblastic Leukemia Cells. [2018]BH3 mimetic drugs may be useful to treat acute lymphoblastic leukemia (ALL) but the sensitivity of primary tumor cells has not been fully evaluated. Here, B-lineage ALL cell cultures derived from a set of primary tumors were studied with respect to sensitivity to the BH3 mimetics ABT-263 and ABT-199 and to Bcl-2 dependence and function. These ALL cells each expressed high levels of Bcl-2 and exhibited great sensitivity to ABT-263 and ABT-199, which induced rapid apoptotic cell death. BH3 profiling indicated that the ALL cultures were Bcl-2 dependent. Coimmunoprecipitation studies revealed a multifaceted role for Bcl-2 in binding proapoptotic partners including Bax, Bak, Bik, and Bim. ABT-263 disrupted Bcl-2:Bim interaction in cells. Mcl-1 overexpression rendered ALL cells resistant to ABT-263 and ABT-199, with Mcl-1 assuming the role of Bcl-2 in binding Bim. Freshly isolated pediatric ALL blasts also expressed high levels of Bcl-2 and exhibited high sensitivity to Bcl-2 inhibition by the BH3 mimetic compounds. Overall, our results showed that primary ALL cultures were both more sensitive to BH3 mimetics and more uniform in their response than established ALL cell lines that have been evaluated previously. Furthermore, the primary cell model characterized here offers a powerful system for preclinical testing of novel drugs and drug combinations to treat ALL.
Clinical profiling of BCL-2 family members in the setting of BRAF inhibition offers a rationale for targeting de novo resistance using BH3 mimetics. [2022]While response rates to BRAF inhibitiors (BRAFi) are high, disease progression emerges quickly. One strategy to delay the onset of resistance is to target anti-apoptotic proteins such as BCL-2, known to be associated with a poor prognosis. We analyzed BCL-2 family member expression levels of 34 samples from 17 patients collected before and 10 to 14 days after treatment initiation with either vemurafenib or dabrafenib/trametinib combination. The observed changes in mRNA and protein levels with BRAFi treatment led us to hypothesize that combining BRAFi with a BCL-2 inhibitor (the BH3-mimetic navitoclax) would improve outcome. We tested this hypothesis in cell lines and in mice. Pretreatment mRNA levels of BCL-2 negatively correlated with maximal tumor regression. Early increases in mRNA levels were seen in BIM, BCL-XL, BID and BCL2-W, as were decreases in MCL-1 and BCL2A. No significant changes were observed with BCL-2. Using reverse phase protein array (RPPA), significant increases in protein levels were found in BIM and BID. No changes in mRNA or protein correlated with response. Concurrent BRAF (PLX4720) and BCL2 (navitoclax) inhibition synergistically reduced viability in BRAF mutant cell lines and correlated with down-modulation of MCL-1 and BIM induction after PLX4720 treatment. In xenograft models, navitoclax enhanced the efficacy of PLX4720. The combination of a selective BRAF inhibitor with a BH3-mimetic promises to be an important therapeutic strategy capable of enhancing the clinical efficacy of BRAF inhibition in many patients that might otherwise succumb quickly to de novo resistance. Trial registrations: ClinicalTrials.gov NCT01006980; ClinicalTrials.gov NCT01107418; ClinicalTrials.gov NCT01264380; ClinicalTrials.gov NCT01248936; ClinicalTrials.gov NCT00949702; ClinicalTrials.gov NCT01072175.
Therapeutic efficacy of ABT-737, a selective inhibitor of BCL-2, in small cell lung cancer. [2021]Bcl-2 is a central regulator of cell survival that is overexpressed in the majority of small cell lung cancers (SCLC) and contributes to both malignant transformation and therapeutic resistance. We compared primary SCLC xenografts prepared from de novo human tumors with standard cell line-based xenografts in the evaluation of a novel and highly potent small molecule inhibitor of Bcl-2, ABT-737. ABT-737 induced dramatic regressions in tumors derived from some SCLC cell lines. In contrast, only one of three primary xenograft SCLC tumors showed significant growth inhibition with ABT-737. Explanations for this apparent dichotomy may include relatively low expression of Bcl-2 in the primary xenografts or inherent differences in the model systems. The addition of etoposide to ABT-737 in the primary xenografts resulted in significant decreases in tumor growth, underscoring the clinical potential of ABT-737 in combination therapy. To identify factors that may contribute to resistance to ABT-737 and related inhibitors, we isolated resistant derivatives of an initially sensitive cell line-based xenograft. Acquired resistance in this model was associated with decreases in the expression of the primary target Bcl-2, of proapoptotic partners of Bcl-2 (Bax and Bim), and of Bcl-2:Bim heterodimers. Expression profiling reveals 85 candidate genes demonstrating consistent changes in gene expression with acquired resistance. Taken together, these data have specific implications for the clinical development of Bcl-2 inhibitors for SCLC and broader implications for the testing of novel anticancer strategies in relevant preclinical models.