Testing the Addition of Navitoclax to the Combination of Dabrafenib and Trametinib in People Who Have BRAF Mutant Melanoma
Phase I/II Study of Dabrafenib, Trametinib, and Navitoclax in BRAF Mutant Melanoma (Phase I and II) and Other Solid Tumors (Phase I Only)
9 other identifiers
interventional
75
1 country
49
Brief Summary
This phase I/II trial studies the side effects and best dose of dabrafenib, trametinib, and navitoclax and to see how well they work in treating patients with BRAF mutant melanoma or solid tumors that has spread from where it first started (primary site) to other places in the body (metastatic) or cannot be removed by surgery (unresectable). Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Navitoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of tumor cells by blocking Bcl-2, a protein needed for tumor cell survival. Giving navitoclax, dabrafenib, and trametinib may help shrink tumors in patients with melanoma.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_1
Started Mar 2014
Longer than P75 for phase_1
49 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
November 18, 2013
CompletedFirst Posted
Study publicly available on registry
November 21, 2013
CompletedStudy Start
First participant enrolled
March 24, 2014
CompletedPrimary Completion
Last participant's last visit for primary outcome
December 31, 2027
ExpectedStudy Completion
Last participant's last visit for all outcomes
December 31, 2027
April 13, 2026
February 1, 2026
13.8 years
November 18, 2013
April 9, 2026
Conditions
Outcome Measures
Primary Outcomes (3)
Recommended phase II dose of the combination of dabrafenib, trametinib, and navitoclax (Phase I)
Determined by dose-limiting toxicities graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events.
Up to 28 days
Proportion of patients with a complete response (CR) (Phase II)
Assessed per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, in the cohort of patients treated with dabrafenib, trametinib, and navitoclax (DTN). The proportion of patients with a best response of CR will be presented with a 95% confidence interval calculated using the method of Atkinson and Brown.
Up to 4 weeks after last study treatment
Maximal degree of tumor regression (Phase II)
A comparison between the maximal tumor regression for patients treated with DTN and dabrafenib and trametinib (DT) will be conducted using a Wilcoxon rank-sum test.
Up to 4 weeks after last study treatment
Secondary Outcomes (3)
Progression free survival (PFS) (Phase II)
Time from start of treatment to time of progression or death, whichever occurs first, assessed for up to 10 years
Overall survival (OS) (Phase II)
Up to 10 years
Objective response rate (ORR) (Phase II)
Up to 4 weeks after last study treatment
Other Outcomes (7)
Change in terminal deoxynucleotidyl transferase 2´-deoxyuridine, 5´-triphosphate (dUTP) nick end labeling assay (TUNEL) staining
Baseline to up to 1 week
Change in B-cell chronic lymphocytic leukemia/lymphoma 2 (BCL-2)
Baseline to up to 1 week
Change in Ki67
Baseline to up to 1 week
- +4 more other outcomes
Study Arms (2)
Arm I (dabrafenib, trametinib)
EXPERIMENTALARM I: Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA, MRI or CT, biopsy, and collection of blood samples throughout the trial.
Arm II (dabrafenib, trametinib, and navitoclax)
EXPERIMENTALPatients receive navitoclax PO QD days -7 to -1 of cycle 1 only. Patients also receive dabrafenib PO BID, trametinib PO QD, and navitoclax PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA, MRI or CT, biopsy, and collection of blood samples throughout the trial.
Interventions
Undergo biopsy
Undergo collection of blood samples
Given PO
Undergo CT
Undergo echocardiography
Correlative studies
Undergo MRI
Undergo multigated acquisition scan
Given PO
Correlative studies
Given PO
Eligibility Criteria
You may qualify if:
- PHASE I SUBJECTS ONLY: Prior therapy is allowed; for patients enrolled in the Phase I portion of the study, patients may have received any number of prior lines of therapy including treatment with a BRAF and/or MEK inhibitor; prior navitoclax use will not be allowed, unless the patient received \< 7 days of navitoclax lead-in on this or another study and had to stop for reasons other than toxicity or disease progression
- Patients must have histologically confirmed, BRAF-mutant (V600E/K) melanoma (molecularly confirmed using validated, commercially available assay performed in a Clinical Laboratory Improvement Act \[CLIA\]-approved laboratory) that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective
- If test at CLIA-certified lab used a non-Food and Drug Administration (FDA) approved method, information about the assay must be provided; (FDA approved tests for BRAF V600 mutations in melanoma include: THxID BRAF Detection Kit and Cobas 4800 BRAF V600 Mutation Test)
- Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as \>= 20 mm with conventional techniques or as \>= 10 mm with spiral CT scan, MRI, or calipers by clinical exam
- Prior therapy is allowed; for patients enrolled in the Phase II portion of the study, patients may have received prior immunotherapy (including high-dose IL-2, ipilimumab, nivolumab, and other anti-PD1/PDL1 antibodies) or chemotherapy; however prior navitoclax, BRAF inhibitor and/or MEK inhibitor therapy will not be allowed
- Age \>= 18 years. Because no dosing or adverse event data are currently available on the use of navitoclax in combination with dabrafenib and trametinib in patients \< 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials
- Eastern Cooperative Oncology Group (ECOG) performance status =\< 1 (Karnofsky \>= 70%)
- Life expectancy of greater than 3 months
- Leukocytes \>= 3,000/mcL
- Absolute neutrophil count \>= 1 x 10\^9/L
- Hemoglobin \>= 9 g/dl (patients may be transfused to this level)
- Platelets \>= 100,000/mcL
- Total bilirubin =\< 1.5 x institutional upper limit of normal OR \> 1.5 x institutional upper limit of normal allowed if direct bilirubin is within normal range
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x institutional upper limit of normal
- Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) \< 1.3 x upper limit of normal (ULN)
- +6 more criteria
You may not qualify if:
- PHASE I SUBJECTS ONLY: Patients must not have received prior navitoclax, unless the patient received \< 7 days of navitoclax lead-in on this or another study and had to stop for reasons other than toxicity or disease progression
- Patients who have had immunotherapy, chemotherapy or radiotherapy within 14 days prior to the first dose of navitoclax, or prior systemic anti-cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or vaccine therapy) within the last 3 weeks prior to first dose of dabrafenib and/or trametinib; chemotherapy regimens without delayed toxicity within the last 2 weeks preceding the first dose of study treatment; biologics will not be allowed within 30 days prior to, or during, navitoclax administration
- Prior navitoclax, BRAF inhibitor, and MEK inhibitor is prohibited; (exceptions for Phase I are described above)
- Patients who are receiving any other investigational agents have received any other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of study treatment and during the study
- Patients with treated leptomeningeal or brain metastasis are not eligible unless there is demonstrated stability (documented by imaging) for \>= 3 months from any prior treatment of leptomeningeal or brain metastasis. Treatment may include surgery, radiation or systemic therapy. Patients with untreated leptomeningeal or brain metastasis or requiring corticosteroids are not eligible. Subjects on a stable dose of corticosteroids \> 1 month or who have been off of corticosteroids for at least 2 weeks can be enrolled with approval of the Cancer Therapy Evaluation Program (CTEP) medical monitor. Subjects must also be off of enzyme-inducing anticonvulsants for \> 4 weeks
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to navitoclax, dabrafenib, or trametinib, or excipients or to dimethyl sulfoxide (DMSO)
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active serious infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled diabetes, or psychiatric illness/social situations that would limit compliance with study requirements
- Pregnant women are excluded from this study because navitoclax, dabrafenib, and trametinib may have teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with the study drugs, breastfeeding should be discontinued if the mother is treated with the study drugs
- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy that predict to interact with any of the study drugs are ineligible because of the potential for pharmacokinetic interactions with the study drugs; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated; it is not necessary to conduct HIV testing at screening; patients who are HIV-positive with undetectable viral loads, not on interacting antiretroviral therapy, and have CD4 counts above 300/mm\^3 may be eligible after discussion with the principal investigator
- History of another malignancy; exception: patients who have been disease-free for 3 years (depending upon tumor type studied or clinical setting, 3 or 5 years can be used; e.g., for advanced melanoma and pancreatic studies 3 years is more appropriate due to aggressiveness of the disease, while 5 years can be more appropriate for prostate or ovarian cancer or adjuvant setting when life expectancy is longer), or patients with a history of completely resected non-melanoma skin cancer and/or patients with indolent secondary malignancies, are eligible; consult the CTEP medical monitor if unsure whether second malignancies meet the requirements specified above; exception: patients with history of RAS mutation-positive tumors are not eligible regardless of interval from the current study; prospective RAS testing is not required; however, if the results of previous RAS testing are known, they must be used in assessing eligibility
- History of interstitial lung disease or pneumonitis
- History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR):
- History of RVO or CSR, or predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes)
- Visible retinal pathology as assessed by ophthalmic exam that is considered a risk factor for RVO or CSR such as evidence of new optic disc cupping, evidence of new visual field defects, and intraocular pressure \> 21 mmHg
- History or evidence of cardiovascular risk including any of the following:
- +31 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (49)
Mayo Clinic Hospital in Arizona
Phoenix, Arizona, 85054, United States
Mayo Clinic in Arizona
Scottsdale, Arizona, 85259, United States
Los Angeles General Medical Center
Los Angeles, California, 90033, United States
USC / Norris Comprehensive Cancer Center
Los Angeles, California, 90033, United States
USC Norris Oncology/Hematology-Newport Beach
Newport Beach, California, 92663, United States
UC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California, 92868, United States
University of California Davis Comprehensive Cancer Center
Sacramento, California, 95817, United States
UCHealth University of Colorado Hospital
Aurora, Colorado, 80045, United States
UM Sylvester Comprehensive Cancer Center at Aventura
Aventura, Florida, 33180, United States
UM Sylvester Comprehensive Cancer Center at Coral Gables
Coral Gables, Florida, 33146, United States
UM Sylvester Comprehensive Cancer Center at Deerfield Beach
Deerfield Beach, Florida, 33442, United States
University of Miami Miller School of Medicine-Sylvester Cancer Center
Miami, Florida, 33136, United States
UM Sylvester Comprehensive Cancer Center at Kendall
Miami, Florida, 33176, United States
UM Sylvester Comprehensive Cancer Center at Plantation
Plantation, Florida, 33324, United States
Moffitt Cancer Center - McKinley Campus
Tampa, Florida, 33612, United States
Moffitt Cancer Center
Tampa, Florida, 33612, United States
Northwestern University
Chicago, Illinois, 60611, United States
University of Iowa/Holden Comprehensive Cancer Center
Iowa City, Iowa, 52242, United States
University of Kansas Clinical Research Center
Fairway, Kansas, 66205, United States
HaysMed
Hays, Kansas, 67601, United States
University of Kansas Cancer Center
Kansas City, Kansas, 66160, United States
Lawrence Memorial Hospital
Lawrence, Kansas, 66044, United States
The University of Kansas Cancer Center - Olathe
Olathe, Kansas, 66061, United States
University of Kansas Cancer Center-Overland Park
Overland Park, Kansas, 66210, United States
University of Kansas Hospital-Indian Creek Campus
Overland Park, Kansas, 66211, United States
Mercy Hospital Pittsburg
Pittsburg, Kansas, 66762, United States
Salina Regional Health Center
Salina, Kansas, 67401, United States
University of Kansas Health System Saint Francis Campus
Topeka, Kansas, 66606, United States
University of Kansas Hospital-Westwood Cancer Center
Westwood, Kansas, 66205, United States
Massachusetts General Hospital Cancer Center
Boston, Massachusetts, 02114, United States
Dana-Farber Cancer Institute
Boston, Massachusetts, 02215, United States
Mayo Clinic in Rochester
Rochester, Minnesota, 55905, United States
Siteman Cancer Center at Saint Peters Hospital
City of Saint Peters, Missouri, 63376, United States
Siteman Cancer Center at West County Hospital
Creve Coeur, Missouri, 63141, United States
University Health Truman Medical Center
Kansas City, Missouri, 64108, United States
University of Kansas Cancer Center - North
Kansas City, Missouri, 64154, United States
University of Kansas Cancer Center - Lee's Summit
Lee's Summit, Missouri, 64064, United States
University of Kansas Cancer Center at North Kansas City Hospital
North Kansas City, Missouri, 64116, United States
Washington University School of Medicine
St Louis, Missouri, 63110, United States
Siteman Cancer Center-South County
St Louis, Missouri, 63129, United States
Siteman Cancer Center at Christian Hospital
St Louis, Missouri, 63136, United States
Rutgers Cancer Institute of New Jersey
New Brunswick, New Jersey, 08903, United States
Laura and Isaac Perlmutter Cancer Center at NYU Langone
New York, New York, 10016, United States
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
New York, New York, 10032, United States
UNC Lineberger Comprehensive Cancer Center
Chapel Hill, North Carolina, 27599, United States
Duke University Medical Center
Durham, North Carolina, 27710, United States
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, 43210, United States
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania, 19107, United States
M D Anderson Cancer Center
Houston, Texas, 77030, United States
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Ryan J Sullivan
Dana-Farber - Harvard Cancer Center LAO
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- NIH
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
November 18, 2013
First Posted
November 21, 2013
Study Start
March 24, 2014
Primary Completion (Estimated)
December 31, 2027
Study Completion (Estimated)
December 31, 2027
Last Updated
April 13, 2026
Record last verified: 2026-02