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Clinical Trial 19958

Cancer Type: Cutaneous
Study Type: Treatment
NCT#: NCT01989585

Phase: Phase I/II
Principal Investigator: Eroglu, Zeynep

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Study Title

Phase I/II Study of Dabrafenib, Trametinib, and Navitoclax in BRAF Mutant Melanoma (Phase I and II) and Other Solid Tumors (Phase I only)



Phase I Objective: Primary Object To determine the maximum tolerate dose (MTD), toxicity, and safety profile of navitoclax when given in combination with dabrafenib and trametinib in patients with BRAF-mutant solid tumors. Secondary Objectives: To describe pharmacodynamics effects of treatment with dabrafenib, trametinib, and navitoclax on both serial tumor biopsies and serial blood draws in a small subset of patients treated with BRAF-mutant melanoma. - To describe the pharmacokinetics of treatment with dabrafenib, trametinib, and navitoclax. Phase II Objectives: Primary Objectives - To estimate the complete response (CR) rate in patients with BRAF-mutant melanoma treated with dabrafenib, trametinib, and navitoclax as compared to the historical control (DT). - To compare the maximal tumor regression in patients with BRAF-mutant melanoma treated with dabrafenib, trametinib versus dabrafenib, trametinib, and navitoclax Secondary Objectives: - To compare the PFS, OS, and ORR in patients with BRAF-mutant melanoma treated with dabrafenib, trametinib, versus dabrafenib, trametinib, and navitoclax. - To compare the degree of apoptosis induced in on-treatment biopsies of patients with BRAF-mutant melanoma treated with dabrafenib, trametinib versus dabrafenib, trametinib, and navitoclax. - To explore other pharmacodynamic effects in on-treatment biopsies of patients with BRAF-mutant melanoma treated with either dabrafenib, trametinib versus dabrafenib, trametinib, and navitoclax including cell proliferation (Ki-67), proteomics (RPPA), and BCL-2 family gene expression analysis.



Therapy (NOS)


ABT-263 (Navitoclax); GSK1120212 (Trametinib); GSK2118436 (dabrafenib); Navitoclax (); Trametinib (); dabrafenib ()

Inclusion Criteria

  • 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
  • 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 computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
  • Prior therapy is allowed, please see protocol for detail.
  • Eastern Cooperative Oncology Group (ECOG) performance status == 70%)
  • Life expectancy of greater than 3 months
  • Adequate organ function and blood values to protocol specifications.
  • Left ventricular ejection fraction >= institutional lower limit of normal (LLN) by echocardiogram (ECHO)
  • Patients must have a corrected QT (QTc) interval of less than 480 msec
  • Women of child-bearing potential and men with partners of childbearing potential must agree to use adequate contraception (barrier method of birth control, or abstinence; hormonal contraception is not allowed) prior to study entry, for the duration of study participation, and for 4 months after completion of study drug administration; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately
  • Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels
  • Ability to understand and the willingness to sign a written informed consent document; if a patient has impaired decision-making capacity, a legally authorized representative, patients will be allowed to participate

  • Exclusion Criteria

  • 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 must have no clinical evidence of leptomeningeal or brain metastasis causing spinal cord compression that are symptomatic or untreated or not stable for >= 3 months (must be documented by imaging) or requiring corticosteroids; PARTICIPANTS 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; PARTICIPANTS 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 and breastfeeding women
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible; 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, exclusions apply.
  • History of interstitial lung disease or pneumonitis
  • History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR)
  • History or evidence of cardiovascular risk (see protocol for detail)
  • Known history of hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (patients with chronic or cleared HBV and HCV infection are eligible); it is not necessary to conduct HBV and HCV testing at screening
  • Subject has an underlying condition predisposing them to bleeding or currently exhibits signs of clinically significant bleeding
  • Subject has a recent history of non-chemotherapy-induced thrombocytopenic-associated bleeding within 1 year prior to the first dose of study drug
  • A history of glucose-6-phosphate dehydrogenase (G6PD) deficiency
  • Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v. 5.0) grade 2 or higher from previous anti-cancer therapy, except alopecia or an endocrine toxicity related to immunotherapy (e.g. thyroiditis/hypothyroidism, adrenal insufficiency, hypophysitis) requiring replacement therapy, at the time of randomization
  • Other exclusions apply

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