Dabrafenib, Trametinib, and Navitoclax in Treating Patients With Solid Tumors That Are Metastatic or Cannot be Removed by Surgery

Status: Recruiting
Phase: Phase 1/Phase 2
Diagnosis: Cutaneous Skin Cancer
NCT ID: NCT01989585 (View complete trial on ClinicalTrials.gov)
DFCI Protocol ID: 13-424

 

This partially randomized 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 solid tumors that are metastatic or cannot be removed by surgery. Dabrafenib, trametinib, and navitoclax may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

 

Conducting Institutions:
Massachusetts General Hospital, Beth-Israel Deaconess Medical Center, Dana-Farber Cancer Institute

Overall PI:
Ryan Sullivan, MD, Beth Israel Deaconess Medical Center

Site-responsible Investigators:

Contacts:
Massachusetts General Hospital: Cancer Trials Call Center, 877-789-6100

Eligibility Criteria

Inclusion Criteria: - For phase I: patients must have histologically confirmed, BRAF-mutant (V600E/K) malignancy (molecularly confirmed using Cobas assay or a comparable, Food and Drug Administration [FDA]-approved assay) that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective - For phase II: patients must have histologically confirmed, BRAF-mutant (V600E/K) melanoma (molecularly confirmed using Cobas assay or a comparable FDA-approved assay) 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; 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 mitogen-activated protein kinase kinase (MEK) inhibitor; for patients enrolled in the phase II portion of the study, patients may have received prior immunotherapy (including high-dose interleukin [IL]-2, ipilimumab, nivolumab, and other anti-programmed cell death 1 [PD1]/CD274 molecule [PDL1] antibodies) or chemotherapy, however prior BRAF inhibitor and/or MEK inhibitor therapy will not be allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%) - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,200/mcL - 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 - 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) - Creatinine within normal institutional limits OR - Creatinine clearance >= 50 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal - Patients must have a corrected QT (QTc) interval of less than 480 msec - Women of child-bearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 4 months after completion of study drug administration; additional contraceptive measures should be in place such as barrier method of birth control and abstinence; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of study drug administration - Ability to understand and the willingness to sign a written informed consent document - Able to swallow and retain oral medication Exclusion Criteria: - Patients who have had immunotherapy, chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study - Patients must not have received prior navitoclax; in the phase II portion of the study, prior BRAF inhibitor and/or MEK inhibitor will be prohibited - Patients who are receiving any other investigational agents - Patients must have no clinical evidence of brain metastasis; patients with prior resection, stereotactic radiosurgery, or whole brain radiation for brain metastasis are eligible, provided that disease is asymptomatic, corticosteroids are not needed, and that imaging is stable for a least 4 weeks prior to enrollment in the study - 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; breastfeeding should be discontinued if the mother is treated with the study drugs - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible - History of another malignancy; exception: patients who have been disease-free for 3 years, or patients with a history of completely resected non-melanoma skin cancer and/or patients with indolent secondary malignancies, are eligible; subjects with any malignancy with confirmed activating RAS mutation are excluded; prospective retrovirus-associated deoxyribonucleic acid (DNA) sequence (RAS) testing is not required; however, if the results of previous RAS testing are known, they must be used in assessing eligibility; consult the Cancer Therapy Evaluation Program (CTEP) medical monitor if unsure whether second malignancies meet the requirements - History of interstitial lung disease or pneumonitis - Current use of a prohibited medication; the following medications or non-drug therapies are prohibited: - Other anti-cancer therapy while on study treatment; (note: megestrol [Megace] if used as an appetite stimulant is allowed) - Concurrent treatment with bisphosphonates is permitted; however, treatment must be initiated prior to the first dose of study therapy; prophylactic use of bisphosphonates in patients without bone disease is not permitted, except for the treatment of osteoporosis - Concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, St. John's wort, kava, ephedra [ma huang], ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng) - Anticoagulants or antiplatelet agents except for low-dose, 81 mg aspirin - 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 mm Hg - History or evidence of cardiovascular risk including any of the following: - Left ventricular ejection fraction (LVEF) < lower limit of normal (LLN) - A QT interval corrected for heart rate using the Bazett's formula QTcB >= 480 msec - History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for > 30 days prior to randomization are eligible) - History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization - History or evidence of current >= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system - Treatment-refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy - Abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study - Active hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (patients with chronic or cleared HBV and HCV infection are eligible) - Anti-cancer therapy including chemotherapy, immunotherapy, radiotherapy, hormonal (with the exception of hormones for thyroid conditions or estrogen replacement therapy [ERT]), and other investigational agents will not be allowed within 14 days prior to the first dose of navitoclax, and 21 days prior to first dose of dabrafenib and trametinib; additionally, participants must have recovered to less than grade 2 clinically significant adverse effect(s)/toxicity(ies) of the previous therapy; biologics will not be allowed within 30 days prior to, or during, navitoclax administration - The following concomitant medications are not allowed during navitoclax administration: clopidogrel, ibuprofen, tirofiban, warfarin, and other anticoagulants, drugs, or herbal supplements that affect platelet function are excluded, with the exception of low-dose anticoagulation medications (such as heparin) that are used to maintain the patency of a central intravenous catheter; aspirin will not be allowed within 7 days prior to the first dose of navitoclax or during navitoclax administration; however, subjects who have previously received aspirin therapy for thrombosis prevention may resume a low dose (i.e., maximum 100 mg QD) of aspirin if platelet counts are stable (>= 50,000/mm^3) through 6 weeks of navitoclax administration; all decisions regarding treatment with aspirin therapy will be determined by the investigator in conjunction with the medical monitor - Preclinical studies indicate that navitoclax is metabolized by cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4), is a moderate inhibitor of cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8), and is a strong inhibitor of cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9); therefore, caution should be exercised when dosing navitoclax concurrently with CYP2C8 and CYP2C9 substrates; common CYP2C8 substrates include paclitaxel, statins, and glitazones, whereas CYP2C9 substrates include phenytoin; when possible, investigators should switch to alternative medications or monitor the patients closely; CYP3A inhibitors such as ketoconazole and clarithromycin are not allowed 7 days prior to the first dose of navitoclax or during navitoclax administration - 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 - Subject has a significant history of cardiovascular disease (e.g., myocardial infarction [MI], thrombotic or thromboembolic event in the last 6 months) - Patients receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A (CYP3A) or CYP2C8 are ineligible; current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded; below are a few examples of the agents: - Antibiotics: clarithromycin, telithromycin, rifamycin class agents (e.g., rifampin, rifabutin, rifapentine), troleandomycin - Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole - Antidepressants: nefazodone - Hyperlipidemia: gemfibrozil - Miscellaneous: carbamazepine, Phenobarbital, amiodarone, phenytoin, S- mephenytoin - Immunosuppressive agents: cyclosporine - A history of glucose-6-phosphate dehydrogenase (G6PD) deficiency - Any participant who has ingested grapefruit juice within three days of commencing therapy
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