A Study of the Experimental Combination of Dabrafenib, Trametinib, and Navitoclax For BRAF Mutant Melanoma or Solid Tumors

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"Volunteer for research at UC Davis and contribute to discoveries that may improve health care for you, your family, and your community!"
Age: 18 years or older
Gender:
Any
Healthy Volunteers: No
Keywords: BRAF Mutant Melanoma, melanoma, skin cancer, mutant melanoma, solid tumors, solid tumor cancer, tumors
Type: Drug study, Phase [1, 2]
Target:
18 Participants
Investigator:
Description
The purpose of this study is to test the safety of navitoclax in combination with dabrafenib and trametinibat. It will be given at different doses to find out what effects, if any, it has on people.

Dabrafenib blocks a protein caled BRAF. Trametinib blocks a protein called MEK. Both are drugs that individually have been shown to be effective for patients with BRAF-mutant melanoma. Given together, these two drugs have been shown to be more effective than dabrafenib for patients with BRAF-mutant melanoma.

Navitoclax is a drug that makes tumor cells more likely to die in response to other treatments (like chemotherapy). It is an investigational drug (not FDA-approved) that has been studied in a number of diseases. All three drugs are in pill form and taken by mouth.
This study requires

The study team will make sure you qualify to take part in the study. Qualified participants will receive detailed information about the study. This may include a list of study-related tests and procedures.

Who can participate

Inclusion criteria:

  • 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 computed tomography (CT) scan, magnetic resonance imaging (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
  • 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)
  • Serum creatinine =< 1.5 mg/dL OR creatinine clearance >= 50 mL/min/1.73 m^2
  • 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:

  • 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 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; 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; 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; 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:
  • A QT interval corrected for heart rate using the Bazett's formula QTcB >= 480 msec on screening electrocardiography (ECG)
  • 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
  • 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
  • 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
  • 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
  • Caution should be exercised when dosing navitoclax concurrently with cytochrome P450, family 2, subfamily C, peptide 8 (CYP2C8) and cytochrome P450, family 2, subfamily C, peptide 9 (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; cytochrome P450, family 3, subfamily A (CYP3A) inhibitors such as ketoconazole and clarithromycin are not allowed 7 days prior to the first dose of navitoclax or during navitoclax administration
  • Patients receiving any medications or substances that are strong inhibitors or inducers of 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 permeability-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded; below are a few examples of the agents:
  • Strong inducers of CYP3A or CYP2C8:
  • Antibiotics: rifamycin class agents (e.g., rifampin, rifabutin, rifapentine)
  • Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin, s-mephenytoin
  • Miscellaneous: bosentan, St. John's wort
  • Strong inhibitors of CYP3A or CYP2C8
  • Antibiotics: clarithromycin, telithromycin, troleandomycin
  • Antidepressants: nefazodone
  • Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole
  • Hyperlipidemia: gemfibrozil
  • Antiretroviral: ritonavir, saquinavir, atazanavir
  • Miscellaneous: conivaptan
Benefits and risks of participating
BENEFITS:

We cannot promise any benefits to you as a result of taking part in this research study.


RISKS:

The study doctor will discuss the risks associated with taking part in this research study.
Compensation
You will not be paid to take part in this research study.
Resources
Schedule
Study duration and period
You will receive the study drugs as long as you respond to treatment and tolerate therapy.
Recruitment period
From March 21, 2018
Location
UC Davis Comprehensive Cancer Center
4501 X Street
Sacramento, CA 95817
Research Topic
Conditions:
  • BRAF V600E Mutation Present
  • BRAF V600K Mutation Present
  • Metastatic Melanoma
  • Solid Neoplasm
  • Stage III Cutaneous Melanoma AJCC v7
  • Stage IIIA Cutaneous Melanoma AJCC v7
  • Stage IIIB Cutaneous Melanoma AJCC v7
  • Stage IIIC Cutaneous Melanoma AJCC v7
  • Stage IV Cutaneous Melanoma AJCC v6 and v7

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