Phase I/II Study of Dabrafenib, Trametinib, and Navitoclax in BRAF Mutant Melanoma and Other Solid Tumors
You are being asked to take part in this study because a mutation, a change in a cancer gene that helps cancer grow, in a gene called BRAF has been detected in your cancer. Since BRAF mutations are very common in melanoma, most of the people on this study will have melanoma. You may have already been treated with other treatments for your cancer and your disease is now growing. People who are not in a study are usually treated with standard treatment options. These options are very different depending on the type of cancer you have, but often include chemotherapy, radiation therapy, surgery, and immune therapy. For example, if you have melanoma, than the standard treatment options include a chemotherapy called dacarbazine, two types of immune therapies (treatments that boost the body’s defense system) called high-dose interleukin-2 and ipilimumab, two BRAF inhibitors called dabrafenib and vemurafenib, and a MEK inhibitor called trametinib. You may also choose to receive a combination of dabrafenib and trametinib outside of this study. Study Title for Study Participants: Testing the addition of navitoclax to the combination of the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib Official Study Title for Internet Search on http://www.ClinicalTrials.gov: Phase I/II study of dabrafenib, trametinib, and navitoclax in BRAF mutant melanoma and other solid tumors (Phase I Consent) What are my other choices if I do not take part in this study? If you decide not to take part in this study, you have other choices. For example: you may choose to have the usual approach described above you may choose to take part in a different study, if one is available or you could decide not to be treated Why is this study being done? The purpose of the first part (Phase I) of the study is to test the safety of navitoclax in combination with dabrafenib and trametinib at different doses to find out what effects, if any, it has on people. There will be about 18 people treated in this part of the study. Dabrafenib and trametinib are drugs that individually have been shown to be effective for patients with BRAF-mutant melanoma. Both have been approved by the FDA for the treatment of BRAF-mutant melanoma. The combination treatment of dabrafenib and trametinib is investigational. Navitoclax is an investigational drug that has been studied in a number of diseases. All three drugs are in pill form and taken by mouth. This will be the first study to test all three drugs together. By participating in this study, you may be passing up a chance to receive an FDA-approved agent that has been proven to be effective for treating this disease.
Disease Group: Melanoma
Treatment Agent: Dabrafenib,Trametinib
Treatment Location: Both at MDACC & and Other Sites
Sponsor: Dana-Farber/Harvard Cancer Center,NCI-CTEP,Trametinib
Phase I Objectives Primary Objective 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 navitocalx 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. 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.
IRB Review and Approval Date: 11/20/2015
Recruitment Status: Open
Projected Accrual: up to 68
1) For Phase I: Patients must have histologically confirmed, BRAF-mutant
(V600E/K) malignancy (molecularly confirmed using validated,
commercially available assay performed in a CLIA-approved laboratory)
that is metastatic or unresectable and for which standard curative or
palliative measures do not exist or are no longer effective. •If test at
CLIA-certified lab used a non-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
2) For Phase II: Patients must have histologically confirmed, BRAF-mutant (V600E/K) melanoma (molecularly confirmed using validated, commercially available assay performed in a 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-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).
3) 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. See Section 11 for the evaluation of measurable disease
4) Prior therapy is allowed. Phase I: 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. Phase II: 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.
5) 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.
6) ECOG performance status =1 (Karnofsky =70%, see Appendix A).
7) Life expectancy of greater than 3 months.
8) Patients must have normal organ and marrow function as defined below: a) leukocytes >/=3,000/mcL b) absolute neutrophil count >/=1 x 10 ^ 9/L c) hemoglobin > 9 g/dl (patients may be transfused to this level) d) platelets >/=100,000/mcL e) 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. f) AST(SGOT)/ALT(SGPT) </= 2.5 x institutional upper limit of normal g) PT/INR and PTT< 1.3 x ULN h) Serum creatinine </=.5 mg/dL OR i) creatinine clearance >/= 50 mL/min/1.73 m2 j) Left ventricular ejection fraction = institutional lower limit of normal (LLN) by ECHO
9) Patients must have a QTc interval of less than 480 msec
10) The effects of navitoclax, dabrafenib, and trametinib on the developing human fetus are unknown. For this reason, 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 due to drug-drug interactions which can render hormonal contraceptives ineffective) 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.
11) Continuation of Inclusion 10 - Based on studies in animals, it is also known that dabrafenib may cause damage to the tissue that makes sperm. This may cause sperm to be abnormal in shape and size and could lead to infertility, which may be irreversible. Safety and efficacy of the combination of dabrafenib and trametinib in pediatric populations have not been investigated. Dabrafenib or trametinib-dabrafenib combination should not be administered to pediatric populations outside clinical trials.
12) Therapeutic level dosing of warfarin can be used with close monitoring of PT/INR by the site. Exposure may be decreased due to enzyme induction when on treatment, thus warfarin dosing may need to be adjusted based upon PT/INR. Consequently, when discontinuing dabrafenib, warfarin exposure may be increased and thus close monitoring via PT/INR and warfarin dose adjustments must be made as clinically appropriate. Prophylactic low dose warfarin may be given to maintain central catheter patency.
13) 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.
14) Ability to understand and the willingness to sign a written informed consent document.
1) 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.
2) In the phase I portion of the study, 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. In the phase II portion of the study, prior navitoclax, BRAF inhibitor, and MEK inhibitor will be prohibited.
3) 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.
4) 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 CTEP medical monitor. Subjects must also be off of enzyme-inducing anticonvulsants for >4 weeks.
5) 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).
6) 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.
7) 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.
8) HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with the study drugs. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated. It is not necessary to conduct HIV testing at screening.
9) 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.
10) History of interstitial lung disease or pneumonitis.
11) 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.
12) History or evidence of cardiovascular risk including any of the following: LVEF<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;
13) contd. #12. 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.
14) 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.
15) Subject has an underlying condition predisposing them to bleeding or currently exhibits signs of clinically significant bleeding.
16) Subject has a recent history of non-chemotherapy-induced thrombocytopenic-associated bleeding within 1 year prior to the first dose of study drug.
17) A history of glucose-6-phosphate dehydrogenase (G6PD) deficiency.
18) Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE v4.0) grade 2 or higher from previous anti-cancer therapy, except alopecia, at the time of randomization.
19) Due to the expected dose-limiting toxicity of thrombocytopenia, 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/mm3) 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.
20) 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 P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded. Below are a few examples of the agents.
21) A history of glucose-6-phosphate dehydrogenase (G6PD) deficiency.
22) Any participant who has ingested grapefruit juice within three days of commencing therapy.
Information and next steps
Phase I/Phase II
Melanoma Medical Oncology
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