A Study of Dabrafenib and/or Trametinib in Patients With Relapsed and/or Refractory Multiple Myeloma

Exclusion Criteria

• •Prior treatment with a BRAF inhibitor or a MEK inhibitor. Treatment by localized radiotherapy is not an exclusion criterion if an interval of at least two weeks between the end of radiotherapy and initiation of protocol therapy is observed.
• •Primary amyloidosis (AL) or myeloma complicated by amyloidosis
• •Nonsecretory multiple myeloma based upon standard M-component criteria (ie, measurable serum/urine M-component) unless the baseline serum free light chain level is elevated. Patients with plasmacytomas with biopsy proven known mutations may be included as long as they have evaluable disease by imaging.
• •Participants receiving any other investigational agents within 2 weeks of the start of this trial and throughout the duration of this trial. Participants receiving anti-cancer treatment (chemotherapy, immunotherapy, biologic therapy, vaccine therapy, or investigational treatment) within 3 weeks prior to first dose of dabrafenib or trametinib. Participants receiving proteasome inhibitors or immunomodulatory drugs (-imid), or chemotherapy without delayed toxicity within 2 weeks prior to first dose of dabrafenib or trametinib. Treatment by localized radiotherapy is not an exclusion criterion if an interval of at least two weeks between the end of radiotherapy and initiation of protocol therapy is observed.
• •Current use of a prohibited medication as described in Section 6.4.
• •Participants with platelet level \<50,000/mm3, within 21 days of initiation of protocol therapy for patients in whom \<50% of bone marrow nucleated cells are plasma cells; or platelet count \<30,000/mm3 for participants in whom \>50% of bone marrow nucleated cells are plasma cells. Transfusion within 7 days of screening is not allowed to meet platelet eligibility criteria.
• •Participants with an absolute neutrophil count (ANC) \<1000/mm3, within 21 days of initiation of protocol therapy. Growth factor within 7 days of screening is not allowed to meet ANC eligibility criteria.
• •Participants with hemoglobin level \< 8 g/dL, within 21 days of initiation of protocol therapy. Transfusion may be used to meet hemoglobin eligibility criteria.
• •Hepatic impairment, defined as total bilirubin \> 1.5 x institutional ULN (patients with benign hyperbilirubinemia (e.g., Gilbert's syndrome) are eligible.) or AST (SGOT), or ALT (SGPT), or alkaline phosphatase \> 2 x institutional ULN, within 21 days of initiation of protocol therapy.
• •Renal insufficiency, defined as serum creatinine \>2.0 mg/dL.
• •Participant had myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class II, III or IV heart failure (see Appendix G), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities, or treatment refractory hypertension defined as a blood pressure of systolic \>140mmHg and/ or diastolic \> 90 mmHg which cannot be controlled by anti-hypertensive therapy. Prior to study entry, any ECG abnormality at screening must be documented by the investigator as not medically relevant.
• •A history or evidence of cardiovascular risk including any of the following:
• •* A QT interval corrected for heart rate using the Bazett's formula (QTcB; Appendix E) ≥ 480 msec;
• •* A history or evidence of current clinically significant uncontrolled arrhythmias; Clarification: Subjects with atrial fibrillation controlled for \>30 days prior to dosing are eligible.
• •* A history of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within 6 months prior to alternate assignment.
• •* A history or evidence of current ≥ Class II congestive heart failure as defined by the New York Heart Association (NYHA) guidelines (Appendix G);
• •* Patients with intra-cardiac defibrillators;
• •* 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.
• •* Treatment refractory hypertension defined as a blood pressure of systolic\> 140 mmHg and/or diastolic \> 90 mm Hg which cannot be controlled by anti-hypertensive therapy;
• •Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the subject's safety, obtaining informed consent, or compliance with study procedures.
• •A history of Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (subjects with laboratory evidence of cleared HBV and/or HCV will be permitted.
• •Diagnosed or treated for another malignancy within 2 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy or subjects with indolent second malignancies.
• •Female participants pregnant or breast-feeding. Pregnant women are excluded from this study because 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. Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the human exposure at the recommended clinical dose.
• •A history or current evidence of retinal vein occlusion (RVO)
• •History of interstitial lung disease or pneumonitis
• •Patients with known human immunodeficiency virus (HIV) on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with dabrafenib and trametinib. In addition, these participants are at increased risk of lethal infections when treated with marrow-suppressive therapy.
• •Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO).