Skip to main content

Trametinib with or without Dabrafenib Mesylate in Treating Patients with BRAF, KRAS, or NRAS Gene Mutation and Recurrent Multiple Myeloma

Trial Status: Active

This phase II trial studies how well trametinib with or without dabrafenib mesylate works in treating patients with BRAF, KRAS, or NRAS gene mutation and multiple myeloma that has come back. Trametinib and dabrafenib mesylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Inclusion Criteria

  • Participants must have a confirmed diagnosis of multiple myeloma as defined by at least one of the following criteria: * Measurable disease by imaging such as plasmocytoma * Monoclonal plasma cells in the bone marrow greater than or equal to 10% and/or presence of a biopsy-proven plasmacytoma * Monoclonal protein present in the serum and/or urine * Measurable disease as defined by at least one of the following: ** Immunoglobulin G (IgG) multiple myeloma: Serum monoclonal paraprotein (M-protein) level greater than or equal to 0.5 g/dL or urine M-protein level greater than or equal to 200 mg/24 hours ** Immunoglobulin A (IgA) multiple myeloma: Serum M-protein level greater than or equal to 0.5 g/dL or urine M-protein level greater than or equal to 200 mg/24 hours ** Immunoglobulin D (IgD) multiple myeloma: Serum M-protein level greater than or equal to 0.5 g/dL or urine M-protein level greater than or equal to 200 mg/24 hours ** Light chain multiple myeloma: Serum immunoglobulin free light chain >= 10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio
  • Participants must have myeloma that is measurable by either serum or urine evaluation of the monoclonal component or by assay of serum free light chains or by imaging studies; measurable disease is defined as one or more of the following: serum M-protein >= 0.5 g/dL, urine M-protein >= 200 mg/24 hour (h), and/or serum free light chain (FLC) assay: involved FLC level >= 10 mg/dL with abnormal serum FLC ratio
  • Participants with plasma cell leukemia are eligible
  • Relapsed disease after at least 2 lines of therapy
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Participants with platelet level >= 50,000/mm^3, 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/mm^3 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/mm^3, 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 upper limit of normal (ULN) (patients with benign hyperbilirubinemia [e.g., Gilbert’s syndrome] are eligible) or
  • Hepatic impairment, defined as aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]), or alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2 x institutional ULN, within 21 days of initiation of protocol therapy, or
  • Hepatic impairment, defined as alkaline phosphatase =< 2 x institutional ULN, within 21 days of initiation of protocol therapy
  • Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.3 x institutional upper limit of normal; subjects receiving anticoagulation treatment may be allowed to participate with INR established within the therapeutic range prior to alternate assignment
  • Total bilirubin =< 1.5 x institutional upper limit of normal, except subjects with known Gilbert’s syndrome.
  • Creatinine =< 2.0 mg/dl
  • Serum calcium or albumin-adjusted serum calcium >= 2.0 mmol/L (8.0 mg/dL) and =< 2.9 mmol/L (11.5 mg/dL)
  • Left ventricular ejection fraction (LVEF) >= lower limit of normal (LLN) per institutional standard by echocardiogram (ECHO)
  • Harboring a mutation in the BRAF oncogene or the KRAS or the NRAS oncogene
  • Women of child-bearing potential must have a negative serum pregnancy test within 14 days prior to enrollment and agree to use adequate contraception as outlined (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and for 4 months after the last dose of study treatment; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately; a pregnancy test is not required for female participants over age 60 who have been postmenopausal for at least 24 months; male participants, even if surgically sterilized (i.e., status post vasectomy) must use a condom during intercourse, and for a minimum of 16 weeks after the last dose of study drug (4 weeks for dabrafenib monotherapy) and should not father a child during these periods, or completely abstain from heterosexual intercourse
  • Ability to understand and the willingness to sign a written informed consent document
  • Participant must be able to swallow pills and retain oral medication and must not have clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels

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 (i.e., 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
  • Participants with platelet level < 50,000/mm^3 prior to initiation of protocol therapy for patients in whom < 50% of bone marrow nucleated cells are plasma cells; or platelet count < 30,000/mm^3 for participants in whom > 50% of bone marrow nucleated cells are plasma cells; transfusion within 7 days of initiation of protocol therapy
  • Participants with an absolute neutrophil count (ANC) < 1000/mm^3 prior to initiation of protocol therapy; growth factor within 7 days of initiation of protocol therapy
  • Participants with hemoglobin level < 8 g/dL prior to initiation of protocol therapy
  • Hepatic impairment, defined as total bilirubin > 1.5 x institutional ULN (patients with benign hyperbilirubinemia [e.g., Gilbert’s syndrome] are eligible) prior to initiation of protocol therapy or
  • Hepatic impairment, defined as AST (SGOT), or ALT (SGPT) > 2 x institutional ULN prior to initiation of protocol therapy
  • Hepatic impairment, defined as alkaline phosphatase > 2 x institutional ULN, prior to 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, 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 electrocardiogram (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) >= 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; * 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 mmHg 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; breastfeeding should be discontinued if the mother is treated with the study drugs
  • 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
  • Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO)

Arkansas

Little Rock
University of Arkansas for Medical Sciences
Status: ACTIVE
Contact: Maurizio Zangari

Georgia

Atlanta
Emory University Hospital / Winship Cancer Institute
Status: ACTIVE
Contact: Jonathan Lyle Kaufman

Massachusetts

Boston
Brigham and Women's Hospital
Status: ACTIVE
Contact: Nikhil C. Munshi
Phone: 617-632-5607
Dana-Farber Cancer Institute
Status: ACTIVE
Contact: Nikhil C. Munshi
Phone: 617-632-5607
Massachusetts General Hospital Cancer Center
Status: ACTIVE
Contact: Noopur S. Raje
Phone: 617-726-0711

Michigan

Detroit
Wayne State University / Karmanos Cancer Institute
Status: ACTIVE
Contact: Jeffrey Allan Zonder
Phone: 313-576-8673

New York

New York
Memorial Sloan Kettering Cancer Center
Status: ACTIVE
Contact: Malin Hultcrantz
Phone: 212-639-7986

PRIMARY OBJECTIVE:

I. To evaluate the objective response rate of 3 treatments (dabrafenib mesylate [dabrafenib]/trametinib combination OR dabrafenib single-agent treatment OR trametinib single-agent treatment) in patients with multiple myeloma whose tumors harbor either a mutation in the BRAF or NRAS or KRAS gene.

SECONDARY OBJECTIVE:

I. To evaluate the safety and tolerability of 3 treatments (dabrafenib/trametinib combination OR dabrafenib single-agent treatment OR trametinib single-agent treatment) in patients with multiple myeloma whose tumors harbor either a mutation in the BRAF or NRAS or KRAS gene.

EXPLORATORY OBJECTIVES:

I. To evaluate the role of circulating multiple myeloma (MM) cells and circulating deoxyribonucleic acid (DNA) in patients treated with dabrafenib/trametinib, or dabrafenib, or trametinib.

II. To determine genetic predictive biomarkers for response or resistance to therapy.

III. To assess the inhibition of the BRAF/MEK/ERK pathway by dabrafenib and trametinib and additional exploratory analyses on remaining material from samples collected during the study (blood, tumor) that could help in the understanding of the action of dabrafenib and trametinib and/or identify potential markers that may correlate with efficacy and safety.

OUTLINE: Patients with BRAF V600 gene mutation are randomized to Arms I or III. Patients with only KRAS or NRAS gene mutations are assigned to Arm II. Patients with BRAF (any BRAF gene mutation) and KRAS, or any BRAF (any BRAF gene mutation) and NRAS gene mutations are assigned to Arm III.

ARM I: Patients receive dabrafenib mesylate orally (PO) twice daily (BID) on days 1-28. Patients =< 75 years old also receive dexamethasone PO once daily (QD) on days 1, 2, 8, 9, 15, 116, 22, and 23; patients > 75 years old receive dexamethasone PO QD on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive trametinib PO QD on days 1-28. Patients =< 75 years old also receive dexamethasone PO QD on days 1, 2, 8, 9, 15, 116, 22, and 23; patients > 75 years old receive dexamethasone PO QD on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM III: Patients receive dabrafenib mesylate as in Arm I and trametinib as in Arm II. Patients =< 75 years old also receive dexamethasone PO QD on days 1, 2, 8, 9, 15, 116, 22, and 23; patients > 75 years old receive dexamethasone PO QD on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Noopur S. Raje

  • Primary ID 16-352
  • Secondary IDs NCI-2017-01202
  • Clinicaltrials.gov ID NCT03091257