Clinical Trials /

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

NCT03091257

Description:

This research study is studying a targeted therapy as a possible treatment for multiple myeloma. The names of the study drugs involved in this study are: - Trametinib - Dabrafenib

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study of Dabrafenib and/or Trametinib in Patients With Relapsed and/or Refractory Multiple Myeloma
  • Official Title: An Open-label, Pilot Study of Dabrafenib and/or Trametinib in Patients With Relapsed and/or Refractory Multiple Myeloma

Clinical Trial IDs

  • ORG STUDY ID: 16-352
  • NCT ID: NCT03091257

Conditions

  • Multiple Myeloma

Interventions

DrugSynonymsArms
DabrafenibTafinlarDabrafenib
TrametinibMekinistDabrafenib and Trametinib

Purpose

This research study is studying a targeted therapy as a possible treatment for multiple myeloma. The names of the study drugs involved in this study are: - Trametinib - Dabrafenib

Detailed Description

      This research study is a Pilot Study, which is the first time investigators are examining
      this study drug in this disease. "Investigational" means that the combination of drugs is
      being studied. It also means that the FDA (U.S. Food and Drug Administration) has not
      approved the drugs for your type of cancer.

      The FDA has not approved Trametinib or Dabrafenib for your specific disease but they have
      been approved for other uses.

      Some cancers have changes (mutations) in a gene called BRAF or other genes, called KRAS or
      NRAS. These three genes tell the body to make a protein called BRAF, KRAS, or NRAS,
      respectively, which are all involved in sending signals in cells that can lead to cell
      growth. Certain mutations in these three genes cause a change in these proteins that can
      increase the growth and spread of cancer cells.

      Dabrafenib and trametinib work to prevent these altered proteins from working and sending
      signals in cancer cells, and thereby may block the growth and spread of cancer cells in
      people with cancers with BRAF, KRAS, or NRAS gene mutations. Dabrafenib and trametinib have
      been used in the treatment for other cancers in other research studies, and information from
      those research studies suggest that these agents may help to kill multiple myeloma cells.

      Dabrafenib and trametinib, which are investigated in this research study may or may not kill
      myeloma cells effectively. We would like to see if these drugs given alone or in combination
      safely and effectively kill these cancer cells.
    

Trial Arms

NameTypeDescriptionInterventions
DabrafenibExperimentalDetermine if mutation in BRAF, KRAS, NRAS BRAF V600 mutated Treat cohort with Dabrafenib Analysis Treat cohort with Dabrafenib
  • Dabrafenib
Dabrafenib and TrametinibExperimentalDetermine if mutation in BRAF, KRAS, NRAS BRAF V600 mutated, BRAF/KRAS mutated, or BRAF/NRAS mutated, or BRAF non-V600 mutated Treat cohort with Dabrafenib and Trametinib Analysis Treat cohort with Dabrafenib and Trametinib
  • Dabrafenib
  • Trametinib
TrametinibExperimentalDetermine if mutation in BRAF, KRAS, NRAS KRAS or NRAS mutated Treat cohort with Trametinib Analysis Treat cohort with Trametinib
  • Trametinib

Eligibility Criteria

        Inclusion Criteria:

          -  Participants must have a confirmed diagnosis of multiple myeloma as defined by the
             following criteria:

               -  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 the following:

                    -  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

                    -  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

                    -  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. Measurable disease
             is defined as one or more of the following: serum M-protein ≥0.5 g/dL, urine M-protein
             ≥200 mg/24 h, and/or serum FLC assay: involved FLC level ≥10 mg/dL with abnormal serum
             FLC ratio.

          -  Relapsed disease after at least 2 line of therapy

          -  Age ≥ 18 years years at the time of signing the informed consent form.

          -  ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)

          -  Participants must have sufficient organ and marrow function as defined below:

               -  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.

               -  PT/INR and 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 × 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) ≥ LLN by ECHO. --- Abbreviations: ALT =
                  alanine transaminase; ANC = absolute neutrophil count; AST = aspartate
                  aminotransferase; INR = international normalized ratio; LLN = lower limit of
                  normal; PT = prothrombin time; PTT = partial thromboplastin time;

          -  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 (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 agree to 1 of the following: practice effective barrier contraception
             during the entire study treatment period and through a minimum of 30 days after the
             last dose of study drug, 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 (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).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate
Time Frame:100 weeks
Safety Issue:
Description:Response rate by IMWG criteria

Secondary Outcome Measures

Measure:Number of Participants with Severe Adverse Events
Time Frame:100 weeks
Safety Issue:
Description:NCI Toxicity

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Massachusetts General Hospital

Trial Keywords

  • Multiple Myeloma

Last Updated