Tivantinib in Treating Patients With Relapsed, or Relapsed and Refractory Multiple Myeloma
Condition: Refractory Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Tivantinib; Diagnostic laboratory biomarker analysis; Questionnaire administration; Quality-of-life assessment
Intervention description: Given at a dose of 360 mg oral (PO) twice daily continuously for each day of every 4-week treatment cycle, which will be taken as three tablets of 120 mg each.; Correlative studies; Ancillary studies; Ancillary studies
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 16.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: c-Met Inhibitor ARQ-197; tivantinib; multiple myeloma; plasma cell proliferative disorder; Hypercalcemia; hematologic malignancy; plasma cell dyscrasia; cast nephropathy; amyloidosis; osteolysis; Renal insufficiency; Anemia; Bone lytic lesions; severe osteopenia; pathologic fractures; biopsy-proven plasmacytoma

Summary:

      This phase II trial studies the side effects and how well tivantinib works in treating
      patients with relapsed, or relapsed and refractory multiple myeloma. Tivantinib may stop the
      growth of cancer cells by blocking some of the enzymes needed for cell growth.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients must have been previously diagnosed with histologically or cytologically
             confirmed symptomatic multiple myeloma, which requires the presence of all three of
             the following International Myeloma Working Group criteria, except as noted:

               -  Clonal bone marrow plasma cells >= 10%

               -  A monoclonal protein in either serum or urine

               -  Evidence of end-organ damage that can be attributed to the underlying plasma cell
                  proliferative disorder (to include one of the following):

                    -  Hypercalcemia (corrected calcium > 2.75 mmol/L or 11.5 mg/dL)

                    -  Renal insufficiency attributable to myeloma (serum creatinine > 1.9 mg/dL)

                    -  Anemia; normochromic, normocytic with a hemoglobin value >= 2 g/dL below the
                       lower limit of normal, or a hemoglobin or < 10 g/dL

                    -  Bone lytic lesions, severe osteopenia, or pathologic fractures

                    -  Patients with a biopsy-proven plasmacytoma and either a serum or urine
                       monoclonal protein will also be considered to have met the diagnostic
                       criteria for multiple myeloma in the absence of clonal marrow plasmacytosis
                       of >= 10%

          -  Patients must have measurable disease, as defined by at least one of the following:

               -  Serum monoclonal protein level >= 0.5 g/dL for immunoglobulin (Ig)G, IgA, or IgM
                  disease

               -  Monoclonal protein or total serum IgD >= 0.5 g/dL for IgD disease

               -  Urinary M-protein excretion of >= 200 mg over a 24-hour period

               -  Involved free light chain level >= 10 mg/dL, along with an abnormal free light
                  chain ratio

          -  Patients must have had at least one, but not more than four prior lines of therapy for
             their disease, with lines of therapy being separated by the presence of documented
             disease progression; using this definition, treatment with induction therapy, followed
             by high-dose chemotherapy and autologous stem cell transplantation, and finally by
             maintenance therapy, would constitute one line, provided that multiple myeloma did not
             meet criteria for progression at any time during this period

          -  Patients with relapsed disease will be considered to be those who have had
             progression, as defined above, off of any therapy, and who completed their therapy
             more than 60 days prior to the finding of progression; patients with relapsed and
             refractory disease will be considered to be those who have had progression, as defined
             above, while still on their last line of therapy, or who progressed within 60 days of
             finishing their most recent therapy

          -  Patients must have completed their most recent drug therapy directed at multiple
             myeloma in the following time frames:

               -  Chemotherapy, biological therapy, immunotherapy, or an investigational therapy at
                  least 3 weeks prior to starting c-Met inhibitor ARQ197

               -  Corticosteroids at least 3 weeks prior to starting ARQ 197, except for a dose
                  equivalent to dexamethasone of no greater than 4 mg/day

               -  Nitrosoureas, nitrogen mustards, mitomycin C, or monoclonal antibodies at least 6
                  weeks prior to starting ARQ 197

               -  Autologous stem cell transplantation at least 12 weeks prior to starting ARQ 197

               -  Allogeneic stem cell transplantation at least 24 weeks prior to starting ARQ 197,
                  and these patients must also not have moderate to severe active acute or chronic
                  graft-versus-host disease

          -  Patients must be willing and able to provide voluntary written informed consent, with
             the understanding that consent may be withdrawn by the subject at any time without
             prejudice to their future medical care

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (Karnofsky
             >= 60%)

          -  Absolute neutrophil count (ANC) >= 1,000 cells/mm^3 without growth factors within 1
             week of the initiation of treatment

          -  Total white blood cell count (WBC) >= 2,000 cells/mm^3 without growth factors within 1
             week of the initiation of treatment

          -  Hemoglobin >= 8 g/dL without red blood cell transfusions within 2 weeks of the
             initiation of treatment

          -  Platelet counts of >= 100,000 cells/mm^3 for patients who have bone marrow
             plasmacytosis of < 50%, or >= 50,000 cells/mm^3 for patients who have bone marrow
             plasmacytosis of >= 50%

          -  Total bilirubin =< 1.5 times the upper limit of the institutional normal (ULN) values

          -  Total aspartate aminotransferase (AST) (serum glutamic oxaloacetic acid transaminase
             [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase
             [SGPT]) =< 2.5 times ULN values

          -  Serum creatinine within the institutional normal limits OR if the creatinine is
             elevated, creatinine clearance (CrCl) >= 30 mL/min., as measured by a 24-hour urine
             collection, or estimated by the Cockcroft and Gault formula

          -  Patients must have evidence of adequate cardiac function, as defined by the following:

               -  Absence of New York Heart Association (NYHA) class II, III, or IV congestive
                  heart failure

               -  Absence of uncontrolled angina or hypertension

               -  Absence of myocardial infarction in the previous 6 months

               -  Absence of clinically significant bradycardia or other uncontrolled cardiac
                  arrhythmia defined as grade 3 or 4 according to National Cancer Institute (NCI)
                  Common Terminology Criteria for Adverse Events (CTCAE), version 4.0

          -  Patients who have received radiation therapy must have completed this at least 4 weeks
             prior to starting therapy with ARQ 197, with the following exceptions:

               -  Local radiation therapy to enhance bone healing of a pathologic fracture may have
                  been performed, as long as it was completed at least 2 weeks prior to starting
                  ARQ 197

               -  Local radiation therapy to treat post-fracture pain that is refractory to
                  analgesics may have been performed, as long as it was completed at least 2 weeks
                  prior to starting ARQ197

          -  Patients who have undergone any recent major surgery must have done so at least 4
             weeks prior to starting therapy with ARQ 197, with the following exceptions:

               -  Vertebroplasty and/or kyphoplasty, which must have been performed at least 1 week
                  prior to starting ARQ 197

               -  Planned elective surgery unrelated to the patient's diagnosis of multiple
                  myeloma, such as hernia repair, may be allowed, at the discretion of the
                  Principal Investigator, as long as it was performed at least 2 weeks prior to
                  starting ARQ 197, and patients have recovered fully from this procedure

          -  Human immunodeficiency virus (HIV)-seropositive patients with acceptable organ
             function who meet the patient selection criteria, and who are not on combination
             antiretroviral therapy, and whose absolute CD4+ count is >= 400 cells per cubic
             millimeter of blood, will be eligible; however, HIV positive patients on combination
             antiretroviral therapy will be ineligible

          -  Male patients must agree to use an adequate method of contraception for the duration
             of the study since the effects of ARQ 197 on the developing human fetus are unknown;
             female patients must be either post- menopausal, free from menses for >= 2 years,
             surgically sterilized, or willing to use two adequate barrier methods of contraception
             to prevent pregnancy, or must agree to abstain from heterosexual activity throughout
             the study; female patients of childbearing potential must have a negative serum
             (beta-human chorionic gonadotropin [beta-HCG]) or urine pregnancy test before
             receiving the first dose of ARQ 197; should a woman become pregnant or suspect she is
             pregnant while she or her partner is participating in this study, she should inform
             her treating physician immediately

        Exclusion Criteria:

          -  Patients who are receiving any concurrent investigational agent with known or
             suspected activity against multiple myeloma, or those whose adverse events due to
             agents administered more than 4 weeks earlier have not recovered to a severity of
             grade 0 or grade 1

          -  Patients who have known central nervous system involvement with multiple myeloma will
             be excluded from this clinical trial

          -  Patients who have previously been treated with another agent targeting the HGF/c-Met
             axis, including either monoclonal antibodies to HGF or c-Met, or small molecule
             inhibitors of c-Met

          -  Patients with a known history of allergic reactions attributed to compounds of similar
             chemical or biologic composition to ARQ 197

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements, in the opinion of the Principal Investigator

          -  Pregnant or lactating women are excluded from this study

          -  HIV positive patients on combination antiretroviral therapy are ineligible because of
             the potential for pharmacokinetic interactions with ARQ 197; however, HIV seropositive
             patients with acceptable organ function who meet the patient selection criteria, and
             who are not on combination antiretroviral therapy, will be eligible

          -  Patients with non-secretory multiple myeloma, active plasma cell leukemia, defined as
             either having 20% of peripheral white blood cells comprised of CD138+ plasma cells, or
             an absolute plasma cell count of 2 x 10^9/L, known amyloidosis, or known POEMS
             syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy,
             monoclonal protein, and skin changes)

          -  Patients who have required plasmapheresis and exchange less than 2 weeks prior to
             initiation of therapy with ARQ 197

          -  Patients with known active hepatitis A, B, and/or C infection

          -  Patients with a "currently active" second malignancy, other than non-melanoma skin
             cancer and carcinoma in situ of the cervix, should not be enrolled; patients are not
             considered to have a "currently active" malignancy if they have completed therapy for
             a prior malignancy, are disease free from prior malignancies for > 5 years, and are
             considered by their physician to be at less than 30% risk of relapse; in addition,
             patients with basal cell carcinoma of the skin, superficial carcinoma of the bladder,
             carcinoma of the prostate with a current prostate-specific antigen (PSA) value of <
             0.5 ng/mL, or cervical intraepithelial neoplasia will be eligible; finally, patients
             who are on hormonal therapy for a history of either prostate cancer or breast cancer
             may enroll, provided that there has been no evidence of disease progression during the
             previous three years