SMAC Mimetic LCL161 Alone or With Cyclophosphamide in Treating Patients With Relapsed or Refractory Multiple Myeloma
Condition: Recurrent Plasma Cell Myeloma; Refractory Plasma Cell Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Cyclophosphamide; Laboratory Biomarker Analysis; Pharmacological Study; Quality-of-Life Assessment; Smac Mimetic LCL161
Intervention description: Given PO; Correlative studies; Correlative studies; Ancillary studies; Given PO
Intervention MeSH terms: Cyclophosphamide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 25.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This phase II trial studies how well second mitochondrial-derived activator of caspases
      (SMAC) mimetic LCL161 alone or with cyclophosphamide works in treating patients with multiple
      myeloma that has returned or does not respond to treatment. Biological therapies, such as
      SMAC mimetic LCL161, may stimulate the immune system in different ways and stop cancer cells
      from growing. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to
      stop the growth of cancer cells, either by killing the cells or by stopping them from
      dividing. It is not yet known whether giving SMAC mimetic LCL161 alone or with
      cyclophosphamide is more effective in treating multiple myeloma.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Relapsed or refractory multiple myeloma and has already received =< 4 standard
             treatment regimens; note: induction, transplant, consolidation, and maintenance is
             considered one regimen

          -  Have received prior therapy with an immunomodulatory agent, a proteosome inhibitor,
             and glucocorticoids

          -  Absolute neutrophil count (ANC) >= 1000/uL

          -  Untransfused platelet count >= 75,000/uL

          -  Aspartate aminotransferase (AST) =< 3 x upper limit of normal (ULN)

          -  Alanine aminotransferase (ALT) =< 3 x ULN

          -  Total bilirubin =< 1.5 mg/dL

          -  Serum creatinine =< 2.5 mg/dL

          -  Hemoglobin >= 8 g/dL

          -  Measurable disease of multiple myeloma as defined by at least ONE of the following:

               -  Serum monoclonal protein >= 1.0 g/dL

               -  >= 200 mg of monoclonal protein in the urine on 24 hour electrophoresis

               -  Serum immunoglobulin free light chain >= 10 mg/dL AND abnormal serum
                  immunoglobulin kappa to lambda free light chain ratio

               -  Monoclonal plasmacytosis >= 30% (evaluable disease)

               -  Measurable plasmacytoma that has not been radiated

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, 2

          -  Willing and able to comply with scheduled visits, treatment plan and laboratory tests

          -  Able to swallow and retain oral medication

          -  Provide informed written consent

          -  Negative serum pregnancy test done =< 7 days prior to registration, for women of
             childbearing potential only

          -  Willing to provide all biological specimens as required by the protocol for
             correlative research purposes

          -  Willing to return to enrolling institution for follow-up (during the active monitoring
             phase of the study)

          -  Mayo Clinic Arizona only: Willing to participate in associated biobanking study,
             919-04; the patient must sign consent to enroll onto the mandatory companion
             biobanking study in order to participate in this treatment study

          -  Mayo Clinic Rochester and Florida only: Willing to participate in associated
             biobanking study, 521-93; the patient must sign consent to enroll onto the mandatory
             companion biobanking study in order to participate in this treatment study

        Exclusion Criteria:

          -  Prior use of investigational drugs =< 14 days prior to registration

          -  Prior use of growth factors =< 14 days prior to registration

          -  Prior radiation therapy =< 14 days prior to registration

          -  Prior autologous stem cell transplant =< 12 weeks prior to registration

          -  Any of the following:

               -  Pregnant women

               -  Nursing women

               -  Women of childbearing potential who are unwilling to employ adequate
                  contraception while receiving treatment on this study and for 4 months after
                  stopping treatment on this study

               -  Men who are unwilling to use a condom (even if they have undergone a prior
                  vasectomy) while having intercourse with any woman, while receiving treatment on
                  this study and for 4 months after stopping treatment on this study NOTE:
                  Postmenopausal women are allowed to participate in this study; women are
                  considered post-menopausal and not of child bearing potential if they have had 12
                  months of natural (spontaneous) amenorrhea with an appropriate clinical profile
                  (e.g. age appropriate, history of vasomotor symptoms) or have had surgical
                  bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least
                  six weeks ago; in the case of oophorectomy alone, a woman is considered to be of
                  not child bearing potential only when her reproductive status has been confirmed
                  by follow-up hormone level assessment

          -  Prior allogeneic transplant of any kind

          -  Known active infection requiring parenteral or oral anti-infective treatment

          -  Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or
             confuse follow-up evaluation

          -  Known human immunodeficiency virus (HIV) or active hepatitis B or C viral infection

          -  Active autoimmune/inflammatory conditions requiring ongoing immunosuppressive therapy

          -  Use of more than low dose corticosteroids (e.g., prednisone up to but no more than 10
             mg PO QD or its equivalent) for symptom management and comorbid conditions, except for
             the following:

               -  Topical applications (e.g. rash)

               -  Inhaled sprays (e.g. obstructive airways diseases)

               -  Eye drops or local injections (e.g. intra-articular)

               -  Joint injections (e.g. arthritis) Doses of corticosteroid should be stable for at
                  least 7 days prior to registration

          -  Any concurrent severe and/or uncontrolled medical conditions that could increase the
             patient's risk for toxicity while in the study or that could confound discrimination
             between disease- and study treatment-related toxicities

          -  Impaired cardiac function or clinically significant cardiac diseases, including any of
             the following:

               -  History or presence of ventricular tachyarrhythmia

               -  Presence of unstable atrial fibrillation (ventricular response > 100 bpm) (NOTE:
                  patients with stable atrial fibrillation are eligible, provided they do not meet
                  any of the other cardiac exclusion criteria)

               -  Clinically significant resting bradycardia (< 50 bpm)

               -  Angina pectoris or acute myocardial infarction =< 3 months prior to registration

               -  Other clinically significant heart disease (e.g., symptomatic congestive heart
                  failure; uncontrolled arrhythmia or hypertension; history of labile hypertension
                  or poor compliance with an antihypertensive regimen)

          -  Currently receiving treatment with agents that are metabolized solely through
             cytochrome P450, family 3, subfamily A, polypeptide 4/5 (CYP3A4/5) and have a narrow
             therapeutic index or are strong cytochrome P450, family 2, subfamily C, polypeptide 8
             (CYP2C8) inhibitors; or are receiving treatment with agents that carry a risk for QT
             prolongation and are CYP3A substrates; caution should be used in patients taking other
             CYP2C8- or CYP3A4/5-interacting agents

          -  Impaired gastrointestinal (GI) function or GI disease that may significantly alter the
             absorption of LCL161