Phase I Trial of Everolimus, Pomalidomide and Dexamethasone in Patients With Relapsed/Refractory Multiple Myeloma
Condition: Multiple Myeloma in Relapse
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Recurrence
Intervention: Combination therapy
Intervention description: Following determination of the maximum tolerated dosages in the phase I portion of this study, all patients enrolled in the extension portion will receive the predetermined dosage combination of pomalidomide, everolimus and dexamethasone.
Cycles will span 28 days. Dosage schedules will be:
Everolimus daily for 28 days of a 28 day cycle;
Pomalidomide daily for 21 days of a 28 day cycle
Dexamethasone once weekly (on days 1,8,15,22) of a 28 day cycle.
Intervention MeSH terms: Everolimus; Pomalidomide
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 1.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: myeloma; relapse; refractory; relapsed; pomalidomide; pomalyst; everolimus; afinitor; dexamethasone

Summary:

      This study is being conducted to test the possibility that a combination of three drugs,
      pomalidomide and everolimus with dexamethasone, may improve patient responses when compared
      with use of either drug alone, with dexamethasone in refractory/relapsed multiple myeloma.
    

Eligibility criteria:

        Inclusion Criteria:

        Age > 18 years

        Relapsed or progressive multiple myeloma (MM) (Progressive Disease), defined as a 25%
        increase from the lowest response value in ANY of the following:

        Serum M-protein (absolute increase ≥0.5 g/dL)

        Urine M-protein (absolute increase of ≥200 mg/24 hours)

        Bone marrow plasma cell percentage (≥ 10% absolute increase) in absence of measurable
        M-protein

        Difference in kappa & lambda free light chain levels (ratio must be abnormal; absolute
        change must be >10 mg/dL)

        Patients are also considered to have progressive disease when:

        New bone or soft tissue lesions (e.g. plasmacytomas) are identified; or

        There is an unequivocal increase in the size of previously existing lesions; or

        The development of an otherwise unexplained serum calcium >11.5 mg/dL

        Have received 1, but no more than 4 prior treatment regimens or lines of therapy for MM
        (Induction therapy followed by stem cell transplant & consolidation/maintenance therapy
        will be considered as one line of therapy)

        ECOG Performance status 0 - 2

        Life expectancy of at least 12 weeks

        Evaluable MM with, at least one of the following, assessed within 21 days prior to
        randomization:

        Serum M-protein ≥ 0.5 g/dL, or Urine M-protein ≥ 200 mg/24 hour, or

        In absence of detectable serum or urine M-protein, serum FLC (SFLC) > 100 mg/L (involved
        light chain) and/or an abnormal kappa/lamda ratio (>4:1 or <2:1), or

        Monoclonal plasma cells in a bone marrow biopsy/aspirate of >5%

        Adequate organ and marrow function as defined below:

          -  Leukocytes ≥ 2,500/mcL

          -  Absolute neutrophil count ≥ 1,500/mcL

          -  Platelets ≥ 100,000/mcL

          -  Total bilirubin < 2 X ULN

          -  AST(SGOT)/ALT(SPGT) ≤ 2.5 X ULN

          -  Creatinine < 1.5 X ULN

        Contraception Women of child-bearing potential and men must agree to use adequate
        contraception prior to study entry, for duration of study, and for 90 days after completion
        of therapy.

        A female of child-bearing potential is considered to be any woman (regardless of sexual
        orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets
        the following criteria:

          -  No hysterectomy or bilateral oophorectomy; or

          -  Not naturally postmenopausal for at least 12 consecutive months (i.e., has had menses
             at any time in the preceding 12 consecutive months).

        Male patients must use an effective barrier method of contraception during study and for 3
        months following the last dose if sexually active with a female of child-bearing potential.

        No prior therapy with pomalidomide or everolimus.

        Ability to understand and the willingness to sign a written informed consent document.

        Exclusion Criteria:

        Have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those
        who have not recovered from adverse events due to agents administered more than 4 weeks
        earlier.

        Receiving any other investigational agents. Minimum 4 week "washout" period is required.

        History of allergic reactions attributed to compounds of similar chemical or biologic
        composition to pomalidomide, everolimus, or other agents used in the study.

        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.

        Pregnant or nursing (due to the rick for congenital abnormalities and the potential of this
        regimen to harm nursing infants).

        Glucocorticoid therapy (prednisone > 30 mg/day or equivalent) within 14 days prior to
        randomization.

        POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin
        changes).

        Plasma cell leukemia or circulating plasma cells ≥ 2 × 10^9/L.

        Waldenstrom's Macroglobulinemia.

        Patients with known amyloidosis.

        Focal radiation therapy within 7 days prior to randomization. Radiation therapy to an
        extended field involving a significant volume of bone marrow within 21 days prior to
        randomization (i.e., prior radiation must have been to less than 30% of the bone marrow).

        Immunotherapy within 21 days prior to randomization.

        Myelodysplastic syndrome

        Major surgery (excluding kyphoplasty) within 28 days

        Known cirrhosis.

        Significant neuropathy (Grades 3 to 4, or Grade 2 with pain) within 14 days

        Ongoing graft-vs-host disease.

        Using CYP3A4 inhibitors such as Ketoconazole, Ritonavir, Itraconazole, Erythromycin,
        Clarithromycin, Nelfinavir, Fluconazole, Amiodarone, Cyclosporine, Diltiazem,
        nefazadone,fluvoxamine, verapamil, chloramphenicol, Indinavir or saquinavir within 7 days
        of treatment.