Phase 1b Multicenter Study of Carfilzomib With Lenalidomide and Dexamethasone in Relapsed Multiple Myeloma
Condition: Relapsed Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Carfilzomib; Lenalidomide; Dexamethasone
Intervention description: Carfilzomib for Injection was administered intravenously over 10 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for the first 12 cycles. Each dose of Carfilzomib for Injection was normalized to body surface area.; Lenalidomide was administered orally on Days 1 to 21 of each 28-day cycle.; Dexamethasone 40 mg orally or intravenous equivalent was administered 30 minutes to 4 hours before carfilzomib on Days 1, 8, and 15, as well as on Day 22 of each 28-day cycle.
Intervention MeSH terms: Dexamethasone; Lenalidomide
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 84.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      To evaluate the safety and maximum tolerated dose (MTD) of carfilzomib in combination with
      lenalidomide and dexamethasone in patients with relapsed multiple myeloma
    

Eligibility criteria:

        Inclusion Criteria:

        Disease related:

          1. Symptomatic multiple myeloma

          2. Relapsed or progressive disease after at least one but no more than three prior
             therapeutic treatments or regimens for multiple myeloma

          3. Prior therapeutic treatment regimens may have included bortezomib, lenalidomide,
             and/or thalidomide, among other agents.

          4. If previously treated with lenalidomide or bortezomib, the subject must not have
             progressed during the first 3 months of treatment with the drug and must not have
             discontinued treatment due to lenalidomide intolerance (bortezomib intolerant subjects
             may enroll).

          5. Measurable disease, as indicated by one or more of the following:

               -  Serum M-protein ≥ 0.5 g/dL

               -  Urine Bence-Jones protein ≥ 200 mg/24 h

               -  If Serum Protein Electrophoresis is felt to be unreliable for routine M-protein
                  measurement (particularly for patients with Immunoglobulin (Ig)A multiple
                  myeloma), then quantitative immunoglobulin levels can be accepted.

          6. Prior to enrollment, sites must provide evidence of myeloma progression/relapse, with
             start and stop dates of the most recent treatment regimen, as well as best tumor
             response to all prior treatment regimens.

             Demographic

          7. Males and females ≥ 18 years of age

          8. Life expectancy of more than three months

          9. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2

             Laboratory

         10. Adequate hepatic function, with bilirubin < 2 times the upper limit of normal (ULN)
             and alanine aminotransferase (ALT) < 3 times ULN

         11. Absolute neutrophil count (ANC) ≥ 1,000/mm³, hemoglobin ≥ 8 gm/dL, platelet count ≥
             50,000/ mm³ (≥ 30 × 10^9/L if myeloma involvement in the bone marrow is > 50%)

               -  Screening ANC should be independent of granulocyte- and granulocyte/macrophage
                  colony stimulating factor (G-CSF and GM-CSF) support for at least 1 week and of
                  pegylated G-CSF for at least 2 weeks.

               -  Subjects may receive red blood cell (RBC) or platelet transfusions, if clinically
                  indicated, in accordance with institutional guidelines

               -  Screening platelet count should be independent of platelet transfusions for at
                  least 2 weeks

         12. Calculated or measured creatinine clearance of ≥ 50 mL/minute, calculated using the
             formula of Cockcroft and Gault [(140 - Age) x Mass (kg) / (72 x creatinine mg/dL)];
             multiply result by 0.85 (if female). Other generally accepted calculation methods can
             be substituted.

             Ethical/Other

         13. Written informed consent in accordance with federal, local, and institutional
             guidelines

         14. Females of childbearing potential (FCBP) must agree to ongoing pregnancy testing

         15. FCBP* must have a negative serum or urine pregnancy test, with a sensitivity of at
             least 50 mIU/mL within 10-14 days (US/RevAssist®) or 25 mIU/mL within 7-14 days
             (Canada/RevAidSM), prior to and again within 24 hours of starting lenalidomide and
             must either commit to continued abstinence from heterosexual intercourse or to use two
             methods of reliable birth control, including at least one highly effective method AND
             one additional effective method of birth control (contraception) AT THE SAME TIME,
             beginning 4 weeks prior to initiating treatment with lenalidomide, during therapy,
             during therapy delay, and continuing for 4 weeks following discontinuation of
             lenalidomide therapy. If a hormonal method (birth control pills, injections, patch or
             implants) or intrauterine device (IUD) is not medically possible for the subject, the
             subject may use another highly effective method or two barrier methods AT THE SAME
             TIME.

         16. Male subjects must agree to NEVER have unprotected sexual contact with a female who
             can become pregnant and must agree to either completely abstain from sexual contact
             with females who are pregnant or are able to become pregnant, or he must use a latex
             condom EVERY TIME he engages in any sexual contact with females who are pregnant or
             may become pregnant while he is taking lenalidomide and for 4 weeks after he stops
             taking the drug, even if he has had a successful vasectomy. The subject must agree to
             inform his physician if he has had unprotected sexual contact with a female who can
             become pregnant or if he thinks FOR ANY REASON, that his sexual partner may be
             pregnant.

         17. Male subjects cannot donate semen or sperm while taking lenalidomide.

         18. All study participants must be registered into the mandatory RevAssist (US) or RevAid
             (Canada) programs and be willing and able to comply with the requirements of Rev
             Assist/RevAid

         19. Subjects must adhere to the study visit schedule and other protocol requirements and
             receive outpatient treatment and laboratory monitoring at the institute that
             administers the drug

         20. Subjects must agree to take enteric-coated aspirin 81-325 mg orally daily, or if
             history of prior thrombotic disease or allergy to aspirin, must be fully
             anticoagulated with warfarin (INR 2-3) or be treated with full-dose, low molecular
             weight heparin, as if to treat deep venous thrombosis (DVT)/pulmonary embolism.

        Exclusion Criteria:

        Disease related

          1. Subjects with non-secretory or hyposecretory multiple myeloma, defined as < 0.5 g/dL
             M-protein in serum, < 200 mg/24 hr Bence Jones protein in urine, or disease only
             measured by serum free light chain (FLC)

          2. Subjects who never achieved at least a durable minimal response (MR, ≥ 25% reduction
             in M-protein for at least 6 weeks) on any prior therapy

          3. Corticosteroid therapy in a dose equivalent to dexamethasone ≥ 4 mg/day or prednisone
             ≥ 20 mg/day within 3 weeks prior to first dose

          4. Use of any other experimental drug or therapy within 28 days of baseline

          5. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and
             skin changes)

          6. Plasma cell leukemia

          7. Waldenström's macroglobulinemia

          8. Chemotherapy with approved or investigative anticancer therapeutics, including steroid
             therapy dose as defined above, within 3 weeks prior to first dose

          9. Radiation therapy or immunotherapy within 4 weeks prior to first dose; localized
             radiation therapy within 1 week prior to first dose

         10. Planned radiation therapy that occurs after the start of treatment

         11. Participation in an investigational therapeutic study within 3 weeks or within 5 drug
             half-lives (t1/2) prior to first dose, whichever time is greater.

             Concurrent conditions

         12. Pregnant or lactating females

         13. History of allergy to boron or mannitol

         14. Major surgery within 3 weeks prior to first dose

         15. Congestive heart failure (New York Heart Association class III to IV), symptomatic
             ischemia, conduction abnormalities uncontrolled by conventional intervention or
             myocardial infarction in the previous six months

         16. Uncontrolled hypertension

         17. Acute active infection requiring systemic antibiotics, antivirals, or antifungals
             within two weeks prior to first dose

         18. Known or suspected human immunodeficiency virus (HIV) infection, known HIV
             seropositivity, or active hepatitis A, B, or C infection

         19. Non-hematologic malignancy within the past three years except

               1. adequately treated basal cell or squamous cell skin cancer,

               2. carcinoma in situ of the cervix, or

               3. prostate cancer < Gleason Grade 6 with stable prostate specific antigen (PSA)
                  levels

         20. Serious psychiatric or medical conditions that could interfere with treatment

         21. Significant neuropathy (Grade 3, Grade 4, or Grade 2 with pain) at the time of the
             first dose and/or within 14 days before enrollment

         22. Contraindication to any of the required concomitant drugs, including proton-pump
             inhibitor (e.g., lansoprazole), enteric-coated aspirin or other anticoagulant, or if a
             history of prior thrombotic disease, warfarin or low molecular weight heparin

         23. Subjects in whom the required program of oral and intravenous fluid hydration is
             contraindicated, e.g., due to pre-existing pulmonary, cardiac, or renal impairment

         24. Subjects with known or suspected amyloidosis

         25. Subjects with pleural effusions requiring thoracentesis or ascites requiring
             paracentesis

         26. Prior carfilzomib treatment