a randomized, multicenter, phase 3 study comparing carfilzomib, lenalidomide, and dexamethasone...

A Randomized, Multicenter, Phase 3 Study Comparing

Carfilzomib, Lenalidomide, and Dexamethasone (CRd) vs

Lenalidomide and Dexamethasone (Rd) in Subjects with Relapsed Multiple Myeloma

Michael Wang, M.D.Associate Professor

Department of Lymphoma and MyelomaM. D. Anderson Cancer Center

Background

A Randomized, Multicenter, Phase 3 Study Comparing

Carfilzomib, Lenalidomide, and Dexamethasone (CRd) vs

Lenalidomide and Dexamethasone (Rd) in Subjects with Relapsed Multiple Myeloma

Michael Wang, M.D.Associate Professor

Department of Lymphoma and MyelomaM. D. Anderson Cancer Center

To compare progression-free survival in subjects with

relapsed multiple myeloma who are receiving CRd vs

subjects receiving Rd alone in a randomized

multicenter setting.

PRIMARY OBJECTIVES

Phase 3, randomized, open-label, multicenter study comparing two treatment regimens for subjects with relapsed multiple myeloma.

Subjects will be randomized in a 1:1 ratio toreceive either the control Rd or CRd.

Randomization will be stratified by β2 microglobulin levels (< vs ≥ 2.5 mg/L), prior bortezomib (no vsyes), and prior lenalidomide (no vs yes).

Estimated sample size is 700 subjects and will take place at approximately 200 centers.

Primary endpoint is progression-free survival.

STUDY DESIGN

Subjects will receive the treatment determined by randomization in 28-day cycles until disease progression or unacceptable toxicity.

Subjects will be followed for 30 additional days after completion or early discontinuation of treatment for safety follow-up.

Long-term follow-up for disease status and survival will continue until the subject has withdrawn consent for further participation, is lost to follow-up, has died, or the Sponsor makes a decision to close the study.

STUDY DESIGN Continued

Symptomatic multiple myeloma with measurable disease, as defined by one or both of the following (assessed within 14 days prior to randomization):

• Serum M-protein ≥ 0.5 g/dL• Urine Bence-Jones protein ≥ 200 mg/24 hours

Prior treatment with at least one, but no more than three, regimens for multiple myeloma

Documented relapse or progressive disease on or after any regimen (subjects refractory to the most recent line of therapy are eligible)

Achieved a response to at least one prior regimen (defined as≥ 25% decrease in M-protein

Age ≥ 18 years and Life expectancy ≥ 3 months

Eligibility Criteria - Inclusion

• Eastern Cooperative Oncology Group performance status 0–2• Adequate hepatic function, with serum ALT ≤ 3.5 times the upper

limit of normal and serum direct bilirubin ≤ 2 mg/dL (34 μmol/L) within 14 days prior to randomization• Absolute neutrophil count ≥ 1.0 × 109/L within 14 days prior to

randomization•Hemoglobin ≥ 8 g/dL (80 g/L) within 14 days prior to

randomization (subjects may be receiving red blood celltransfusions in accordance with institutional guidelines)

• Platelet count ≥ 50 × 109/L (≥ 30 × 109/L if myeloma involvementin the bone marrow is > 50%) within 14 days prior torandomization

• Creatinine clearance (CrCl) ≥ 50 mL/minute (either measured or calculated using a standard formula such as Cockcroft and Gault) within 7 days prior to randomization


• Written informed consent in accordance with federal, local, andinstitutional guidelines

• Females of childbearing potential must agree to ongoing

pregnancy testing and to practice contraception as outlined

• Male subjects must agree to practice contraception as outlined


1. If previously treated with bortezomib (alone or in combination),progression during treatment

2. If previously treated with a lenalidomide and dexamethasone(len/dex) combination:

• Progression during the first 3 months of initiating treatment• Any progression during treatment if the len/dex regimen was the

subject’s most recent line of therapy3. Discontinuation of previous lenalidomide or dexamethasone due

to intolerance; subjects who are intolerant to bortezomib are not excluded4. Prior carfilzomib treatment5. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy,

monoclonal protein, and skin changes)6. Waldenström’s macroglobulinemia or IgM myeloma7. Plasma cell leukemia (> 2.0 × 109/L circulating plasma cells by

standard differential)8. Chemotherapy (approved or investigational) within 3 weeks prior

to randomization or antibody therapy within 6 weeks prior torandomization

Eligibility Criteria - Exclusion

9. Radiotherapy to multiple sites or immunotherapy/antibody therapywithin 28 days prior to randomization; localized radiotherapy to asingle site within 7 days prior to randomization

10. Corticosteroid therapy at dose equivalent to dexamethasone> 4 mg/day within 21 days prior to randomization

11. Pregnant or lactating females12. Major surgery within 21 days prior to randomization13. Acute active infection requiring treatment (systemic antibiotics,

antivirals, or antifungals) within 14 days prior to randomization14. Known human immunodeficiency virus infection15. Active hepatitis B or C infection16. Myocardial infarction within 4 months prior to randomization,

NYHA Class III or IV heart failure, uncontrolled angina, historyof severe coronary artery disease, severe uncontrolled ventriculararrhythmias, sick sinus syndrome, or electrocardiographicevidence of acute ischemia or Grade 3 conduction systemabnormalities unless subject has a pacemaker

17. Uncontrolled hypertension or uncontrolled diabetes within 14 daysprior to randomization


18. Other malignancy within the past 3 years with the exception ofa) adequately treated basal cell carcinoma, squamous cell skincancer, or thyroid cancer; b) carcinoma in situ of the cervix orbreast; c) prostate cancer of Gleason Grade 6 or less with stableprostate-specific antigen levels; or d) cancer considered cured bysurgical resection or unlikely to impact survival during theduration of the study, such as localized transitional cell carcinomaof the bladder or benign tumors of the adrenal or pancreas

19. Significant neuropathy (Grades 3–4, or Grade 2 with pain) within14 days prior to randomization

20. Known history of allergy to Captisol® (a cyclodextrin derivativeused to solubilize carfilzomib)

21. Contraindication to any of the required concomitant drugs orsupportive treatments, including hypersensitivity to allanticoagulation and antiplatelet options, antiviral drugs, orintolerance to hydration due to preexisting pulmonary or cardiac impairment

22. Ongoing graft-vs-host disease23. Subjects with pleural effusions requiring thoracentesis or ascites

requiring paracentesis within 14 days prior to randomization24. Any other clinically significant medical disease or condition that,

in the Investigator’s opinion, may interfere with protocoladherence or a subject’s ability to give informed consent


Rd ArmCycles 1 and higher (28 days each) Dexamethasone 40 mg PO or IV on Days 1, 8, 15, 22 Lenalidomide 25 mg PO on Days 1–21

CRd ArmCycles 1 through 12 (28 days each) Dexamethasone 40 mg PO or IV on Days 1, 8, 15, 22 Carfilzomib 20 mg/m2 IV on Days 1 and 2 of Cycle 1, escalating

to 27 mg/m2 IV on Days 8, 9, 15, 16 of Cycle 1 and continuing onDays 1, 2, 8, 9, 15, 16 of Cycles 2 through Cycle 12

Lenalidomide 25 mg PO on Days 1–21Cycles 13 through 18 (28 days each) Dexamethasone 40 mg PO or IV on Days 1, 8, 15, 22 Carfilzomib 27 mg/m2 IV on Days 1, 2, 15, 16 Lenalidomide 25 mg PO on Days 1–21Cycles 19 and higher (28 days each) Dexamethasone 40 mg PO or IV on Days 1, 8, 15, 22 Lenalidomide 25 mg PO on Days 1–21

Study Treatment

Primary : Progression-free survival (PFS)

Endpoints

Secondary : Overall survival Overall response rate: stringent complete response + complete response + very good partial response +

partial response Disease control rate: overall responses + stable disease lasting at least 8 weeks Duration of response Safety Time to progression (exploratory) Time to next treatment (exploratory)

Discussion

a randomized, multicenter, phase 3 study comparing carfilzomib, lenalidomide, and dexamethasone...

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