Clinical trial NCT01029054: Carfilzomib and Lenalidomide With Dexamethasone Combination in Newly Diagnosed, Previously Untreated Multiple Myeloma
Official title: Multicenter, Open-label, Single-arm, Phase 1b/2 Study of the Safety and Efficacy of Combination Treatment w/ Carfilzomib, Lenalidomide (Revlimid®) and Dexamethasone (CRD) in Subjects w/ Newly Diagnosed, Previously Untreated Multiple Myeloma Requiring Systemic Chemotherapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Multiple Myeloma
Keywords: Multiple Myeloma
Lead sponsor: University of Michigan Rogel Cancer Center
Sponsor class: OTHER
Collaborators: name: Onyx Therapeutics, Inc.
name: Celgene
First posted: 2009-12-09
Enrollment: 53
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: HEALTH_SERVICES_RESEARCH

Brief summary: This study is designed to evaluate the safety and to determine the maximum tolerated dose of carfilzomib + lenalidomide in combination with dexamethasone in newly diagnosed Multiple Myeloma patients who have not received treatment.

Detailed description: During the Phase I portion of this clinical trial, the dose of Revlimid® and carfilzomib will be increased until the best and safest amount (or dose) is identified in combination with standard doses of Revlimid® and dexamethasone. "Investigational" means that the drug combination is still being studied and that research doctors are trying to find out more about it such as the safest dose to use, the side effects it may cause and how effective the Revlimid® and carfilzomib and dexamethasone investigational combination is for treating newly diagnosed multiple myeloma. In this clinical trial we are looking for the highest dose of the combination that can be given safely and see how well it works as a combination in newly diagnosed patients.

The drug, carfilzomib, has not yet been approved by the FDA (U.S. Food and Drug Administration). Revlimid® and Dexamethasone have been approved by the FDA. The drugs have not been approved in this combination for use for your type of cancer or any other type of cancer. Carfilzomib is being researched to treat multiple myeloma. Dexamethasone is commonly used, either alone, or in combination with other drugs, to treat multiple myeloma. Revlimid® is currently approved by the US FDA in combination with dexamethasone for the treatment of patients with multiple myeloma who have received at least 1 prior therapy.

After the Phase I clinical trial defines the safest doses of Revlimid® and carfilzomib and dexamethasone that can be taken together, the research study will move on to its second portion, a Phase II clinical trial. The Phase II portion of the clinical trial will test the clinical effectiveness of the best dose combination of the three drugs.

Eligibility criteria: Inclusion Criteria

1. Newly diagnosed, histologically confirmed, previously untreated Stage I, II, or III multiple myeloma requiring systemic chemotherapy
2. Diagnosis of symptomatic multiple myeloma per IMWG uniform criteria within the past 90 days
3. Measurable disease, per IMWG (International Myeloma Working Group) criteria (\>= one of the following) within the past 4 weeks:

   * Monoclonal protein \>= 0.5 g/dL by serum protein electrophoresis
   * Monoclonal light chain \>= 200 mg by 24-hour urine protein electrophoresis
   * If serum protein electrophoresis is felt to be unreliable for routine M-protein measurement, then quantitative immunoglobulin levels are acceptable
4. Life expectancy \> 3 months
5. Eastern Cooperative Oncology Group (ECOG) performance status 0-2
6. Adequate hepatic function, with bilirubin \< 1.5 x the ULN, and AST (Aspartate Aminotransferase) and ALT (Alanine Transaminase) \< 2.5 x ULN
7. Absolute neutrophil count (ANC) \>=1.0 x 109/L, hemoglobin \>= 8 g/dL, platelet count \>= 75 x 109/L
8. Calculated creatinine clearance (by Cockroft-Gault) \>= 60 ml/min
9. Written informed consent in accordance with federal, local, and institutional guidelines.
10. Subjects must agree to adhere to all study requirements, including birth control measures and pregnancy testing, visit schedule, outpatient treatment, required concomitant medications, and laboratory monitoring.
11. Must be able to take either 81 mg or 325 mg aspirin daily as prophylactic anticoagulation.

Exclusion Criteria

1. Non-secretory or hyposecretory multiple myeloma, defined as \<0.5 g/dL M-protein in serum, \<200 mg/24 hr urine M-protein, or disease only measured by serum free light chain
2. POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Gammopathy, and Skin Changes) syndrome
3. Plasma cell leukemia
4. Waldenström's macroglobulinemia or IgM myeloma
5. Radiotherapy to multiple sites or immunotherapy within 2 weeks before start of protocol treatment (localized radiotherapy to a single site at least 1 week before start is permissible)
6. Patient must not have been previously treated with any prior systemic therapy for the treatment of multiple myeloma

   * Prior treatment of hypercalcemia or spinal cord compression or aggressively progressing myeloma with corticosteroids does not disqualify the patient (the dose should not exceed the equivalent of 160 mg of dexamethasone in a 2 week period)
   * Bisphosphonates are permitted
7. Participation in an investigational therapeutic study within 3 weeks or within 5 drug halflives (t1/2) prior to first dose, whichever time is greater
8. Pregnant or lactating females
9. History of allergy to mannitol
10. Major surgery within 3 weeks prior to first dose
11. Myocardial infarction within 3 months prior to enrollment, NYHA (New York Heart Association) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
12. Uncontrolled hypertension or diabetes
13. Acute active infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to first dose
14. Known or suspected HIV infection, known HIV seropositivity
15. Active hepatitis infection
16. Non-hematologic malignancy within the past 3 years except a) adequately treated basal cell, squamous cell skin cancer, thyroid cancer, carcinoma in situ of the cervix, or prostate cancer \< Gleason Grade 6 with stable prostate specific antigen levels or cancer considered cured by surgical resection alone
17. Any clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent
18. Significant neuropathy (Grade \>2) at the time of the first dose and/or within 14 days before enrollment
19. Contraindication to any of the required concomitant drugs
20. Subjects in whom the required program of PO and IV fluid hydration is contraindicated
21. Subjects with known or suspected amyloidosis of any organ
22. Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis

Primary outcomes:
measure: The Maximum Tolerated Dose (MTD) of Carfilzomib
timeFrame: 6 Months
measure: The Percentage of Patients That Achieve a Response to Treatment
timeFrame: 4 Months After Treatment Start
Secondary outcomes:
measure: The Percentage of Patients Alive Without Progression
timeFrame: 12 Months and 24 Months Post Treatment
Other outcomes:
Locations:
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: St. Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: New York
country: United States
facility: Mt. Sinai Medical Center
state: New York
Study officials:
affiliation: University of Michigan Rogel Cancer Center
name: Mark Kaminski, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Jakubowiak AJ, Dytfeld D, Griffith KA, Lebovic D, Vesole DH, Jagannath S, Al-Zoubi A, Anderson T, Nordgren B, Detweiler-Short K, Stockerl-Goldstein K, Ahmed A, Jobkar T, Durecki DE, McDonnell K, Mietzel M, Couriel D, Kaminski M, Vij R. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012 Aug 30;120(9):1801-9. doi: 10.1182/blood-2012-04-422683. Epub 2012 Jun 4.