Carfilzomib, Lenalidomide, and Dexamethasone in New Multiple Myeloma Patients

NCT01402284 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 11022111-C-0221
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 1

Brief Summary

Background: \- Carfilzomib is an experimental anti-cancer drug that has not yet been approved for treating multiple myeloma. Lenalidomide is a drug that may stop tumor growth and help the immune system kill cancer cells. Dexamethasone is a drug that helps stop inflammation. It is sometimes used to treat (alone or with other drugs) certain types of cancer, especially multiple myeloma. This combination of drugs has not been tested in people with multiple myeloma. Researchers want to see whether it is safe and effective for this group. Objectives: \- To test the effectiveness of combined carfilzomib, lenalidomide, and dexamethasone in treating multiple myeloma. Eligibility: \- People at least 18 years of age who have multiple myeloma that has not been treated. Design:

• Participants will be screened with a medical history and physical exam. They will also have blood and urine tests, a bone marrow sample, and molecular imaging studies.
• Participants will have eight 28-day cycles of treatment. The combined study drugs will be given as tablets and injections. Those in the study will be monitored with frequent blood tests, bone marrow samples, and molecular imaging studies. In addition to current standard measures to determine clinical responses, molecular tests will be conducted to define evidence of minimal residual disease.
• After the first four cycles of therapy, those who are eligible for a stem cell transplant will have stem cells collected and stored for use if the cancer returns.
• After stem cell collection, participants will have the second four treatment cycles.
• , If the disease has improved or is stable at the end of eight cycles, those in the study may have another 12 cycles of low-dose (maintenance) lenalidomide alone.
• Participants will have regular follow-up visits after the end of the study chemotherapy.

Conditions

Multiple Myeloma

Keywords

Novel Drug Combinations; Protease Inhibitors; Decreased Peripheral Neuropathy; Auto Stem Cell Transplant; Multiple Myeloma

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Serious and Non-serious Adverse Events

  Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

  4 years and 9 months and 2 days

Secondary Outcomes (7)

• Overall Response Rate

  48.3 months

• Progression Free Survival (PFS) at 48 Months

  48 months

• Percentage of Responders With Duration of Response (DOR) at 48 Months

  48 months

• Overall Survival (OS) Rate

  up to 6 months

• Cluster of Differentiation 138 (CD138) + Plasma Cells Gene Expression Profiling on Pre and Post Carfilzomib Exposure Bone Marrow Samples

  Cycle 1 Day 1, an average of 28 days ± 2 days

Study Arms (1)

Carfilzomib, Lenalidomide, Dexamethasone

EXPERIMENTAL

Patients will receive 8 cycles of induction combination therapy of carfilzomib, lenalidomide, and dexamethasone (CRd). Patients achieving stable disease or better after 8 cycles of CRd will receive lenalidomide extended dosing (phase I) for 12 cycles. After 12 cycles, patients will have the option to continue extended dosing (phase II) for one additional year

Drug: Carfilzomib; Drug: Lenalidomide; Drug: Dexamethasone

Interventions

Carfilzomib DRUG

Cycle 1: 20 mg/m(2) intravenous (IV) infusion over 30 minutes on days 1 and 2, then 36 mg/m(2) IV on days 8, 9, 15, and 16 Cycle 2-8: 36mg/ m(2) IV infusion over 30 minutes on days 1, 2, 8, 9, 15, and 16

Also known as: Kyprolis

Carfilzomib, Lenalidomide, Dexamethasone

Lenalidomide DRUG

Cycle 1: 25 mg oral days 2-21 of 28-day cycle; Cycle 2 - 8: 25 mg oral days 1-21 of 28-day cycle; After 8 cycles of combination carfilzomib, lenalidomide, and dexamethasone (CRd), patients may continue Lenalidomide for 12 cycles; After 12 cycles of extended dosing of Lenalidomide, patients may continue Lenalidomide for one year

Also known as: Revlimid

Carfilzomib, Lenalidomide, Dexamethasone

Dexamethasone DRUG

Cycle 1: 20 mg oral or IV on days 2, 8, 9, 15, 16, 22, and 23 Cycle 2-4: 20 mg oral or IV on days 1, 2, 8, 9, 15, 16, 22, and 23 Cycle 5-8: 10 mg oral or IV on days 1, 2, 8, 9, 15, 16, 22, and 23

Also known as: Ozurdex

Carfilzomib, Lenalidomide, Dexamethasone

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Newly diagnosed patients with histologically confirmed multiple myeloma (MM) based on the following criteria:
• Clonal plasma cells in the bone marrow
• Measurable disease within the past 4 weeks defined by any one of the following:
• Serum monoclonal protein greater than or equal to 1.0 g/dL
• Urine monoclonal protein greater than 200 mg/24 hour
• Serum immunoglobulin free light chain greater than 10 mg/dL AND abnormal kappa/lambda ratio
• Evidence of underlying end organ damage attributed to underlying plasma cell proliferative disorder meeting at least one of the following:
• Hypercalcemia: serum calcium greater than or equal to 2.65 mmol/L
• Renal Insufficiency: serum creatinine greater than 2.0 mg/dL
• Anemia: hemoglobin value less than10 g/dL or 2 g/dL less than normal reference
• Bone disease: lytic lesions, severe osteopenia or pathological fractures
• Creatinine Clearance (CrCl) greater than or equal to 60 ml/min. CrCl will be calculated by Cockcroft-Gault method. CrCl (calculated) = (140 Age) x Mass (in kilograms) x \[0.85 if Female\] 72 times Serum Creatinine (in mg/dL). If calculated CrCl based on Cockcroft-Gault method is \<60 mL/min, patient will have a 24 hr urine collection to measure CrCl. The measured CrCl must be also greater than or equal to 60 ml/min.
• Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of carfilzomib in combination with lenalidomide in patients less than18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Absolute neutrophil count (ANC) greater than or equal to 1.0 K/uL, hemoglobin greater than or equal to 8 g/dL (transfusions are permissible), and platelet count greater than or equal to 75 K/uL

You may not qualify if:

• Prior or concurrent systemic treatment for MM.
• Treatment of hypercalcemia or spinal cord compression or aggressively progressing myeloma with corticosteroids is permitted.
• Bisphosphonates are permitted.
• Treatment with corticosteroids for indications other than MM is permitted.
• Radiotherapy is permitted.
• Treatment for smoldering myeloma is permitted.
• Plasma cell leukemia
• Pregnant or lactating females. Because there is a potential risk for adverse events in nursing infants secondary to treatment of the mother with carfilzomib in combination with lenalidomide, breastfeeding should be discontinued if the mother is treated with carfilzomib and lenalidomide. These potential risks may also apply to other agents used in this study.
• Uncontrolled hypertension or diabetes
• Active hepatitis B or C infection
• Has significant cardiovascular disease with New York Heart Association (NYHA) Class III or IV symptoms, or hypertrophic cardiomyopathy, or restrictive cardiomyopathy, or myocardial infarction within 3 months prior to enrollment, or unstable angina, or unstable arrhythmia as determined by history and physical examination. Echocardiogram will be performed if clinically warranted.
• Has refractory gastrointestinal (GI) disease with refractory nausea/vomiting, inflammatory bowel disease, or bowel resection that would prevent absorption
• Uncontrolled intercurrent illness including but not limited to active infection or psychiatric illness/social situations that would compromise compliance with study requirements
• Significant neuropathy greater than or equal to Grade 3 at baseline
• Contraindication to any concomitant medication, including antivirals, anticoagulation prophylaxis, tumor lysis prophylaxis, or hydration given prior to therapy

Sponsors & Collaborators

• National Cancer Institute (NCI): lead
• Celgene: collaborator
• Onyx Therapeutics, Inc.: collaborator

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (7)

• International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 2003 Jun;121(5):749-57.

  PMID: 12780789 BACKGROUND

• Kristinsson SY, Landgren O, Dickman PW, Derolf AR, Bjorkholm M. Patterns of survival in multiple myeloma: a population-based study of patients diagnosed in Sweden from 1973 to 2003. J Clin Oncol. 2007 May 20;25(15):1993-9. doi: 10.1200/JCO.2006.09.0100. Epub 2007 Apr 9.

  PMID: 17420512 BACKGROUND

• Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, Zeldenrust SR, Dingli D, Russell SJ, Lust JA, Greipp PR, Kyle RA, Gertz MA. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008 Mar 1;111(5):2516-20. doi: 10.1182/blood-2007-10-116129. Epub 2007 Nov 1.

  PMID: 17975015 BACKGROUND

• Landgren O, Kazandjian D, Roussel M, Jasielec J, Dytfeld D, Anderson A, Kervin TA, Iskander K, McFadden I, Jakubowiak AJ. Efficacy and safety of carfilzomib-lenalidomide-dexamethasone in newly diagnosed multiple myeloma: pooled analysis of four single-arm studies. Leuk Lymphoma. 2022 Oct;63(10):2413-2421. doi: 10.1080/10428194.2022.2068001. Epub 2022 May 12.

  PMID: 35549810 DERIVED

• Huang PA, Beedie SL, Chau CH, Venzon DJ, Gere S, Kazandjian D, Korde N, Mailankody S, Landgren O, Figg WD. Cereblon gene variants and clinical outcome in multiple myeloma patients treated with lenalidomide. Sci Rep. 2019 Oct 16;9(1):14884. doi: 10.1038/s41598-019-51446-9.

  PMID: 31619706 DERIVED

• Acosta-Alvear D, Cho MY, Wild T, Buchholz TJ, Lerner AG, Simakova O, Hahn J, Korde N, Landgren O, Maric I, Choudhary C, Walter P, Weissman JS, Kampmann M. Paradoxical resistance of multiple myeloma to proteasome inhibitors by decreased levels of 19S proteasomal subunits. Elife. 2015 Sep 1;4:e08153. doi: 10.7554/eLife.08153.

  PMID: 26327694 DERIVED

• Korde N, Roschewski M, Zingone A, Kwok M, Manasanch EE, Bhutani M, Tageja N, Kazandjian D, Mailankody S, Wu P, Morrison C, Costello R, Zhang Y, Burton D, Mulquin M, Zuchlinski D, Lamping L, Carpenter A, Wall Y, Carter G, Cunningham SC, Gounden V, Sissung TM, Peer C, Maric I, Calvo KR, Braylan R, Yuan C, Stetler-Stevenson M, Arthur DC, Kong KA, Weng L, Faham M, Lindenberg L, Kurdziel K, Choyke P, Steinberg SM, Figg W, Landgren O. Treatment With Carfilzomib-Lenalidomide-Dexamethasone With Lenalidomide Extension in Patients With Smoldering or Newly Diagnosed Multiple Myeloma. JAMA Oncol. 2015 Sep;1(6):746-54. doi: 10.1001/jamaoncol.2015.2010.

  PMID: 26181891 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Multiple Myeloma

Interventions

carfilzomib; Lenalidomide; Dexamethasone; Calcium Dobesilate

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidones; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds

Results Point of Contact

• Title: Dr. Dickran Kazandijian
• Organization: National Cancer Institute

kazandijiandg@mail.nih.gov

301-480-8870

Study Officials

• Dickran Kazandjian, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: July 23, 2011
• First Posted: July 26, 2011
• Study Start: July 21, 2011
• Primary Completion: July 10, 2016
• Study Completion: September 24, 2020
• Last Updated: March 2, 2021
• Results First Posted: May 16, 2017

Record last verified: 2021-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)