Clinical trial NCT01402284: Carfilzomib, Lenalidomide, and Dexamethasone in New Multiple Myeloma Patients
Official title: Carfilzomib, Lenalidomide, and Dexamethasone in Newly Diagnosed Multiple Myeloma: Clinical and Correlative Phase II Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Multiple Myeloma
Keywords: Novel Drug Combinations
Protease Inhibitors
Decreased Peripheral Neuropathy
Auto Stem Cell Transplant
Multiple Myeloma
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
Collaborators: name: Celgene
name: Onyx Therapeutics, Inc.
First posted: 2011-07-26
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Detailed description: Background:

* Multiple myeloma (MM) is an incurable plasma cell neoplasm with a median survival of 3-4 years.
* Novel agent combinations with proteasome inhibitors demonstrate improved response rates while increasing survival in MM patients.
* A common debilitating side effect of the proteasome inhibitor bortezomib is neuropathy.
* Carfilzomib is a new proteasome inhibitor with potent anti-MM effects and decreased peripheral neuropathy

Objectives:

-Evaluate toxicity, including peripheral neuropathy, of carfilzomib, lenalidomide, and dexamethasone (CRd) in untreated MM patients

Eligibility:

* Newly diagnosed patients with histologically confirmed multiple myeloma
* Age greater than or equal to 18 years
* Creatinine Clearance (CrCl) greater than or equal to 60 ml/min. CrCl will be calculated using the Cockcroft- Gault method. If the 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 also be greater than or equal to 60 ml/min.
* Without serious co-morbidity that would interfere with receipt of CRd
* Absolute neutrophil count (ANC) greater than or equal to 1.0 K/uL, hemoglobin greater than or equal to 8 g/dL, and platelet count greater than or equal to 75 K/uL
* Adequate hepatic function, with bilirubin less than 1.5 x the upper limit of normal (ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than 3.0 x ULN

Design:

* Single arm, single stage phase II trial of combination therapy (carfilzomib, lenalidomide, and dexamethasone) for untreated multiple myeloma patients with an early stopping rule for toxicity
* Patients will receive 8 cycles of induction combination therapy of CRd
* Each cycle consists of 28-days
* After 4 cycles of therapy, transplant eligible patients will undergo stem cell collection
* 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.
* Patients will have routine blood work with serum protein electrophoresis (SPEP) and free light chains monthly
* Pre- and post-treatment bone marrow biopsies will be obtained for confirmation of diagnosis and correlative studies
* Patients will also undergo evaluation for minimal residual disease at regular interval time points, using multi-parametric flow cytometry and fludeoxyglucose 18F-positron emission tomography - computed tomography (FDG PET-CT)
* A single stage phase II design will be employed, with an early stopping rule. Unless 4 or more patients in the first 20 have Grade 3 or higher neurologic toxicity in the first 2 completed cycles, a total of 45 evaluable patients will be enrolled in this study.

Eligibility criteria: * INCLUSION CRITERIA:
* Newly diagnosed patients with histologically confirmed multiple myeloma (MM) based on the following criteria:

  1. Clonal plasma cells in the bone marrow
  2. Measurable disease within the past 4 weeks defined by any one of the following:

     1. Serum monoclonal protein greater than or equal to 1.0 g/dL
     2. Urine monoclonal protein greater than 200 mg/24 hour
     3. Serum immunoglobulin free light chain greater than 10 mg/dL AND abnormal kappa/lambda ratio
  3. Evidence of underlying end organ damage attributed to underlying plasma cell proliferative disorder meeting at least one of the following:

     1. Hypercalcemia: serum calcium greater than or equal to 2.65 mmol/L
     2. Renal Insufficiency: serum creatinine greater than 2.0 mg/dL
     3. Anemia: hemoglobin value less than10 g/dL or 2 g/dL less than normal reference
     4. 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
* Adequate hepatic function, with bilirubin less than 1.5 times the upper limit of normal (ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than 3.0 times ULN.
* All study participants must be able to tolerate one of the following thromboprophylactic strategies: aspirin, low molecular weight heparin or warfarin (coumadin).
* All study participants must be registered into the mandatory RevAssist program, and be willing and able to comply with the requirements of RevAssist .
* Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test within 10-14 days and again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 7 days) and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. Females of child bearing potential (FCBP) must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy.
* Subjects must be able to give informed consent

EXCLUSION CRITERIA:

* 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
* Major surgery within 1 month prior to enrollment
* Recruitment Strategies:

  * Patients that progress from the smoldering multiple myeloma (SMM) and monoclonal gammopathy of undetermined significance (MGUS) Natural History Study (NCI Protocol: 10-C-0096) will be potential candidates.
  * Other participant sources will be from outside physician referrals.
  * Our ongoing natural history study and outside physician referral network has a high representation of minorities.

Primary outcomes:
measure: Number of Participants With Serious and Non-serious Adverse Events
timeFrame: 4 years and 9 months and 2 days
Secondary outcomes:
measure: Overall Response Rate
timeFrame: 48.3 months
measure: Progression Free Survival (PFS) at 48 Months
timeFrame: 48 months
measure: Percentage of Responders With Duration of Response (DOR) at 48 Months
timeFrame: 48 months
measure: Overall Survival (OS) Rate
timeFrame: up to 6 months
measure: Cluster of Differentiation 138 (CD138) + Plasma Cells Gene Expression Profiling on Pre and Post Carfilzomib Exposure Bone Marrow Samples
timeFrame: Cycle 1 Day 1, an average of 28 days ± 2 days
measure: Rate of Minimal Residual Disease (MRD) by Flow Cytometry
timeFrame: Day 100
measure: Complete Response (CR) and Minimal Residual Disease Neg (MRDneg) CR Rates at Treatment Intervals With Carfilzomib, Lenalidomide & Dexamethasone (CRd) in New Multiple Myeloma Patients After 8 Cycles of Induction, 1 Year Maintenance, and 2 Years Maintenance
timeFrame: up to 2 years
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Dickran Kazandjian, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.