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Carfilzomib + High Dose Melphalan as Preparative Regimen for Autologous Hematopoietic Stem Cell Transplantation

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01690143
Recruitment Status : Completed
First Posted : September 21, 2012
Results First Posted : July 10, 2018
Last Update Posted : August 7, 2018
Information provided by (Responsible Party):
Luciano Jose Costa, MD, University of Alabama at Birmingham

Brief Summary:

This study is for patients that have multiple myeloma that has come back or relapsed and their condition indicates a procedure called an Autologous Hematopoietic Stem Cell Transplantation (AHSCT). AHSCT is a procedure when stem cells from bone marrow or blood are removed before high-dose chemotherapy. Afterwards, the removed stem cells are put back into the patient's body to form a new population of blood cells.

The high-dose chemotherapy administered before the AHSCT is called "Conditioning Therapy." The FDA has approved the use of the drug melphalan as a conditioning therapy. This research study will look at whether adding the study drug called carfilzomib will improve participant outcomes. Carfilzomib is considered investigational and is not approved by the FDA for the treatment of relapsed multiple myeloma.

This study is divided into two phases.

Phase I: Dose Escalation Phase:

The main purpose of Part I of this study is to examine the safety of the study drug, carfilzomib, and determine the safest amount of the study drug that can be given to subjects who have multiple myeloma. Subjects on this study will receive different dose levels of the study drug. If you are one of the first three subjects to receive the study drug, it will be at what is called the 'starting dose' for the study which is the lowest dose that is expected to be tolerated based on prior research. After the first set of participants receive the study drug, the study doctor will review their health to see how they are tolerating the treatment. This will decide if the study drug dosage will be increased or decreased for the next set of subjects who join the study. It is anticipated that 12- 18 participants will enroll in the Phase I portion of this study.

Phase II: Safety Confirmation Phase:

Once the study doctor has discovered the highest possible dose of study drug that subjects can tolerate, up to 28 more subjects may be enrolled at that dose level. The main purpose of the Phase II portion of the study is look at how effective the combination of carfilzomib and melphalan when given before your stem cell transplantation is in treating multiple myeloma. This expansion phase will also include evaluation of two single agent carfilzomib maintenance therapy regimens for patients without disease progression at day 100.

Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: Carfilzomib Drug: Melphalan Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 45 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1/2A Study Carfilzomib + High Dose Melphalan as Preparative Regimen for Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma
Study Start Date : May 2012
Actual Primary Completion Date : November 1, 2017
Actual Study Completion Date : November 1, 2017

Arm Intervention/treatment
Experimental: Carfilzomib + high dose melphalan
Single arm.
Drug: Carfilzomib
Subjects will receive the appropriate dose of carfilzomib (according to assigned cohort in phase 1 and at the determined MTD in phase 2) on days -3 and -2. Carfilzomib will be infused over 30 minutes. Prophylaxis of chemotherapy induced nausea and vomiting will follow institutional guidelines and SOPs.

Drug: Melphalan
Subjects will receive 200 mg/m2 of intravenous melphalan on Day -2. Administered as an intravenous push or a fast infusion according to institutional standard operating procedure (SOP). Prophylaxis of chemotherapy induced nausea and vomiting will follow institutional guidelines and SOPs.

Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) of Carfilzomib Plus Melphalan as Conditioning for Autologous Hematopoietic Cell Transplantation in Patients With Relapsed Multiple Myeloma(MM) [Phase I Portion of Study] [ Time Frame: Up to 4 1/2 months ]
    The maximum tolerated dose of carfilzomib that can be safely combined with high dose melphalan as conditioning regimen prior to autologous hematopoietic cell transplantation in patients with relapsed multiple myeloma meeting eligibility criteria.

  2. Very Good Partial Response (VGPR) Rate. [ Time Frame: Up to 17 months ]

    VGPR defined as any one of the following:

    ≥ 90% reduction of serum M-protein; ≥ 90% reduction in 24-hour urinary M-protein or decrease to < 100 mg per 24 hour; ≥ 50% decrease in the difference between involved and uninvolved FLC levels or a 50% decrease in level of involved FLC with 50% decrease in ratio; ≥ 50% reduction in bone marrow plasma cells; ≥ 50% reduction in the size of soft tissue plasmacytomas.

  3. Complete Response (CR) Rate. [ Time Frame: Up to 17 months ]
    CR defined as the following: Negative immunofixation of the serum and urine. If only the measurable non-bone marrow parameter was free light chain, normalization of free light chain ratio. < 5% plasma cells in bone marrow. And, disappearance of any soft tissue plasmacytomas.

  4. Median Time for Neutrophil and Platelet Engraftment. [ Time Frame: Up to 1 month. ]
    Neutrophil engraftment is defined as the first of three consecutive days with absolute neutrophil count >500/mm3. Platelet engraftment is defined as the first of 3 consecutive days of platelets > 20,000/mm3 without platelet transfusion in the prior 7 days.

  5. Frequency of Grades 3 and 4 Non-hematologic Adverse Events During the Transplant Component ( 135 Days) [ Time Frame: Up to 4 1/2 months ]
    Grading of AE's is performed using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Age ≥ 18 years and ≤ 70 years
  2. Life expectancy ≥ 12 months
  3. Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  4. Diagnosis of symptomatic multiple myeloma, relapsed after initial therapy.
  5. At least minimal response (defined as 25% decrease in the M protein in serum or urine) to the most recent treatment regimen.
  6. Evaluable disease prior to most recent treatment regimen as defined by at least one of the following:

    • Serum monoclonal (M) protein ≥0.5 g/dl by protein electrophoresis

      • 200 mg of M protein in the urine on 24 hour electrophoresis
    • Serum immunoglobulin free light chain ≥10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio
    • Monoclonal bone marrow plasmacytosis ≥30%
  7. 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 start of therapy
  8. Hemoglobin ≥ 8 g/dL (80 g/L) within 14 days prior to registration (subjects may be receiving red blood cell [RBC] transfusions in accordance with institutional guidelines)
  9. Creatinine clearance (CrCl) ≥ 40 mL/minute within 14 days prior to registration, either measured or calculated using a standard formula (eg, Cockcroft and Gault).
  10. Prior storage of at least 2 x 106 CD34+ cells/kg available for autologous transplantation. During the phase 1 component of the study, at least the same amount of cells is required as "back up" in the unlikely event of non-engraftment.
  11. Subjects may have had a prior AHSCT for the treatment of MM as long as it was performed greater than 12 months from study registration.
  12. Subjects must meet institutional general eligibility criteria for autologous transplantation.
  13. Written informed consent in accordance with federal, local, and institutional guidelines.
  14. Female of childbearing potential (FCBP) must agree to ongoing pregnancy testing and to practice contraception.
  15. Male subjects must agree to practice contraception.

Exclusion Criteria:

  1. Pregnant or lactating females.
  2. Major surgery within 30 days prior to start of treatment.
  3. Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14 days prior to registration.
  4. Known human immunodeficiency virus infection.
  5. Active hepatitis B or C infection.
  6. Unstable angina or myocardial infarction within 4 months prior to registration, NYHA Class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a pacemaker.
  7. Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to registration.
  8. Nonhematologic malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumors of the adrenal or pancreas.
  9. Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days prior to registration.
  10. Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib).
  11. Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to registration.
  12. Any other 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01690143

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United States, Alabama
Birmingham, Alabama, United States, 35294
United States, New York
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
United States, South Carolina
Medical University of South Carolina Hollings Cancer Center
Charleston, South Carolina, United States, 29425
United States, Wisconsin
Medical College of Wisconsin
Milwaukee, Wisconsin, United States, 53226
Sponsors and Collaborators
University of Alabama at Birmingham
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Principal Investigator: Luciano Costa, MD University of Alabama at Birmingham
  Study Documents (Full-Text)

Documents provided by Luciano Jose Costa, MD, University of Alabama at Birmingham:
Study Protocol  [PDF] November 21, 2014
Statistical Analysis Plan  [PDF] November 21, 2014

Publications of Results:
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Responsible Party: Luciano Jose Costa, MD, Associate Professor of Medicine, University of Alabama at Birmingham Identifier: NCT01690143    
Other Study ID Numbers: CTO 101669
Onyx IST-CAR-536 ( Other Identifier: Onyx Pharmaceuticals )
First Posted: September 21, 2012    Key Record Dates
Results First Posted: July 10, 2018
Last Update Posted: August 7, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs