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

NCT01690143 | Completed Phase 1 Results DMC

• 2 other identifiers: CTO 101669Onyx IST-CAR-536
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 4

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.

Conditions

Multiple Myeloma

Outcome Measures

Primary Outcomes (5)

• 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]

  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.

  Up to 4 1/2 months

• Very Good Partial Response (VGPR) Rate.

  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.

  Up to 17 months

• Complete Response (CR) Rate.

  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.

  Up to 17 months

• Median Time for Neutrophil and Platelet Engraftment.

  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.

  Up to 1 month.

• Frequency of Grades 3 and 4 Non-hematologic Adverse Events During the Transplant Component ( 135 Days)

  Grading of AE's is performed using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

  Up to 4 1/2 months

Study Arms (1)

Carfilzomib + high dose melphalan

EXPERIMENTAL

Single arm.

Drug: Carfilzomib; Drug: Melphalan

Interventions

Carfilzomib DRUG

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.

Carfilzomib + high dose melphalan

Melphalan DRUG

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.

Carfilzomib + high dose melphalan

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 years and ≤ 70 years
• Life expectancy ≥ 12 months
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Diagnosis of symptomatic multiple myeloma, relapsed after initial therapy.
• At least minimal response (defined as 25% decrease in the M protein in serum or urine) to the most recent treatment regimen.
• 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
• 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%
• 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
• 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)
• Creatinine clearance (CrCl) ≥ 40 mL/minute within 14 days prior to registration, either measured or calculated using a standard formula (eg, Cockcroft and Gault).
• 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.
• 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.

You may not qualify if:

• Pregnant or lactating females.
• Major surgery within 30 days prior to start of treatment.
• Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14 days prior to registration.
• Known human immunodeficiency virus infection.
• Active hepatitis B or C infection.
• 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.
• Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to registration.
• 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.
• Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days prior to registration.
• Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib).
• Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to registration.
• 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.

Sponsors & Collaborators

• University of Alabama at Birmingham: lead
• Amgen: collaborator

Study Sites (4)

UAB

Birmingham, Alabama, 35294, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Medical University of South Carolina Hollings Cancer Center

Charleston, South Carolina, 29425, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Related Publications (1)

• Costa LJ, Landau HJ, Chhabra S, Hari P, Innis-Shelton R, Godby KN, Hamadani M, Tamari R, Anderton K, Dixon P, Giralt SA. Phase 1/2 Trial of Carfilzomib Plus High-Dose Melphalan Preparative Regimen for Salvage Autologous Hematopoietic Cell Transplantation Followed by Maintenance Carfilzomib in Patients with Relapsed/Refractory Multiple Myeloma. Biol Blood Marrow Transplant. 2018 Jul;24(7):1379-1385. doi: 10.1016/j.bbmt.2018.01.036. Epub 2018 Feb 2.

  PMID: 29410301 RESULT

MeSH Terms

Conditions

Multiple Myeloma

Interventions

carfilzomib; Melphalan

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)

Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins

Results Point of Contact

• Title: Luciano J Costa, Principal Investigator
• Organization: University of Alabama at Birmingham

ljcosta@uabmc.edu

205-209-6038

Study Officials

• Luciano Costa, MD

  University of Alabama at Birmingham

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Medicine

Study Record Dates

• First Submitted: July 17, 2012
• First Posted: September 21, 2012
• Study Start: May 1, 2012
• Primary Completion: November 1, 2017
• Study Completion: November 1, 2017
• Last Updated: August 7, 2018
• Results First Posted: July 10, 2018

Record last verified: 2018-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (4)