ClinicalTrials.gov
ClinicalTrials.gov Menu

Study of Carfilzomib in Multiple Myeloma Relapsed After High-dose Melphalan With Autologous Stem Cell Support (CARFI)

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02572492
Recruitment Status : Recruiting
First Posted : October 9, 2015
Last Update Posted : October 9, 2015
Sponsor:
Collaborator:
Nordic Myeloma Study Group
Information provided by (Responsible Party):
Henrik Gregersen, Aalborg Universitetshospital

Brief Summary:
This study evaluates induction therapy with carfilzomib-cyclophosphamide-dexamethasone before salvage high-dose melphalan with autologous stem cell support (HDT) in multiple myeloma patients with relapse after HDT done at diagnosis. In addition, the study evaluates the effect of maintenance therapy after salvage HDT in multiple myeloma. After salvage HDT half of the patients receive maintenance therapy with carfilzomib/dexamethasone while the other half are observed without maintenance therapy.

Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: Induction with CAR-CY-DEX and conditioning with carfilzomib and highdose melphalan Drug: Carfilzomib/dexamethasone maintenance Drug: Observation without carfilzomib/dexamethasone maintenance Phase 2

Detailed Description:

The survival in younger myeloma patients improved in the nineties with the introduction of high-dose melphalan with autologous stem cell support (HDT) and despite the emergence of novel therapies HDT remains a keystone in myeloma treatment. However, all patients will eventually experience relapse after HDT performed at diagnosis. Eligible patients with late relapse are considered for salvage HDT. The duration of response after salvage HDT is in most studies reported to be approximately half the length of the response after initial HDT. The choice of induction treatment before HDT might affect the outcome after the induction therapy as well as the outcome after the HDT. In other settings the novel proteasome inhibitor Carfilzomib has showed superiority to the first-in-class proteasome inhibitor bortezomib. In addition, carfilzomib has a favourable profile of side effects. Thus, the aim of this phase 2 study is to evaluate induction therapy with carfilzomib-cyclophosphamide-dexamethasone before salvage HDT. The primary end-point in this part of the study is comparison of time to progression after the initial HDT and time to progression after salvage HDT when four series of carfilzomib-cyclophosphamide-dexamethasone are used as induction therapy. In the study Carfilzomib is also included in the conditioning regimen with administration of Iv carfilzomib 27 mg/sqm on day -2 and -1. The standard conditioning regime consists of Iv melphalan 200 mg/sqm on day -2 and reinfusion of at least 2.0 x 10m CD34+ stem cells/kg body weight on day 0.

The purpose of maintenance therapy in multiple myeloma is to prolong the time to progression of disease. There are limited data on the impact of maintenance therapy after salvage HDT. Another important aim of the study is therefore to evaluate the effect of carfilzomib/dexamethasone given every other week compared to observation without maintenance therapy. This part of the study starts two months after HDT. The randomization is stratified according to relapse 1 - 2 years or > 2 years after HDT, ISS stage and standard versus high-risk cytogenetics. The primary end-point of this part of the study is comparison of time to progression in carfilzomib-dexamethasone maintenance arm and in the observational arm. Patients will continue on maintenance therapy/observation until progression, end of study or fulfil standard criteria for discontinuation of treatment according to the protocol.

The study will include 200 patients with relapse of multiple myeloma more than one year after initial HDT. It is a prerequisite that the patients have at least 2.0 x 10m CD34+ stem cells/kg body weight saved in the freezer. The study is conducted by the Nordic Myeloma Study Group (NMSG) at clinics in Denmark, Sweden, Norway, Finland and Lithuania. The first patient was included in January 2015 and enrolment is expected to continue until December 2017. The study ends when the last included patient has been followed for 9 months after randomization.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Study of Carfilzomib-cyclophosphamide-dexamethasone and High-dose Melphalan (HDT) Followed by Randomization Between Observation or Maintenance With Carfilzomib and Dexamethasone in Patients With Relapsed Multiple Myeloma After HDT
Study Start Date : January 2015
Estimated Primary Completion Date : December 2017
Estimated Study Completion Date : April 2019


Arm Intervention/treatment
Experimental: Carfilzomib/dexamethasone maintenance
Carfilzomib/dexamethasone maintenance after salvage HDT
Drug: Induction with CAR-CY-DEX and conditioning with carfilzomib and highdose melphalan

All patients entering the study receive four series of CAR-CY-DEX (Cycle 1 with iv carfilzomib 20 mg/sqm on days 1 and 2, and iv carfilzomib 36 mg/sqm on days 8, 9, 15 and 16. Cycle 2 - 4 with iv carfilzomib 36 mg/sqm on days 1, 2, 8, 9, 15 and 16. P.o. cyclophosphamide 300 mg/sqm on days 1, 8 and 15 and p.o. dexamethasone 20 mg on days 1, 2, 8, 9, 15 and 16 in each 28-days series)

Subsequently all patients receive the conditioning regimen:

Iv carfilzomib 27 mg/sqm on day -2 and -1 Iv melphalan 200 mg/sqm on day -2 > 2.0 m CD34+ stem cells/kg body weight on day 0

Other Name: Kyprolis

Drug: Carfilzomib/dexamethasone maintenance
Maintenance therapy two months after salvage HDT with iv carfilzomib 27 mg/sqm every second week and p.o. dexamethasone 20 mg every second week. The maintenance dose of carfilzomib will be escalated to 56 mg/sqm after 4 weeks provided acceptable side effects.
Other Name: Kyprolis

Sham Comparator: Observation without maintenance
Observation without maintenance after salvage HDT
Drug: Induction with CAR-CY-DEX and conditioning with carfilzomib and highdose melphalan

All patients entering the study receive four series of CAR-CY-DEX (Cycle 1 with iv carfilzomib 20 mg/sqm on days 1 and 2, and iv carfilzomib 36 mg/sqm on days 8, 9, 15 and 16. Cycle 2 - 4 with iv carfilzomib 36 mg/sqm on days 1, 2, 8, 9, 15 and 16. P.o. cyclophosphamide 300 mg/sqm on days 1, 8 and 15 and p.o. dexamethasone 20 mg on days 1, 2, 8, 9, 15 and 16 in each 28-days series)

Subsequently all patients receive the conditioning regimen:

Iv carfilzomib 27 mg/sqm on day -2 and -1 Iv melphalan 200 mg/sqm on day -2 > 2.0 m CD34+ stem cells/kg body weight on day 0

Other Name: Kyprolis

Drug: Observation without carfilzomib/dexamethasone maintenance
Observation without carfilzomib/dexamethasone maintenance




Primary Outcome Measures :
  1. Comparison of time to progression after high-dose melphalan with stem cell support (HDT) performed at diagnosis and time to progression after a salvage HDT combined with carfilzomib-cyclophosphamide-dexamethasone [ Time Frame: 3 years ]
  2. Comparison of time to progression between carfilzomib-dexamethasone maintenance and observation in patients treated with salvage HDT. [ Time Frame: 3 years ]

Secondary Outcome Measures :
  1. Adverse events assessed by CTCAE v4.0 in carfilzomib-cyclophosphamide-dexamethasone induction regime and carfilzomib as part of the high-dose melphalan conditioning [ Time Frame: 5 months ]
  2. Response rates of carfilzomib-cyclophosphamide-dexamethasone induction therapy and HDT [ Time Frame: 5 months ]
  3. Time to marrow regeneration (neutrophil- and platelet recovery) after the HDT [ Time Frame: 3 weeks ]
  4. Adverse events assessed by CTCAE v4.0 in maintenance treatment with carfilzomib-dexamethasone [ Time Frame: 3 years ]
  5. Comparison of overall survival between carfilzomib-dexamethasone maintenance and observation in patients treated with a salvage HDT [ Time Frame: 3 years ]
  6. Quality of life assessed by EORTC QLQ-MY20 and EORTC QLQ-C30 [ Time Frame: 3 years ]


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.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Myeloma diagnosis according to IMWG criteria
  • First treatment demanding relapse after HDT according to IMWG criteria
  • More than 2.0 x 10m CD34+ stem cells / kg body weight in the freezer for stem cell support
  • Signed informed consent given prior to any study related activities have been performed
  • Age > 18 years

Exclusion Criteria:

Demographic

  • Allogeneic transplantation scheduled as a part of the treatment
  • Treatment demanding relapse less than one year after HDT
  • Myeloma treatment after the first HDT, except radiotherapy, bisphosphonates, denosumab and corticosteroids less than 6 days for symptom control
  • Patients not having received HDT as first line treatment
  • Previous treatment with carfilzomib
  • Expected survival of less than six months
  • Performance status (WHO) ≥ 3

Laboratory

  • Serum M-component < 5 g/l and urine M-component < 200 mg/l
  • Any of the following laboratory abnormalities:

    • Absolute neutrophil count (ANC) < 1.0 × 109/L
    • Hemoglobin < 5 mmol/L (<80 g/L) (prior RBC transfusion or recombinant human erythropoietin use is permitted)
    • Platelet count < 50 × 109/L (< 30 × 109/L if myeloma involvement in the bone marrow is > 50%)
    • Serum ALT or AST > 3.5 times the upper limit of normal and serum direct bilirubin > 34 µmol/L (2 mg/dL)
    • Creatinine clearance (CrCl) < 15 mL/minute, either measured or calculated using a standard formula

Concurrent conditions

  • Concurrent disease making treatment with carfilzomib, cyclophosphamide or dexamethasone unsuitable
  • Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days prior to enrolment
  • Major surgery within 21 days prior to enrolment
  • Acute active infection requiring treatment
  • Known or suspected hypersensitivity or intolerance to melphalan, dexamethasone or Captisol® (a cyclodextrin derivative)
  • Uncontrolled or severe cardiovascular disease including myocardial infarction within 6 months of enrolment, NYHA Class III or IV heart failure, uncontrolled angina, clinically significant pericardial disease, uncontrolled severe arrhythmias, or cardiac amyloidosis
  • LVEF <40%, determined by 2-D transthoracic echocardiogram (ECHO) or Multigated Acquisition Scan (MUGA)
  • Pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to enrolment
  • Serious hepatic disorder, including active hepatitis B or C infection
  • Other serious medical or psychiatric illness likely to interfere with participation in this clinical study
  • Use of any investigational agents or experimental medical device within 28 days prior to enrolment into the study

Ethical/other

  • Pregnant or lactating females
  • Females of childbearing potential must agree to ongoing pregnancy testing and to practice contraception
  • Male subjects must agree to practice contraception

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 ClinicalTrials.gov identifier (NCT number): NCT02572492


Contacts
Contact: Ulla Kjaer +45 9766 3882 u.kjaer@rn.dk
Contact: Sanne Kjaer +45 9766 3884 smk@rn.dk

Locations
Denmark
Aalborg University Hospital Recruiting
Aalborg, Denmark, 9000
Principal Investigator: Henrik Gregersen, MD         
Finland
Turku University Hospital Recruiting
Turku, Finland, 20520
Contact: Kari Remes, MD       kari.remes@tyks.fi   
Lithuania
Vilnius University hospital "Santariskiu Clinics" Not yet recruiting
Vilnius, Lithuania
Contact: Valdas Peceliunas, MD       valdas.peceliunas@santa.lt   
Norway
Oslo University Hospital Recruiting
Oslo, Norway, 4950
Contact: Nina Gulbrandsen, MD       uxniul@ous-hf.no   
Sweden
Skåne University Hospital Not yet recruiting
Lund, Sweden, SE-221 85
Contact: Markus Hansson, MD       markus.hansson@med.lu.se   
Sponsors and Collaborators
Henrik Gregersen
Nordic Myeloma Study Group
Investigators
Principal Investigator: Henrik Gregersen, MD Aalborg Universitetshospital

Responsible Party: Henrik Gregersen, Consultant, Aalborg Universitetshospital
ClinicalTrials.gov Identifier: NCT02572492     History of Changes
Other Study ID Numbers: NMSG#20/13
2013-003789-15 ( EudraCT Number )
First Posted: October 9, 2015    Key Record Dates
Last Update Posted: October 9, 2015
Last Verified: October 2015

Keywords provided by Henrik Gregersen, Aalborg Universitetshospital:
Multiple Myeloma
Recurrence
Carfilzomib
Salvage Therapy
Transplantation, Autologous

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone acetate
Dexamethasone
Cyclophosphamide
Melphalan
BB 1101
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents