High-Dose Weekly Carfilzomib Plus Cyclophosphamide and Dexamethasone in the Treatment of Relapsed Multiple Myeloma

Sponsor
Canadian Cancer Trials Group (Other)
Overall Status
Active, not recruiting
CT.gov ID
NCT02597062
Collaborator
Amgen (Industry), Canadian Myeloma Research Group (Other)
76
Enrollment
9
Locations
1
Arm
81.1
Anticipated Duration (Months)
8.4
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to find out what effects carfilzomib has on relapsed multiple myeloma when administered in combination with cyclophosphamide and dexamethasone.

Condition or DiseaseIntervention/TreatmentPhase
Phase 2

Detailed Description

Multiple Myeloma is a cancer that affects the bone marrow where the cells in our blood system are formed. This includes the white cells, red cells, platelets and lymphoid cells. In multiple myeloma the plasma cell (one of the lymphoid cells) starts to reproduce out of control. This results in crowding of the bone marrow with abnormal production of all the cells and a malfunction of the plasma cells. They can also cause damage to the normal bone resulting in pain, fractures and other complications.

The standard or usual treatments for your disease are lenalidomide (an immunomodulatory drug) or bortezomib (a proteasome inhibitor) based treatments.

Carfilzomib is a new type of proteasome inhibitor that is approved for the treatment of relapsed multiple myeloma in the United States.

Study Design

Study Type:
Interventional
Actual Enrollment :
76 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Single Arm Phase II Study of High-Dose Weekly Carfilzomib Plus Cyclophosphamide and Dexamethasone in the Treatment of Relapsed Multiple Myeloma After 1-3 Prior Therapies
Actual Study Start Date :
Mar 29, 2016
Actual Primary Completion Date :
Jun 19, 2019
Anticipated Study Completion Date :
Dec 31, 2022

Arms and Interventions

ArmIntervention/Treatment
Experimental: Carfilzomib plus cyclophosphamide plus dexamethasone

20 mg/m2 day 1 of first cycle then escalated to 70 mg/m2 for all subsequent doses) given on days 1, 8, and 15 of a 28 day cycle plus weekly oral dexamethasone (< 70 years, 40 mg; ≥ 70 years 20mg) and cyclophosphamide 300 mg/m2 capped at 500 mg

Drug: Carfilzomib

Drug: Cyclophosphamide

Drug: Dexamethasone

Outcome Measures

Primary Outcome Measures

  1. Overall Response Rate After 4 Cycles [4 months]

    Response rate to protocol treatment after 4 cycles is define by stringent complete response, complete response, partial response, very good partial response, minimal response. Complete response: Negative immunofixation on the serum and urine and Disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow biopsy Stringent complete response: Complete response plus Absence of clonal cells in bone marrow d by immunohistochemistry or immunofluorescence Very good partial response: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein with urine M-protein level <100 mg/24 hours. Partial response: ≥50% reduction in serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 mg/24 hours Minimal response: 25-49% reduction in serum M-protein, and 50-89% reduction in 24-hour urinary M-protein, if ≥ 200 mg/24 hours at baseline

Secondary Outcome Measures

  1. Progression-free Survival [3 years]

    Median time to progression or death assessed by biochemistry, radiology and immunology tests will be reported. Progression is evaluated in this study using the International Myeloma Working Group Uniform Response Criteria (IMWG-URC) with any one or more of the following: Increase of ≥ 25% from lowest response value in: Serum M-component and/or Urine M-component and/or Only in patients without measurable serum and urine M-protein levels; the difference between involved and uninvolved FLC levels or Bone marrow plasma cell percentages. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL (0.115 g/L) or 2.65 mmol/L) that can be attributed solely to the plasma cell proliferative disorder.

  2. Overall Survival [3 years]

    Median time to death in months will be reported

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
  • Relapsed symptomatic multiple myeloma as per the International Myeloma Working group criteria [Palumbo 2009].

  • Measurable disease, as defined by one or more of the following (assessed within 21 days prior to registration):

  • Serum M-protein ≥ 5 g/L (0.5g/dL)

  • Urine Bence-Jones protein ≥ 200 mg/24 hours

  • Involved serum free light chain (FLC) measurement ≥ 100 mg/L (10 mg/dL), provided serum FLC ratio is abnormal (abnormal if FLC ratio is <0.26 or >1.65)

  • Biopsy proven plasmacytoma

  • For IgA patients whose disease can only be reliably measured by serum quantitative immunoglobulin (qIgA) ≥ 750 mg/dL (0.75 g/dL)

  • Prior treatment with at least one, but no more than three, regimens for multiple myeloma

  • Documented relapse or progressive disease on or after any regimen (subjects refractory to the most recent line of therapy are eligible except those who are refractory to bortezomib and cyclophosphamide as described in exclusion criteria 1.

  • Achieved a response to at least one prior regimen (defined as ≥ 25% decrease in M-protein)

  • Age ≥ 18 years.

  • Life expectancy ≥ 3 months.

  • ECOG performance status 0-2.

  • Laboratory Requirements (must be done within 21 days of registration):

  • Hematology:

  • Absolute neutrophil count (ANC) ≥ 1.0 × 10^9/L

  • Hemoglobin ≥ 8 g/dL (80 g/L) (subjects may be receiving red blood cell (RBC) transfusions in accordance with institutional guidelines)

  • Platelet count ≥ 50 × 109/L, independent of platelet transfusions for 7 days. (≥ 30 × 109/L if myeloma involvement in the bone marrow is ≥ 50%)

  • Biochemistry:

  • ALT ≤ 3.5 x UNL

  • Serum direct bilirubin ≤ 2 mg/dL (34 μmol/L) (only required if total bilirubin ≥ 2mg/dL (34μmol/L)

  • Creatinine clearance (CrCl) ≥ 30 mL/minute (Crockcroft and Gault formula) and not on dialysis.

  • Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrollment in the trial to document their willingness to participate.

  • Patients must be accessible for treatment and follow up. Patients registered on this trial must be treated and followed at the participating centre.

  • In accordance with CRO policy, protocol treatment is to begin within 2 working days of patient registration.

  • Women/men of childbearing potential must have agreed to use a highly effective contraceptive method.

Exclusion Criteria:
  • Refractory to any proteasome inhibitor therapy (bortezomib, ixazomib, etc.) Refractory disease is defined as failure to respond to the proteasome inhibitor, initial response followed by progression while on a proteasome inhibitor, or relapse within 60 days of stopping proteasome inhibitor therapy.

  • Prior carfilzomib treatment.

  • POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)

  • Waldenström's macroglobulinemia or IgM myeloma

  • Current or previous Plasma cell leukemia defined as (> 2.0 × 10^9/L circulating plasma cells by standard differential)

  • Chemotherapy or investigational agent within 3 weeks prior to registration or antibody therapy within 6 weeks prior to registration

  • Radiotherapy to multiple sites within 28 days prior to registration; localized radiotherapy to a single site within 7 days prior to registration

  • Plasmapheresisis within 14 days of registration.

  • Pregnant or lactating females.

  • Major surgery within 21 days prior to registration.

  • Active, uncontrolled bacterial, fungal, or viral infection.

  • Concurrent amyloidosis

  • Known human immunodeficiency virus infection.

  • Active hepatitis B or C infection.

  • 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.

  • Other malignancy, including MDS, within the past 3 years with the exception of adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; carcinoma in situ of the cervix or breast; prostate cancer of Gleason Score 6 or less with stable prostate-specific antigen levels; or 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 tumours of the adrenal or pancreas.

  • Significant neuropathy (≥ grade 3, or grade 2 with pain) within 14 days prior to registration.

  • Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib).

  • Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment.

  • Ongoing graft-versus-host disease.

  • 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.

Contacts and Locations

Locations

SiteCityStateCountryPostal Code
1Cross Cancer InstituteEdmontonAlbertaCanadaT6G 1Z2
2Regional Health Authority B, Zone 2Saint JohnNew BrunswickCanadaE2L 4L2
3QEII Health Sciences CentreHalifaxNova ScotiaCanadaB3H 1V7
4Kingston Health Sciences CentreKingstonOntarioCanadaK7L 2V7
5London Regional Cancer ProgramLondonOntarioCanadaN6A 5W9
6Ottawa Hospital Research InstituteOttawaOntarioCanadaK1H 8L6
7University Health NetworkTorontoOntarioCanadaM5G 2M9
8CIUSSS de l'Est-de-I'lle-de-MontrealMontrealQuebecCanadaH1T 2M4
9CHUQ-Pavillon Hotel-Dieu de QuebecQuebec CityQuebecCanadaG1R 2J6

Sponsors and Collaborators

  • Canadian Cancer Trials Group
  • Amgen
  • Canadian Myeloma Research Group

Investigators

  • Study Chair: Christopher Venner, Cross Cancer Institute, Edmonton Alberta Canada

Study Documents (Full-Text)

More Information

Publications

None provided.
Responsible Party:
Canadian Cancer Trials Group
ClinicalTrials.gov Identifier:
NCT02597062
Other Study ID Numbers:
  • MYX1
  • MCRN003
First Posted:
Nov 4, 2015
Last Update Posted:
May 12, 2021
Last Verified:
Apr 1, 2021
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail
Arm/Group TitleCarfilzomib Plus Cyclophosphamide Plus Dexamethasone
Arm/Group Description20 mg/m2 day 1 of first cycle then escalated to 70 mg/m2 for all subsequent doses) given on days 1, 8, and 15 of a 28 day cycle plus weekly oral dexamethasone (< 70 years, 40 mg; ≥ 70 years 20mg) and cyclophosphamide 300 mg/m2 capped at 500 mg Carfilzomib Cyclophosphamide Dexamethasone
Period Title: Overall Study
STARTED76
COMPLETED75
NOT COMPLETED1

Baseline Characteristics

Arm/Group TitleCarfilzomib Plus Cyclophosphamide Plus Dexamethasone
Arm/Group Description20 mg/m2 day 1 of first cycle then escalated to 70 mg/m2 for all subsequent doses) given on days 1, 8, and 15 of a 28 day cycle plus weekly oral dexamethasone (< 70 years, 40 mg; ≥ 70 years 20mg) and cyclophosphamide 300 mg/m2 capped at 500 mg Carfilzomib Cyclophosphamide Dexamethasone
Overall Participants75
Age (years) [Median (Full Range) ]
Median (Full Range) [years]
66.0
Sex: Female, Male (Count of Participants)
Female
27
36%
Male
48
64%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
3
4%
Asian
1
1.3%
Native Hawaiian or Other Pacific Islander
0
0%
Black or African American
2
2.7%
White
68
90.7%
More than one race
0
0%
Unknown or Not Reported
1
1.3%
Region of Enrollment (participants) [Number]
Canada
75
100%

Outcome Measures

1. Primary Outcome
TitleOverall Response Rate After 4 Cycles
DescriptionResponse rate to protocol treatment after 4 cycles is define by stringent complete response, complete response, partial response, very good partial response, minimal response. Complete response: Negative immunofixation on the serum and urine and Disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow biopsy Stringent complete response: Complete response plus Absence of clonal cells in bone marrow d by immunohistochemistry or immunofluorescence Very good partial response: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein with urine M-protein level <100 mg/24 hours. Partial response: ≥50% reduction in serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 mg/24 hours Minimal response: 25-49% reduction in serum M-protein, and 50-89% reduction in 24-hour urinary M-protein, if ≥ 200 mg/24 hours at baseline
Time Frame4 months

Outcome Measure Data

Analysis Population Description
All eligible patients how have received treatment.
Arm/Group TitleCarfilzomib Plus Cyclophosphamide Plus Dexamethasone
Arm/Group Description20 mg/m2 day 1 of first cycle then escalated to 70 mg/m2 for all subsequent doses) given on days 1, 8, and 15 of a 28 day cycle plus weekly oral dexamethasone (< 70 years, 40 mg; ≥ 70 years 20mg) and cyclophosphamide 300 mg/m2 capped at 500 mg Carfilzomib Cyclophosphamide Dexamethasone
Measure Participants75
stringent complete response
4
5.3%
complete response
3
4%
very good partial response
32
42.7%
partial response
21
28%
minimal response
1
1.3%
no response
14
18.7%
2. Secondary Outcome
TitleProgression-free Survival
DescriptionMedian time to progression or death assessed by biochemistry, radiology and immunology tests will be reported. Progression is evaluated in this study using the International Myeloma Working Group Uniform Response Criteria (IMWG-URC) with any one or more of the following: Increase of ≥ 25% from lowest response value in: Serum M-component and/or Urine M-component and/or Only in patients without measurable serum and urine M-protein levels; the difference between involved and uninvolved FLC levels or Bone marrow plasma cell percentages. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL (0.115 g/L) or 2.65 mmol/L) that can be attributed solely to the plasma cell proliferative disorder.
Time Frame3 years

Outcome Measure Data

Analysis Population Description
All treated patients were included in the analysis
Arm/Group TitleCarfilzomib Plus Cyclophosphamide Plus Dexamethasone
Arm/Group Description20 mg/m2 day 1 of first cycle then escalated to 70 mg/m2 for all subsequent doses) given on days 1, 8, and 15 of a 28 day cycle plus weekly oral dexamethasone (< 70 years, 40 mg; ≥ 70 years 20mg) and cyclophosphamide 300 mg/m2 capped at 500 mg Carfilzomib Cyclophosphamide Dexamethasone
Measure Participants75
Median (95% Confidence Interval) [months]
17.15
3. Secondary Outcome
TitleOverall Survival
DescriptionMedian time to death in months will be reported
Time Frame3 years

Outcome Measure Data

Analysis Population Description
All treated patients
Arm/Group TitleCarfilzomib Plus Cyclophosphamide Plus Dexamethasone
Arm/Group Description20 mg/m2 day 1 of first cycle then escalated to 70 mg/m2 for all subsequent doses) given on days 1, 8, and 15 of a 28 day cycle plus weekly oral dexamethasone (< 70 years, 40 mg; ≥ 70 years 20mg) and cyclophosphamide 300 mg/m2 capped at 500 mg Carfilzomib Cyclophosphamide Dexamethasone
Measure Participants75
Median (95% Confidence Interval) [months]
27.43

Adverse Events

Time Frame3 years
Adverse Event Reporting Description
Arm/Group TitleCarfilzomib Plus Cyclophosphamide Plus Dexamethasone
Arm/Group Description20 mg/m2 day 1 of first cycle then escalated to 70 mg/m2 for all subsequent doses) given on days 1, 8, and 15 of a 28 day cycle plus weekly oral dexamethasone (< 70 years, 40 mg; ≥ 70 years 20mg) and cyclophosphamide 300 mg/m2 capped at 500 mg Carfilzomib Cyclophosphamide Dexamethasone
All Cause Mortality
Carfilzomib Plus Cyclophosphamide Plus Dexamethasone
Affected / at Risk (%)# Events
Total31/75 (41.3%)
Serious Adverse Events
Carfilzomib Plus Cyclophosphamide Plus Dexamethasone
Affected / at Risk (%)# Events
Total39/75 (52%)
Blood and lymphatic system disorders
Febrile neutropenia3/75 (4%)
Other blood and lymphatic system disorders1/75 (1.3%)
Thrombotic thrombocytopenic purpura2/75 (2.7%)
Cardiac disorders
Heart failure2/75 (2.7%)
Mitral valve disease1/75 (1.3%)
Right ventricular dysfunction1/75 (1.3%)
General disorders
Death NOS1/75 (1.3%)
Fatigue1/75 (1.3%)
Fever4/75 (5.3%)
Malaise1/75 (1.3%)
Non-cardiac chest pain2/75 (2.7%)
Infections and infestations
Abdominal infection1/75 (1.3%)
Device related infection1/75 (1.3%)
Lung infection14/75 (18.7%)
Other infections and infestations1/75 (1.3%)
Sepsis4/75 (5.3%)
Upper respiratory infection3/75 (4%)
Injury, poisoning and procedural complications
Ankle fracture1/75 (1.3%)
Fracture1/75 (1.3%)
Investigations
Alanine aminotransferase increased3/75 (4%)
Aspartate aminotransferase increased3/75 (4%)
Blood bilirubin increased1/75 (1.3%)
Metabolism and nutrition disorders
Dehydration1/75 (1.3%)
Musculoskeletal and connective tissue disorders
Bone pain1/75 (1.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Other neoplasms benign, malignant and unspecified1/75 (1.3%)
Nervous system disorders
Ischemia cerebrovascular1/75 (1.3%)
Other nervous system disorders1/75 (1.3%)
Psychiatric disorders
Delirium1/75 (1.3%)
Renal and urinary disorders
Acute kidney injury1/75 (1.3%)
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome1/75 (1.3%)
Dyspnea1/75 (1.3%)
Pleural effusion1/75 (1.3%)
Vascular disorders
Other vascular disorders1/75 (1.3%)
Thromboembolic event2/75 (2.7%)
Other (Not Including Serious) Adverse Events
Carfilzomib Plus Cyclophosphamide Plus Dexamethasone
Affected / at Risk (%)# Events
Total28/75 (37.3%)
General disorders
Fatigue12/75 (16%)
Infections and infestations
Lung infection15/75 (20%)
Sepsis5/75 (6.7%)
Respiratory, thoracic and mediastinal disorders
Dyspnea5/75 (6.7%)
Vascular disorders
Hypertension7/75 (9.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Name/TitleBingshu Chen
OrganizationCanadian Cancer Trials Group
Phone613-533-6000 ext 77703
Emailbechen@ctg.queensu.ca
Responsible Party:
Canadian Cancer Trials Group
ClinicalTrials.gov Identifier:
NCT02597062
Other Study ID Numbers:
  • MYX1
  • MCRN003
First Posted:
Nov 4, 2015
Last Update Posted:
May 12, 2021
Last Verified:
Apr 1, 2021