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

• Sponsor: Canadian Cancer Trials Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT02597062
• Collaborator: Amgen (Industry), Canadian Myeloma Research Group (Other)
• Enrollment: 76
• Locations: 9
• Arm: 1
• Actual Duration (Months): 70.1
• Patients Per Site: 8.4
• Patients Per Site Per Month: 0.1

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 Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: Carfilzomib; Drug: Cyclophosphamide; Drug: Dexamethasone	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
• Actual Study Completion Date: Feb 1, 2022

Arms and Interventions

Arm	Intervention/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 × 10^{9/L, independent of platelet transfusions for 7 days. (≥ 30 × 10}9/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

	Site	City	State	Country	Postal Code
1	Cross Cancer Institute	Edmonton	Alberta	Canada	T6G 1Z2
2	Regional Health Authority B, Zone 2	Saint John	New Brunswick	Canada	E2L 4L2
3	QEII Health Sciences Centre	Halifax	Nova Scotia	Canada	B3H 1V7
4	Kingston Health Sciences Centre	Kingston	Ontario	Canada	K7L 2V7
5	London Regional Cancer Program	London	Ontario	Canada	N6A 5W9
6	Ottawa Hospital Research Institute	Ottawa	Ontario	Canada	K1H 8L6
7	University Health Network	Toronto	Ontario	Canada	M5G 2M9
8	CIUSSS de l'Est-de-I'lle-de-Montreal	Montreal	Quebec	Canada	H1T 2M4
9	CHUQ-Pavillon Hotel-Dieu de Quebec	Quebec City	Quebec	Canada	G1R 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)

• Study Protocol - Oct 11, 2017
• Statistical Analysis Plan - Jan 26, 2018

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: Feb 8, 2022
• Last Verified: Feb 1, 2022

• 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: Multiple Myeloma; Neoplasms, Plasma Cell; Dexamethasone; Cyclophosphamide

Study Results

Participant Flow

Arm/Group Title	Carfilzomib Plus Cyclophosphamide Plus Dexamethasone
Arm/Group Description	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 Carfilzomib Cyclophosphamide Dexamethasone
Period Title: Overall Study
STARTED	76
COMPLETED	75
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Carfilzomib Plus Cyclophosphamide Plus Dexamethasone
Arm/Group Description	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 Carfilzomib Cyclophosphamide Dexamethasone
Overall Participants	75
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

Title	Overall Response Rate After 4 Cycles
Description	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
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

All eligible patients how have received treatment.

Arm/Group Title	Carfilzomib Plus Cyclophosphamide Plus Dexamethasone
Arm/Group Description	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 Carfilzomib Cyclophosphamide Dexamethasone
Measure Participants	75
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

Title	Progression-free Survival
Description	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.
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

All treated patients were included in the analysis

Arm/Group Title	Carfilzomib Plus Cyclophosphamide Plus Dexamethasone
Arm/Group Description	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 Carfilzomib Cyclophosphamide Dexamethasone
Measure Participants	75
Median (95% Confidence Interval) [months]	17.15

3. Secondary Outcome

Title	Overall Survival
Description	Median time to death in months will be reported
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

All treated patients

Arm/Group Title	Carfilzomib Plus Cyclophosphamide Plus Dexamethasone
Arm/Group Description	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 Carfilzomib Cyclophosphamide Dexamethasone
Measure Participants	75
Median (95% Confidence Interval) [months]	27.43

Adverse Events

Time Frame	3 years
Arm/Group Title	Carfilzomib Plus Cyclophosphamide Plus Dexamethasone
Arm/Group Description	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 Carfilzomib Cyclophosphamide Dexamethasone
All Cause Mortality
	Carfilzomib Plus Cyclophosphamide Plus Dexamethasone
	Affected / at Risk (%)	# Events
Total	31/75 (41.3%)
Serious Adverse Events
	Carfilzomib Plus Cyclophosphamide Plus Dexamethasone
	Affected / at Risk (%)	# Events
Total	39/75 (52%)
Blood and lymphatic system disorders
Febrile neutropenia	3/75 (4%)
Other blood and lymphatic system disorders	1/75 (1.3%)
Thrombotic thrombocytopenic purpura	2/75 (2.7%)
Cardiac disorders
Heart failure	2/75 (2.7%)
Mitral valve disease	1/75 (1.3%)
Right ventricular dysfunction	1/75 (1.3%)
General disorders
Death NOS	1/75 (1.3%)
Fatigue	1/75 (1.3%)
Fever	4/75 (5.3%)
Malaise	1/75 (1.3%)
Non-cardiac chest pain	2/75 (2.7%)
Infections and infestations
Abdominal infection	1/75 (1.3%)
Device related infection	1/75 (1.3%)
Lung infection	14/75 (18.7%)
Other infections and infestations	1/75 (1.3%)
Sepsis	4/75 (5.3%)
Upper respiratory infection	3/75 (4%)
Injury, poisoning and procedural complications
Ankle fracture	1/75 (1.3%)
Fracture	1/75 (1.3%)
Investigations
Alanine aminotransferase increased	3/75 (4%)
Aspartate aminotransferase increased	3/75 (4%)
Blood bilirubin increased	1/75 (1.3%)
Metabolism and nutrition disorders
Dehydration	1/75 (1.3%)
Musculoskeletal and connective tissue disorders
Bone pain	1/75 (1.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Other neoplasms benign, malignant and unspecified	1/75 (1.3%)
Nervous system disorders
Ischemia cerebrovascular	1/75 (1.3%)
Other nervous system disorders	1/75 (1.3%)
Psychiatric disorders
Delirium	1/75 (1.3%)
Renal and urinary disorders
Acute kidney injury	1/75 (1.3%)
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	1/75 (1.3%)
Dyspnea	1/75 (1.3%)
Pleural effusion	1/75 (1.3%)
Vascular disorders
Other vascular disorders	1/75 (1.3%)
Thromboembolic event	2/75 (2.7%)
Other (Not Including Serious) Adverse Events
	Carfilzomib Plus Cyclophosphamide Plus Dexamethasone
	Affected / at Risk (%)	# Events
Total	28/75 (37.3%)
General disorders
Fatigue	12/75 (16%)
Infections and infestations
Lung infection	15/75 (20%)
Sepsis	5/75 (6.7%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	5/75 (6.7%)
Vascular disorders
Hypertension	7/75 (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.