Cyclophosphamide, Bortezomib, and Dexamethasone in Treating Patients With Newly Diagnosed Multiple Myeloma

Multiple Myeloma and Plasma Cell Neoplasm Clinical Trial

Official title:

A Phase II Trial of Cyclophosphamide, Bortezomib and Dexamethasone (CYBOR-D) in Patients With Newly Diagnosed Active Multiple Myeloma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00609167
• Other study ID #: CDR0000583225
• Secondary ID: P30CA015083MC068
• Status: Completed
• Phase: Phase 2
• First received: January 31, 2008
• Last updated: May 13, 2011
• Start date: December 2006
• Est. completion date: November 2010

Study information

• Verified date: May 2011
• Source: Mayo Clinic
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Drugs used in chemotherapy such as cyclophosphamide and dexamethasone work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving cyclophosphamide and dexamethasone together with bortezomib may kill more cancer cells.

PURPOSE: This phase II trial is studying giving cyclophosphamide and dexamethasone together with bortezomib to see how well it works in treating patients with newly diagnosed multiple myeloma.

Description:

OBJECTIVES:

Primary

• To evaluate the response rate (complete response [CR], near CR [nCR], and very good partial response) in patients with newly diagnosed multiple myeloma treated with bortezomib in combination with cyclophosphamide and dexamethasone .

Secondary

• Determine the overall response rate (partial response, PR, or better) in these patients after 4, 8, and 12 courses of this regimen.

• Determine the duration of progression-free and overall survival of patients treated with this regimen.

• To evaluate the toxicity of this regimen in these patients.

• To evaluate the ability to successfully collect peripheral blood stem cells from these patients after 4 months of this regimen.

• To evaluate the CR or nCR rate in these patients after 8 and 12 courses of this regimen.

OUTLINE: This is a multicenter study.

Patients receive oral cyclophosphamide on days 1, 8, 15, and 22; bortezomib IV on days 1, 4, 8 , and 11 OR days 1, 8, 15 and 22; and dexamethasone on days 1-4, 9-12, and 17-20 in courses 1 and 2 and days 1, 18, 15, and 22 in all subsequent courses. Courses repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 63
• Est. completion date: November 2010
• Est. primary completion date: January 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

DISEASE CHARACTERISTICS:

• Confirmed diagnosis of symptomatic multiple myeloma

• Durie Salmon stage 2 or higher

• Previously untreated multiple myeloma (including immunomodulatory drugs such as thalidomide) with the exception of bisphosphonates

• Evaluable or measurable disease, as defined by at least one of the following:

• Serum monoclonal protein = 1 g/dL (measurable disease)

• Urine monoclonal protein = 200 mg/24 hours by protein electrophoresis (measurable disease)

• Serum-free light chains (FLC) = 10 mg/dL, kappa or lambda, accompanied by an abnormal kappa/lambda ratio

Serum FLC's should only be used for patients without measurable serum or urine m-spike

• Monoclonal bone marrow plasmacytosis = 30% (evaluable disease)

• Patients diagnosed with smoldering myeloma or monoclonal gammopathy of undetermined significance are not eligible

PATIENT CHARACTERISTICS:

Inclusion criteria:

• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0, 1, or 2

• ECOG PS of 3 will be allowed if secondary to pain in the opinion of the Investigator

• Total bilirubin normal OR direct bilirubin = 2.0 mg/dL

• Alkaline phosphatase = 3 times upper limit of normal (ULN)

• AST = 3 times ULN

• Creatinine = 3.5 mg/dL

• Absolute neutrophil count = 1,000/mm³ without transfusion or growth factor

• Platelet count = 100,000/mm³ without transfusion or growth factor

• Willingness and the physical and mental capability to provide written informed consent

• Willingness to return to Mayo Clinic Arizona/Princess Margaret Hospital for follow-up

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

Exclusion criteria:

• Peripheral sensory neuropathy = grade 2 as defined by National Cancer Institute (NCI) Common Terminology for Common Adverse Events (CTCAE) version 3.0

• Known hypersensitivity to compounds containing boron or mannitol

• Active uncontrolled infection

• Severe cardiac comorbidity including but not limited to:

• New York Heart Association class III or IV heart failure

• History of myocardial infarction within the past 6 months

• Uncontrolled angina or electrocardiographic (ECG) evidence of acute ischemia

• Severe uncontrolled ventricular arrhythmias or ECG evidence of active conduction system abnormalities

• Cardiac amyloidosis with hypotension (i.e., systolic blood pressure < 100 mm Hg)

• Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent study compliance or completion of study treatment

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• Prior high-dose corticosteroid therapy for 12 days or less is permitted for emergent complications from newly diagnosed multiple myeloma

• More than 14 days since prior investigational agents

• No concurrent steroids or any other anticancer agents or treatments

• Patients may receive the equivalent of up to 20 mg prednisone per day for concurrent illness or adrenal replacement therapy

• Concurrent palliative radiotherapy for bony pain or fracture is allowed

Study Design

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Multiple Myeloma
• Multiple Myeloma and Plasma Cell Neoplasm
• Neoplasms, Plasma Cell
• Plasmacytoma

Intervention

Drug:
• bortezomib
First 33 patients: 1.3 mg/m^2 IV Days 1, 4, 8 & 11 Remaining 30 patients: 1.5 mg/m^2 IV Days 1, 8, 15 & 22
• cyclophosphamide
300mg/m^2 PO days 1, 8, 15 & 22
• dexamethasone
First 33 patients: 40 mg PO Days 1-4, 9-12, 17-20 Remaining 30 patients: 40 mg PO Days 1-4, 9-12, 17-20 for cycles 1-2; Days 1, 8, 15, 22 for cycle 3+2 for cycle 3 and beyond

Locations

Country	Name	City	State
Canada	Princess Margaret Hospital	Toronto	Ontario
United States	Mayo Clinic in Arizona	Scottsdale	Arizona

Sponsors (2)

Lead Sponsor	Collaborator
Mayo Clinic	National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (2)

Reeder CB, Reece DE, Kukreti V, Chen C, Trudel S, Hentz J, Noble B, Pirooz NA, Spong JE, Piza JG, Zepeda VH, Mikhael JR, Leis JF, Bergsagel PL, Fonseca R, Stewart AK. Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple my — View Citation

Reeder CB, Reece DE, Kukreti V, Chen C, Trudel S, Laumann K, Hentz J, Pirooz NA, Piza JG, Tiedemann R, Mikhael JR, Bergsagel PL, Leis JF, Fonseca R, Stewart AK. Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants Who Achieved a Confirmed Responses Defined as a Complete Response (CR), Near CR or Very Good Partial Response (VGPR) After the First 4 Months of Treatment	Response that was confirmed on 2 consecutive evaluations during the first 4 months of treatment.; Complete Response(CR): Complete disappearance of M-protein from serum and urine on immunofixation, normalization of Free Light Chain (FLC) ratio and <5% plasma cells in bone marrow.; near Complete Response (nCR): Patients who meet all criteria for CR except a positive immunofixation will be classified as nCR.; Very Good Partial Response(VGPR): >=90% reduction in serum M-component; Urine M-Component <100mg per 24hours; <=5% plasma cells in bone marrow.	After 4 months of treatment	No
Secondary	Progression Free Survival (PFS)	PFS was defined as the time from registration to progression or death due to any cause.; Progression was defined as any one or more of the following: An increase of 25% from lowest confirmed response in: Serum M-component (absolute increase >= 0.5g/dl); Urine M-component (absolute increase >= 200mg/24hour; Difference between involved and uninvolved Free Light Chain levels (absolute increase >= 10mg/dl); Bone marrow plasma cell percentage (absolute increase of >=10%); Definite development of new bone lesion or soft tissue plasmacytomas	up to 5 years	No
Secondary	Overall Survival (OS)	OS was defined as the time from registration to death of any cause.	From date of registration until death (up to 5 years)	No
Secondary	Number of Participants Who Responded to Treatment (Complete Response,CR; Near Complete Response, nCR; Very Good Partial Response, VGPR; or Partial Response, PR) After 4 Cycles	Response that was confirmed on 2 consecutive evaluations after 8 months of treatment.; CR, nCR and VGPR as defined in the primary outcome.; Partial Response(PR): >=50% reduction in serum M-component and/or; Urine M-Component >=90% reduction or <200mg per 24hours; or >=50% decrease in difference between involved and uninvolved FLC levels.	4 cycles	No
Secondary	Duration of Response	Duration of response was calculated from the documentation (date) of first response (CR, nCR, VGPR, or PR) until the date of progression or last follow-up in the subset of patients who responded.	Duration of study (up to 12 cycles)	No
Secondary	Number of Participants Who Responded to Treatment (CR, nCR, VGPR or PR) After 8 Cycles	Response that was confirmed on 2 consecutive evaluations after 8 cycles of treatment.; Criteria for CR, nCR, VGPR and PR are defined in prior outcomes.	After 8 cycles of treatment	No
Secondary	Number of Participants Who Responded to Treatment (CR, nCR, VGPR or PR) After 12 Cycles	Response that was confirmed on 2 consecutive evaluations after 12 cycles of treatment.; Criteria for CR, nCR, VGPR and PR are defined in prior outcomes.	After 12 cycles of treatment	No
Secondary	Number of Participants With Severe Adverse Events	Severe adverse events were defined as grade 3 or higher, regardless of attribution to study drugs. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.	Every cycle during treatment (up to 12 cycles)	Yes
Secondary	Participants Who Successfully Completed Collection of Peripheral Blood Stem Cells for Transplant	Evaluation of the ability to successfully collect peripheral blood stem cells following four months (cycles) of combination therapy.	After 4 cycles of treatment	No