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Lenalidomide, Cyclophosphamide, and Dexamethasone in Treating Patients With Primary Systemic Amyloidosis

Primary Purpose

Multiple Myeloma and Plasma Cell Neoplasm

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

cyclophosphamide

dexamethasone

lenalidomide

About this trial

This is an interventional treatment trial for Multiple Myeloma and Plasma Cell Neoplasm focused on measuring primary systemic amyloidosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

DISEASE CHARACTERISTICS:

Histochemical diagnosis of AL amyloidosis based on detection of green birefringent material in Congo red-stained tissue specimens by polarizing microscopy
Measurable disease, as defined by one of the following:
- Serum monoclonal protein ≥ 1.0 g by serum electrophoresis
- Urine monoclonal protein > 200 mg by 24-hour urine electrophoresis
- Serum immunoglobulin free light chain ≥ 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio
Symptomatic organ involvement with amyloid to justify therapy
- May include liver involvement, cardiac involvement, renal involvement, grade 1 peripheral neuropathy, or soft tissue involvement
- Must have more than skin purpura or carpal tunnel syndrome
No amyloid-specific syndrome, such as carpal tunnel syndrome or skin purpura, as only evidence of disease
- Vascular amyloid only in a bone marrow biopsy specimen or in a plasmacytoma is not indicative of systemic amyloidosis
No clinically overt multiple myeloma (i.e., monoclonal BMPC > 30%, bone lesions, or hypercalcemia)

PATIENT CHARACTERISTICS:

ECOG performance status 0-2
ANC ≥ 1,000/μL
Platelet count ≥ 75,000/μL
Creatinine < 3.0 mg/dL
Not pregnant
Negative pregnancy test
Fertile patients must use two acceptable methods of contraception for ≥ 28 days prior to, during, and for ≥ 28 days after completion of study treatment
No nursing during and for ≥ 28 days after completion of study treatment
No blood, semen, or sperm donation during and for ≥ 28 days after completion of study treatment
No malignancies within the past 5 years except treated basal cell or squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast
No neuropathy ≥ grade 2, defined as motor neuropathy (symptomatic weakness interfering with function, but not interfering with activities of daily living [ADL]) or sensory neuropathy (sensory alteration or paresthesia [including tingling], interfering with function, but not interfering with ADL)
No uncontrolled infection
No syncope within the past 30 days
No known hypersensitivity to thalidomide, including desquamating rash with thalidomide in the past
No known seropositivity for HIV
No active hepatitis A, B, or C
No New York Heart Association class III or IV heart disease
No venous thromboembolic event within the past 42 days
Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation - Patients intolerant to aspirin may use low molecular weight heparin

PRIOR CONCURRENT THERAPY:

No prior lenalidomide
More than 2 weeks since prior and no other concurrent anticancer agents or treatments
More than 4 weeks since prior experimental agents
No other concurrent corticosteroids except chronic steroids (maximum dose 20 mg/day of prednisone equivalent) for disorders other than amyloidosis (e.g., adrenal insufficiency or rheumatoid arthritis)

Sites / Locations

Mayo Clinic in Arizona
Mayo Clinic in Florida
Mayo Clinic

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

CRD

Arm Description

Lenalidomide 15mg daily (days 1-21) Cyclophosphamide 300 mg/m^2 (days 1, 8, 15) Dexamethasone 40 mg weekly

Outcomes

Primary Outcome Measures

Number of Participants Who Achieved a Confirmed Response Defined as a Complete Response (CR), Very Good Partial Response (VGPR) or Partial Response (PR)

Response that was confirmed on 2 consecutive evaluations during 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. Very Good Partial Response(VGPR): >=90% reduction in serum M-component; Urine M-Component <=100 mg per 24 hours. Partial Response(PR): >=50% reduction in serum M-component and/or Urine M-Component >=90% reduction or <200 mg per 24 hours; or >=50% decrease in difference between involved and uninvolved FLC levels.

Secondary Outcome Measures

Number of Patients With Organ Response

Organ response was evaluated on the basis of improvement of one or more affected organ; only one parameter was required to satisfy the criteria. Response needed to be maintained for a minimum of 3 months to be considered valid. Renal response required a 50% reduction in 24-hour urine protein excretion (at least 0.5 g/d) with stable creatinine. Cardiac response required one of >= 2-mm reduction in the interventricular septal (IVS) thickness by echocardiogram, or improvement of ejection fraction by >= 20%, or improvement by 2 NYHA classes without an increase in diuretic use. Hepatic response required either >= 50% decrease in (or normalization of) an initially elevated alkaline phosphatase level or reduction in the size of the liver by at least 2 cm by radiographic determination. Gastrointestinal tract improvement was defined as normalization of a low serum carotene level, or reduction of diarrhea to < 50% of previous movements/day, or decrease in fecal fat excretion by 50%.

Number of Participants With Severe Adverse Events

Severe adverse events were defined as grade 3 or higher, at least possibly related to study drugs. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.

Progression Free Survival (PFS)

Progression free survival (PFS) was defined as the time from registration to hematologic progression or death of any cause. Progression free and alive patients were censored at the date of last follow-up. The median PFS with 95% CI was estimated using the Kaplan Meier method.

Overall Survival (OS)

Overall survival (OS) was defined as the time from registration to death of any cause. Surviving patients were censored at the date of last follow-up. The median OS with 95% CI was estimated using the Kaplan Meier method.

Full Information

NCT ID

NCT00564889

First Posted

November 28, 2007

Last Updated

April 10, 2013

Sponsor

Mayo Clinic

Collaborators

National Cancer Institute (NCI)

1. Study Identification

Unique Protocol Identification Number

NCT00564889

Brief Title

Lenalidomide, Cyclophosphamide, and Dexamethasone in Treating Patients With Primary Systemic Amyloidosis

Official Title

A Phase II Trial of Lenalidomide (Revlimid®), Cyclophosphamide and Dexamethasone in Patients With Primary Systemic Amyloidosis

Study Type

Interventional

2. Study Status

Record Verification Date

April 2013

Overall Recruitment Status

Completed

Study Start Date

December 2007 (undefined)

Primary Completion Date

February 2009 (Actual)

Study Completion Date

June 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Mayo Clinic

Collaborators

National Cancer Institute (NCI)

4. Oversight

5. Study Description

Brief Summary

RATIONALE: Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop plasma cells from growing. Drugs used in chemotherapy, such as cyclophosphamide and dexamethasone, work in different ways to stop the growth of plasma cells, either by killing the cells or by stopping them from dividing. Giving lenalidomide together with cyclophosphamide and dexamethasone may be an effective treatment for primary systemic amyloidosis. PURPOSE: This phase II trial is studying how well giving lenalidomide together with cyclophosphamide and dexamethasone works in treating patients with primary systemic amyloidosis.

Detailed Description

OBJECTIVES: Primary * Assess the hematologic response rate in patients with primary systemic amyloidosis treated with lenalidomide, cyclophosphamide, and dexamethasone. Secondary Determine the organ response rate in patients treated with this regimen. Determine the toxicity of this regimen in these patients. Determine the time to progression in patients treated with this regimen. Determine the survival of patients treated with this regimen. OUTLINE: Patients receive oral lenalidomide on days 1-21, oral cyclophosphamide* on days 1, 8, and 15, and oral dexamethasone on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. NOTE: *Patients may receive cyclophosphamide for up to 1 year. After completion of study treatment, patients are followed every 6 months for up to 3 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Multiple Myeloma and Plasma Cell Neoplasm

Keywords

primary systemic amyloidosis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

35 (Actual)

8. Arms, Groups, and Interventions

Arm Title

CRD

Arm Type

Experimental

Arm Description

Lenalidomide 15mg daily (days 1-21) Cyclophosphamide 300 mg/m^2 (days 1, 8, 15) Dexamethasone 40 mg weekly

Intervention Type

Drug

Intervention Name(s)

cyclophosphamide

Intervention Description

300 mg/m^2 days 1, 8 & 15 of a 28 day cycle taken orally with food

Intervention Type

Drug

Intervention Name(s)

dexamethasone

Intervention Description

40 mg weekly taken orally

Intervention Type

Drug

Intervention Name(s)

lenalidomide

Intervention Description

15 mg daily days 1-21 of a 28 day cycle taken orally with food

Primary Outcome Measure Information:

Title

Number of Participants Who Achieved a Confirmed Response Defined as a Complete Response (CR), Very Good Partial Response (VGPR) or Partial Response (PR)

Description

Time Frame

Duration on study (up to 3 years)

Secondary Outcome Measure Information:

Title

Number of Patients With Organ Response

Description

Time Frame

Duration of study (up to 3 years)

Title

Number of Participants With Severe Adverse Events

Description

Time Frame

Duration of study (up to 3 years)

Title

Progression Free Survival (PFS)

Description

Time Frame

Duration of study (up to 3 years)

Title

Overall Survival (OS)

Description

Time Frame

Duration of study (up to 3 years)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

DISEASE CHARACTERISTICS: Histochemical diagnosis of AL amyloidosis based on detection of green birefringent material in Congo red-stained tissue specimens by polarizing microscopy Measurable disease, as defined by one of the following: Serum monoclonal protein ≥ 1.0 g by serum electrophoresis Urine monoclonal protein > 200 mg by 24-hour urine electrophoresis Serum immunoglobulin free light chain ≥ 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio Symptomatic organ involvement with amyloid to justify therapy May include liver involvement, cardiac involvement, renal involvement, grade 1 peripheral neuropathy, or soft tissue involvement Must have more than skin purpura or carpal tunnel syndrome No amyloid-specific syndrome, such as carpal tunnel syndrome or skin purpura, as only evidence of disease - Vascular amyloid only in a bone marrow biopsy specimen or in a plasmacytoma is not indicative of systemic amyloidosis No clinically overt multiple myeloma (i.e., monoclonal BMPC > 30%, bone lesions, or hypercalcemia) PATIENT CHARACTERISTICS: ECOG performance status 0-2 ANC ≥ 1,000/μL Platelet count ≥ 75,000/μL Creatinine < 3.0 mg/dL Not pregnant Negative pregnancy test Fertile patients must use two acceptable methods of contraception for ≥ 28 days prior to, during, and for ≥ 28 days after completion of study treatment No nursing during and for ≥ 28 days after completion of study treatment No blood, semen, or sperm donation during and for ≥ 28 days after completion of study treatment No malignancies within the past 5 years except treated basal cell or squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast No neuropathy ≥ grade 2, defined as motor neuropathy (symptomatic weakness interfering with function, but not interfering with activities of daily living [ADL]) or sensory neuropathy (sensory alteration or paresthesia [including tingling], interfering with function, but not interfering with ADL) No uncontrolled infection No syncope within the past 30 days No known hypersensitivity to thalidomide, including desquamating rash with thalidomide in the past No known seropositivity for HIV No active hepatitis A, B, or C No New York Heart Association class III or IV heart disease No venous thromboembolic event within the past 42 days Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation - Patients intolerant to aspirin may use low molecular weight heparin PRIOR CONCURRENT THERAPY: No prior lenalidomide More than 2 weeks since prior and no other concurrent anticancer agents or treatments More than 4 weeks since prior experimental agents No other concurrent corticosteroids except chronic steroids (maximum dose 20 mg/day of prednisone equivalent) for disorders other than amyloidosis (e.g., adrenal insufficiency or rheumatoid arthritis)

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Shaji K. Kumar, MD

Organizational Affiliation

Mayo Clinic

Official's Role

Study Chair

First Name & Middle Initial & Last Name & Degree

Craig B. Reeder, MD

Organizational Affiliation

Mayo Clinic

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Vivek Roy, MD, FACP

Organizational Affiliation

Mayo Clinic

Official's Role

Principal Investigator

Facility Information:

Facility Name

Mayo Clinic in Arizona

City

Scottsdale

State/Province

Arizona

ZIP/Postal Code

85259-5499

Country

United States

Facility Name

Mayo Clinic in Florida

City

Jacksonville

State/Province

Florida

ZIP/Postal Code

32224

Country

United States

Facility Name

Mayo Clinic

City

Rochester

State/Province

Minnesota

ZIP/Postal Code

55905

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

22504925

Citation

Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. doi: 10.1182/blood-2012-01-407791. Epub 2012 Apr 13.

Results Reference

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Lenalidomide, Cyclophosphamide, and Dexamethasone in Treating Patients With Primary Systemic Amyloidosis

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