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

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT00564889
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 35
• Locations: 3
• Arm: 1
• Duration (Months): 54
• Patients Per Site: 11.7
• Patients Per Site Per Month: 0.2

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma and Plasma Cell Neoplasm	Drug: cyclophosphamide; Drug: dexamethasone; Drug: lenalidomide	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 35 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of Lenalidomide (Revlimid®), Cyclophosphamide and Dexamethasone in Patients With Primary Systemic Amyloidosis
• Study Start Date: Dec 1, 2007
• Actual Primary Completion Date: Feb 1, 2009
• Actual Study Completion Date: Jun 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CRD Lenalidomide 15mg daily (days 1-21) Cyclophosphamide 300 mg/m^2 (days 1, 8, 15) Dexamethasone 40 mg weekly	Drug: cyclophosphamide; 300 mg/m^2 days 1, 8 & 15 of a 28 day cycle taken orally with food; Drug: dexamethasone; 40 mg weekly taken orally; Drug: lenalidomide; 15 mg daily days 1-21 of a 28 day cycle taken orally with food

Outcome Measures

Primary Outcome Measures

1. Number of Participants Who Achieved a Confirmed Response Defined as a Complete Response (CR), Very Good Partial Response (VGPR) or Partial Response (PR) [Duration on study (up to 3 years)]

   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

1. Number of Patients With Organ Response [Duration of study (up to 3 years)]

   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%.

2. Number of Participants With Severe Adverse Events [Duration of study (up to 3 years)]

   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.

3. Progression Free Survival (PFS) [Duration of study (up to 3 years)]

   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.

4. Overall Survival (OS) [Duration of study (up to 3 years)]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic in Arizona	Scottsdale	Arizona	United States	85259-5499
2	Mayo Clinic in Florida	Jacksonville	Florida	United States	32224
3	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic
• National Cancer Institute (NCI)

Investigators

• Study Chair: Shaji K. Kumar, MD, Mayo Clinic
• Principal Investigator: Craig B. Reeder, MD, Mayo Clinic
• Principal Investigator: Vivek Roy, MD, FACP, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT00564889
• Other Study ID Numbers: MC0685; P30CA015083; MC0685; NCI-2010-01954; 06-005711
• First Posted: Nov 29, 2007
• Last Update Posted: May 14, 2013
• Last Verified: Apr 1, 2013

• Keywords provided by Mayo Clinic: primary systemic amyloidosis
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Plasmacytoma; Immunoglobulin Light-chain Amyloidosis; Amyloidosis; Dexamethasone; Cyclophosphamide; Lenalidomide

Study Results

Participant Flow

Recruitment Details	Thirty-five(35) participants were recruited between December 2007 and November 2008 at Mayo Clinic.

Arm/Group Title	Len/Cyc/Dex
Arm/Group Description	Lenalidomide (Len) 15mg daily (days 1-21) Cyclophosphamide (Cyc) 300 mg/m^2 (days 1, 8, 15) Dexamethasone (Dex) 40 mg weekly
Period Title: Overall Study
STARTED	35
COMPLETED	6
NOT COMPLETED	29

Baseline Characteristics

Arm/Group Title	Len/Cyc/Dex
Arm/Group Description	Lenalidomide (Len) 15mg daily (days 1-21); Cyclophosphamide (Cyc) 300 mg/m^2 (days 1, 8, 15); Dexamethasone (Dex) 40 mg weekly
Overall Participants	35
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	64
Sex: Female, Male (Count of Participants)
Female	16 45.7%
Male	19 54.3%
Region of Enrollment (participants) [Number]
United States	35 100%
Received Previous Treatment (participants) [Number]
Yes	11 31.4%
No	24 68.6%
Had a Prior Stem Cell Transplant (participants) [Number]
Yes	7 20%
No	28 80%

Outcome Measures

1. Primary Outcome

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	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.
Time Frame	Duration on study (up to 3 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Len/Cyc/Dex
Arm/Group Description	Lenalidomide (Len) 15mg daily (days 1-21); Cyclophosphamide (Cyc) 300 mg/m^2 (days 1, 8, 15); Dexamethasone (Dex) 40 mg weekly
Measure Participants	35
Number [participants]	21 60%

2. Secondary Outcome

Title	Number of Patients With Organ Response
Description	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%.
Time Frame	Duration of study (up to 3 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Len/Cyc/Dex
Arm/Group Description	Lenalidomide (Len) 15mg daily (days 1-21); Cyclophosphamide (Cyc) 300 mg/m^2 (days 1, 8, 15); Dexamethasone (Dex) 40 mg weekly
Measure Participants	35
Number [participants]	11 31.4%

3. Secondary Outcome

Title	Number of Participants With Severe Adverse Events
Description	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.
Time Frame	Duration of study (up to 3 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Len/Cyc/Dex
Arm/Group Description	Lenalidomide (Len) 15mg daily (days 1-21); Cyclophosphamide (Cyc) 300 mg/m^2 (days 1, 8, 15); Dexamethasone (Dex) 40 mg weekly
Measure Participants	35
Number [participants]	26 74.3%

4. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	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.
Time Frame	Duration of study (up to 3 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Len/Cyc/Dex
Arm/Group Description	Lenalidomide (Len) 15mg daily (days 1-21); Cyclophosphamide (Cyc) 300 mg/m^2 (days 1, 8, 15); Dexamethasone (Dex) 40 mg weekly
Measure Participants	35
Median (95% Confidence Interval) [months]	28.3

5. Secondary Outcome

Title	Overall Survival (OS)
Description	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.
Time Frame	Duration of study (up to 3 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Len/Cyc/Dex
Arm/Group Description	Lenalidomide (Len) 15mg daily (days 1-21); Cyclophosphamide (Cyc) 300 mg/m^2 (days 1, 8, 15); Dexamethasone (Dex) 40 mg weekly
Measure Participants	35
Median (95% Confidence Interval) [months]	37.8

Adverse Events

Arm/Group Title	Len/Cyc/Dex
Arm/Group Description	Dexamethasone (Dex) 40 mg weekly
All Cause Mortality
	Len/Cyc/Dex
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Len/Cyc/Dex
	Affected / at Risk (%)	# Events
Total	24/35 (68.6%)
Blood and lymphatic system disorders
Febrile neutropenia	1/35 (2.9%)	1
Hemoglobin decreased	4/35 (11.4%)	4
Cardiac disorders
Atrial fibrillation	1/35 (2.9%)	1
Cardiac disorder	3/35 (8.6%)	3
Left ventricular failure	3/35 (8.6%)	4
Myocardial ischemia	1/35 (2.9%)	1
Restrictive cardiomyopathy	1/35 (2.9%)	1
Sinus bradycardia	1/35 (2.9%)	1
Ventricular arrhythmia	2/35 (5.7%)	2
Gastrointestinal disorders
Abdominal pain	2/35 (5.7%)	2
Constipation	1/35 (2.9%)	1
Diarrhea	3/35 (8.6%)	3
Gastritis	1/35 (2.9%)	2
Intestinal necrosis	1/35 (2.9%)	1
Lower gastrointestinal hemorrhage	2/35 (5.7%)	3
Nausea	3/35 (8.6%)	3
Small intestinal obstruction	1/35 (2.9%)	1
Vomiting	1/35 (2.9%)	1
General disorders
Edema limbs	4/35 (11.4%)	6
Fatigue	2/35 (5.7%)	2
Multi-organ failure	2/35 (5.7%)	2
Hepatobiliary disorders
Cholecystitis	2/35 (5.7%)	2
Hepatic failure	1/35 (2.9%)	1
Infections and infestations
Colitis, infectious (e.g., Clostridium difficile)	1/35 (2.9%)	1
Infection	1/35 (2.9%)	1
Pneumonia	4/35 (11.4%)	4
Sepsis	5/35 (14.3%)	6
Urinary tract infection	1/35 (2.9%)	1
Investigations
Activated partial thromboplastin time prolonged	1/35 (2.9%)	1
Alanine aminotransferase increased	2/35 (5.7%)	2
Aspartate aminotransferase increased	2/35 (5.7%)	2
Bilirubin increased	2/35 (5.7%)	2
Creatinine increased	3/35 (8.6%)	3
Gamma-glutamyltransferase increased	1/35 (2.9%)	1
INR increased	1/35 (2.9%)	1
Leukocyte count decreased	2/35 (5.7%)	2
Lymphocyte count decreased	2/35 (5.7%)	2
Neutrophil count decreased	3/35 (8.6%)	4
Platelet count decreased	5/35 (14.3%)	5
Metabolism and nutrition disorders
Alkalosis	1/35 (2.9%)	1
Anorexia	2/35 (5.7%)	2
Blood glucose increased	2/35 (5.7%)	2
Dehydration	5/35 (14.3%)	5
Serum albumin decreased	2/35 (5.7%)	3
Serum calcium decreased	2/35 (5.7%)	2
Serum potassium decreased	2/35 (5.7%)	2
Serum sodium decreased	3/35 (8.6%)	3
Nervous system disorders
Peripheral motor neuropathy	1/35 (2.9%)	1
Syncope	3/35 (8.6%)	4
Psychiatric disorders
Confusion	1/35 (2.9%)	1
Renal and urinary disorders
Glomerular filtration rate decreased	1/35 (2.9%)	1
Renal failure	2/35 (5.7%)	2
Respiratory, thoracic and mediastinal disorders
Atelectasis	1/35 (2.9%)	1
Dyspnea	4/35 (11.4%)	7
Hypoxia	2/35 (5.7%)	2
Pleural effusion	3/35 (8.6%)	5
Pneumonitis	1/35 (2.9%)	4
Respiratory disorder	2/35 (5.7%)	2
Skin and subcutaneous tissue disorders
Erythema multiforme	1/35 (2.9%)	1
Vascular disorders
Hematoma	3/35 (8.6%)	3
Hemorrhage	1/35 (2.9%)	1
Hypotension	6/35 (17.1%)	7
Thrombosis	4/35 (11.4%)	6
Other (Not Including Serious) Adverse Events
	Len/Cyc/Dex
	Affected / at Risk (%)	# Events
Total	35/35 (100%)
Blood and lymphatic system disorders
Hemoglobin decreased	32/35 (91.4%)	250
Cardiac disorders
Atrial fibrillation	1/35 (2.9%)	1
Atrial flutter	1/35 (2.9%)	1
Left ventricular dysfunction	1/35 (2.9%)	1
Sinus bradycardia	10/35 (28.6%)	17
Endocrine disorders
Hypothyroidism	1/35 (2.9%)	1
Eye disorders
Cataract	1/35 (2.9%)	4
Eye disorder	1/35 (2.9%)	1
Gastrointestinal disorders
Abdominal pain	1/35 (2.9%)	1
Constipation	21/35 (60%)	124
Diarrhea	21/35 (60%)	90
Ear, nose and throat examination abnormal	1/35 (2.9%)	2
Enteritis	1/35 (2.9%)	1
Mucositis oral	1/35 (2.9%)	1
Nausea	2/35 (5.7%)	2
General disorders
Edema limbs	31/35 (88.6%)	188
Fatigue	33/35 (94.3%)	320
Fever	1/35 (2.9%)	1
Gait abnormal	1/35 (2.9%)	1
Infections and infestations
Bladder infection	1/35 (2.9%)	1
Colitis, infectious (e.g., Clostridium difficile)	1/35 (2.9%)	1
Gingival infection	1/35 (2.9%)	1
Infection	1/35 (2.9%)	1
Pneumonia	3/35 (8.6%)	3
Sepsis	9/35 (25.7%)	11
Sinusitis	3/35 (8.6%)	4
Skin infection	2/35 (5.7%)	4
Tooth infection	1/35 (2.9%)	1
Upper respiratory infection	5/35 (14.3%)	5
Injury, poisoning and procedural complications
Bruising	1/35 (2.9%)	1
Wound dehiscence	1/35 (2.9%)	1
Investigations
Alkaline phosphatase increased	2/35 (5.7%)	3
Aspartate aminotransferase increased	15/35 (42.9%)	45
Creatinine increased	18/35 (51.4%)	156
INR increased	1/35 (2.9%)	1
Leukocyte count decreased	29/35 (82.9%)	180
Lipase increased	1/35 (2.9%)	1
Lymphocyte count decreased	2/35 (5.7%)	6
Neutrophil count decreased	21/35 (60%)	128
Platelet count decreased	24/35 (68.6%)	207
Metabolism and nutrition disorders
Anorexia	1/35 (2.9%)	1
Blood uric acid increased	1/35 (2.9%)	1
Serum albumin decreased	2/35 (5.7%)	3
Serum calcium decreased	2/35 (5.7%)	3
Serum calcium increased	1/35 (2.9%)	1
Serum potassium decreased	1/35 (2.9%)	1
Musculoskeletal and connective tissue disorders
Bone pain	1/35 (2.9%)	2
Muscle weakness	8/35 (22.9%)	10
Muscle weakness lower limb	2/35 (5.7%)	2
Myalgia	2/35 (5.7%)	2
Nervous system disorders
Cognitive disturbance	10/35 (28.6%)	56
Memory impairment	1/35 (2.9%)	1
Peripheral motor neuropathy	9/35 (25.7%)	52
Peripheral sensory neuropathy	20/35 (57.1%)	176
Syncope	4/35 (11.4%)	6
Psychiatric disorders
Anxiety	2/35 (5.7%)	3
Depression	3/35 (8.6%)	8
Insomnia	10/35 (28.6%)	22
Renal and urinary disorders
Cystitis	6/35 (17.1%)	7
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/35 (2.9%)	1
Pleural effusion	2/35 (5.7%)	5
Skin and subcutaneous tissue disorders
Rash desquamating	13/35 (37.1%)	29
Vascular disorders
Hypertension	1/35 (2.9%)	1
Hypotension	1/35 (2.9%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.