A Pilot Study of Lenalidomide, Melphalan and Dexamethasone in AL Amyloidosis

• Sponsor: Stanford University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00890552
• Collaborator: Celgene Corporation (Industry)
• Enrollment: 25
• Location: 1
• Arm: 1
• Duration (Months): 42
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

This open-label trial will evaluate the use of lenalidomide; melphalan; and dexamethasone (MDR) to treat newly diagnosed or relapsed AL amyloidosis, over the course of nine 28-day cycles.

Condition or Disease	Intervention/Treatment	Phase
Leukemia; Amyloidosis	Drug: Lenalidomide; Drug: Melphalan; Drug: Dexamethasone	N/A

Detailed Description

The study will evaluate the 3-drug combination of lenalidomide; melphalan; and dexamethasone (MDR) as the absence of disease progression or toxicity, patients will complete nine 28-day cycles of MDR therapy, with the option of continuing treatment with lenalidomide as single-agent. Patients received up to nine cycles of treatment, with the option to continue on lenalidomide as a single agent if they responded to treatment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot Study of Lenalidomide, Melphalan and Dexamethasone in AL Amyloidosis
• Study Start Date: Apr 1, 2009
• Actual Primary Completion Date: Aug 1, 2012
• Actual Study Completion Date: Oct 1, 2012

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Lenalidomide+Melphalan+Dexamethasone Patients received lenalidomide 10 mg/day orally on days 1-21, melphalan 0.18 mg/kg orally on days 1-4, and dexamethasone 40 mg orally once weekly of a 28-day cycle (MDR treatment).

Drug: Lenalidomide; Lenalidomide is a a derivative of thalidomide. Orally-administered lenalidomide 10 mg will be taken daily on days 1 to 21 of 28-day cycle.; Other Names: Revlimid L04AX04 ; Drug: Melphalan; Melphalan is a phenylalanine derivative of mechlorethamine. Orally-administered melphalan 0.18 mg/kg will be taken on days 1 to 4 of a 28-day cycle; Other Names: Alkeran Evomela Sarcolysin L-phenylalanine mustard (L-PAM) 4-[Bis(2-chloroethyl)amino]-L-phenylalanine ; Drug: Dexamethasone; Dexamethasone is an anti-inflammatory and immunosuppressant steroid medication. Orally-administered dexamethasone 40 mg orally once weekly of a 28-day cycle; Other Names: Intensol Decadron Baycadron Dexpak® Taperpak Maxidex (dexamethasone ophthalmic suspension) Ozurdex (dexamethasone intravitreal implant)

Outcome Measures

Primary Outcome Measures

1. Hematologic Response Rate [8 weeks]

   At the end of each treatment cycle (4 weeks), hematologic response rate as assessed. Hematologic response was considered to be amyloid complete response (normal FLC ratio and negative serum and urine immunofixation); very good partial response (difference between involved and uninvolved FLCs [dFLC] < 40 mg/L); or partial response (dFLC decrease > 50%).

Secondary Outcome Measures

1. Overall Survival (OS) [12 months]

   Participants alive 12 months after starting MDR treatment.

2. Event-free Survival (EFS) [12 months]

   Assessed as the median value for EFS 12 months after starting MDR treatment

3. Duration of Response [32 months]

   Assessed as the median value for the time from first partial response until progression; death; or last follow-up.

Eligibility Criteria

Criteria

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

INCLUSION CRITERIA

• Newly diagnosed or relapsed AL amyloidosis

• Biopsy-proven amyloidosis with evidence of an underlying plasma cell dyscrasia

• abnormal clonal dominance of plasma cells in the bone marrow

• detection of a monoclonal gammopathy by immunofixation electrophoresis of serum and/or urine

• an abnormal serum free light chain or ratio, or AL fibrils seen on biopsy)

• Measurable disease defined by an abnormal serum-free light chain or monoclonal protein by immunofixation

• proteinuria ≥ 0.5 g/day, cardiac involvement with interventricular septal thickness ≥ 15 mm

• hepatomegaly in the absence of congestive heart failure with elevated alkaline phosphatase

• Age ≥ 18 years at the time of signing the informed consent form.

• All previous cancer therapy must have been discontinued at least 4 weeks prior to treatment in this study

• ECOG performance status of ≤ 3 at study entry

• Laboratory test results:

• Absolute neutrophil count ≥ 1.0 x 10e9 / L

• Platelet count ≥ 75 x 10e9 / L

• Creatinine clearance ≥ 15 mL/ minute

• Total bilirubin ≤ 2-fold upper limits of normal

• Disease-free of prior malignancies (excluding multiple myeloma) for ≥ 3 years with exception of:

• currently treated basal cell

• squamous cell carcinoma of the skin

• carcinoma "in situ" of the cervix or breast.

• Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test

• Females of childbearing potential must either:

• commit to continued abstinence from heterosexual intercourse

• acceptable methods of birth control and agree to ongoing pregnancy testing

• Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy

• All study participants must be registered into the mandatory RevAssist program, and able to comply with its requirements

• Able to take aspirin (81 mg) daily • Understand and voluntarily sign an informed consent form

• Able to adhere to the study visit schedule and other protocol requirements

EXCLUSION CRITERIA

• Any serious medical condition that would prevent the subject from signing the informed consent form

• Pregnant

• breast-feeding females

• Use of any other experimental drug or therapy within 28 days of baseline

• Known hypersensitivity to thalidomide

• Erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs

• Any prior use of lenalidomide

• Concurrent use of other anti-cancer agents or treatments

• Known positivity for human immunodeficiency virus HIV)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University Cancer Institute	Stanford	California	United States	94305

Sponsors and Collaborators

• Stanford University
• Celgene Corporation

Investigators

• Principal Investigator: Stanley L Schrier, MD, Stanford University

Study Documents (Full-Text)

None provided.

More Information

Publications

• Palladini G, Dispenzieri A, Gertz MA, Kumar S, Wechalekar A, Hawkins PN, Schönland S, Hegenbart U, Comenzo R, Kastritis E, Dimopoulos MA, Jaccard A, Klersy C, Merlini G. New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes. J Clin Oncol. 2012 Dec 20;30(36):4541-9. doi: 10.1200/JCO.2011.37.7614. Epub 2012 Oct 22.

• Responsible Party: Stanley L Schrier, Professor of Medicine, Stanford University
• ClinicalTrials.gov Identifier: NCT00890552
• Other Study ID Numbers: IRB-15213; RV-AMYL-PI-0375; SU-09192008-1300; HEM0010
• First Posted: Apr 30, 2009
• Last Update Posted: Mar 22, 2017
• Last Verified: Feb 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Immunoglobulin Light-chain Amyloidosis; Amyloidosis; Dexamethasone; Dexamethasone acetate; Lenalidomide; Melphalan; BB 1101

Study Results

Participant Flow

Arm/Group Title	Lenalidomide, Melphalan and Dexamethasone (MDR)
Arm/Group Description	The 3-drug combination of orally-administered lenalidomide; melphalan; and dexamethasone (MDR) will be administered as nine 28-day cycles, with the option of continuing treatment with lenalidomide as single-agent. Lenalidomide: Orally-administered lenalidomide 10 mg will be taken daily on days 1 to 21 of 28-day cycle. Lenalidomide is a a derivative of thalidomide. Melphalan: Orally-administered melphalan 0.18 mg/kg will be taken on days 1 to 4 of a 28-day cycle. Melphalan is a phenylalanine derivative of mechlorethamine. Dexamethasone: Orally-administered dexamethasone 40 mg will be taken on days 1; 8; 15; and 22 of a 28-day cycle. Dexamethasone is an anti-inflammatory and immunosuppressant steroid medication.
Period Title: Enrollment and Pre-treatment
STARTED	25
COMPLETED	24
NOT COMPLETED	1
Period Title: Enrollment and Pre-treatment
STARTED	24
COMPLETED	14
NOT COMPLETED	10

Baseline Characteristics

Arm/Group Title	Lenalidomide, Melphalan and Dexamethasone (MDR)
Arm/Group Description	The 3-drug combination of orally-administered lenalidomide; melphalan; and dexamethasone (MDR) will be administered as nine 28-day cycles, with the option of continuing treatment with lenalidomide as single-agent.
Overall Participants	25
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	67
Sex: Female, Male (Count of Participants)
Female	9 36%
Male	16 64%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 8%
Not Hispanic or Latino	21 84%
Unknown or Not Reported	2 8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 4%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	23 92%
More than one race	0 0%
Unknown or Not Reported	1 4%
ECOG Performance Status (PS) (participants) [Number]
ECOG PS 1	12 48%
ECOG PS 2	9 36%
ECOG PS 3	4 16%
Hematologic disease burden (Percentage of participants) [Number]
Kappa free light chain (%)	20 80%
Lambda free light chain (%)	80 320%

Outcome Measures

1. Primary Outcome

Title	Hematologic Response Rate
Description	At the end of each treatment cycle (4 weeks), hematologic response rate as assessed. Hematologic response was considered to be amyloid complete response (normal FLC ratio and negative serum and urine immunofixation); very good partial response (difference between involved and uninvolved FLCs [dFLC] < 40 mg/L); or partial response (dFLC decrease > 50%).
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Subjects completing at least one full cycle of study treatment

Arm/Group Title	Lenalidomide, Melphalan and Dexamethasone (MDR)
Arm/Group Description	The 3-drug combination of orally-administered lenalidomide; melphalan; and dexamethasone (MDR) will be administered as nine 28-day cycles, with the option of continuing treatment with lenalidomide as single-agent. Lenalidomide: Orally-administered lenalidomide 10 mg will be taken daily on days 1 to 21 of 28-day cycle. Lenalidomide is a a derivative of thalidomide. Melphalan: Orally-administered melphalan 0.18 mg/kg will be taken on days 1 to 4 of a 28-day cycle. Melphalan is a phenylalanine derivative of mechlorethamine. Dexamethasone: Orally-administered dexamethasone 40 mg will be taken on days 1; 8; 15; and 22 of a 28-day cycle. Dexamethasone is an anti-inflammatory and immunosuppressant steroid medication.
Measure Participants	24
Complete Response (CR)	2 8%
Very good Partial Response (VGPR)	4 16%
Partial Response (PR)	8 32%
No Response (NR)	9 36%
Response not evaluable	1 4%

2. Secondary Outcome

Title	Overall Survival (OS)
Description	Participants alive 12 months after starting MDR treatment.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

All subjects receiving MDR treatment.

Arm/Group Title	Lenalidomide, Melphalan and Dexamethasone (MDR)
Arm/Group Description	The 3-drug combination of orally-administered lenalidomide; melphalan; and dexamethasone (MDR) will be administered as nine 28-day cycles, with the option of continuing treatment with lenalidomide as single-agent. Lenalidomide: Orally-administered lenalidomide 10 mg will be taken daily on days 1 to 21 of 28-day cycle. Lenalidomide is a a derivative of thalidomide. Melphalan: Orally-administered melphalan 0.18 mg/kg will be taken on days 1 to 4 of a 28-day cycle. Melphalan is a phenylalanine derivative of mechlorethamine. Dexamethasone: Orally-administered dexamethasone 40 mg will be taken on days 1; 8; 15; and 22 of a 28-day cycle. Dexamethasone is an anti-inflammatory and immunosuppressant steroid medication.
Measure Participants	24
Number [percentage of participants]	58 232%

3. Secondary Outcome

Title	Event-free Survival (EFS)
Description	Assessed as the median value for EFS 12 months after starting MDR treatment
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

All participants starting MDR treatment

Arm/Group Title	Lenalidomide, Melphalan and Dexamethasone (MDR)
Arm/Group Description	The 3-drug combination of orally-administered lenalidomide; melphalan; and dexamethasone (MDR) will be administered as nine 28-day cycles, with the option of continuing treatment with lenalidomide as single-agent. Lenalidomide: Orally-administered lenalidomide 10 mg will be taken daily on days 1 to 21 of 28-day cycle. Lenalidomide is a a derivative of thalidomide. Melphalan: Orally-administered melphalan 0.18 mg/kg will be taken on days 1 to 4 of a 28-day cycle. Melphalan is a phenylalanine derivative of mechlorethamine. Dexamethasone: Orally-administered dexamethasone 40 mg will be taken on days 1; 8; 15; and 22 of a 28-day cycle. Dexamethasone is an anti-inflammatory and immunosuppressant steroid medication.
Measure Participants	14
Median (Full Range) [months]	3.15

4. Secondary Outcome

Title	Duration of Response
Description	Assessed as the median value for the time from first partial response until progression; death; or last follow-up.
Time Frame	32 months

Outcome Measure Data

Analysis Population Description

All participants who achieved at least a partial response (9 subjects were not included due to not having any response)

Arm/Group Title	Lenalidomide, Melphalan and Dexamethasone (MDR)
Arm/Group Description	The 3-drug combination of orally-administered lenalidomide; melphalan; and dexamethasone (MDR) will be administered as nine 28-day cycles, with the option of continuing treatment with lenalidomide as single-agent. Lenalidomide: Orally-administered lenalidomide 10 mg will be taken daily on days 1 to 21 of 28-day cycle. Lenalidomide is a a derivative of thalidomide. Melphalan: Orally-administered melphalan 0.18 mg/kg will be taken on days 1 to 4 of a 28-day cycle. Melphalan is a phenylalanine derivative of mechlorethamine. Dexamethasone: Orally-administered dexamethasone 40 mg will be taken on days 1; 8; 15; and 22 of a 28-day cycle. Dexamethasone is an anti-inflammatory and immunosuppressant steroid medication.
Measure Participants	14
Median (Full Range) [months]	9.1

Adverse Events

Time Frame	12 months
Arm/Group Title	Lenalidomide, Melphalan and Dexamethasone (MDR)
Arm/Group Description	The 3-drug combination of orally-administered lenalidomide; melphalan; and dexamethasone (MDR) will be administered as nine 28-day cycles, with the option of continuing treatment with lenalidomide as single-agent.
All Cause Mortality
	Lenalidomide, Melphalan and Dexamethasone (MDR)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Lenalidomide, Melphalan and Dexamethasone (MDR)
	Affected / at Risk (%)	# Events
Total	19/25 (76%)
Blood and lymphatic system disorders
Anemia in Neoplastic disease	1/25 (4%)
Edema	1/25 (4%)
Neutrophils/granulocytes	1/25 (4%)
Hypoglycemia	1/25 (4%)
Hypovolemia	1/25 (4%)
Cardiac disorders
Atrial fibrillation	4/25 (16%)
Ventricular tachycardia	1/25 (4%)
Atrial flutter	1/25 (4%)
Bradycardia	1/25 (4%)
Gastrointestinal disorders
Hemorrhage	2/25 (8%)
Dehydration	2/25 (8%)
Constipation	1/25 (4%)
General disorders
Death	7/25 (28%)
Syncope	4/25 (16%)
Infections and infestations
Febrile neutropenia	1/25 (4%)
Pneumonia	1/25 (4%)
Metabolism and nutrition disorders
Hyponatremia	3/25 (12%)
Primary Amyloidosis	1/25 (4%)
Renal failure	1/25 (4%)
Psychiatric disorders
Altered mental status	1/25 (4%)
Other (Not Including Serious) Adverse Events
	Lenalidomide, Melphalan and Dexamethasone (MDR)
	Affected / at Risk (%)	# Events
Total	23/25 (92%)
Blood and lymphatic system disorders
Bone and Blood Marrow	5/25 (20%)
Hypocalcemia	3/25 (12%)
Hemolysis	6/25 (24%)
INR	2/25 (8%)
Leukocytes	2/25 (8%)
Neutrophils/granulocytes	4/25 (16%)
Platelets	18/25 (72%)
Coagulation	1/25 (4%)
Edema: head and neck	1/25 (4%)
Edema: trunk/genital	1/25 (4%)
Lymphatics	1/25 (4%)
Cardiac disorders
Hypotension	3/25 (12%)
Thrombotic microangiopathy	2/25 (8%)
Sinus arrhythmia	2/25 (8%)
Sinus bradycardia	1/25 (4%)
Ear and labyrinth disorders
Auditory/Ear	1/25 (4%)
Hearing loss	1/25 (4%)
Eye disorders
Vision-blurred	2/25 (8%)
Dry eye syndrome	1/25 (4%)
Ocular/Visual	1/25 (4%)
Gastrointestinal disorders
Anorexia	4/25 (16%)
Constipation	6/25 (24%)
Diarrhea	5/25 (20%)
Distension/bloating	3/25 (12%)
Dry mouth	3/25 (12%)
Gastrointestinal	8/25 (32%)
Nausea	3/25 (12%)
Vomitting	2/25 (8%)
weight loss	5/25 (20%)
Ascites (non-malignant)	1/25 (4%)
Dysphagia	1/25 (4%)
General disorders
Fatigue	16/25 (64%)
Fever	5/25 (20%)
Insomnia	4/25 (16%)
Mood alteration- Anxiety	3/25 (12%)
Pain	12/25 (48%)
Dehydration	1/25 (4%)
Rigors/chills	1/25 (4%)
dysarthria	1/25 (4%)
Hepatobiliary disorders
Hematoma	2/25 (8%)
Hemoglobin	2/25 (8%)
Infections and infestations
Edema: limbs	11/25 (44%)
Infection	11/25 (44%)
abscess	1/25 (4%)
Metabolism and nutrition disorders
Hypoalbuminemia	2/25 (8%)
Creatinine	3/25 (12%)
Hyperglycemia	3/25 (12%)
Hypokalemia	4/25 (16%)
Hyponatremia	5/25 (20%)
Alkaline phosphatase	1/25 (4%)
AST, SGOT	1/25 (4%)
Hyperbilirubinemia	1/25 (4%)
Musculoskeletal and connective tissue disorders
Muscle weakness	2/25 (8%)
Nervous system disorders
Dizziness	7/25 (28%)
Neuropathy: sensory	6/25 (24%)
Neuropathy: motor	1/25 (4%)
Psychiatric disorders
Depression	1/25 (4%)
Renal and urinary disorders
Cystitis	1/25 (4%)
Dysuria	1/25 (4%)
Respiratory, thoracic and mediastinal disorders
Cough	2/25 (8%)
Dysphagia	10/25 (40%)
Skin and subcutaneous tissue disorders
Dermatology	2/25 (8%)
Rash/desquamation	11/25 (44%)
Dry skin	1/25 (4%)
Alopecia	1/25 (4%)
Petechiae/purpura	1/25 (4%)
Sweating	1/25 (4%)
Wound complication	1/25 (4%)

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.