Bortezomib and Dexamethasone Followed by High-Dose Melphalan and Stem Cell Transplantation for Primary (AL) Amyloidosis

• Sponsor: Boston Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01083316
• Collaborator: Millennium Pharmaceuticals, Inc. (Industry)
• Enrollment: 35
• Location: 1
• Arm: 1
• Actual Duration (Months): 132.1
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The drugs dexamethasone and bortezomib are both FDA-approved for the treatment of multiple myeloma, a disease very similar to amyloidosis. However, they are currently investigational for the treatment of amyloidosis.

We want to find out if the addition of dexamethasone and bortezomib to standard high dose chemotherapy and stem cell transplant can help improve response.

Standard treatment includes four steps: 1) Stem Cell Mobilization (standard) 2) Stem Cell Collection (standard) 3) Conditioning Regimen (Melphalan chemotherapy). The conditioning regimen helps to kill the abnormal cells in the body and makes room in the bone marrow for new blood stem cells to grow. 4) Stem Cell Infusion

Participants in this study will have an additional treatment step called "induction therapy", designed as the first step towards reducing the number of abnormal cells in the body. Two cycles of the investigational drugs bortezomib and dexamethasone will be given during induction therapy. In addition, bortezomib will given as part of the conditioning regimen, in addition to the standard melphalan chemotherapy.

Condition or Disease	Intervention/Treatment	Phase
Amyloidosis	Drug: Bortezomib; Drug: Dexamethasone; Drug: Melphalan	Phase 2

Detailed Description

The drugs dexamethasone and bortezomib are both FDA-approved drugs for the treatment of multiple myeloma, a disease very similar to amyloidosis. However, they are currently investigational for the treatment of amyloidosis.

The investigators want to find out if the addition of dexamethasone and bortezomib to standard treatment of high dose chemotherapy and stem cell transplant can help improve response to treatment.

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: Phase II Trial of Induction Therapy With Bortezomib and Dexamethasone Followed by High-Dose Melphalan and Stem Cell Transplantation in Patients With AL Amyloidosis
• Actual Study Start Date: Sep 1, 2009
• Actual Primary Completion Date: Aug 1, 2013
• Actual Study Completion Date: Sep 4, 2020

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Single Arm - Investigational Induction: Bortezomib (Velcade) 1.3 mg/m2/dose IV Days 1, 4, 8, 11 repeated every 21 days Dexamethasone 20 mg PO/IV Days 1, 4, 8, 11 repeated every 21 days Conditioning: Bortezomib 1.0 mg/m2/dose will be administered on Days +6, -3, +1, + 4 Melphalan 70-100 mg/m2/day IV on days -2 and -1

Drug: Bortezomib; Induction: Velcade 1.3 mg/m2/dose IV Days 1, 4, 8, 11 repeated every 21 days Conditioning: Bortezomib 1.0 mg/m2/dose will be administered on Days +6, -3, +1, + 4; Other Names: Velcade ; Drug: Dexamethasone; Induction: Dexamethasone 20 mg PO/IV Days 1, 4, 8, 11 repeated every 21 days; Other Names: Decadron ; Drug: Melphalan; Conditioning: Melphalan 70-100 mg/m2/day IV on days -2 and -1; Other Names: Alkeran

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Disease Response [One year]

   Complete response: Normal serum free light chain ratio and Negative serum and urine immunofixation electrophoresis Very good partial response: Difference in serum free light chains less than 40 mg/L Partial Response: >50% Reduction in the difference in serum free light chains

2. Number of Participants Surviving at 100 Days Post Transplant [100 days]

3. Number of Participants Proceeding to Transplant Following Induction [2 months]

Secondary Outcome Measures

1. Number of Participants Surviving at 5 Years [5 years]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histological diagnosis of primary systemic (AL) amyloidosis based on:

1. Deposition of amyloid material by congo red stain showing characteristic green birefringence, and

2. monoclonal light chain protein in the serum or urine or immunohistochemical studies or serum free light chain assay and

3. evidence of tissue involvement other than carpal tunnel syndrome, i.e. positive immunohistochemical staining of bone marrow demonstrating clonal plasma cells; or tissue amyloid deposits with anti-kappa or anti-lambda anti-serum; evidence for a plasma cell dyscrasia (PCD) by serum/urine or bone marrow; or overwhelmingly convincing clinical features e.g. macroglossia, associated with other systemic manifestations.

Note: Patients with senile, secondary, localized, dialysis-related or familial amyloidosis are not eligible. Confirmation of tissue diagnosis at all sites of organ dysfunction is encouraged, but not required.

• Must be at least 18 years of age.

• Must have a performance status of 0-2 by Southwest Oncology Group criteria

• Must have left ventricular ejection fraction (LVEF) at least 45% by echocardiogram within 60 days of enrollment

• Prior chemotherapy with alkylating agent allowed only if no evidence of Myelodysplastic Dysplastic Syndrome (MDS) morphologically or cytogenetically. Total cumulative dose of oral melphalan must be less than 300 mg. Patients should not have received any cytotoxic therapy less than 4 weeks prior to registration and should have fully recovered from the effects of such therapy.

• Pulmonary Function Tests must show Diffusing capacity of the lungs for carbon monoxide (DLCO) at least 50%.

• Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.

• Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study.

• Male subject agrees to use an acceptable method for contraception for the duration of the study.

Exclusion Criteria:

• No overt multiple myeloma (over 30% bone marrow plasmacytosis, extensive (great than

1. lytic lesions, hypercalcemia).

• No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for 3 years.

• No known to be HIV positive.

• No platelet count of less than or equal to 70,000 within 14 days before enrollment.

• No absolute neutrophil count of less than or equal to 1000 within 14 days before enrollment.

• No greater than or equal to Grade 2 peripheral neuropathy within 14 days before enrollment.

• No myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure (see section 8.4), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant.

• No hypersensitivity to bortezomib, boron or mannitol.

• No pregnant or breast-feeding females. Confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotropin (beta-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women.

• Must not have received other investigational drugs with 14 days before enrollment

• No serious medical or psychiatric illness likely to interfere with participation in this clinical study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Boston Medical Center	Boston	Massachusetts	United States	02118

Sponsors and Collaborators

• Boston Medical Center
• Millennium Pharmaceuticals, Inc.

Investigators

• Principal Investigator: Vaishali Sanchorawala, MD, Boston Medical Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Boston Medical Center Active Clinical Trials

Publications

None provided.

• Responsible Party: Boston Medical Center
• ClinicalTrials.gov Identifier: NCT01083316
• Other Study ID Numbers: H-28441; X05292
• First Posted: Mar 9, 2010
• Last Update Posted: Sep 25, 2020
• Last Verified: Sep 1, 2020

• 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
• Product Manufactured in and Exported from the U.S.: Yes
• Keywords provided by Boston Medical Center: Amyloid; Amyloidosis; AL Amyloidosis; Primary Amyloidosis; Stem Cell Transplant
• Additional relevant MeSH terms: Amyloidosis; Dexamethasone; Bortezomib; Melphalan

Study Results

Participant Flow

Arm/Group Title	Bortezomib and Dexamethasone
Arm/Group Description	Induction: Bortezomib (Velcade) 1.3 mg/m2/dose IV Days 1, 4, 8, 11 repeated every 21 days Dexamethasone 20 mg PO/IV Days 1, 4, 8, 11 repeated every 21 days Conditioning: Bortezomib 1.0 mg/m2/dose will be administered on Days +6, -3, +1, + 4 Melphalan 70-100 mg/m2/day IV on days -2 and -1 Bortezomib (Velcade) and Dexamethasone: Induction: Velcade 1.3 mg/m2/dose IV Days 1, 4, 8, 11 repeated every 21 days Dexamethasone 20 mg PO/IV Days 1, 4, 8, 11 repeated every 21 days Conditioning: Bortezomib 1.0 mg/m2/dose will be administered on Days +6, -3, +1, + 4 Melphalan 70-100 mg/m2/day IV on days -2 and -1
Period Title: Overall Study
STARTED	35
COMPLETED	32
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Bortezomib and Dexamethasone
Arm/Group Description	Induction: Bortezomib (Velcade) 1.3 mg/m2/dose intravenous (IV) Days 1, 4, 8, 11 repeated every 21 days Dexamethasone 20 mg PO/IV Days 1, 4, 8, 11 repeated every 21 days Conditioning: Bortezomib 1.0 mg/m2/dose will be administered on Days +6, -3, +1, + 4 Melphalan 70-100 mg/m2/day IV on days -2 and -1 Bortezomib (Velcade) and Dexamethasone: Induction: Velcade 1.3 mg/m2/dose IV Days 1, 4, 8, 11 repeated every 21 days Dexamethasone 20 mg PO/IV Days 1, 4, 8, 11 repeated every 21 days Conditioning: Bortezomib 1.0 mg/m2/dose will be administered on Days +6, -3, +1, + 4 Melphalan 70-100 mg/m2/day IV on days -2 and -1
Overall Participants	35
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	30 85.7%
>=65 years	5 14.3%
Sex: Female, Male (Count of Participants)
Female	22 62.9%
Male	13 37.1%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Disease Response
Description	Complete response: Normal serum free light chain ratio and Negative serum and urine immunofixation electrophoresis Very good partial response: Difference in serum free light chains less than 40 mg/L Partial Response: >50% Reduction in the difference in serum free light chains
Time Frame	One year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bortezomib and Dexamethasone
Arm/Group Description	Induction: Bortezomib (Velcade) 1.3 mg/m2/dose IV Days 1, 4, 8, 11 repeated every 21 days Dexamethasone 20 mg PO/IV Days 1, 4, 8, 11 repeated every 21 days Conditioning: Bortezomib 1.0 mg/m2/dose will be administered on Days +6, -3, +1, + 4 Melphalan 70-100 mg/m2/day IV on days -2 and -1 Bortezomib (Velcade) and Dexamethasone: Induction: Velcade 1.3 mg/m2/dose IV Days 1, 4, 8, 11 repeated every 21 days Dexamethasone 20 mg PO/IV Days 1, 4, 8, 11 repeated every 21 days Conditioning: Bortezomib 1.0 mg/m2/dose will be administered on Days +6, -3, +1, + 4 Melphalan 70-100 mg/m2/day IV on days -2 and -1
Measure Participants	26
Count of Participants [Participants]	20 57.1%

2. Primary Outcome

Title	Number of Participants Surviving at 100 Days Post Transplant
Time Frame	100 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bortezomib and Dexamethasone
Arm/Group Description	Induction: Bortezomib (Velcade) 1.3 mg/m2/dose IV Days 1, 4, 8, 11 repeated every 21 days Dexamethasone 20 mg PO/IV Days 1, 4, 8, 11 repeated every 21 days Conditioning: Bortezomib 1.0 mg/m2/dose will be administered on Days +6, -3, +1, + 4 Melphalan 70-100 mg/m2/day IV on days -2 and -1 Bortezomib (Velcade) and Dexamethasone: Induction: Velcade 1.3 mg/m2/dose IV Days 1, 4, 8, 11 repeated every 21 days Dexamethasone 20 mg PO/IV Days 1, 4, 8, 11 repeated every 21 days Conditioning: Bortezomib 1.0 mg/m2/dose will be administered on Days +6, -3, +1, + 4 Melphalan 70-100 mg/m2/day IV on days -2 and -1
Measure Participants	30
Count of Participants [Participants]	27 77.1%

3. Primary Outcome

Title	Number of Participants Proceeding to Transplant Following Induction
Time Frame	2 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bortezomib and Dexamethasone
Arm/Group Description	Induction: Bortezomib (Velcade) 1.3 mg/m2/dose IV Days 1, 4, 8, 11 repeated every 21 days Dexamethasone 20 mg PO/IV Days 1, 4, 8, 11 repeated every 21 days Conditioning: Bortezomib 1.0 mg/m2/dose will be administered on Days +6, -3, +1, + 4 Melphalan 70-100 mg/m2/day IV on days -2 and -1 Bortezomib (Velcade) and Dexamethasone: Induction: Velcade 1.3 mg/m2/dose IV Days 1, 4, 8, 11 repeated every 21 days Dexamethasone 20 mg PO/IV Days 1, 4, 8, 11 repeated every 21 days Conditioning: Bortezomib 1.0 mg/m2/dose will be administered on Days +6, -3, +1, + 4 Melphalan 70-100 mg/m2/day IV on days -2 and -1
Measure Participants	35
Count of Participants [Participants]	30 85.7%

4. Secondary Outcome

Title	Number of Participants Surviving at 5 Years
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

number of patients that completed at least one cycle of induction therapy

Arm/Group Title	Bortezomib and Dexamethasone
Arm/Group Description	Induction: Bortezomib (Velcade) 1.3 mg/m2/dose IV Days 1, 4, 8, 11 repeated every 21 days Dexamethasone 20 mg PO/IV Days 1, 4, 8, 11 repeated every 21 days Conditioning: Bortezomib 1.0 mg/m2/dose will be administered on Days +6, -3, +1, + 4 Melphalan 70-100 mg/m2/day IV on days -2 and -1 Bortezomib: Induction: Velcade 1.3 mg/m2/dose IV Days 1, 4, 8, 11 repeated every 21 days Conditioning: Bortezomib 1.0 mg/m2/dose will be administered on Days +6, -3, +1, + 4 Dexamethasone: Induction: Dexamethasone 20 mg PO/IV Days 1, 4, 8, 11 repeated every 21 days Melphalan: Conditioning: Melphalan 70-100 mg/m2/day IV on days -2 and -1
Measure Participants	35
Count of Participants [Participants]	29 82.9%

Adverse Events

Time Frame	100 days
Arm/Group Title	Bortezomib and Dexamethasone
Arm/Group Description	Induction: Bortezomib (Velcade) 1.3 mg/m2/dose IV Days 1, 4, 8, 11 repeated every 21 days Dexamethasone 20 mg PO/IV Days 1, 4, 8, 11 repeated every 21 days Conditioning: Bortezomib 1.0 mg/m2/dose will be administered on Days +6, -3, +1, + 4 Melphalan 70-100 mg/m2/day IV on days -2 and -1 Bortezomib (Velcade) and Dexamethasone: Induction: Velcade 1.3 mg/m2/dose IV Days 1, 4, 8, 11 repeated every 21 days Dexamethasone 20 mg PO/IV Days 1, 4, 8, 11 repeated every 21 days Conditioning: Bortezomib 1.0 mg/m2/dose will be administered on Days +6, -3, +1, + 4 Melphalan 70-100 mg/m2/day IV on days -2 and -1
All Cause Mortality
	Bortezomib and Dexamethasone
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Bortezomib and Dexamethasone
	Affected / at Risk (%)	# Events
Total	35/35 (100%)
Blood and lymphatic system disorders
neutropenic fever	7/35 (20%)	7
Epstein Barr Virus-related Polymorphous Post Transplant Lymphoproliferative disorder	1/35 (2.9%)	1
thrombocytopenia	1/35 (2.9%)	1
Cardiac disorders
cardiac arrest	1/35 (2.9%)	1
Gastrointestinal disorders
diarrhea	15/35 (42.9%)	15
gastrointestinal bleed	1/35 (2.9%)	1
hemorrhoidal hemmorhage	1/35 (2.9%)	1
General disorders
fever	7/35 (20%)
fatigue	18/35 (51.4%)	18
multiorgan failure	1/35 (2.9%)	1
nausea	6/35 (17.1%)	6
Immune system disorders
autograft versus host disease	2/35 (5.7%)	2
Infections and infestations
invasive aspirgillosis	1/35 (2.9%)	1
sepsis	4/35 (11.4%)	4
stomatitis	1/35 (2.9%)	1
Investigations
creatinine increased	1/35 (2.9%)	1
Nervous system disorders
syncope	8/35 (22.9%)	9
Dizziness	2/35 (5.7%)	2
Renal and urinary disorders
Acute kidney failure	3/35 (8.6%)	3
Respiratory, thoracic and mediastinal disorders
Adult Respiratory Distress Syndrome	1/35 (2.9%)	1
epistaxis	1/35 (2.9%)	1
Skin and subcutaneous tissue disorders
skin rash	3/35 (8.6%)	3
Vascular disorders
hypotension	11/35 (31.4%)	11
Other (Not Including Serious) Adverse Events
	Bortezomib and Dexamethasone
	Affected / at Risk (%)	# Events
Total	35/35 (100%)
Blood and lymphatic system disorders
drug rash	3/35 (8.6%)	3
petechiae	4/35 (11.4%)	4
Cardiac disorders
sinus tachycardia	16/35 (45.7%)	16
Ear and labyrinth disorders
tinnitus	2/35 (5.7%)	2
Endocrine disorders
adrenal insufficiency	4/35 (11.4%)	4
Eye disorders
Blurred vision	7/35 (20%)	7
Gastrointestinal disorders
nausea	15/35 (42.9%)	15
diarrhea	14/35 (40%)	14
constipation	13/35 (37.1%)	13
anorexia	5/35 (14.3%)	5
abdominal distension	4/35 (11.4%)	4
Abdominal pain	3/35 (8.6%)	3
oral mucositis	3/35 (8.6%)	3
General disorders
peripheral edema	5/35 (14.3%)	5
Investigations
alkaline phosphatase elevated	4/35 (11.4%)	4
Musculoskeletal and connective tissue disorders
muscle weakness	5/35 (14.3%)	5
Bone pain	12/35 (34.3%)	14
Nervous system disorders
dizziness	4/35 (11.4%)	6
anxiety	7/35 (20%)	12
Respiratory, thoracic and mediastinal disorders
dyspnea	10/35 (28.6%)	10
cough	6/35 (17.1%)	7
Skin and subcutaneous tissue disorders
alopecia	14/35 (40%)	14
rash	7/35 (20%)	7
Vascular disorders
hypotension	8/35 (22.9%)	8

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.