Amyloidosis, Light Chain and Heavy Chain Deposition Disease (LHCDD or MIDD), Light Chain Deposition Disease (LCDD or MIDD), Monoclonal Immunoglobulin Deposition Disease (MIDD)
Conditions
Keywords
BORTEZOMIB (VELCADE), CYCLOPHOSPHAMIDE (CYTOXAN), DEXAMETHASONE, MELPHALAN, 11-061
Brief summary
The goal of this clinical trial is to determine the toxicity and also the efficacy of a treatment that includes the following treatment: Two medications, bortezomib and dexamethasone (or BD), followed by autologous stem cell transplantation, and a prolonged course of treatment with bortezomib and dexamethasone after transplantation. This type of treatment has been very effective in multiple myeloma. However, there is little experience with this treatment in patients who have Monoclonal Immunoglobulin Deposition Disease (MIDD) or amyloidosis. The investigators and others have treated patients who have MIDD and amyloidosis with bortezomib and autologous stem cell transplantation and have had success with this treatment. But the combination of autologous transplant with BD given before and after the transplant is a new way of treating these diseases, which the investigators believe will be very effective.
Interventions
DRUGBortezomib/Dexamethasone (BD), Followed By Autologous STC & Maintenance Bortezomib/Dexamethasone
The treatment has three phases: 1\) Initial treatment phase: This phase consists of 1-3 21-day-cycles of a combination regimen that includes bortezomib 1.3 mg/m2, IV or Subcutaneous Injection (SQ), on days 1, 4, 8, and 11; and dexamethasone 40 mg PO or IV, on days 1, 4, 8, and 11. Stem cell mobilization and HDM/ASCT. Post-ASCT consolidation/maintenance treatment phase: This phase consists of six cycles of bortezomib 1.3 mg/m2, IV or (SQ) with dexamethasone 20 mg PO or IV administered on days 1, 8, 15, and 22 every 12 weeks +/- 2 weeks. Long Term Follow Up will cease when all patients on study have fulfilled the requirements for at least five follow up appointments.
Sponsors
Millennium Pharmaceuticals, Inc.
Memorial Sloan Kettering Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age \> or = to 18 * New diagnosis of MIDD or AL amyloidosis based on pathologic findings confirmed at Memorial Sloan Kettering Cancer Center. * Patients must show the ability to understand the investigational nature of the treatment and to give voluntary 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 postmenopausal for at least 1 year before the screening visit, is surgically sterilized or if they are of childbearing potential, agree to practice 2 effective methods of contraception from the time of signing the informed consent form through 30 days after the last dose of bortezomib, or agree to completely abstain from heterosexual intercourse. * Male subjects, even if surgically sterilized (i.e., status post-vasectomy) must agree to 1 of the following: practice effective barrier contraception during the entire study treatment period and through a minimum of 30 days after the last dose of study drug, or completely abstain from heterosexual intercourse. * Adequate organ function defined as follows: Absolute granulocytes \> 1,000/mm3 and platelets \> 70,000/mm3, unless low granulocyte and platelets counts are due to multiple myeloma; total bilirubin \< 1.5 ULN; AST, ALT, and alkaline phosphatase \< 3 times upper limit of laboratory normal; LVEF \> 50% by MUGA or ECHO (the method used at baseline must be used for later monitoring); DLCO \> 50 % confirmed at MSKCC; elevated creatinine is not a contraindication to enrollment * Performance status (ECOG) \< or = to 2
Exclusion criteria
* Patient has received other investigational drugs with 14 days before enrollment * Prior initial treatment chemotherapy for MIDD, AL amyloidosis or multiple myeloma with the exception of one cycle of high dose dexamethasone * Prior bortezomib treatment * Myocardial infarction within 6 months prior to enrollment or New York Heart Association Class III or IV heart failure (see Appendix 20.2), 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. * Pregnant or lactating women are ineligible. A pregnancy test will be performed on each fertile premenopausal female 2 weeks prior to entry into the study. Treatment may not begin until the results of the pregnancy test are ascertained. All patients (men and women) must agree to use medically approved contraceptive measures for at least 4 weeks before starting therapy, during therapy, and for at least 3 months after therapy has stopped. * Pre existing neuropathy, sensory or neuropathic pain findings, grade 2 or higher on the NCI CTC neurotoxicity scale. * Concurrent active malignancy other than non melanoma skin cancers or carcinoma in situ of the cervix. Patients with previous malignancies, but which have not required anti tumor treatment within the preceding 24 months will be allowed to enter the trial. Patients with a history of a T1a or b prostate cancer (detected incidentally at TURP and comprising less than 5% of resected tissue) may participate if the PSA has remained within normal limits since TURP. * Patients with known HIV positivity or AIDS related illness. This is based upon the possibility of increasing HIV viral load with therapy * Any other medical condition or reason that, in the principal investigator's opinion, makes the patient unsuitable to participate in a clinical trial * Patients with a history of hypersensitivity reactions attributed to bortezomib, boron, or mannitol. * Radiation therapy within 3 weeks before randomization. Enrollment of subjects who require concurrent radiotherapy (which must be localized in its field size) should be deferred until the radiotherapy is completed and 3 weeks have elapsed since the last date of therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Experiencing Progression Free Survival at 12 Months | 12 months | of a 3-phase comprehensive treatment approach including induction with BD followed by risk adapted HDM/ASCT, followed by consolidation/maintenance therapy with BD in patients with AL amyloidosis. |
| Participants Evaluated for Toxicity | 2 years | Toxicities will be assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Organ Response - Cardiac Involvement at 12 Months | 12 months | 12 months post-initiation of treatment following the 3 phase comprehensive treatment approach including induction with BD, followed by risk adapted HDM/ASCT, followed by consolidation/maintenance therapy with BD in patients with AL amyloidosis. |
| Progression Free Survival at 24 Months | 24 months | following the 3-phase comprehensive treatment approach including induction with BD, followed by risk adapted HDM/ASCT, followed by consolidation/maintenance therapy with BD in patients with AL amyloidosis. |
| Organ Response - Renal Involvement at 24 Months | 24 months | 24 months post-initiation of treatment following the 3 phase comprehensive treatment approach including induction with BD, followed by risk adapted HDM/ASCT, followed by consolidation/maintenance therapy with BD in patients with AL amyloidosis. |
| Organ Response - Renal Involvement at 12 Months | 12 months | 12 months post-initiation of treatment following the 3 phase comprehensive treatment approach including induction with BD, followed by risk adapted HDM/ASCT, followed by consolidation/maintenance therapy with BD in patients with AL amyloidosis. |
| Organ Response - Cardiac Involvement at 24 Months | 24 months | 24 months post-initiation of treatment following the 3 phase comprehensive treatment approach including induction with BD, followed by risk adapted HDM/ASCT, followed by consolidation/maintenance therapy with BD in patients with AL amyloidosis. |
| To Estimate the Hematologic Response Rate | 2 years | \[Complete Response (CR) (Normalization of the free light chain (FLC)levels and ratio; Negative serum and urine ; \<5% plasma cells in bone marrow), Very Good Partial Response (VGPR) (Reduction in the dFLC (difference between involved \[iFLC\] and uninvolved FLC) to\<4mg/dl) and Partial Response (PR)\] (\>/= 50% reduction in the dFLC), achieved at 12 month, and at 24 months post-initiation of treatment following the 3-phase comprehensive treatment approach. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Amyloidosis Participants with newly diagnosed AL amyloidosis | 19 |
| Monoclonal Ig DepositionDisease (MIDD) Participants with newly diagnosed Monoclonal Ig DepositionDisease (MIDD) | 1 |
| Total | 20 |
Baseline characteristics
| Characteristic | Amyloidosis | Total | Monoclonal Ig DepositionDisease (MIDD) |
|---|---|---|---|
| Age, Continuous | 60 years | 60 years | 63 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants | 20 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 16 Participants | 17 Participants | 1 Participants |
| Region of Enrollment United States | 19 Participants | 20 Participants | 1 Participants |
| Sex: Female, Male Female | 6 Participants | 6 Participants | 0 Participants |
| Sex: Female, Male Male | 13 Participants | 14 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 7 / 19 | 0 / 1 |
| other Total, other adverse events | 19 / 19 | 1 / 1 |
| serious Total, serious adverse events | 17 / 19 | 1 / 1 |
Outcome results
Primary
Participants Evaluated for Toxicity
Toxicities will be assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0.
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Amyloidosis | Participants Evaluated for Toxicity | 19 Participants |
| Monoclonal Ig DepositionDisease (MIDD) | Participants Evaluated for Toxicity | 1 Participants |
Primary
Percentage of Participants Experiencing Progression Free Survival at 12 Months
of a 3-phase comprehensive treatment approach including induction with BD followed by risk adapted HDM/ASCT, followed by consolidation/maintenance therapy with BD in patients with AL amyloidosis.
Time frame: 12 months
Population: Data were not collected for MIDD group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Amyloidosis | Percentage of Participants Experiencing Progression Free Survival at 12 Months | 84 percentage of patients |
Secondary
Organ Response - Cardiac Involvement at 12 Months
12 months post-initiation of treatment following the 3 phase comprehensive treatment approach including induction with BD, followed by risk adapted HDM/ASCT, followed by consolidation/maintenance therapy with BD in patients with AL amyloidosis.
Time frame: 12 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Amyloidosis | Organ Response - Cardiac Involvement at 12 Months | Participants without cardiac involvement | 7 Participants |
| Amyloidosis | Organ Response - Cardiac Involvement at 12 Months | Cardiac involvement, improved | 8 Participants |
| Amyloidosis | Organ Response - Cardiac Involvement at 12 Months | Cardiac involvement, progressed | 2 Participants |
| Amyloidosis | Organ Response - Cardiac Involvement at 12 Months | Cardiac involvement, died during induction | 2 Participants |
Secondary
Organ Response - Cardiac Involvement at 24 Months
24 months post-initiation of treatment following the 3 phase comprehensive treatment approach including induction with BD, followed by risk adapted HDM/ASCT, followed by consolidation/maintenance therapy with BD in patients with AL amyloidosis.
Time frame: 24 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Amyloidosis | Organ Response - Cardiac Involvement at 24 Months | Participants without cardiac involvement | 7 Participants |
| Amyloidosis | Organ Response - Cardiac Involvement at 24 Months | Cardiac involvement, improved | 8 Participants |
| Amyloidosis | Organ Response - Cardiac Involvement at 24 Months | Cardiac involvement, progressed | 2 Participants |
| Amyloidosis | Organ Response - Cardiac Involvement at 24 Months | Cardiac involvement, died during induction | 2 Participants |
Secondary
Organ Response - Renal Involvement at 12 Months
12 months post-initiation of treatment following the 3 phase comprehensive treatment approach including induction with BD, followed by risk adapted HDM/ASCT, followed by consolidation/maintenance therapy with BD in patients with AL amyloidosis.
Time frame: 12 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Amyloidosis | Organ Response - Renal Involvement at 12 Months | No renal involvment | 7 Participants |
| Amyloidosis | Organ Response - Renal Involvement at 12 Months | Renal involvment, improved | 9 Participants |
| Amyloidosis | Organ Response - Renal Involvement at 12 Months | Renal involvment, profressed | 2 Participants |
| Amyloidosis | Organ Response - Renal Involvement at 12 Months | Renal involvment, died | 1 Participants |
Secondary
Organ Response - Renal Involvement at 24 Months
24 months post-initiation of treatment following the 3 phase comprehensive treatment approach including induction with BD, followed by risk adapted HDM/ASCT, followed by consolidation/maintenance therapy with BD in patients with AL amyloidosis.
Time frame: 24 months
Population: 1 participants died at the previous 12 month follow up point
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Amyloidosis | Organ Response - Renal Involvement at 24 Months | No renal involvement | 7 Participants |
| Amyloidosis | Organ Response - Renal Involvement at 24 Months | Renal Involvement, improved | 9 Participants |
| Amyloidosis | Organ Response - Renal Involvement at 24 Months | Normal Renal Function after Kidney Transplant | 2 Participants |
Secondary
Progression Free Survival at 24 Months
following the 3-phase comprehensive treatment approach including induction with BD, followed by risk adapted HDM/ASCT, followed by consolidation/maintenance therapy with BD in patients with AL amyloidosis.
Time frame: 24 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Amyloidosis | Progression Free Survival at 24 Months | 68 percentage of patients |
Secondary
To Estimate the Hematologic Response Rate
\[Complete Response (CR) (Normalization of the free light chain (FLC)levels and ratio; Negative serum and urine ; \<5% plasma cells in bone marrow), Very Good Partial Response (VGPR) (Reduction in the dFLC (difference between involved \[iFLC\] and uninvolved FLC) to\<4mg/dl) and Partial Response (PR)\] (\>/= 50% reduction in the dFLC), achieved at 12 month, and at 24 months post-initiation of treatment following the 3-phase comprehensive treatment approach.
Time frame: 2 years
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Amyloidosis | To Estimate the Hematologic Response Rate | Partial Response (PR) | 4 Participants |
| Amyloidosis | To Estimate the Hematologic Response Rate | Stable Disease (SD) | 1 Participants |
| Amyloidosis | To Estimate the Hematologic Response Rate | Progression of Disease (POD) | 1 Participants |
| Amyloidosis | To Estimate the Hematologic Response Rate | Very Good Partial Response (VGPR) | 6 Participants |
| Amyloidosis | To Estimate the Hematologic Response Rate | Complete Response (CR) | 7 Participants |
| Monoclonal Ig DepositionDisease (MIDD) | To Estimate the Hematologic Response Rate | Very Good Partial Response (VGPR) | 1 Participants |
| Monoclonal Ig DepositionDisease (MIDD) | To Estimate the Hematologic Response Rate | Complete Response (CR) | 0 Participants |
| Monoclonal Ig DepositionDisease (MIDD) | To Estimate the Hematologic Response Rate | Partial Response (PR) | 0 Participants |
| Monoclonal Ig DepositionDisease (MIDD) | To Estimate the Hematologic Response Rate | Progression of Disease (POD) | 0 Participants |
| Monoclonal Ig DepositionDisease (MIDD) | To Estimate the Hematologic Response Rate | Stable Disease (SD) | 0 Participants |