AL Amyloidosis
Conditions
Brief summary
This study seeks to enroll patients with AL amyloidosis, for whom treatment with one of the standard melphalan chemotherapy-based regimens is either not recommended or is not their preference. Pomalidomide (CC-4047) is a drug given by mouth, which can change or regulate the functioning of the immune system. So, in theory, it may reduce or prevent the production of the amyloid protein. Pomalidomide is not currently FDA-approved for AL Amyloidosis. Pomalidomide is chemically similar to thalidomide and lenalidomide, both of these drugs have been approved by the FDA for treatment of patients with multiple myeloma (MM), a disease similar to AL Amyloidosis. Participants in this study will receive pomalidomide and dexamethasone. Phase I is a dose-escalation study and dose escalation will proceed through 3 dose-levels according to standard rules in which dose levels are started sequentially after complete evaluation of the occurrence of dose-limiting toxicities. In the Phase II portion, participants will receive pomalidomide and dexamethasone using the defined maximum tolerated dose.
Detailed description
Primary objective: Determine dose-limiting toxicity (DLT) and the maximal tolerated dose (MTD) of pomalidomide combined with dexamethasone in subjects with previously- treated light-chain (AL)-amyloidosis Secondary objectives: Determine the following at the MTD: * Hematological complete (CR) very good partial (VGPR) and partial (PR) rates * duration of response * organ response * Time-to-event * Survival Exploratory study objective: To investigate the relationship of changes in the levels of the biomarkers B-type natriuretic peptide (BNP) and troponin I to frequency of specific adverse events and the occurrence of DLT
Interventions
DRUGPomalidomide
Cohort 1 = 2 mg/day, Cohort 2 = 3 mg/day, Cohort 3 = 4 mg/day: Days 1-21 of a 28 day cycle
DRUGDexamethasone
10-20 mg on days 1, 8, 15, and 22
Sponsors
Celgene Corporation
Boston Medical Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Understand and voluntarily sign informed consent form. 2. ≥18yrs old 3. Able to adhere to the study visit schedule and other protocol requirements. 4. Biopsy proven tissue amyloid deposits or positive fat aspirate 5. Proof of AL type (a or b) 6. Measurable plasma cell dyscrasia (a or b and c of the following required): 1. Monoclonal protein in the serum or urine by immunofixation electrophoresis 2. Plasmacytosis of bone marrow (\<30% plasma cells) with monoclonal staining for kappa or lambda light-chain isotype 3. dFLC of 50mg/L (dFLC=difference in involved and uninvolved serum free light-chain levels) 7. Must have received ≥1 prior treatment for AL amyloidosis, if it is intensive chemotherapy and an autotransplant it must be ≥6 months prior to enrollment on this study 8. Must have recovered from the reversible side effects of any prior therapy; permanent and stable side effects/changes are acceptable. Prior treatment for AL amyloidosis with chemotherapy, thalidomide, lenalidomide or steroids is not an exclusion 9. Eastern Cooperative Group (ECOG) performance status ≤2 at study entry 10. Lab test results within these ranges: d. Neutrophil ≥1.5 x10e9/L e. Platelets ≥100x10e9/L f. Total bilirubin \<1.5mg/dL g. Aspartate aminotransferase (AST or SGOT) and Alanine Aminotransferase (ALT or SGPT) \< 2 x Upper limit of normal h. Serum creatinine \<2.5mg/dL 11. Disease free of prior malignancies for at least 5yrs with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix or breast. 12. Females of childbearing potential (FCBP) (a FCBP is a sexually mature woman who has not undergone a hysterectomy or bilateral oophorectomy, or has not been naturally postmenopausal for at least 24 consecutive months) must have a negative serum or urine pregnancy test with a sensitivity ≥ 50 milli-International unit/mL 10-14 days prior to and again ≤ 24 hours of starting pomalidomide and must either commit to continued abstinence from heterosexual intercourse or begin two (2) acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, ≥ 28 days before she starts taking pomalidomide. FCBP must also 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 vasectomy. All subjects must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. 13. Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (subjects intolerant to aspirin may use warfarin or low molecular weight heparin).
Exclusion criteria
1. Secondary or familial amyloidosis 2. Multiple myeloma (≥30% plasma cells in a bone marrow biopsy specimen or lytic bone lesions) 3. Cytotoxic chemo or radiation therapy ≤4 weeks of study entry or following baseline evaluation 4. Symptomatic cardiac arrhythmias or O2-dependent restrictive cardiomyopathy 5. Dialysis-dependent 6. Untreated or uncontrolled infections. 7. Serious medical conditions, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form. 8. Pregnant or breast feeding females (lactating females must agree not to breast feed while taking pomalidomide). 9. Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study. 10. Use of any other experimental drug or therapy within 28 days of baseline. 11. Known intolerance to steroids. 12. Known hypersensitivity to thalidomide or lenalidomide 13. The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs. 14. Concurrent use of other anti-cancer agents or treatments. 15. Known HIV positivity is not an exclusion, unless cluster of differentiation 4 (CD4) counts \<200/microliter and/or patient has multi-drug resistant HIV infections and/or other concurrent AIDS-defining conditions. HIV b-DNA \< 75 copies/mL.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Assessing Dose-limiting Toxicity to Determine Maximal Tolerated Dosage at 2 Milligram Dose | one month | Number of patients in Phase I cohort 1 experiencing dose-limiting toxicity at the 2 milligram dose of pomalidomide combined with dexamethasone in subjects with previously- treated light-chain amyloidosis |
| Assessing Dose-limiting Toxicity to Determine Maximal Tolerated Dosage at 3 Milligram Dose | One month | Number of patients in Phase I cohort 2 experiencing dose limiting toxicity in the 3 milligram dose level, cohort 2. |
| Assessing Dose-limiting Toxicity to Determine Maximal Tolerated Dosage at 4 Milligram Dose | One month | Number of patients in Phase I cohort 3 experiencing dose-limiting toxicity at the 4 milligram dose for participants within the third dose cohort |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Response to the Maximal Tolerated Dose | one year | Number of participants with a response to treatment at that maximal tolerated dose (including partial, very good, or complete responses) |
Countries
United States
Participant flow
Recruitment details
Protocol was open to accrual between January 2012 and August 2016. Participants were recruited from within the amyloidosis clinic within Boston Medical Center.
Participants by arm
| Arm | Count |
|---|---|
| Phase I - Cohort 1 (Pomalidomide 2mg) Plus Dexam Pomalidomide: Cohort 1 = 2 mg/day, Cohort 2 = 3 mg/day, Cohort 3 = 4 mg/day: Days 1-28
Dexamethasone: 10-20 mg on days 1, 8, 15, and 22 | 6 |
| Phase I - Cohort 2 (Pomalidomide 3mg) Pomalidomide 3 mg/day on days 1-28 plus dexamethasone 10-20 mg on days 1-21 of a 28 day cycle | 3 |
| Phase I - Cohort 3 (Pomalidomide 4mg) Pomalidomide 4 mg/day on days 1-28 plus dexamethasone 10-20 mg on days 1-21 of a 28 day cycle | 6 |
| Phase II Expansion- (Pomalidomide 4mg) Plus Dexa Pomalidomide 4 mg/day (MTD) on days 1-28 plus dexamethasone 10-20 mg on days 1-21 of a 28 day cycle | 12 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 0 |
| Overall Study | Death | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Phase I - Cohort 1 (Pomalidomide 2mg) Plus Dexam | Phase I - Cohort 2 (Pomalidomide 3mg) | Phase I - Cohort 3 (Pomalidomide 4mg) | Phase II Expansion- (Pomalidomide 4mg) Plus Dexa |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 18 Participants | 3 Participants | 3 Participants | 5 Participants | 7 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 3 Participants | 0 Participants | 1 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 26 Participants | 6 Participants | 3 Participants | 6 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Prior treatments 1 to 2 prior treatments | 16 Participants | 4 Participants | 3 Participants | 1 Participants | 8 Participants |
| Prior treatments greater than 2 prior treatments | 11 Participants | 2 Participants | 0 Participants | 5 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 24 Participants | 6 Participants | 2 Participants | 5 Participants | 11 Participants |
| Sex: Female, Male Female | 11 Participants | 4 Participants | 1 Participants | 1 Participants | 5 Participants |
| Sex: Female, Male Male | 16 Participants | 2 Participants | 2 Participants | 5 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 6 | 0 / 3 | 0 / 6 | 1 / 12 |
| other Total, other adverse events | 6 / 6 | 3 / 3 | 6 / 6 | 12 / 12 |
| serious Total, serious adverse events | 2 / 6 | 0 / 3 | 3 / 6 | 3 / 12 |
Outcome results
Primary
Assessing Dose-limiting Toxicity to Determine Maximal Tolerated Dosage at 2 Milligram Dose
Number of patients in Phase I cohort 1 experiencing dose-limiting toxicity at the 2 milligram dose of pomalidomide combined with dexamethasone in subjects with previously- treated light-chain amyloidosis
Time frame: one month
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pom Plus Dex | Assessing Dose-limiting Toxicity to Determine Maximal Tolerated Dosage at 2 Milligram Dose | 0 Participants |
Primary
Assessing Dose-limiting Toxicity to Determine Maximal Tolerated Dosage at 3 Milligram Dose
Number of patients in Phase I cohort 2 experiencing dose limiting toxicity in the 3 milligram dose level, cohort 2.
Time frame: One month
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pom Plus Dex | Assessing Dose-limiting Toxicity to Determine Maximal Tolerated Dosage at 3 Milligram Dose | 0 Participants |
Primary
Assessing Dose-limiting Toxicity to Determine Maximal Tolerated Dosage at 4 Milligram Dose
Number of patients in Phase I cohort 3 experiencing dose-limiting toxicity at the 4 milligram dose for participants within the third dose cohort
Time frame: One month
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pom Plus Dex | Assessing Dose-limiting Toxicity to Determine Maximal Tolerated Dosage at 4 Milligram Dose | 1 Participants |
Secondary
Response to the Maximal Tolerated Dose
Number of participants with a response to treatment at that maximal tolerated dose (including partial, very good, or complete responses)
Time frame: one year
Population: Number of evaluable patients treated at the maximal tolerated dose of 4mg including the Phase I cohort 3 participants and the Phase II expansion participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pom Plus Dex | Response to the Maximal Tolerated Dose | 10 Participants |