A Phase I/II Trial of Pomalidomide and Dexamethasone in Subjects With Previously-Treated AL Amyloidosis

Study Overview
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Brief Summary
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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
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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

Official Title
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A Phase I/II Trial of Pomalidomide and Dexamethasone in Subjects With Previously-Treated AL Amyloidosis

Conditions
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AL Amyloidosis

Intervention / Treatment
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* Drug: Pomalidomide
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Understand and voluntarily sign informed consent form. ≥18yrs old Able to adhere to the study visit schedule and other protocol requirements. Biopsy proven tissue amyloid deposits or positive fat aspirate Proof of AL type (a or b) Measurable plasma cell dyscrasia (a or b and c of the following required): Monoclonal protein in the serum or urine by immunofixation electrophoresis Plasmacytosis of bone marrow (<30% plasma cells) with monoclonal staining for kappa or lambda light-chain isotype dFLC of 50mg/L (dFLC=difference in involved and uninvolved serum free light-chain levels) 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 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 Eastern Cooperative Group (ECOG) performance status ≤2 at study entry 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 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. 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. 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: Secondary or familial amyloidosis Multiple myeloma (≥30% plasma cells in a bone marrow biopsy specimen or lytic bone lesions) Cytotoxic chemo or radiation therapy ≤4 weeks of study entry or following baseline evaluation Symptomatic cardiac arrhythmias or O2-dependent restrictive cardiomyopathy Dialysis-dependent Untreated or uncontrolled infections. Serious medical conditions, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form. Pregnant or breast feeding females (lactating females must agree not to breast feed while taking pomalidomide). 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. Use of any other experimental drug or therapy within 28 days of baseline. Known intolerance to steroids. Known hypersensitivity to thalidomide or lenalidomide The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs. Concurrent use of other anti-cancer agents or treatments. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I - cohort 1 (Pomalidomide 2mg) plus Dexamethasone<br>Pomalidomide 2 mg/day on days 1-28 plus dexamethasone 10-20 mg on days 1-21 of a 28 day cycle | Drug: Pomalidomide<br>* Cohort 1 = 2 mg/day, Cohort 2 = 3 mg/day, Cohort 3 = 4 mg/day: Days 1-21 of a 28 day cycle<br>* Other names: imnovist;Drug: Dexamethasone<br>* 10-20 mg on days 1, 8, 15, and 22<br>* Other names: Dexamethasone Acetate;|
| Experimental: Phase I - cohort 2 (Pomalidomide 3mg) plus Dexamethasone<br>Pomalidomide 3 mg/day on days 1-28 plus dexamethasone 10-20 mg on days 1-21 of a 28 day cycle | Drug: Pomalidomide<br>* Cohort 1 = 2 mg/day, Cohort 2 = 3 mg/day, Cohort 3 = 4 mg/day: Days 1-21 of a 28 day cycle<br>* Other names: imnovist;Drug: Dexamethasone<br>* 10-20 mg on days 1, 8, 15, and 22<br>* Other names: Dexamethasone Acetate;|
| Experimental: Phase I - cohort 3 (Pomalidomide 4mg) plus Dexamethasone<br>Pomalidomide 4 mg/day on days 1-28 plus dexamethasone 10-20 mg on days 1-21 of a 28 day cycle | Drug: Pomalidomide<br>* Cohort 1 = 2 mg/day, Cohort 2 = 3 mg/day, Cohort 3 = 4 mg/day: Days 1-21 of a 28 day cycle<br>* Other names: imnovist;Drug: Dexamethasone<br>* 10-20 mg on days 1, 8, 15, and 22<br>* Other names: Dexamethasone Acetate;|
| Experimental: Phase II Expansion- (Pomalidomide 4mg) plus Dexamethasone<br>Expansion Phase: Pomalidomide 4 mg/day on days 1-28 plus dexamethasone 10-20 mg on days 1-21 of a 28 day cycle | Drug: Pomalidomide<br>* Cohort 1 = 2 mg/day, Cohort 2 = 3 mg/day, Cohort 3 = 4 mg/day: Days 1-21 of a 28 day cycle<br>* Other names: imnovist;Drug: Dexamethasone<br>* 10-20 mg on days 1, 8, 15, and 22<br>* Other names: Dexamethasone Acetate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | one month | 
| 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. | One month | 
| 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 | One month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | one year |