A Phase I Trial of Venetoclax (ABT-199) and Dexamethasone for Relapsed or Refractory Systemic AL Amyloidosis
Overview
- Phase
- Phase 1
- Intervention
- Venetoclax
- Conditions
- AL Amyloidosis
- Sponsor
- Tufts Medical Center
- Enrollment
- 3
- Locations
- 1
- Primary Endpoint
- Participants with treatment related adverse events using NCI CTCAE version 4.03.
- Status
- Terminated
- Last Updated
- 5 years ago
Overview
Brief Summary
This is a study to determine the safety, tolerability and maximum tolerated dose of Venetoclax (ABT-199) and dexamethasone in relapsed or refractory amyloid light chain (AL) amyloidosis patients.
Detailed Description
The study is being conducted to determine the safety, tolerability and maximum tolerated dose of Venetoclax and dexamethasone in relapsed or refractory amyloid light chain (AL) amyloidosis patients. AL amyloidosis is a disease involving cells called plasma cells that make antibodies as part of your immune system. These cells are not functioning the way they are supposed to and they start to produce abnormal fragments of antibodies that are toxic to your body and can form amyloid. The antibody fragments are called "light chains." They can cause damage to organs, especially the kidneys, heart, skin, liver, and lungs. Researchers are looking for ways to stop the light chains from being formed to treat the disease. Under some circumstances, patients will receive chemotherapy drugs in order to manage the disease. However, researchers do not know what the best treatment is for relapsed AL amyloidosis, so the researchers are testing new drugs or new combinations of drugs to see what will work best with the least side effects. The researchers want to find out if Venetoclax (ABT-199) in addition to dexamethasone will reduce or eliminate AL amyloidosis plasma cells. In this study, varying doses of Venetoclax will be given to determine the maximum tolerated and safe dose for further study. The researchers may also gain a better understanding of whether Venetoclax and dexamethasone can counter the plasma cell disease that causes AL amyloidosis.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologic diagnosis of AL amyloidosis, confirmed by positive Congo red stained biopsy, with evidence of measurable clonal disease according that requires active treatment
- •Eastern Cooperative Oncology Group (ECOG) status of 0 to 2
- •Relapsed or refractory after at least 1 prior therapy for AL amyloidosis and, in the investigator's opinion, require further treatment. Participants with a history of autologous stem cell transplantation must have adequate blood counts independent of growth factor support and have recovered from any transplant-related toxicities and be at least 100 days post-autologous transplant.
- •Less than 30% plasma cells in the bone marrow biopsy and no bone lesions or hypercalcemia.
- •The pre-screening test of CD138+ patient marrow plasma cells must show that the patient's CD138+ plasma cells have an apoptosis ratio of Venetoclax treated over untreated cells of greater than 1.
- •Objective, measurable organ involvement. Skin purpura, carpal tunnel syndrome, or the presence of vascular amyloid on a bone marrow biopsy alone are not sufficient to meet criteria for "symptomatic organ involvement". Patients may have any of the following amyloid-related organ involvement as defined below:
- •Renal: albuminuria higher than 0.5 g/day in a 24-hour urine collection.
- •Cardiac: involvement is defined as the presence of a mean left ventricular wall thickness on echocardiogram more than 12 mm in the absence of a history of hypertension or valvular heart disease, or unexplained low voltage (\< 0.5 mV) on electrocardiogram; or an NT-proBNP \> 332 ng/L in CKD 1 or 2 patients or a BNP \> 100ng/L in those who are CKD
- •Hepatic: hepatomegaly on physical examination with alkaline phosphatase \> 1.5 X the upper limit of normal (ULN).
- •Autonomic or peripheral neuropathy: based on clinical history, autonomic dysfunction with orthostasis, symptoms of nausea or dysgeusia, gastric atony by gastric emptying scan, diarrhea or constipation, or abnormal sensory and/or motor findings on neurologic examination.
Exclusion Criteria
- •Treatment with any investigational products within 28 days before the first dose of study drug.
- •Requirement for other concomitant chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered to be investigational.
- •Failure to have fully recovered (ie, \> Grade 1 toxicity) from the effects of prior chemotherapy regardless of the interval since last treatment.
- •Active fungal infection requiring continued therapy.
- •Cardiac system:
- •QTc \> 470 milliseconds (msec) on a 12 lead ECG obtained during the Screening period. If a machine reading is above this value, the ECG should be reviewed by a qualified reader and confirmed on a subsequent ECG.
- •AL Amyloidosis Risk Stage IIIb disease. Stage IIIb is defined by NT-proBNP \> 8500 pg/mL and troponin I \> 0.10 ng/mL.
- •New York Heart Association (NYHA) classification III or IV.
- •Enzyme-documented myocardial infarction within 6 months before enrollment.
- •Chronic atrial fibrillation.
Arms & Interventions
Venetoclax and Dexamethasone
Venetoclax will be given at one of four escalating doses (100 mg/day, 200 mg/day, 400 mg/day, or 800 mg/day) by mouth on each day of the cycle. Dexamethasone will be given at 20mg by mouth on days 1, 8, 15, and 22 of each cycle.
Intervention: Venetoclax
Venetoclax and Dexamethasone
Venetoclax will be given at one of four escalating doses (100 mg/day, 200 mg/day, 400 mg/day, or 800 mg/day) by mouth on each day of the cycle. Dexamethasone will be given at 20mg by mouth on days 1, 8, 15, and 22 of each cycle.
Intervention: Dexamethasone
Outcomes
Primary Outcomes
Participants with treatment related adverse events using NCI CTCAE version 4.03.
Time Frame: Up to 8 months after beginning study drug
Dose limiting toxicity will be based on hematologic and non-hematologic adverse events that are considered by the investigator to be possibly related to Venetoclax include any Grade 4 thrombocytopenia lasting more than 7 days, any Grade 4 neutropenia lasting more than 7 days, any Grade 3 or higher nonhematologic toxicity, a delay of more than 2 weeks in the initiation of Cycle 2 of treatment because of a lack of adequate recovery of Venetoclax-related hematological or nonhematologic toxicities, and any other Venetoclax-related nonhematologic toxicities Grade 2 or greater than, in the opinion of the investigator, requires discontinuation of therapy with Venetoclax. Also, events of concern that may be related to Venetoclax therapy will include worsening neuropathy, ventricular or atrial arrhythmia with hemodynamic instability, fluid retention that does not resolve with 3 or 4 days of intravenous diuretic therapy and bedrest, symptomatic congestive heart failure, and hypotension.
Secondary Outcomes
- Hematologic response based on serum free light chain (FLC) response criteria.(Up to 8 months after beginning study drug)
- Overall survival of subjects(From time of end of treatment to death for up to three (3) years)
- Proportion of subjects with progression-free survival(Until disease progression up to three (3) years)