Trial of Venetoclax (ABT-199) and Dexamethasone for Relapsed or Refractory Systemic AL Amyloidosis

NCT03000660 | Terminated Phase 1 FDA Drug

• 1 other identifier: AbbVie ABT-199
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

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.

Conditions

AL Amyloidosis

Keywords

Amyloidosis; AL Amyloidosis; Amyloid Light Chain Amylodosis; ABT-199; Venetoclax

Outcome Measures

Primary Outcomes (1)

• Participants with treatment related adverse events using NCI CTCAE version 4.03.

  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.

  Up to 8 months after beginning study drug

Secondary Outcomes (3)

• Hematologic response based on serum free light chain (FLC) response criteria.

  Up to 8 months after beginning study drug

• Proportion of subjects with progression-free survival

  Until disease progression up to three (3) years

• Overall survival of subjects

  From time of end of treatment to death for up to three (3) years

Study Arms (1)

Venetoclax and Dexamethasone

EXPERIMENTAL

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.

Drug: Venetoclax; Drug: Dexamethasone

Interventions

Venetoclax DRUG

Venetoclax at one of four escalating doses

Also known as: ABT-199

Venetoclax and Dexamethasone

Dexamethasone DRUG

Dexamethasone 20mg by mouth on days 1, 8, 15, and 22 of each cycle.

Also known as: Ozurdex, Maxidex, Baycadron

Venetoclax and Dexamethasone

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 1.4.
• 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 CKD3.
• 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.
• AL Amyloidosis Cardiac Risk stage I, II or IIIa disease. Staging system defined by: NT-proBNP cut off of \< 332 pg/mL and troponin I cut-off of \< 0.10 ng/mL as thresholds for stages I, II and III; NT-proBNP \< 8500 for stage IIIa.
• Stage I, both under threshold;
• Stage II, either troponin or NT-proBNP \[but not both\] over threshold;
• Stage III, both over threshold;
• Stage IIIa, both over threshold but NT-proBNP \< 8500 pg/ml.

You may not qualify if:

• 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.
• Grade 2 or 3 atrioventricular (AV) block (Mobitz, Type I permitted).
• Supine systolic blood pressure \< 90 mmHg, or symptomatic orthostatic hypotension, or a decrease in systolic blood pressure on standing of \> 20 mm Hg in spite of being treated for orthostatic hypotension.
• History of a bleeding diathesis or currently receiving treatment with warfarin. Patients are allowed to take aspirin.
• GI system:
• Severe diarrhea (= Grade 3) not controllable with medication (such as octreotide) or requires administration of total parenteral nutrition.

Sponsors & Collaborators

• Tufts Medical Center: lead

Study Sites (1)

Tufts Medical Center

Boston, Massachusetts, 02111, United States

Location

MeSH Terms

Conditions

Immunoglobulin Light-chain Amyloidosis; Amyloidosis

Interventions

venetoclax; Dexamethasone; Calcium Dobesilate

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Paraproteinemias

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds

Study Officials

• Raymond Comenzo, MD

  Tufts Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 12, 2016
• First Posted: December 22, 2016
• Study Start: January 1, 2017
• Primary Completion: October 1, 2019
• Study Completion: October 10, 2019
• Last Updated: August 21, 2020

Record last verified: 2020-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)