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

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT03000660
• Date of registration: 12/12/2016
• Prospective Registration: Yes
• Primary sponsor: Tufts Medical Center
• Public title: Trial of Venetoclax (ABT-199) and Dexamethasone for Relapsed or Refractory Systemic AL Amyloidosis
• Scientific title: A Phase I Trial of Venetoclax (ABT-199) and Dexamethasone for Relapsed or Refractory Systemic AL Amyloidosis
• Date of first enrolment: January 2017
• Target sample size: 3
• Recruitment status: Terminated
• URL: https://clinicaltrials.gov/show/NCT03000660
• Study type: Interventional
• Study design: Allocation: N/A. Intervention model: Single Group Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 1

Countries of recruitment

United States

Contacts

• Name: Raymond Comenzo, MD
• Affiliation: Tufts Medical Center

Key inclusion & exclusion 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 1.4.

- 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:

1. Renal: albuminuria higher than 0.5 g/day in a 24-hour urine collection.

2. 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.

3. Hepatic: hepatomegaly on physical examination with alkaline phosphatase > 1.5 X
the upper limit of normal (ULN).

4. 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.

1. Stage I, both under threshold;

2. Stage II, either troponin or NT-proBNP [but not both] over threshold;

3. Stage III, both over threshold;

4. Stage IIIa, both over threshold but NT-proBNP < 8500 pg/ml.

- Clinical laboratory values as specified below before the first dose of study drug:

1. Echocardiographic ejection fraction > 45% within 28 days before the first dose of
study drug.

2. Within the 3 days of the first dose of study drug: i. Platelet count > 75 x
109/L; ii. Neutrophil count > 1.0 x 109/L; iii. Total bilirubin < 2 x ULN; iv.
Alkaline phosphatase < 5 x ULN; v. Alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) < 3 x ULN; vi. eGFR > 30 mL/min/1.73 m2

- Female patients who are postmenopausal for at least 1 year before the screening visit,
OR are surgically sterile, OR, if they are of childbearing potential, agree to
practice 2 effective methods of contraception, at the same time, from the time of
signing the informed consent through 30 days after the last dose of study drug, or
agree to completely abstain from heterosexual intercourse.

- Male patients, even if surgically sterilized (ie, status post vasectomy), who agree to
practice effective barrier contraception during the entire study treatment period and
through 30 days after the last dose of study drug, OR agree to completely abstain from
heterosexual intercourse.

- Voluntary written consent must be given before performance of any study-related
procedure not part of standard medical care with the understanding that consent may be
withdrawn by the patient at any time without prejudice to future medical care.

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:

1. 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.

2. AL Amyloidosis Risk Stage IIIb disease. Stage IIIb is defined by NT-proBNP > 8500
pg/mL and troponin I > 0.10 ng/mL.

3. New York Heart Association (NYHA) classification III or IV.

4. Enzyme-documented myocardial infarction within 6 months before enrollment.

5. Chronic atrial fibrillation.

6. Grade 2 or 3 atrioventricular (AV) block (Mobitz, Type I permitted).

7. 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.

8. History of a bleeding diathesis or currently receiving treatment with warfarin.
Patients are allowed to take aspirin.

- GI system:

1. Severe diarrhea (= Grade 3) not controllable with medication (such as octreotide)
or requires administration of total parenteral nutrition.

2. Known GI disease or GI procedure that could interfere with the oral absorption or
tolerance of study drug, including difficulty swallowing.

- Neurologic/ Social system:

1. Patients with > Grade 2 peripheral neuropathy or painful peripheral neuropathy on
clinical examination will be excluded.

2. Previous or ongoing psychiatric illness.

3. Social situations that would limit compliance with study requirements.

- Systemic infections:

1. Known to be human immunodeficiency virus (HIV)-positive.

2. Known to be hepatitis B surface antigen-positive or has known active hepatitis C
infection.

3.


Age minimum: 18 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

AL Amyloidosis

Intervention(s)

Drug: Dexamethasone

Drug: Venetoclax

Primary Outcome(s)

Participants with treatment related adverse events using NCI CTCAE version 4.03. [Time Frame: Up to 8 months after beginning study drug]

Secondary Outcome(s)

Overall survival of subjects [Time Frame: From time of end of treatment to death for up to three (3) years]

Hematologic response based on serum free light chain (FLC) response criteria. [Time Frame: Up to 8 months after beginning study drug]

Proportion of subjects with progression-free survival [Time Frame: Until disease progression up to three (3) years]

Secondary ID(s)

AbbVie ABT-199

Source(s) of Monetary Support

Please refer to primary and secondary sponsors