venetoclax-dexamethasone in relapsed and/or refractory t(11;14) amyloidosis

Conditions: AL Amyloidosis

Summary: the purpose of this study is assess safety, safest dose, and effectiveness of venetoclax in combination with dexamethasone in participants with t(11;14) positive relapsed (comes back) or refractory (did not get better) light chain amyloidosis.

this study is a phase 1/2 study of venetoclax-dexamethasone combination therapy in relapsed/refractory t(11;14) systemic immunoglobulin light chain amyloidosis (al) amyloidosis. the phase 1 is a dose escalation designed to determine the maximum tolerated dose (mtd) and the recommended phase 2 dose (rp2d) of venetoclax in combination with low-dose weekly dexamethasone. there will be four candidate-dosing cohorts of venetoclax with or without dexamethasone in the phase i dose-escalation. dose escalation will be guided by the bayesian optimal interval (boin) design with accelerated titration up to a total sample size of 15 participants. the phase 2 portion is a randomized open-label study comparing the mtd or rp2d of venetoclax in combination with dexamethasone versus investigator's choice (daratumumab, pomalidomide, bendamustine, or ixazomib (with or without dexamethasone).

Eligibility criteria:
inclusion criteria: * age ≥ 18 years at time of signing informed consent form * ability to comply with the study protocol, in the investigator's judgment * confirmed diagnosis of systemic al amyloidosis by mass spectrometry or immunohistochemistry (ihc) on a tissue biopsy * has received ≥1 prior lines of therapy, including an anti-cluster of differentiation 38 (cd 38) monoclonal antibody * participants with a history of autologous hematopoietic cell transplantation must have recovered from any transplant-related toxicities * presence of t(11;14) on fish at any time since diagnosis (eligibility must confirmed by fish testing at columbia university irving medical center (cuimc) * eastern cooperative oncology group (ecog) performance status of 0, 1, or 2 exclusion criteria: * known hypersensitivity to any of the study drugs * history of other malignancy that could affect compliance with the protocol or interpretation of results (patients with a history of curatively treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix, breast cancer, or hodgkin's lymphoma are generally eligible. patients with a malignancy that has been treated, but not with curative intent, will be excluded, unless the malignancy has been in remission without treatment for ≥ 2 years prior to enrollment.) * evidence of other clinically significant uncontrolled condition(s) including, but not limited to, uncontrolled systemic infection (viral, bacterial, or fungal) * patients on renal replacement therapy * known gi disease or gi procedure that could interfere with oral absorption (including difficulty swallowing) * new york heart association (nyha) class iii or iv heart failure * mayo stage three-b (iiib) with n-terminal pro-hormone b-type natriuretic peptide (nt-pro bnp) \> 8500 pg/ml * prior exposure to anti-apoptotic protein b-cell lymphoma 2 (bcl-2) inhibitors * patients with human immunodeficiency virus (hiv) who are not on highly active antiretroviral therapy (haart) or those with active hepatitis a, b, or c infection * patients meeting criteria for symptomatic multiple myeloma by one of the following:(a) lytic lesions on imaging (b) plasmacytoma, (c) hypercalcemia without any alternate etiology, or (c) bone marrow plasma cell infiltrate of greater than 60%

Keywords: light chain amyloidosis protein misfolding disorder