Venetoclax-Dexamethasone in Relapsed and/or Refractory t(11;14) Amyloidosis

Rajshekhar Chakraborty, MD

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: AL Amyloidosis

Treatments: Device: FISH assay; Drug: Pomalidomide; Drug: Venetoclax MTD with Dexamethasone; Drug: Dexamethasone Oral, 10 mg; Drug: Dexamethasone Oral, 20 mg; Drug: Bendamustine; Drug: Ixazomib; Drug: Venetoclax Oral Tablet, 200 mg; Drug: Venetoclax Oral Tablet, 400 mg; Drug: Daratumumab Injection

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT05451771

AAAT8639

Details and patient eligibility

About

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.

Full description

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).

Enrollment: 53 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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%

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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53 participants in 6 patient groups

Phase 1: Venetoclax 200 mg

Experimental group

Description:

Cohort 1: Venetoclax 200 mg tablet, once daily for up to 2 cycles after achieving best response, for a maximum of 6 cycles (1 cycle = 28 days)

Treatment:

Drug: Venetoclax Oral Tablet, 200 mg

Device: FISH assay

Phase 1: Venetoclax 400mg

Experimental group

Description:

Cohort 2: Venetoclax 400 mg tablet, once daily for up to 2 cycles after achieving best response, for a maximum of 6 cycles (1 cycle = 28 days)

Treatment:

Drug: Venetoclax Oral Tablet, 400 mg

Device: FISH assay

Phase 1: Venetoclax 400mg + Dexamethasone 10 mg

Experimental group

Description:

Cohort 3: Venetoclax 400 mg tablet, once daily and Dexamethasone 10 mg tablet once weekly, for up to 2 cycles after achieving best response, for a maximum of 6 cycles (1 cycle = 28 days)

Treatment:

Drug: Venetoclax Oral Tablet, 400 mg

Drug: Dexamethasone Oral, 10 mg

Device: FISH assay

Phase 1: Venetoclax 400mg + Dexamethasone 20 mg

Experimental group

Description:

Cohort 4: Venetoclax 400 mg tablet, once daily and Dexamethasone 20 mg tablet once weekly, for up to 2 cycles after achieving best response, for a maximum of 6 cycles (1 cycle = 28 days)

Treatment:

Drug: Venetoclax Oral Tablet, 400 mg

Drug: Dexamethasone Oral, 20 mg

Device: FISH assay

Phase 2: Venetoclax MTD with Dexamethasone

Experimental group

Description:

Venetoclax MTD (200 mg or 400 mg) with Dexamethasone (10 mg or 20 mg) as determined by the phase I results

Treatment:

Drug: Venetoclax MTD with Dexamethasone

Phase 2: Control Arm (Investigator's Choice)

Active Comparator group

Description:

Participants will receive one of the following as determined by the investigator: Daratumumab, Pomalidomide, Bendamustine, or Ixazomib (+/- dexamethasone)

Treatment:

Drug: Daratumumab Injection

Drug: Ixazomib

Drug: Bendamustine

Drug: Dexamethasone Oral, 20 mg

Drug: Pomalidomide