Clinical trial NCT05451771: Venetoclax-Dexamethasone in Relapsed and/or Refractory t(11;14) Amyloidosis
Official title: An Open-label Phase I/II Trial of Venetoclax-Dexamethasone in Relapsed and/or Refractory t(11;14) Systemic Light-Chain Amyloidosis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: AL Amyloidosis
Keywords: Light Chain Amyloidosis
Protein Misfolding Disorder
Lead sponsor: Columbia University
Sponsor class: OTHER
Collaborators: name: Genentech, Inc.
First posted: 2022-07-11
Enrollment: 53
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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).

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%

Primary outcomes:
measure: Number of Participants with Dose Limiting Toxicities (DLT) (Phase 1)
timeFrame: Up to 6 cycles (approximately 6 months)
measure: Hematologic ≥ Very Good Partial Response (VGPR) Rate (Phase 2)
timeFrame: Up to 6 cycles (approximately 6 months)
Secondary outcomes:
measure: Overall Organ Response Rate (ORR) (Phase 2)
timeFrame: Up to 1 year
measure: Progression Free Survival (PFS) (Phase 2)
timeFrame: Up to 1 year
measure: Overall Hematologic Response Rate (HRR) (Phase 2)
timeFrame: Up to 1 year
measure: Duration of Hematologic Response (DOHR) (Phase 2)
timeFrame: Up to 1 year
measure: Time to hematologic ≥VGPR (Phase 2)
timeFrame: Up to 1 year
measure: Time to next treatment (TTNT) (Phase 2)
timeFrame: Up to 1 year
measure: Major Organ Deterioration-Progression Free Survival (MOD-PFS) (Phase 2)
timeFrame: Up to 1 year
measure: Overall Survival (OS) (Phase 2)
timeFrame: Up to 1 year
measure: Patient-reported outcomes (PROs) (Phase 2)
timeFrame: Start of each cycle (Day 1 of each 28 day cycle) and Follow-up (every 8 weeks for up to 1 year)
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: New York
country: United States
facility: New York Presbyterian Hospital/Columbia University Irving Medical Center
state: New York
city: Milwaukee
country: United States
facility: Froedtert Hospital & the Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Columbia University
name: Rajshekhar Chakraborty, MD
role: PRINCIPAL_INVESTIGATOR
References: