RecruitingInterventionalPhase 1/Phase 2

An Open-label Phase I/II Trial of Venetoclax-Dexamethasone in Relapsed and/or Refractory t(11;14) Systemic Light-Chain Amyloidosis

NCT ID: NCT05451771Sponsor: Columbia UniversityLast updated: 2026-06-18

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).

Arms & interventions

DrugVenetoclax Oral Tablet, 200 mg
200 mg oral tablet daily
DeviceFISH assay
Cytogenetic analysis is intended for evaluation of relapsed/refractory AL amyloidosis using fluorescence in situ hybridization (FISH) using known translocation probes. Bone marrow aspirate (BMA) samples are collected in lavender top (Ethylenediaminetetraacetic acid (EDTA)) or green top (Sodium heparin) tubes. Specimen tubes shall be transported at room temperature to the laboratory on the same day of collection.
DrugVenetoclax Oral Tablet, 400 mg
400 mg oral tablet daily
DrugDexamethasone Oral, 10 mg
10 mg oral tablet weekly
DrugDexamethasone Oral, 20 mg
20 mg oral tablet weekly
DrugDaratumumab Injection
Daratumumab will be administered at a dose of 16 mg/kg by IV infusion once weekly for weeks 1 to 8, every 2 weeks for weeks 9 to 24, and every 4 weeks thereafter for a maximum of 6 months of therapy. If subcutaneous formulation is available, participants can also receive subcutaneous daratumumab (1800 mg in 15 ml) in the same schedule.
DrugBendamustine
Bendamustine will be given at an initial dose of 100 mg/m\^2 intravenously on days 1 and 2 in each 28-day cycle.
DrugPomalidomide
Pomalidomide will be administered at an initial dose of 2 mg per days on days 1-21 every 28 days.
DrugIxazomib
Ixazomib will be administered at an initial dose of 4 mg per days on days 1, 8, and 15 every 28 days.
DrugVenetoclax MTD with Dexamethasone
Venetoclax MTD (200 mg or 400 mg) with Dexamethasone (10 mg or 20 mg) as determined by the phase I results

Outcome measures

Primary

Number of Participants with Dose Limiting Toxicities (DLT) (Phase 1)
The number of participants with dose limiting toxicities for each treatment dose will be used to determine the MTD. Dose limiting toxicity defined as grade 4 neutropenia lasting more than 5 days, any grade febrile neutropenia, grade 4 thrombocytopenia, grade 3 thrombocytopenia with bleeding, other therapy related non-hematologic toxicity of grade 2 or higher that requires discontinuation of therapy, clinical tumor lysis syndrome (TLS), laboratory TLS if the metabolic abnormalities are considered clinically significant by the investigator. All other grade 3 or higher adverse events (AEs) will be considered as DLTs with a few exceptions.
Time frame: Up to 6 cycles (approximately 6 months)
Hematologic ≥ Very Good Partial Response (VGPR) Rate (Phase 2)
Hematologic ≥VGPR rate defined as proportion of participants achieving VGPR, low serum differential free light chain concentration (dFLC) partial response (PR), or a complete (CR). VGPR is defined as the difference between involved and uninvolved free light chain (FLC) \[dFLC\] \< 40 mg/L. Low dFLC PR is defined as achieving a dFLC\<10 mg/L, low dFLC PR will be considered as a deep hematologic response and included in the ≥VGPR category). CR is defined as negative serum and urine immunofixation electrophoresis along with a serum free light chain ratio that lies within the normal range or skewed towards the non-amyloid forming light chain, as per institutional laboratory values
Time frame: Up to 6 cycles (approximately 6 months)

Secondary

Overall Organ Response Rate (ORR) (Phase 2)
Time frame: Up to 1 year
Progression Free Survival (PFS) (Phase 2)
Time frame: Up to 1 year
Overall Hematologic Response Rate (HRR) (Phase 2)
Time frame: Up to 1 year
Duration of Hematologic Response (DOHR) (Phase 2)
Time frame: Up to 1 year
Time to hematologic ≥VGPR (Phase 2)
Time frame: Up to 1 year
Time to next treatment (TTNT) (Phase 2)
Time frame: Up to 1 year
Major Organ Deterioration-Progression Free Survival (MOD-PFS) (Phase 2)
Time frame: Up to 1 year
Overall Survival (OS) (Phase 2)
Time frame: Up to 1 year
Patient-reported outcomes (PROs) (Phase 2)
Time frame: Start of each cycle (Day 1 of each 28 day cycle) and Follow-up (every 8 weeks for up to 1 year)

Eligibility criteria

Sex: AllAge: 18 Years and olderHealthy volunteers: No

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%

Study locations (6)

The University of Alabama at Birmingham Hospital

Birmingham, Alabama, 35294

Withdrawn

Boston Medical Center

Boston, Massachusetts, 02118

Recruiting

Boston Medical Center · Contact

617-638-8265

Vaishali Sanchorawala, MD · Principal Investigator

Mayo Clinic Rochester

Rochester, Minnesota, 55905

Recruiting

Mayo Clinic Rochester · Contact

8557760015

Prashant Kapoor, MD · Principal Investigator

Washington University School of Medicine

St Louis, Missouri, 63110

Active Not Recruiting

New York Presbyterian Hospital/Columbia University Irving Medical Center

New York, New York, 10032

Recruiting

Research Nurse Navigator · Contact

212-342-5162 cancerclinicaltrials@cumc.columbia.edu

Rajshekhar Chakraborty, MD · Principal Investigator

Froedtert Hospital & the Medical College of Wisconsin

Milwaukee, Wisconsin, 53226

Recruiting

Froedtert Hospital & the Medical College of Wisconsin · Contact

414-805-8900 cccto@mcw.edu

Anita D'Souza, MD · Principal Investigator

References

Locke M, Nieto M. AL Amyloidosis: Current Treatment and Outcomes. Adv Hematol. 2025 Mar 3;2025:7280805. doi: 10.1155/ah/7280805. eCollection 2025.(PubMed)