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

NCT05451771 | Recruiting Phase 1 DMC FDA Drug FDA Device

• 1 other identifier: AAAT8639
• Study Type: interventional
• Target: 53
• Locations: 1 country
• Sites: 4

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.

Conditions

AL Amyloidosis

Keywords

Light Chain Amyloidosis; Protein Misfolding Disorder

Outcome Measures

Primary Outcomes (2)

• 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.

  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

  Up to 6 cycles (approximately 6 months)

Secondary Outcomes (9)

• Overall Organ Response Rate (ORR) (Phase 2)

  Up to 1 year

• Progression Free Survival (PFS) (Phase 2)

  Up to 1 year

• Overall Hematologic Response Rate (HRR) (Phase 2)

  Up to 1 year

• Duration of Hematologic Response (DOHR) (Phase 2)

  Up to 1 year

• Time to hematologic ≥VGPR (Phase 2)

  Up to 1 year

Study Arms (6)

Phase 1: Venetoclax 200 mg

EXPERIMENTAL

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)

Drug: Venetoclax Oral Tablet, 200 mg; Device: FISH assay

Phase 1: Venetoclax 400mg

EXPERIMENTAL

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)

Device: FISH assay; Drug: Venetoclax Oral Tablet, 400 mg

Phase 1: Venetoclax 400mg + Dexamethasone 10 mg

EXPERIMENTAL

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)

Device: FISH assay; Drug: Venetoclax Oral Tablet, 400 mg; Drug: Dexamethasone Oral, 10 mg

Phase 1: Venetoclax 400mg + Dexamethasone 20 mg

EXPERIMENTAL

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)

Device: FISH assay; Drug: Venetoclax Oral Tablet, 400 mg; Drug: Dexamethasone Oral, 20 mg

Phase 2: Venetoclax MTD with Dexamethasone

EXPERIMENTAL

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

Drug: Venetoclax MTD with Dexamethasone

Phase 2: Control Arm (Investigator's Choice)

ACTIVE COMPARATOR

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

Drug: Dexamethasone Oral, 20 mg; Drug: Daratumumab Injection; Drug: Bendamustine; Drug: Pomalidomide; Drug: Ixazomib

Interventions

Venetoclax Oral Tablet, 200 mg DRUG

200 mg oral tablet daily

Also known as: Venclexta

Phase 1: Venetoclax 200 mg

FISH assay DEVICE

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.

Also known as: t(11;14) FISH assay

Phase 1: Venetoclax 200 mg; Phase 1: Venetoclax 400mg; Phase 1: Venetoclax 400mg + Dexamethasone 10 mg; Phase 1: Venetoclax 400mg + Dexamethasone 20 mg

Venetoclax Oral Tablet, 400 mg DRUG

400 mg oral tablet daily

Also known as: Venclexta

Phase 1: Venetoclax 400mg; Phase 1: Venetoclax 400mg + Dexamethasone 10 mg; Phase 1: Venetoclax 400mg + Dexamethasone 20 mg

Dexamethasone Oral, 10 mg DRUG

10 mg oral tablet weekly

Also known as: Decadron, Hemady

Phase 1: Venetoclax 400mg + Dexamethasone 10 mg

Dexamethasone Oral, 20 mg DRUG

20 mg oral tablet weekly

Also known as: Decadron, Hemady

Phase 1: Venetoclax 400mg + Dexamethasone 20 mg; Phase 2: Control Arm (Investigator's Choice)

Daratumumab Injection DRUG

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.

Also known as: Darzalex

Phase 2: Control Arm (Investigator's Choice)

Bendamustine DRUG

Bendamustine will be given at an initial dose of 100 mg/m\^2 intravenously on days 1 and 2 in each 28-day cycle.

Also known as: Treanda

Phase 2: Control Arm (Investigator's Choice)

Pomalidomide DRUG

Pomalidomide will be administered at an initial dose of 2 mg per days on days 1-21 every 28 days.

Also known as: Pomalyst

Phase 2: Control Arm (Investigator's Choice)

Ixazomib DRUG

Ixazomib will be administered at an initial dose of 4 mg per days on days 1, 8, and 15 every 28 days.

Also known as: Ninlaro

Phase 2: Control Arm (Investigator's Choice)

Venetoclax MTD with Dexamethasone DRUG

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

Phase 2: Venetoclax MTD with Dexamethasone

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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%

Sponsors & Collaborators

• Rajshekhar Chakraborty, MD: lead
• Genentech, Inc.: collaborator

Study Sites (4)

Boston Medical Center

Boston, Massachusetts, 02118, United States

RECRUITING

Mayo Clinic Rochester

Rochester, Minnesota, 55905, United States

RECRUITING

New York Presbyterian Hospital/Columbia University Irving Medical Center

New York, New York, 10032, United States

RECRUITING

Froedtert Hospital & the Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

RECRUITING

Related Publications (1)

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

  PMID: 40226119 DERIVED

MeSH Terms

Conditions

Immunoglobulin Light-chain Amyloidosis; Proteostasis Deficiencies

Interventions

venetoclax; Dexamethasone; Calcium Dobesilate; daratumumab; Bendamustine Hydrochloride; pomalidomide; ixazomib

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Amyloidosis; Metabolic Diseases; Nutritional and Metabolic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Paraproteinemias

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Butyrates; Acids, Acyclic; Carboxylic Acids; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Rajshekhar Chakraborty, MD

  Columbia University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Research Nurse Navigator

CONTACT

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

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor of Medicine

Study Record Dates

• First Submitted: July 6, 2022
• First Posted: July 11, 2022
• Study Start: October 26, 2022
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): September 1, 2026
• Last Updated: July 8, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (4)