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

ConditionAL Amyloidosis
Trial statusRecruiting
Trial phasePhase 1, Phase 2
Trial typeInterventional
Biological sexAll
Age18+
SponsorColumbia University

About this trial

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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

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

Disqualifiers

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

Trial design

Design model

Parallel

Treatments tested in this trial

  • Venetoclax Oral Tablet, 200 mg

    Drug

    200 mg oral tablet daily

  • 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.

  • Venetoclax Oral Tablet, 400 mg

    Drug

    400 mg oral tablet daily

  • Dexamethasone Oral, 10 mg

    Drug

    10 mg oral tablet weekly

  • Dexamethasone Oral, 20 mg

    Drug

    20 mg oral tablet weekly

  • 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.

  • 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.

  • Pomalidomide

    Drug

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

  • Ixazomib

    Drug

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

  • 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

Treatment groups

53 Participants
are divided into 6 treatment groups

6

Treatment groups

See each treatment group below.

Group A: Phase 1: Venetoclax 200 mgExperimental treatment 2 interventions
Group B: Phase 1: Venetoclax 400mgExperimental treatment 2 interventions
Group C: Phase 1: Venetoclax 400mg + Dexamethasone 10 mgExperimental treatment 3 interventions
Group D: Phase 1: Venetoclax 400mg + Dexamethasone 20 mgExperimental treatment 3 interventions
Group E: Phase 2: Venetoclax MTD with DexamethasoneExperimental treatment 1 intervention
Group F: Phase 2: Control Arm (Investigator's Choice)Active comparator 5 interventions

Trial outcomes

Primary outcomes

1

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)
2

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 outcomes

1

Overall Organ Response Rate (ORR) (Phase 2)

ORR defined as proportion of evaluable participants achieving organ response in each involved organ

Time frame
Up to 1 year
2

Progression Free Survival (PFS) (Phase 2)

PFS defined as time from the date of enrollment to hematologic progression or death, whichever is earlier

Time frame
Up to 1 year
3

Overall Hematologic Response Rate (HRR) (Phase 2)

HRR defined as proportion of patients achieving partial response (PR) or better

Time frame
Up to 1 year
4

Duration of Hematologic Response (DOHR) (Phase 2)

DOHR defined as time from the date of first documentation of hematologic response to the date of first documented hematologic disease progression

Time frame
Up to 1 year

Other outcomes

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

Columbia University

Lead sponsor

Genentech, Inc.

Collaborator

Source ClinicalTrials.gov
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