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English Lavender

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)

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)

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)

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)

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

Participants will receive one of the following as determined by the investigator:

Daratumumab, Pomalidomide, Bendamustine, or Ixazomib (+/- dexamethasone)

Venetoclax Oral Tablet, 200 mg

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.

FISH assay

Venetoclax Oral Tablet, 400 mg

Dexamethasone Oral, 10 mg

Dexamethasone Oral, 20 mg

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.

Daratumumab Injection

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

Bendamustine

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

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

Research Nurse Navigator

Rajshekhar Chakraborty, MD

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.

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).

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

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

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.

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

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

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

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

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

Time to hematologic ≥VGPR defined as time from the first dose of study treatment to achievement of deep hematologic response (VGPR, low dFLC PR, or a CR)

TTNT defined as time from the date of enrollment to initiation of a subsequent line of therapy

MOD-PFS defined as time from the date of enrollment to one of the following events (whichever occurs first): death, clinical manifestation of cardiac/renal failure, or development of hematologic progression of disease

OS defined as the time from the date of enrollment to death from any cause

PROs defined as longitudinal score of "Physical Functioning" domain of Patient-Reported Outcomes Measurement Information System (PROMIS)-29 Profile v2.0 The Physical Functioning domain contains four items with a 1 (unable to do) to 5 (without any difficulty) numeric rating.

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