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

Primary Purpose

AL Amyloidosis

Status

Recruiting

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Venetoclax Oral Tablet, 200 mg

FISH assay

Venetoclax Oral Tablet, 400 mg

Dexamethasone Oral, 10 mg

Dexamethasone Oral, 20 mg

Daratumumab Injection

Bendamustine

Pomalidomide

Ixazomib

Venetoclax MTD with Dexamethasone

About this trial

This is an interventional treatment trial for AL Amyloidosis focused on measuring Light Chain Amyloidosis, Protein Misfolding Disorder

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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%

Sites / Locations

New York Presbyterian Hospital/Columbia University Irving Medical CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Active Comparator

Arm Label

Phase 1: Venetoclax 200 mg

Phase 1: Venetoclax 400mg

Phase 1: Venetoclax 400mg + Dexamethasone 10 mg

Phase 1: Venetoclax 400mg + Dexamethasone 20 mg

Phase 2: Venetoclax MTD with Dexamethasone

Phase 2: Control Arm (Investigator's Choice)

Arm Description

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)

Outcomes

Primary Outcome Measures

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.

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

Secondary Outcome Measures

Overall Organ Response Rate (ORR) (Phase 2)

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

Progression Free Survival (PFS) (Phase 2)

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

Overall Hematologic Response Rate (HRR) (Phase 2)

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

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 to hematologic ≥VGPR (Phase 2)

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)

Time to next treatment (TTNT) (Phase 2)

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

Major Organ Deterioration-Progression Free Survival (MOD-PFS) (Phase 2)

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

Overall Survival (OS) (Phase 2)

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

Patient-reported outcomes (PROs) (Phase 2)

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.

Full Information

NCT ID

NCT05451771

First Posted

July 6, 2022

Last Updated

October 26, 2022

Sponsor

Rajshekhar Chakraborty, MD

Collaborators

Genentech, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT05451771

Brief Title

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

2. Study Status

Record Verification Date

October 2022

Overall Recruitment Status

Recruiting

Study Start Date

October 26, 2022 (Actual)

Primary Completion Date

September 2026 (Anticipated)

Study Completion Date

September 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Rajshekhar Chakraborty, MD

Collaborators

Genentech, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Yes

Data Monitoring Committee

Yes

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

AL Amyloidosis

Keywords

Light Chain Amyloidosis, Protein Misfolding Disorder

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

53 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Phase 1: Venetoclax 200 mg

Arm Type

Experimental

Arm Description

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)

Arm Title

Phase 1: Venetoclax 400mg

Arm Type

Experimental

Arm Description

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)

Arm Title

Phase 1: Venetoclax 400mg + Dexamethasone 10 mg

Arm Type

Experimental

Arm Description

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)

Arm Title

Phase 1: Venetoclax 400mg + Dexamethasone 20 mg

Arm Type

Experimental

Arm Description

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)

Arm Title

Phase 2: Venetoclax MTD with Dexamethasone

Arm Type

Experimental

Arm Description

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

Arm Title

Phase 2: Control Arm (Investigator's Choice)

Arm Type

Active Comparator

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

Venetoclax Oral Tablet, 200 mg

Other Intervention Name(s)

Venclexta

Intervention Description

200 mg oral tablet daily

Intervention Type

Device

Intervention Name(s)

FISH assay

Other Intervention Name(s)

t(11;14) FISH assay

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Venetoclax Oral Tablet, 400 mg

Other Intervention Name(s)

Venclexta

Intervention Description

400 mg oral tablet daily

Intervention Type

Drug

Intervention Name(s)

Dexamethasone Oral, 10 mg

Other Intervention Name(s)

Decadron, Hemady

Intervention Description

10 mg oral tablet weekly

Intervention Type

Drug

Intervention Name(s)

Dexamethasone Oral, 20 mg

Other Intervention Name(s)

Decadron, Hemady

Intervention Description

20 mg oral tablet weekly

Intervention Type

Drug

Intervention Name(s)

Daratumumab Injection

Other Intervention Name(s)

Darzalex

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Bendamustine

Other Intervention Name(s)

Treanda

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Pomalidomide

Other Intervention Name(s)

Pomalyst

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Ixazomib

Other Intervention Name(s)

Ninlaro

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Venetoclax MTD with Dexamethasone

Intervention Description

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

Primary Outcome Measure Information:

Title

Number of Participants with Dose Limiting Toxicities (DLT) (Phase 1)

Description

Time Frame

Up to 6 cycles (approximately 6 months)

Title

Hematologic ≥ Very Good Partial Response (VGPR) Rate (Phase 2)

Description

Time Frame

Up to 6 cycles (approximately 6 months)

Secondary Outcome Measure Information:

Title

Overall Organ Response Rate (ORR) (Phase 2)

Description

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

Time Frame

Up to 1 year

Title

Progression Free Survival (PFS) (Phase 2)

Description

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

Time Frame

Up to 1 year

Title

Overall Hematologic Response Rate (HRR) (Phase 2)

Description

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

Time Frame

Up to 1 year

Title

Duration of Hematologic Response (DOHR) (Phase 2)

Description

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

Title

Time to hematologic ≥VGPR (Phase 2)

Description

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)

Time Frame

Up to 1 year

Title

Time to next treatment (TTNT) (Phase 2)

Description

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

Time Frame

Up to 1 year

Title

Major Organ Deterioration-Progression Free Survival (MOD-PFS) (Phase 2)

Description

Time Frame

Up to 1 year

Title

Overall Survival (OS) (Phase 2)

Description

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

Time Frame

Up to 1 year

Title

Patient-reported outcomes (PROs) (Phase 2)

Description

Time Frame

Start of each cycle (Day 1 of each 28 day cycle) and Follow-up (every 8 weeks for up to 1 year)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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%

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Research Nurse Navigator

Phone

212-342-5162

cancerclinicaltrials@cumc.columbia.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Rajshekhar Chakraborty, MD

Organizational Affiliation

Columbia University

Official's Role

Principal Investigator

Facility Information:

Facility Name

New York Presbyterian Hospital/Columbia University Irving Medical Center

City

New York

State/Province

New York

ZIP/Postal Code

10032

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Research Nurse Navigator

Phone

212-342-5162

cancerclinicaltrials@cumc.columbia.edu

First Name & Middle Initial & Last Name & Degree

Rajshekhar Chakraborty, MD

12. IPD Sharing Statement

Learn more about this trial

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

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