Venetoclax, Daratumumab, and Dexamethasone for Systemic Light-Chain Amyloidosis With Translocation (11;14) (ALTITUDE)

NCT05486481 | Withdrawn Phase 1 DMC FDA Drug FDA Device

• 2 other identifiers: 22253NCI-2022-05530
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

This phase I/II trial tests the safety, side effects, and best dose of venetoclax, daratumumab, and dexamethasone for the treatment of systemic light-chain amyloidosis in patients with a deoxyribonucleic acid (DNA) abnormality called a translocation involving chromosomes 11 and 14, or "t(11;14)". Venetoclax works by attaching to a protein called Bcl-2, in order to kill cancer cells. Daratumumab works by binding to a target on the surface of cancer cells called Cluster of differentiation 38 (CD38). When daratumumab binds to CD38, it enables the immune system to find the cancer cell and kill it. Dexamethasone is a type of drug called a corticosteroid. A corticosteroid is a drug made of artificial steroid hormones, that are used to treat symptoms such as inflammation (swelling and irritation to a part of the body). The combination of these medications may more effectively treat patients with systemic light-chain amyloidosis and t(11;14).

Conditions

AL Amyloidosis; Light Chain (AL) Amyloidosis; Systemic Light Chain Disease

Keywords

Translocation

Outcome Measures

Primary Outcomes (4)

• Proportion of participants with reported dose limiting toxicities (Phase 1)

  A dose limiting toxicity (DLT) will be defined as an adverse event that are considered by the investigator to be at least possibly related to the study drugs and are observed within the DLT assessment window (Cycle 1, Days 1 to 28) except those that are clearly and incontrovertibly due to extraneous causes.

  Up to 1 cycle (1 cycle is equal to 28 days)

• Maximum tolerated dose (MTD) (Phase 1)

  The MTD is the last dose cohort at which no more than one instance of dose limiting toxicities (DLT) is observed among 6 participants treated. If the MTD cannot be determined due to lack of DLTs during the DLT window, the maximum dose level of venetoclax administered during the study will be declared the Recommended Phase 2 dose (RP2D).

  Up to 1 cycle (1 cycle is equal to 28 days)

• Recommended phase 2 dose (RP2D) (Phase1)

  If the MTD cannot be determined due to lack of DLTs during the DLT window, the maximum dose level of venetoclax administered during the study will be declared the Recommended phase 2 dose (RP2D).

  Up to 1 cycle (1 cycle is equal to 28 days)

• Proportion of participants who achieve a complete hematologic response (CHR) (Phase 2)

  CHR is defined per updated 2021 International Society of Amyloidosis (ISA) consensus criteria as an absence of amyloidogenic light chains (either free and/or as part of a complete immunoglobulin) defined by negative immunofixation electrophoresis of both serum and urine, and also either a free-light chain (FLC) ratio within the reference range or the uninvolved FLC concentration is greater than involved FLC concentration with or without an abnormal FLC ratio. Participants with positive serum immunofixation (S-IFE) and confirmed daratumumab immunofixation (IFE) interference, that meet all other clinical criteria for CHR, will be considered CHR. CHR requires confirmation by 1 repeat assessment. Proportion and 95% binomial exact confidence interval will be reported

  Up to 2 years

Secondary Outcomes (14)

• Percentage of participants with treatment-emergent adverse events attributable to study treatment

  Up to 2 years

• Proportion of participants with complete hematologic response (CHR) (Phase 2)

  Up to 2 years

• Overall hematologic response rate (ORR) (Phase 2)

  Up to 2 years

• Organ response rate (orRR) (Phase 2)

  Up to 2 years

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

  Up to 2 years

Study Arms (2)

Phase I (venetoclax, dexamethasone, daratumumab)

EXPERIMENTAL

All participants receive 400 mg venetoclax once a day (QD) on days 1-28 of each cycle. Depending on the number of DLTs reported for this dose-level, participants may also receive dexamethasone on days 1, 8, 15, and 22 of each cycle with or without daratumumab on days 1, 8, 15, and 22 of cycles 1-2, days 1 and 15 of cycles 3-6, then on day 1 of cycles thereafter. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

Drug: Venetoclax; Drug: Dexamethasone; Drug: Daratumumab; Device: Cyclin D1 gene (CCDN1) /immunoglobulin heavy chain (IGH) fluorescence in situ hybridization (FISH) assay

Phase II (venetoclax, dexamethasone, daratumumab)

EXPERIMENTAL

Participants will receive the RP2D of venetoclax QD on days 1-28 of each cycle, dexamethasone on days 1, 8, 15, and 22 of each cycle, and daratumumab on days 1, 8, 15, and 22 of cycles 1-2, days 1 and 15 of cycles 3-6, then on day 1 of cycles thereafter. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity

Drug: Venetoclax; Drug: Dexamethasone; Drug: Daratumumab; Device: Cyclin D1 gene (CCDN1) /immunoglobulin heavy chain (IGH) fluorescence in situ hybridization (FISH) assay

Interventions

Venetoclax DRUG

Given orally (PO)

Also known as: Venclexta

Phase I (venetoclax, dexamethasone, daratumumab); Phase II (venetoclax, dexamethasone, daratumumab)

Dexamethasone DRUG

Given PO

Also known as: Ozurdex

Phase I (venetoclax, dexamethasone, daratumumab); Phase II (venetoclax, dexamethasone, daratumumab)

Daratumumab DRUG

Given Subcutaneously (SC)

Also known as: Darzalex, Daratumumab SC

Phase I (venetoclax, dexamethasone, daratumumab); Phase II (venetoclax, dexamethasone, daratumumab)

Cyclin D1 gene (CCDN1) /immunoglobulin heavy chain (IGH) fluorescence in situ hybridization (FISH) assay DEVICE

Lab test

Phase I (venetoclax, dexamethasone, daratumumab); Phase II (venetoclax, dexamethasone, daratumumab)

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
• Histopathological diagnosis of amyloidosis based on detection by immunohistochemistry (IHC) and polarizing light microscopy of green bi-refringent material in Congo red-stained tissue specimens (in an organ other than bone marrow) or characteristic electron microscopy appearance.
• \*Considerations for specific populations where other types of amyloidosis may be encountered:
• \*\*For male subjects 70 years of age or older who have cardiac involvement only, and patients of African descent (black subjects), mass spectrometry typing of AL amyloid in a tissue biopsy is recommended to rule out other types of amyloidosis such as age-related amyloidosis or hereditary amyloidosis (ATTR mutation)
• Presence of t(11;14) on bone marrow plasma cells (BMPC) by fluorescence in-situ hybridization (FISH), performed at the University of California San Francisco (UCSF) cytogenetics laboratory
• \>= 1 prior line of therapy for the treatment of systemic AL amyloidosis.
• \*Note: Induction with only autologous stem cell transplant is considered 1 line of therapy. Steroid monotherapy treatment will not be counted as 1 prior line of therapy per National Comprehensive Cancer Network (NCCN) guidelines. Patients are not required to having progressed from the prior line of therapy
• No prior CD38-directed antibody treatment OR If the patient previously received CD38-directed antibody treatment, the patient achieved \>= partial response (PR) and did not progress while on CD38-directed antibody therapy. Progression on CD38-directed antibody treatment will be defined as progressive disease while on therapy or within 60 days of last dose.

You may not qualify if:

• Measurable disease of light chain amyloidosis as defined by at least ONE of the following:
• Serum M-protein \>= 0.5 g/dL by protein electrophoresis (routine serum protein electrophoresis and immunofixation (IFE) performed at a local laboratory),
• Serum free light chain \>= 40mg/L with an abnormal kappa:lambda ratio or
• The difference between involved and uninvolved free light chains (dFLC) \>= 20 mg/L.
• One or more organs impacted by AL amyloidosis according to consensus guidelines.
• Eastern Cooperative Oncology Group (ECOG) performance status =\< 2.
• Pretreatment clinical laboratory values meeting the following criteria during the Screening Phase (within 1 day of C1D1):
• Absolute neutrophil count \>= 1.0 × 10\^9/L without growth factor support for 7 days (14 days if pegfilgrastim).
• Hemoglobin level \>= 8.0 g/dL (\>= 5 mmol/L).
• Platelet count \>= 100 × 10\^9/L without transfusion for 14 days.
• Alanine aminotransferase level (ALT) =\< 2.5 times the upper limit of normal (ULN).
• Aspartate aminotransferase (AST) =\< 2.5 times the ULN.
• Total bilirubin level =\< 3 × ULN except for subjects with Gilbert syndrome, in which case direct bilirubin =\< 2 × ULN.
• Creatinine clearance of ≥ 30 mL/min based upon Cockcroft-Gault formula calculation or a 24-hour urine collection.
• Patients must have completed other systemic therapy \>= 14 days or investigational drug/vaccine \>= 28 days prior to treatment, focal radiation therapy \>= 14 days, surgery (other than biopsies) \>= 21 days prior to treatment, and any autologous stem cell transplant (ASCT) \>= 100 days prior to start of treatment.

Sponsors & Collaborators

• Alfred Chung, MD: lead
• Janssen Pharmaceuticals: collaborator
• AbbVie: collaborator

MeSH Terms

Conditions

Immunoglobulin Light-chain Amyloidosis; Amyloidosis

Interventions

venetoclax; Dexamethasone; Calcium Dobesilate; daratumumab; In Situ Hybridization; In Situ Hybridization, Fluorescence; Biological Assay

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Proteostasis Deficiencies; 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; Staining and Labeling; Histocytological Preparation Techniques; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Histological Techniques; Investigative Techniques; Nucleic Acid Hybridization; Genetic Techniques; Cytogenetic Analysis

Study Officials

• Alfred Chung, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: August 1, 2022
• First Posted: August 3, 2022
• Study Start: January 8, 2024
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2028
• Last Updated: March 6, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share