Combined Carfilzomib and Hydroxychloroquine in Patients With Relapsed/Refractory Multiple Myeloma

NCT04163107 | Completed Phase 1 DMC

• 2 other identifiers: 2019/9222019-000986-19
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 2

Brief Summary

Multiple myeloma (MM) is a neoplastic expansion of bone marrow plasma cells. Despite advances in treatment in recent years, MM is still a fatal disease. MM is characterized by the ability of malignant cells to produce large amounts of monoclonal immunoglobulin. The secretion of these immunoglobulins can be detected as the "M-protein" in serum, and the measurement of the M-component is used both for diagnosis and to evaluate treatment response and relapse. The high load of secreted proteins in MM cells requires a efficient way to clear these proteins from the cells and targeting protein degradation is an important therapeutic target in MM. This is today done by inhibiting the proteasome, one of the two central ways cells can degrade proteins, by drugs named proteasome inhibitors (including bortezomib, ixazomib and carfilzomib). Patients become resistant to these drugs, and it is therefore likely that myeloma cells also utilise another important system for protein degradation, called autophagy. Pre-clinical studies have shown that the combination of the proteasome inhibitor carfilzomib and the autophagy inhibitor hydroxychloroquine increases myeloma cell death and that hydroxychloroquine is able to reverse MM cell resistance to carfilzomib. This is the rationale for this study, where the investigators add the autophagy inhibitor hydroxychloroquine to a standard regime of carfilzomib and dexamethasone, to determine a maximum tolerated dose of this combination and to study tolerability.

Conditions

Multiple Myeloma

Keywords

Drug Therapy; Administration and Dosage; Hydroxychloroquine; Carfilzomib; Dexamethasone; Drug Therapy, Combination

Outcome Measures

Primary Outcomes (1)

• maximum tolerated dose of hydroxychloroquine when added to standard-dose regimen of carfilzomib/dexamethasone

  3 months

Secondary Outcomes (1)

• estimate of toxicity rate of hydroxychloroquine when added at a maximum tolerated dose to standard-dose regimen of carfilzomib/dexamethasone

  3 months

Study Arms (1)

Combination treatment of carfilzomib/dexamethasone/HCQ

EXPERIMENTAL

Drug: Hydroxychloroquine; Drug: Carfilzomib Injection; Drug: Dexamethasone

Interventions

Hydroxychloroquine DRUG

All patients start with a 14 days run-in with monotherapy with hydroxychloroquine (HCQ) at their assigned dose level. Then they continue with 6 28-day cycles of HCQ/Carfilzomib/Dexamethasone. 3 patients at each dose level.

Combination treatment of carfilzomib/dexamethasone/HCQ

Carfilzomib Injection DRUG

All patients start with a 14 days run-in with monotherapy with hydroxychloroquine (HCQ) at their assigned dose level. Then they continue with 6 28-day cycles of HCQ/Carfilzomib/Dexamethasone. 3 patients at each dose level.

Combination treatment of carfilzomib/dexamethasone/HCQ

Dexamethasone DRUG

All patients start with a 14 days run-in with monotherapy with hydroxychloroquine (HCQ) at their assigned dose level. Then they continue with 6 28-day cycles of HCQ/Carfilzomib/Dexamethasone. 3 patients at each dose level.

Combination treatment of carfilzomib/dexamethasone/HCQ

Eligibility Criteria

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

You may qualify if:

• Demographic and diagnosis
• A prior diagnosis of multiple myeloma according to International Myeloma Working Group (IMWG) criteria with documented disease progression in need of treatment at time of screening.
• \- Must meet all of the following criteria:
• Patients must have received at least two prior therapies including bortezomib and an immunomodulatory agent (may include autologous bone marrow transplantation)
• Patients must not be refractory to carfilzomib
• Relapsed or progressive disease documented according to IMWG criteria
• Patients must have evaluable multiple myeloma with at least one of the following (assessed within 21 days prior to registration)
• Serum M-protein ≥ 10 g/L, or
• Urine M-protein ≥ 200 mg/24 hours
• Involved serum immunoglobulin free light chain (SFLC) \> 100 mg/L AND abnormal kappa/lambda ratio
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Life expectancy ≥ 6 months
• Laboratory:
• Absolute neutrophil count ≥ 1.0 x 109/L
• Hemoglobin ≥ 7 g/dL (with or without transfusion support)

You may not qualify if:

• Female patients who are pregnant or lactating.
• Any reason why, in the opinion of the investigator, the patient should not participate (e.g. not able to comply with study procedures, including being unable to perform full ophthalmologic examination).

Sponsors & Collaborators

• Norwegian University of Science and Technology: lead
• St. Olavs Hospital: collaborator
• Oslo University Hospital: collaborator

Study Sites (2)

Oslo University Hospital, Department of Hematology, Oslo Myeloma Center

Oslo, Norway

Location

St. Olavs Hospital, Department of Hematology

Trondheim, Norway

Location

Related Publications (1)

• Slordahl TS, Askeland FB, Hanssen MSS, Hov H, Sundt-Hansen SM, Lindahl S, Vethe NT, Hjorth-Hansen H, Fenstad MH, Waage A, Hjertner O, Schjesvold F, Sundan A. Combined Proteasome and Autophagy Inhibition in Relapsed/Refractory Multiple Myeloma-A Phase I Trial of Hydroxychloroquine, Carfilzomib, and Dexamethasone. EJHaem. 2025 Jan 23;6(1):e1091. doi: 10.1002/jha2.1091. eCollection 2025 Feb.

  PMID: 39866949 DERIVED

MeSH Terms

Conditions

Multiple Myeloma

Interventions

Hydroxychloroquine; carfilzomib; Dexamethasone

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Chloroquine; Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Study Officials

• Torstein Baade Rø

  NTNU Department of Clinical and Molecular Medicine (IKOM)

  STUDY DIRECTOR

• Tobias S Slørdahl, MD PhD

  Norwegian University of Science and Technology

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: A single arm, dose escalation study in two centers. 3+3 design in five dose levels.

Study Record Dates

• First Submitted: November 11, 2019
• First Posted: November 14, 2019
• Study Start: January 7, 2020
• Primary Completion: December 28, 2021
• Study Completion: December 28, 2021
• Last Updated: March 18, 2022

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will share

Locations

NO (2)