Hydroxychloroquine and Bortezomib in Treating Patients With Relapsed or Refractory Multiple Myeloma

The recruitment status of this study is unknown because the information has not been verified recently.
Verified July 2009 by National Cancer Institute (NCI).
Recruitment status was  Recruiting
Sponsor:
Collaborator:
Information provided by:
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00568880
First received: December 5, 2007
Last updated: July 7, 2009
Last verified: July 2009
  Purpose

RATIONALE: Drugs used in chemotherapy, such as hydroxychloroquine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving hydroxychloroquine together with bortezomib may kill more cancer cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of hydroxychloroquine when given together with bortezomib and to see how well it works in treating patients with relapsed or refractory multiple myeloma.


Condition Intervention Phase
Multiple Myeloma and Plasma Cell Neoplasm
Drug: bortezomib
Drug: hydroxychloroquine
Other: immunologic technique
Other: laboratory biomarker analysis
Other: mass spectrometry
Other: pharmacological study
Procedure: biopsy
Phase 1
Phase 2

Study Type: Interventional
Study Design: Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/II Trial of Hydroxychloroquine Added to Bortezomib for Relapsed/Refractory Myeloma

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Dose-limiting toxicity [ Designated as safety issue: Yes ]
  • Maximum tolerated dose of hydroxychloroquine [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Myeloma response (stringent complete response [sCR], CR, very good partial response [VGPR], PR, stable disease, and progressive disease) [ Designated as safety issue: No ]
  • Overall survival [ Designated as safety issue: No ]
  • Time to treatment failure [ Designated as safety issue: No ]
  • Progression-free survival [ Designated as safety issue: No ]
  • Time to response [ Designated as safety issue: No ]
  • Duration of overall response [ Designated as safety issue: No ]
  • Correlation of hydroxychloroquine and its metabolites blood levels with efficacy by mass spectrometry [ Designated as safety issue: No ]
  • Pre- and post-bortezomib proteasome inhibition assays [ Designated as safety issue: No ]
  • Bone marrow aspirate and peripheral blood mononuclear cell analysis for aggresome formation, autophagy inhibition, and apoptosis [ Designated as safety issue: No ]
  • Rate of overall adverse events and serious adverse events [ Designated as safety issue: Yes ]

Estimated Enrollment: 50
Study Start Date: November 2007
Estimated Primary Completion Date: November 2009 (Final data collection date for primary outcome measure)
Detailed Description:

OBJECTIVES:

Primary

  • To establish the dose-limiting toxicities and maximum tolerated dose of hydroxychloroquine when added to a standard-dose regimen of bortezomib for treatment of patients with relapsed or refractory multiple myeloma.

Secondary

  • To obtain a preliminary estimate of the toxicity rate and response rate of this combination at the maximum tolerated dose.
  • To confirm preclinical evidence showing synergistic effects of hydroxychloroquine and bortezomib by correlating response rate with blood levels of hydroxychloroquine and degree of autophagy inhibition in repeated bone marrow samples.

OUTLINE: This is a phase I dose-escalation study of hydroxychloroquine followed by a phase II study.

  • Phase I: Patients receive oral hydroxychloroquine every other day for 2 weeks. Patients then receive oral hydroxychloroquine 1-3 times daily or every other day and bortezomib IV twice a week for 2 weeks. Treatment with hydroxychloroquine and bortezomib repeats every 3 weeks for at least 2 courses in the absence of disease progression or unacceptable toxicity. Once the maximum tolerated dose (MTD) for hydroxychloroquine is determined, additional patients are accrued to the phase II portion of the study.
  • Phase II: Patients receive hydroxychloroquine (at the MTD determined in phase I) and bortezomib as in phase I.

Blood and bone marrow samples are collected periodically during the study for correlative studies by mass spectrometry, proteasome inhibition assays, pharmacokinetic analysis and assessment of aggresome formation, autophagy inhibition, and apoptosis by protein electrophoresis and serum free light-chain analysis.

After completion of study treatment, patients are followed periodically.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Histologically confirmed multiple myeloma
  • Must meet 1 of the following criteria:

    • Relapsed disease documented
    • Disease refractory to at least one prior treatment regimen (may include autologous and allogeneic bone marrow transplantation)
    • In need of further therapy for myeloma, as determined by the patient's treating physician
  • No known CNS involvement

    • Calvarial lytic lesions or plasmacytomas are not exclusion criteria if there is no CNS involvement

PATIENT CHARACTERISTICS:

  • ECOG performance status 0-2
  • Life expectancy ≥ 3 months
  • Absolute neutrophil count ≥ 500/μL
  • Hemoglobin ≥ 7 g/dL (with or without transfusion support)
  • Platelets ≥ 25,000/μL (with or without transfusion support)
  • Total bilirubin ≤ 2 x upper limit of normal (ULN)
  • AST/ALT ≤ 2.5 x ULN
  • Creatinine ≤ 2 times ULN
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception prior to and during study treatment
  • No baseline peripheral neuropathy ≥ grade 2
  • No history of allergic reactions to compounds of similar chemical or biological composition to bortezomib or hydroxychloroquine
  • No known macular degeneration or retinopathy (diabetic or otherwise), porphyria, or psoriasis

    • Well-controlled psoriasis allowed provided under the care of a specialist who agrees to monitor the patient for exacerbations
  • No other conditions that would require therapy with hydroxychloroquine, including but not limited to, any of the following:

    • Systemic lupus
    • Rheumatoid arthritis
    • Porphyria cutanea tarda
    • Malaria treatment or prophylaxis
  • No concurrent or prior malignancy except for the following:

    • Basal cell or squamous cell carcinoma of the skin
    • Treated carcinoma in situ
    • Localized prostate adenocarcinoma (stage T1a or T1b) with a stable PSA for a period of at least 4 months allowed
    • Patients with a prior malignancy treated with chemotherapy, biologic agents, and/or radiation are eligible for this study if they have completed therapy ≥ 4 years previously with no evidence of recurrent disease
    • Patients with a prior malignancy treated with surgery alone are eligible for this study if they have completed therapy ≥ 2 years previously with no evidence of recurrent disease
  • No uncontrolled intercurrent illness including, but not limited to, any of the following:

    • Uncontrolled ongoing infection
    • Symptomatic congestive heart failure
    • Unstable angina pectoris
    • Cardiac arrhythmia
    • Psychiatric illness or social situations that would limit compliance with study requirements
  • No prior dose-limiting toxicity due to bortezomib administration
  • No inability to understand or unwillingness to sign the informed consent document

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • At least 7 days since prior corticosteroids
  • At least 14 days since prior antimyeloma agents, including thalidomide or lenalidomide
  • Concurrent therapy with bisphosphonates allowed at the discretion of the treating physician
  • Concurrent hematopoietic growth factors allowed, including filgrastim (G-CSF) or pegfilgrastim, epoetin alpha, and darbepoetin alpha
  • Concurrent participation in non-treatment studies allowed, if it will not interfere with participation in this study
  • No concurrent radiotherapy except local radiotherapy during the treatment phase of this study for palliation of pain or prevention of fracture
  • No concurrent treatment with a different investigational regimen
  • No concurrent therapy with other anticancer agents
  • No concurrent participation in other investigational trials that involve novel therapies
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00568880

Locations
United States, Pennsylvania
Abramson Cancer Center of the University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104-4283
Contact: Clinical Trials Office - Abramson Cancer Center of the Univers    800-474-9892      
Sponsors and Collaborators
University of Pennsylvania
Investigators
Study Chair: Dan Vogl, MD Abramson Cancer Center of the University of Pennsylvania
  More Information

Additional Information:
No publications provided

Responsible Party: Dan Vogl, Abramson Cancer Center of the University of Pennsylvania
ClinicalTrials.gov Identifier: NCT00568880     History of Changes
Other Study ID Numbers: CDR0000577505, UPCC-01407, UPCC-IRB-806149
Study First Received: December 5, 2007
Last Updated: July 7, 2009
Health Authority: Unspecified

Keywords provided by National Cancer Institute (NCI):
stage I multiple myeloma
stage II multiple myeloma
stage III multiple myeloma
refractory multiple myeloma

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Plasmacytoma
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Bortezomib
Hydroxychloroquine
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antirheumatic Agents

ClinicalTrials.gov processed this record on October 01, 2014