Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II, Phase I	Biomarker/Laboratory analysis, Treatment	Active	18 and over	NCI	UPCC-01407 UPCC 01407, UPCC-IRB-806149, NCT00568880

Objectives

Primary

1. 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

1. To obtain a preliminary estimate of the toxicity rate and response rate of this combination at the maximum tolerated dose.
2. 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.

Entry 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

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

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

Expected Enrollment

Outcomes

Dose-limiting toxicity
Maximum tolerated dose of hydroxychloroquine

Myeloma response (stringent complete response [sCR], CR, very good partial response [VGPR], PR, stable disease, and progressive disease)
Overall survival
Time to treatment failure
Progression-free survival
Time to response
Duration of overall response
Correlation of hydroxychloroquine and its metabolites blood levels with efficacy by mass spectrometry
Pre- and post-bortezomib proteasome inhibition assays
Bone marrow aspirate and peripheral blood mononuclear cell analysis for aggresome formation, autophagy inhibition, and apoptosis
Rate of overall adverse events and serious adverse events

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.

Trial Contact Information

Trial Lead Organizations

Abramson Cancer Center of the University of Pennsylvania

Dan Vogl, MD, Protocol chair		Ph: 215-662-7910

U.S.A.
Pennsylvania
	Philadelphia
	Abramson Cancer Center of the University of Pennsylvania
		Clinical Trials Office - Abramson Cancer Center of the University of Pennsylvania	Ph:  800-474-9892

Registry Information
Official Title		A Phase I/II Trial of Hydroxychloroquine added to Bortezomib for Relapsed/Refractory Myeloma
Trial Start Date		2007-11-08
Trial Completion Date		2009-11-08 (estimated)
Registered in ClinicalTrials.gov		NCT00568880
Date Submitted to PDQ		2007-11-12
Information Last Verified		2009-07-05
NCI Grant/Contract Number		CA16520

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