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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase I/II Trial of Hydroxychloroquine Added to Bortezomib for Relapsed/Refractory Myeloma

Conditions
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Multiple Myeloma and Plasma Cell Neoplasm

Intervention / Treatment
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* Drug: bortezomib
* Drug: hydroxychloroquine


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Histologically confirmed multiple myeloma Documented relapse or continued disease after at least one prior therapy (which may include autologous and allogeneic bone marrow transplantation) Need for further therapy for myeloma, as determined by the patient's treating physician Age greater than 18 years Exclusion Criteria Baseline peripheral neuropathy of grade 2 or higher History of allergic reactions to compounds of similar chemical or biologic composition to bortezomib or hydroxychloroquine Prior dose-limiting toxicity with bortezomib Known macular degeneration or retinopathy (diabetic or otherwise), porphyria, or psoriasis. Patients with well-controlled psoriasis may participate in the study provided that they are under the care of a specialist in this condition who agrees to monitor the patient for exacerbations. Other conditions that would require therapy with hydroxychloroquine, including but not limited to systemic lupus, rheumatoid arthritis, porphyria cutanea tarda, and malaria treatment or prophylaxis ECOG performance status >2 (for definition, see section 0) Life expectancy of less than 3 months Lack of adequate organ or bone marrow function based on lab values drawn ≤ 14 days before beginning treatment. Concurrent treatment with a different investigational regimen. Concurrent participation in non-treatment studies is allowed, if it will not interfere with participation in this study. Treatment with other anti-myeloma agents, including thalidomide or lenalidomide, within the 14 days prior to initiating hydroxychloroquine. Treatment with corticosteroids will be permitted up to 7 days prior to initiating hydroxychloroquine. Corticosteroids that are being used for other diseases are permitted if the dose is less than the equivalent of 20 mg of prednisone daily. Concurrent therapy with bisphosphonates through the study period is permitted at the discretion of the treating physician. Concurrent hematopoietic growth factors are also permitted, including filgrastim or pegfilgrastim, epoetin alpha, and darbepoetin alpha Known central nervous system involvement. The poor prognosis and progressive neurological dysfunction associated with central nervous system involvement would confound the evaluation of neurological and other adverse events. The presence of calvarial lytic lesions or plasmacytomas is not an exclusion criterion if there is no central nervous system involvement. Concurrent malignancy other than basal cell carcinoma of the skin, squamous cell carcinoma of the skin, any carcinoma in situ, or localized prostate adenocarcinoma (stage T1a or T1b) with a stable PSA for a period of at least 4 months. 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. Uncontrolled intercurrent illness including, but not limited to: uncontrolled ongoing infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Inability to understand the informed consent document or unwillingness to consent. Written informed consent must be obtained from all patients before study entry. Pregnancy or breastfeeding. Unwillingness to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for the duration of study participation for men and women of child-bearing potential.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hydroxychloroquine Added to Bortezomib<br>Dose escalated by cohorts Hydroxychloroquine 200-600 mg pill every other day. Bortezomib 1.0-1.3mg/m2 IV, days 1, 4, 8, and 11 of each 21 day cycle. | Drug: bortezomib<br>* bortezomib 1.0-1.3mg/m2 IV<br>* Other names: Velcade;Drug: hydroxychloroquine<br>* hydroxychloroquine 200 mg pill<br>* Other names: Plaquenil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate | This is assessed using International Working Group criteria. | Day 1 of each cycle (each cycle is 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effects of regimen on the autophagy pathway | Measure peripheral blood mononuclear cells | at baseline, prior to bortezomib on Day1 and 8 of cycle 1, prior to bortezomib on Day 1 of cycle 2 (each cycle is 21 days) | 
| AV accumulation during therapy | mean AVs / Bone Marrow plasma cell | Day 1 and 8 of the first cycle and on Day 1 of each subsequent treatment cycle (each cycle is 21 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage I multiple myeloma, stage II multiple myeloma, stage III multiple myeloma, refractory multiple myeloma