Clinical trial NCT01438177: Chloroquine in Combination With VELCADE and Cyclophosphamide for Relapsed and Refractory Multiple Myeloma
Official title: A Phase II, Trial of Chloroquine in Combination With VELCADE and Cyclophosphamide in Patients With Relapsed and Refractory Myeloma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Multiple Myeloma
Keywords: myeloma
multiple myeloma
relapsed myeloma
refractory myeloma
Lead sponsor: NYU Langone Health
Sponsor class: OTHER
Collaborators: name: Millennium Pharmaceuticals, Inc.
First posted: 2011-09-21
Enrollment: 11
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This pilot phase II trial studies how well giving bortezomib and cyclophosphamide together with chloroquine works in treating patients with relapsed or refractory multiple myeloma.

Detailed description: Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Chloroquine may help chemotherapy drugs work better by making cancer cells more sensitive to the drug. Giving bortezomib and cyclophosphamide together with chloroquine may kill more cancer cells.

Eligibility criteria: Inclusion Criteria:

1. Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
2. Female subject is either post-menopausal for at least 1 year before the screening visit, is surgically sterilized or if they are of childbearing potential, agree to practice 2 effective methods of contraception from the time of signing the informed consent form through 30 days after the last dose of VELCADE, or agree to completely abstain from heterosexual intercourse. Male subjects, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the following: practice effective barrier contraception during the entire study treatment period and through a minimum of 30 days after the last dose of study drug, or completely abstain from heterosexual intercourse.
3. Diagnosis of multiple myeloma based on standard criteria as follows:

   Major Criteria:

   I. Plasmacytomas on tissue biopsy

   II. Bone marrow plasmacytosis (\>30% plasma cells)

   III. Monoclonal immunoglobulin spike on serum electrophoresis (IgG \>3.5 G/dL or IgA \> 2.0 G/dL) or kappa or lambda light chain excretion\> 1 G/day on 24 hour urine protein electrophoresis

   Minor Criteria
   1. Bone marrow plasmacytosis (10 to 30% plasma cells)
   2. Monoclonal immunoglobulin present but of lesser magnitude than given under major criteria
   3. Lytic bone lesions
   4. Normal IgM \< 50 mg/dL, IgA \< 100 mg/dL, or IgG \< 600 mg/dL

   Any of the following sets of criteria will confirm the diagnosis of Multiple Myeloma:
   * Any two of the major criteria
   * Major criterion I plus minor criterion b, c, or d
   * Major criterion III plus minor criterion a or c
   * Minor criteria a, b and c or a, b and d
4. Measurable disease, defined as a monoclonal immunoglobulin spike on serum electrophoresis of ≥ 1 Gm/dL and/or urine monoclonal immunoglobulin spike of ≥ 200 mg/24 hours.
5. Patients must have refractory myeloma as defined by a greater than 25% increase in their M-protein. They should have progressed on a combination of VELCADE and cyclophosphamide.
6. Non-secretors must have measurable protein by Freelite or measurable disease such as plasmacytoma to be eligible.
7. Karnofsky performance status ≥ 50
8. Patients treated with local radiotherapy with or without a brief exposure to steroids are eligible. Patients who require concurrent radiotherapy should have entry to the protocol deferred until the radiotherapy is completed
9. Meets the following pretreatment laboratory criteria at Baseline (Day 1 of Cycle 1, before study drug administration)

   * Absolute neutrophil count ≥ 0.5 x 10\^3/uL
   * Calculated or measured creatinine clearance ≥ 30 mL/min
10. Age 18 years or older

Exclusion Criteria:

1. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein (M-protein) and skin changes)
2. Plasma cell leukemia
3. Receiving steroids daily for other medical conditions, e.g., asthma, systemic lupus erythematosis, rheumatoid arthritis
4. Infection not controlled by antibiotics
5. HIV infection. Patients should provide consent for HIV testing according to the institution's standard practice
6. Known active hepatitis B or C
7. Patient had myocardial infarction within 6 months prior to enrollment, New York Hospital Association (NYHA) Class III or IV heart failure, (see appendix D), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at screening must be documented by the investigator as not medically relevant.
8. Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.
9. Radiation therapy within 3 weeks before randomization. Enrollment of subjects who require concurrent radiotherapy (which must be localized in its field size) should be deferred until the radiotherapy is completed and 3 weeks have elapsed since the last date of therapy.
10. Other serious medical or psychiatric illness that could potentially interfere with the completion of treatment according to this protocol
11. Female subject is pregnant or lactating. Confirmation that the subject is not pregnant must be established by a negative serum B-human chorionic gonadotropin (B hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for postmenopausal or surgically sterilized women.
12. Patient has \> Grade 2 peripheral neuropathy
13. Patient has known hypersensitivity to VELCADE, boron or mannitol, quinidine or quinidine derivatives or to cyclophosphamide or any component of the formulation.
14. Participation in clinical trials with other investigational agents not included in this trial, within 14 days of the start of this trial and throughout the duration of this trial.
15. Patients with preexisting retinal or visual field changes.
16. Patient has \> 1.5 x upper limit of normal Total Bilirubin

Primary outcomes:
measure: Response Rate (CR + PR After 2 Cycles)
timeFrame: Up to 2 years
Secondary outcomes:
measure: Number of Participants With Adverse Events of Grade 3 or Higher
timeFrame: Treatment period plus 30 days post-treatment
measure: Percentage of Subjects Who Have Complete Response or Partial Response and Have 2+ or Higher Autophagy
timeFrame: until clinical response (up to 2 years)
measure: Median Duration of Response of This Regimen
timeFrame: up to 2 years
Other outcomes:
Locations:
city: New York
country: United States
facility: NYU Cancer Institute
state: New York
Study officials:
affiliation: NYU Langone Medical Center
name: Michael Grossbard, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, Gertz M, Dimopoulos M, Westin J, Sonneveld P, Ludwig H, Gahrton G, Beksac M, Crowley J, Belch A, Boccadaro M, Cavo M, Turesson I, Joshua D, Vesole D, Kyle R, Alexanian R, Tricot G, Attal M, Merlini G, Powles R, Richardson P, Shimizu K, Tosi P, Morgan G, Rajkumar SV; International Myeloma Working Group. International uniform response criteria for multiple myeloma. Leukemia. 2006 Sep;20(9):1467-73. doi: 10.1038/sj.leu.2404284. Epub 2006 Jul 20.