Hydroxychloroquine, Cyclophosphamide, Dexamethasone, and Sirolimus in Treating Patients With Relapsed or Refractory Multiple Myeloma

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by OHSU Knight Cancer Institute
Sponsor:
Collaborator:
Information provided by (Responsible Party):
OHSU Knight Cancer Institute
ClinicalTrials.gov Identifier:
NCT01689987
First received: September 17, 2012
Last updated: July 2, 2014
Last verified: July 2014
  Purpose

This phase I trial studies the side effects and best dose of hydroxychloroquine when given together with cyclophosphamide, dexamethasone, and sirolimus in treating patients with relapsed or refractory multiple myeloma. Biological therapies, such as hydroxychloroquine, may stimulate the immune system in different ways and stop cancer cells from growing. Sirolimus may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cyclophosphamide and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells or stopping them from dividing. Giving hydroxychloroquine together with sirolimus, cyclophosphamide, and dexamethasone may be an effective treatment in patients with multiple myeloma.


Condition Intervention Phase
Refractory Multiple Myeloma
Drug: hydroxychloroquine
Drug: sirolimus
Drug: cyclophosphamide
Drug: dexamethasone
Other: laboratory biomarker analysis
Other: pharmacological study
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Dose Escalation Study of Hydroxychloroquine With Infusional Cyclophosphamide, Pulse Dexamethasone and Rapamycin in Patients With Relapsed or Refractory Multiple Myeloma

Resource links provided by NLM:


Further study details as provided by OHSU Knight Cancer Institute:

Primary Outcome Measures:
  • MTD of hydroxychloroquine, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 [ Time Frame: 56 days ] [ Designated as safety issue: Yes ]
    Incidence of dose-limiting toxicities will be tabulated for each dose level. Summarized using descriptive statistics or frequency distributions, as appropriate.


Secondary Outcome Measures:
  • Myeloma response (stringent complete response, complete response, very good partial response, partial response, stable disease, and progressive disease), as assessed by the International Myeloma Working Group [ Time Frame: Up to 12 months ] [ Designated as safety issue: No ]
    Presented with two-sided 95% exact binomial confidence interval.

  • Time to response [ Time Frame: Time from the first day of therapy until the time that measurement criteria are met for response, assessed up to 12 months ] [ Designated as safety issue: No ]
    Will be summarized by 25th, 50th (median), and 75th percentile along with 95% confidence intervals using Kaplan-Meier method.

  • Duration of overall response [ Time Frame: Time that measurement criteria are met for response (whichever status is recorded first) until the first date that recurrent or progressive disease is objectively documented, assessed up to 12 months ] [ Designated as safety issue: No ]
    Will be summarized by 25th, 50th (median), and 75th percentile along with 95% confidence intervals using Kaplan-Meier method.

  • Progression-free survival [ Time Frame: Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 12 months ] [ Designated as safety issue: No ]
    Will be summarized by 25th, 50th (median), and 75th percentile along with 95% confidence intervals using Kaplan-Meier method.


Other Outcome Measures:
  • Mean percentage of p70S6 myeloma cells [ Time Frame: Up to day 5 of course 2 ] [ Designated as safety issue: No ]
    The mean percentage of p70S6 myeloma cells and the number of autophagic vesicles per bone marrow plasma cells will be compared between responders and non-responders using two-sample test if the data follows normal distribution or if the data does not follow normal distribution, transformation or non-parametric method will be considered.

  • Number of autophagic vesicles per bone marrow plasma cells [ Time Frame: Up to day 5 of course 2 ] [ Designated as safety issue: No ]
    The mean percentage of p70S6 myeloma cells and the number of autophagic vesicles per bone marrow plasma cells will be compared between responders and non-responders using two-sample test if the data follows normal distribution or if the data does not follow normal distribution, transformation or non-parametric method will be considered.


Estimated Enrollment: 18
Study Start Date: October 2012
Estimated Primary Completion Date: April 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (HCQ, sirolimus, cy/dex)
Patients receive hydroxychloroquine PO daily on days 1-28 (days 5-28 of course 1), sirolimus PO on days -2 to 4, and cyclophosphamide IV continuously and dexamethasone PO on days 1-4. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Drug: hydroxychloroquine
Given PO
Other Name: HCQ
Drug: sirolimus
Given PO
Other Names:
  • AY 22989
  • Rapamune
  • rapamycin
  • SLM
Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Drug: dexamethasone
Given PO
Other Names:
  • Aeroseb-Dex
  • Decaderm
  • Decadron
  • DM
  • DXM
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of hydroxychloroquine (HCQ) in combination with rapamycin (sirolimus) and infusional cyclophosphamide and pulse dexamethasone (cy/dex) for patients with relapsed/ refractory multiple myeloma.

SECONDARY OBJECTIVES:

I. To evaluate biological activity and efficacy of the combination of cyclophosphamide, dexamethasone, rapamycin and hydroxychloroquine in patients with relapsed/ refractory multiple myeloma.

II. To determine whether this treatment regimen results in mammalian target of rapamycin (mTOR) and autophagy inhibition in primary myeloma cells during therapy and if this corresponds with treatment responses.

OUTLINE: This is a dose-escalation study of hydroxychloroquine.

Patients receive hydroxychloroquine orally (PO) daily on days 1-28 (days 5-28 of course 1), sirolimus PO on days -2 to 4, and cyclophosphamide intravenously (IV) continuously and dexamethasone PO on days 1-4. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 12 months.

  Eligibility

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

Inclusion Criteria:

  • Histologically confirmed multiple myeloma
  • Documented relapse or persistent disease after at least 1 prior therapy containing both bortezomib and lenalidomide; or at least 2 prior therapies containing bortezomib in one and lenalidomide in the other, or if intolerant of bortezomib and/ or lenalidomide; prior autologous and allogeneic bone marrow transplantation are allowed
  • Need for further treatment for myeloma, as determined by the patient's treating physician; this is defined as progression of clinical features (worsening anemia, renal function, bone disease, hypercalcemia, recurrent infections, and constitutional symptoms) OR biochemical progression (increasing M-spike in serum or urine, involved serum or urine free light chain over 2 consecutive time points greater than 4 weeks apart)
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Ability to understand and the willingness to sign a written informed consent document
  • Birth control is required with full barrier contraceptives or complete abstinence for the duration of time receiving therapy and for 6 months after completing the last drug taken

Exclusion Criteria:

  • History of allergic reactions to compounds of similar chemical or biological composition to rapamycin or hydroxychloroquine
  • Patients may not take any of the following medications while on study, but will be considered eligible if medication is discontinued at least 72 hours (hrs) prior to first dose of Rapamycin:

    • Carbamazepine
    • Rifabutin
    • Rifampin
    • Rifapentine
    • St. John's Wort
    • Clarithromycin
    • Cyclosporine
    • Diltiazem
    • Erythromycin
    • Itraconazole
    • Fluconazole
    • Ketoconazole
    • Telithromycin
    • Verapamil
    • Voriconazole
    • Posaconazole
  • 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)
  • Absolute neutrophil count (ANC) =< 1.0 x 10^9/L
  • Platelets =< 50 x 10^9/L for any reason
  • Serum creatinine >= 2.5 mg/dL
  • Total or direct bilirubin >= 2.0 mg/dL
  • Transaminases 2 x the upper limit of normal
  • Fasting glucose >= 200 mg/dL
  • Serum potassium < 3.4 mmol/l
  • Serum phosphorus < 2.4 mg/dl
  • 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
  • Evidence of other active malignancy, except:

    • Basal cell or squamous cell carcinoma of the skin
    • Treated carcinoma in situ
  • Uncontrolled intercurrent illness including, but not limited to, any of the following:

    • Uncontrolled ongoing infection
    • Human immunodeficiency virus (HIV)
    • Hepatitis B infection
    • Known glucose-6-phosphate dehydrogenase (G6PD) deficiency
    • Symptomatic congestive heart failure
    • Unstable angina pectoris
    • Uncontrolled cardiac arrhythmia
    • Psychiatric illness or social situations that would limit compliance with study requirements
    • Active graft-versus-host disease (GvHD)
  • Inability to understand or unwillingness to sign the informed consent document
  • Concurrent anti-myeloma therapy within:

    • 7 days of prior corticosteroids
    • 14 days of prior antimyeloma agents, including thalidomide or lenalidomide
    • 28 days of a different investigational regimen
    • 14 days of any radiation
  • Women of child-bearing who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 30 days after the last dose of study drug
  • Women who are pregnant or breastfeeding
  • History of G6PD deficiency
  • Known history of HIV infection
  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: NCT01689987

Locations
United States, Oregon
OHSU Knight Cancer Institute Recruiting
Portland, Oregon, United States, 97239
Contact: Shara Reasor-Heard    503-494-5074    reasorhe@ohsu.edu   
Principal Investigator: Emma Scott         
Sponsors and Collaborators
OHSU Knight Cancer Institute
Investigators
Principal Investigator: Emma Scott OHSU Knight Cancer Institute
  More Information

No publications provided

Responsible Party: OHSU Knight Cancer Institute
ClinicalTrials.gov Identifier: NCT01689987     History of Changes
Other Study ID Numbers: 8296, NCI-2012-01754, 8296, P30CA069533
Study First Received: September 17, 2012
Last Updated: July 2, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
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
Cyclophosphamide
Sirolimus
Everolimus
Hydroxychloroquine
Dexamethasone
Dexamethasone acetate
Dexamethasone 21-phosphate
BB 1101
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents

ClinicalTrials.gov processed this record on October 01, 2014