Cyclophosphamide, Ixazomib, and Dexamethasone in Treating Patients With Previously Untreated Symptomatic Multiple Myeloma

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by Mayo Clinic
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Mayo Clinic
ClinicalTrials.gov Identifier:
NCT01864018
First received: May 23, 2013
Last updated: September 12, 2014
Last verified: September 2014
  Purpose

This phase I/II trial studies the side effects and the best dose of cyclophosphamide when given together with ixazomib and dexamethasone in treating patients with previously untreated symptomatic multiple myeloma. 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, by stopping them from dividing, or by stopping them from spreading. Ixazomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving cyclophosphamide together with ixazomib and dexamethasone may be an effective treatment for multiple myeloma.


Condition Intervention Phase
Stage I Multiple Myeloma
Stage II Multiple Myeloma
Stage III Multiple Myeloma
Drug: ixazomib
Drug: cyclophosphamide
Drug: dexamethasone
Other: pharmacological study
Other: laboratory biomarker analysis
Other: questionnaire administration
Other: quality-of-life assessment
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase 1/2 Trial of MLN9708 in Combination With Cyclophosphamide and Dexamethasone in Patients With Previously Untreated Symptomatic Multiple Myeloma

Resource links provided by NLM:


Further study details as provided by Mayo Clinic:

Primary Outcome Measures:
  • Maximum tolerated dose of cyclophosphamide, defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least 1/3 of patients, as assessed by NCI CTCAE version 4.0 (Phase I) [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
  • Rate of complete response or VGPR (Phase II) [ Time Frame: Up to 48 weeks ] [ Designated as safety issue: No ]
    The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true success proportion will be calculated.


Secondary Outcome Measures:
  • Survival time [ Time Frame: Time from registration to death due to any cause, assessed up to 5 years ] [ Designated as safety issue: No ]
    The distribution of survival time will be estimated using the method of Kaplan-Meier.

  • Progression-free survival (PFS) [ Time Frame: Time from registration to the earliest date of documentation of disease progression or death due to any cause, assessed up to 5 years ] [ Designated as safety issue: No ]
    The distribution of PFS will be estimated using the method of Kaplan Meier.

  • Incidence of adverse events as assessed by the NCI CTCAE version 4.0 [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
    The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.


Other Outcome Measures:
  • Pharmacokinetic (PK) parameters [ Time Frame: Post-dose, 1 and 4 hours on day 1, pre-dose on days 8, 15, and 22, and day 1 of course 2 ] [ Designated as safety issue: No ]
    Will be estimated using noncompartmental analysis methods. The plasma PK parameters calculated for individual plasma ixazomib concentration-time data will include, but are not limited to: peak concentration, time to first maximum plasma concentration, and area under the curve. PK parameters will be summarized using descriptive statistics.

  • Quality of life, as assessed by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity questionnaire [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Patients will be evaluated by overall score at each time point and changes over time will be calculated. These measures will be correlated with outcome using Fisher's exact test and Kaplan-Meier methods where appropriate.


Estimated Enrollment: 51
Study Start Date: August 2013
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (ixazomib, cyclophosphamide, dexamethasone)

INDUCTION THERAPY: Patients receive ixazomib PO on days 1, 8, and 15 and cyclophosphamide PO and dexamethasone PO on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients receive ixazomib PO on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: ixazomib
Given PO
Other Names:
  • MLN9708
  • proteasome inhibitor MLN9708
Drug: cyclophosphamide
Given PO
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Drug: dexamethasone
Given PO
Other Names:
  • Aeroseb-Dex
  • Decaderm
  • Decadron
  • DM
  • DXM
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: laboratory biomarker analysis
Correlative studies
Other: questionnaire administration
Ancillary studies
Other: quality-of-life assessment
Ancillary studies
Other Name: quality of life assessment

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose of cyclophosphamide that can be combined with MLN9708 (ixazomib) and dexamethasone in patient with previously untreated symptomatic multiple myeloma (MM). (Phase I) II. To determine the complete plus very good partial response rate (>= VGPR) of MLN9708, used in combination with cyclophosphamide and dexamethasone in patients with previously untreated symptomatic MM. (Phase II)

SECONDARY OBJECTIVES:

I. To determine the progression free survival and overall survival among patients with previously untreated symptomatic MM following treatment with MLN9708 in combination with cyclophosphamide and dexamethasone followed by MLN9708 maintenance till progression.

II. To determine the toxicities associated with MLN9708 in combination with cyclophosphamide and dexamethasone in patients with previously untreated symptomatic MM.

TERTIARY OBJECTIVES:

I. To examine the pharmacokinetics of MLN9708 when used in combination with cyclophosphamide and dexamethasone.

II. To assess the incidence of neurotoxicity using patient completed questionnaires.

OUTLINE: This is a phase 1, dose-escalation study of cyclophosphamide followed by a phase II study.

INDUCTION THERAPY: Patients receive ixazomib orally (PO) on days 1, 8, and 15 and cyclophosphamide PO and dexamethasone PO on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients receive ixazomib PO on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3-6 months for 5 years.

  Eligibility

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

Inclusion Criteria:

  • Calculated creatinine clearance (using Cockcroft-Gault equation) >= 30 mL/min
  • Absolute neutrophil count (ANC) >= 1000/mm^3
  • Platelet count >= 75000/mm^3
  • Hemoglobin >= 8.0 g/dL
  • Total bilirubin =< 1.5 x upper limit of normal (ULN)
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN
  • Prior therapy for the treatment of solitary plasmacytoma is permitted, but > 14 days should have elapsed from the last day of radiation; NOTE: prior therapy with clarithromycin, dehydroepiandrosterone (DHEA), anakinra, pamidronate or zoledronic acid is permitted; any additional agents not listed must be approved by the principal investigator
  • Measurable disease of multiple myeloma as defined by at least ONE of the following:

    • Serum monoclonal protein >= 1.0 g/dL
    • > 200 mg of monoclonal protein in the urine on 24 hour electrophoresis
    • Serum immunoglobulin free light chain >= 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2
  • Previously untreated
  • Provide informed written consent
  • Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only
  • Willing to follow strict birth control measures as suggested by the study

    • Female patients: if they are of childbearing potential, agree to one of the following:

      • Practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of study drug, AND must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
      • Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject (periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception)
    • Male patients: even if surgically sterilized (ie, status post-vasectomy), must agree to one of the following:

      • Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR
      • Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
      • Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject (periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception)
  • Willing to return to return to enrolling institution for follow-up (during the active monitoring phase of the study)

Exclusion Criteria:

  • Monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma
  • Prior cytotoxic chemotherapy or corticosteroids for the treatment of multiple myeloma; NOTE: prior corticosteroid use for the treatment of non-malignant disorders is permitted
  • Diagnosed or treated for another malignancy =< 2 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease; NOTE: patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection
  • Any of the following:

    • Pregnant women
    • Nursing women
    • Men or women of childbearing potential who are unwilling to employ adequate contraception
  • Other co-morbidity which would interfere with patient's ability to participate in trial, e.g. uncontrolled infection, uncompensated heart or lung disease
  • Other concurrent chemotherapy, or any ancillary therapy considered investigational; NOTE: bisphosphonates are considered to be supportive care rather than therapy, and are thus allowed while on protocol treatment
  • Peripheral neuropathy >= grade 3 on clinical examination or grade 2 with pain during the screening period
  • Major surgery =<14 days prior to study registration
  • Systemic treatment with strong inhibitors of cytochrome P450 1A2 (CYP1A2) (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of cytochrome P450 3A4 (CYP3A4) (clarithromycin, conivaptan, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A4 inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital, Gingko biloba, St. John's wort) =< 14 days prior to registration
  • Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, congestive heart failure, unstable angina, or myocardial infarction within the past 6 months; Note: prior to study entry, any electrocardiogram (ECG) abnormality at screening must be documented by the investigator as not medically relevant
  • Radiotherapy =< 14 days prior to registration; NOTE: if the involved field is small, 7 days will be considered a sufficient interval between treatment and administration of the MLN9708
  • Known human immunodeficiency virus (HIV) positive
  • Known hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection
  • Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol
  • Known allergy to any of the study medications, their analogues or excipients in the various formulations
  • Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of MLN9708 including difficulty swallowing
  • Diarrhea > grade 1, based on the National Cancer Institute (NCI) Common Terminology Criteria (CTCAE) grading, in the absence of antidiarrheals
  • Participation in clinical trials with other investigational agents not included in this trial, =< 21 days prior to registration
  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: NCT01864018

Locations
United States, Arizona
Mayo Clinic in Arizona Recruiting
Scottsdale, Arizona, United States, 85259
Contact: Clinical Trials Referral Office    855-776-0015      
Principal Investigator: Peter Bergsagel, M.D.         
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Clinical Trials Referral Office    855-776-0015      
Principal Investigator: Shaji K. Kumar         
Sponsors and Collaborators
Mayo Clinic
Investigators
Principal Investigator: Shaji Kumar Mayo Clinic
  More Information

No publications provided

Responsible Party: Mayo Clinic
ClinicalTrials.gov Identifier: NCT01864018     History of Changes
Other Study ID Numbers: MC1382, NCI-2013-01042, X16009, MC1382, P30CA015083
Study First Received: May 23, 2013
Last Updated: September 12, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Blood Protein Disorders
Cardiovascular Diseases
Hematologic Diseases
Hemorrhagic Disorders
Hemostatic Disorders
Immune System Diseases
Immunoproliferative Disorders
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Paraproteinemias
Vascular Diseases
BB 1101
Cyclophosphamide
Dexamethasone
Dexamethasone 21-phosphate
Dexamethasone acetate
Proteasome Inhibitors
Alkylating Agents
Anti-Inflammatory Agents
Antiemetics
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antineoplastic Agents, Hormonal
Antirheumatic Agents
Autonomic Agents
Central Nervous System Agents
Enzyme Inhibitors

ClinicalTrials.gov processed this record on October 21, 2014