- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01864018
Ixazomib With Cyclophosphamide and Dexamethasone in Patients With Previously Untreated Symptomatic Multiple Myeloma or Light Chain Amyloidosis
Phase 1/2 Trial of Ixazomib in Combination With Cyclophosphamide and Dexamethasone in Patients With Previously Untreated Symptomatic Multiple Myeloma or Light Chain Amyloidosis
Study Overview
Status
Conditions
Detailed Description
PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose of cyclophosphamide that can be combined with ixazomib citrate (ixazomib) and dexamethasone in patients with previously untreated symptomatic multiple myeloma (MM). (Phase I Cohort A) II. To determine the complete plus very good partial response rate (>= VGPR) of ixazomib, used in combination with cyclophosphamide and dexamethasone in patients with previously untreated symptomatic MM. (Phase II Cohort A) III. To determine the hematologic response rate of ixazomib, used in combination with cyclophosphamide and dexamethasone in patients with previously untreated light chain amyloidosis. (Phase II Cohort B)
SECONDARY OBJECTIVES:
I. To determine the progression free survival and overall survival among patients with previously untreated symptomatic MM following treatment with ixazomib in combination with cyclophosphamide and dexamethasone followed by ixazomib maintenance till progression. (Cohort A) II. To determine the toxicities associated with ixazomib in combination with cyclophosphamide and dexamethasone in patients with previously untreated symptomatic MM. (Cohort A) III. To determine the organ response rate of ixazomib, used in combination with cyclophosphamide and dexamethasone in patients with previously untreated light chain amyloidosis. (Cohort B) IV. To determine the progression free survival and overall survival among patients with previously untreated light chain amyloidosis following treatment with ixazomib in combination with cyclophosphamide and dexamethasone followed by Ixazomib maintenance till progression. (Cohort B) V. To determine the toxicities associated with ixazomib in combination with cyclophosphamide and dexamethasone in patients with previously untreated light chain amyloidosis. (Cohort B)
TERTIARY OBJECTIVES:
I. To examine the pharmacokinetics of ixazomib when used in combination with cyclophosphamide and dexamethasone. (Cohort A) II. To assess the incidence of neurotoxicity using patient completed questionnaires. (Cohort A)
OUTLINE: This is a phase I, dose-escalation study of cyclophosphamide followed by a phase II study.
INDUCTION THERAPY: Patients receive ixazomib citrate 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 citrate 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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Locations
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-
Arizona
-
Scottsdale, Arizona, United States, 85259
- Mayo Clinic in Arizona
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Minnesota
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Rochester, Minnesota, United States, 55905
- Mayo Clinic
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- PHASE I ONLY:
- COHORT A: multiple myeloma
- COHORT B: biopsy proven light chain amyloidosis with organ involvement requiring therapy
- 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
- COHORT B ONLY: alkaline phosphatase =< 750 U/L
- COHORT B ONLY: N-terminal pro b-type natriuretic peptide (NT-ProBNP) < 7500 ng/dL
- 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
- COHORT B ONLY: serum immunoglobulin free light chain >= 5 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 only
- 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 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 (New York Heart Association [NYHA] class III or IV), including hypertension, 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 ixazomib
- 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 ixazomib including difficulty swallowing
- Diarrhea > grade 1, based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grading, in the absence of antidiarrheals
- Participation in clinical trials with other investigational agents not included in this trial, =< 30 days prior to registration
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Treatment (ixazomib citrate, cyclophosphamide, dexamethasone)
INDUCTION THERAPY: Patients receive ixazomib citrate 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 citrate PO on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. |
Correlative studies
Ancillary studies
Other Names:
Correlative studies
Ancillary studies
Given PO
Other Names:
Given PO
Other Names:
Given PO
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Maximum Tolerated (MTD) Dose of Cyclophosphamide With Ixazomib and Dexamethasone (Phase I)
Time Frame: At 28 days
|
Will be defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least 1/3 of patients, as assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
|
At 28 days
|
Percentage of Patients With Complete Response or Very Good Partial Response (Phase II, Cohort A)
Time Frame: Up to 48 weeks
|
The percentage 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.
|
Up to 48 weeks
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Rate of Complete Response, Very Good Partial Response, or Partial Response (Phase II, Cohort B)
Time Frame: Up to 48 weeks
|
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.
|
Up to 48 weeks
|
Maximum Tolerated (MTD) Dose of Cyclophosphamide (Phase I)
Time Frame: At 28 days
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Will be defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least 1/3 of patients, as assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
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At 28 days
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of Patients Experiencing a Grade 3 or Greater Adverse Event at Least Possibly Related to Treatment as Assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0
Time Frame: Up to 5 years
|
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.
Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
A grade 3 event is one that is severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL.
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Up to 5 years
|
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
|
The distribution of PFS will be estimated using the method of Kaplan Meier.
|
Time from registration to the earliest date of documentation of disease progression or death due to any cause, assessed up to 5 years
|
Survival Time
Time Frame: Time from registration to death due to any cause, assessed up to 5 years
|
The distribution of survival time will be estimated using the method of Kaplan-Meier.
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Time from registration to death due to any cause, assessed up to 5 years
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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
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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.
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Post-dose, 1 and 4 hours on day 1, pre-dose on days 8, 15, and 22, and day 1 of course 2
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Quality of Life, as Assessed by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity Questionnaire
Time Frame: Up to 5 years
|
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.
|
Up to 5 years
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Shaji Kumar, Mayo Clinic
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Cardiovascular Diseases
- Vascular Diseases
- Metabolic Diseases
- Immune System Diseases
- Neoplasms by Histologic Type
- Neoplasms
- Lymphoproliferative Disorders
- Immunoproliferative Disorders
- Hematologic Diseases
- Hemorrhagic Disorders
- Hemostatic Disorders
- Paraproteinemias
- Blood Protein Disorders
- Proteostasis Deficiencies
- Multiple Myeloma
- Neoplasms, Plasma Cell
- Amyloidosis
- Physiological Effects of Drugs
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Autonomic Agents
- Peripheral Nervous System Agents
- Enzyme Inhibitors
- Anti-Inflammatory Agents
- Antirheumatic Agents
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Antiemetics
- Gastrointestinal Agents
- Glucocorticoids
- Hormones
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Antineoplastic Agents, Hormonal
- Protease Inhibitors
- Antineoplastic Agents, Alkylating
- Alkylating Agents
- Myeloablative Agonists
- Dermatologic Agents
- Glycine Agents
- Dexamethasone
- Dexamethasone acetate
- BB 1101
- Cyclophosphamide
- Ixazomib
- Glycine
- Ichthammol
Other Study ID Numbers
- MC1382 (Other Identifier: Mayo Clinic)
- NCI-2013-01042 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
- X16009 (Other Identifier: Sponsor Protocol Number)
- 13-000414 (Other Identifier: Mayo Clinic Institutional Review Board)
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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