Back to resultsA Study of IXAZOMIB in Adult Patients With Lymphoma
Primary Purpose
Lymphoma
Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
IXAZOMIB
Sponsored by
About this trial
This is an interventional treatment trial for Lymphoma
Eligibility Criteria
Inclusion Criteria:
- Male or female patients 18 years or older.
- Eastern Cooperative Oncology Group performance status 0-2.
- Patients must have a confirmed diagnosis of lymphoma that is relapsed and/or refractory after at least 2 prior chemotherapeutic regimens and for which no curative option exists. Patients with Waldenstrom's macroglobulinemia are not eligible for enrollment in this study. Patients with Hodgkin lymphoma are considered eligible for this study.
- Suitable venous access for PK and pharmacodynamic evaluations.
Female patients who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or abstain from heterosexual intercourse.
Male patients who agree to to practice 2 effective methods of contraception or abstain from heterosexual intercourse.
- Voluntary written consent must be obtained.
Adequate blood and chemistry values during the screening period:
- Absolute neutrophil count (ANC) ≥ 1,500/mm3; platelet count ≥ 100,000/mm3.
- Total bilirubin must be ≤ 1.5 × the upper limit of the normal range upper limit of normal (ULN).
- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) must be ≤ 2.5 × the upper limit of normal (ULN). AST and ALT may be elevated up to 5 times the upper limit of normal if their elevation can be reasonably ascribed to the presence of metastatic disease.
- Calculated creatinine clearance ≥ 30 mL/minute.
Exclusion Criteria:
- Peripheral neuropathy ≥ Grade 2.
- Female patients who are lactating or have a positive serum pregnancy test during the screening period .
- Major surgery within 14 days before the first dose of treatment.
- Infection requiring systemic antibiotic therapy or other serious infection within 14 days before the first dose of study treatment.
- Life-threatening illness unrelated to cancer.
- Diarrhea > Grade 1 based on the NCI CTCAE categorization.
- Systemic antineoplastic therapy/or radiotherapy within 21 days before the first dose of study treatment.
- Systemic treatment with prohibited medications.
- Patient has symptomatic brain metastases.
- Evidence of current uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure (CHF), angina, or myocardial infarction within the past 6 months.
- QTc > 470 milliseconds (msec) on a 12-lead electrocardiogram (ECG) obtained during the screening period.
- Known human immunodeficiency virus (HIV), hepatitis B or hepatitis C positive.
- Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
- Treatment with any investigational products within 28 days before the first dose of study treatment.
Sites / Locations
- Tower Cancer Research Center
- Rocky Mountain Cancer Center
- Kansas University Medical Center
- Cornell University
- Thomas Jefferson University
- University of Wisconsin Madison
- Jewish General Hospital
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
IXAZOMIB
Arm Description
Outcomes
Primary Outcome Measures
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event.
Number of Participants Reporting at Least 1 TEAE Related to Laboratory Assessments
The number of participants with any markedly abnormal standard safety laboratory values collected throughout study. Hematology, clinical chemistry and urinalysis were performed. TEAEs related to laboratory assessment observed at any time-points were reported under 3 system organ classes: blood and lymphatic system disorders, metabolism and nutrition disorders, and investigations.
Number of Participants With Clinically Significant Change From Baseline in Vital Signs
Vital signs included body temperature, weight, systolic and diastolic blood pressure and heart rate.
Maximum Tolerated Dose (MTD)
The MTD was defined as the highest dose of ixazomib that generated dose limiting toxicity (DLT) during Cycle 1 in 0 of 3 or 1 of 6 participants. DLT defined as any of the following considered possibly related to therapy by investigator: Grade 4 neutropenia (absolute neutrophil count [ANC] <500 cell per cubic millimeter [cells/mm^3]) for >7 days; Grade 3 neutropenia with fever or infection; Grade 4 thrombocytopenia for >7 days; platelet count <25,000 cells/mm^3; Grade 3 thrombocytopenia with clinically significant bleeding; platelet count <10,000/mm^3; Grade 2 peripheral neuropathy with pain or Grade 3 peripheral neuropathy; >=Grade 3 nausea/emesis, diarrhea controlled by maximal supportive therapy; Grade 3 QTc prolongation>500 millisecond (msec);any >=Grade 3 nonhematologic toxicity except arthralgia/myalgia; <1 week fatigue; delay in the initiation of the subsequent therapy cycle by >=7 days ; other Grade 2 ixazomib-related nonhematologic toxicities requiring therapy discontinuation.
Recommended Phase 2 Dose (RP2D)
The RP2D of Ixazomib was determined in Part 1 (dose escalation) on the basis of the totality of safety, tolerability, pharmacokinetics (PK), pharmacodynamic and preliminary efficacy data observed in Cycles 1 and 2 and beyond.
Secondary Outcome Measures
C0: Initial Plasma Concentration After Bolus Intravenous Administration
C0 is the plasma drug concentration at time zero following bolus intravenous injection, obtained from the plasma concentration-time curve.
AUC(0-168): Area Under the Plasma Concentration-Time Curve From Time 0 to 168 Hours Postdose for Ixazomib
AUC(0-168) is a measure of the area under the plasma concentration time-curve from time 0 to 168 hours postdose
Terminal Phase Elimination Half-life (T1/2) for Ixazomib
Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.
Rac: Accumulation Ratio for Ixazomib
Rac was estimated as the ratio of AUC (0-168) on Day 15 and AUC (0-168) on Day 1. AUC (0-168) is the area under the plasma concentration-time curve from time 0 to 168 hours postdose.
Ae (0-4): Amount of Drug Excreted in Urine From 0 to 4 Hours Postdose
Ae (0-4) is the total amount of drug excreted in the urine from 0 to 4 hours postdose.
Fe (0-4): Fraction of Dose Excreted Unchanged in Urine From 0 to 4 Hours Postdose
Fe (0-4) is the fraction of the dose excreted unchanged in the urine from 0 to 4 hours postdose, calculated as percentage of the exact dose administered.
CLr: Renal Clearance
CLr is the volume of plasma from which the drug is completely removed by the kidney in a given amount of time, calculated as the amount of drug excreted in the urine divided by the area under the plasma concentration-time curve, expressed in liter per hour (L/hr).
Emax: Maximum Observed Effect for Ixazomib
Emax is the maximum inhibition of 20S proteasome activity in whole blood.
TEmax: Time to Maximum Observed Effect (Emax) for Ixazomib
TEmax: Time to reach the maximum observed effect (Emax), equal to time (hours) to Emax.
Overall Best Response
Overall best response is the best response observed for a participant during the study based on International Working Group (IWG) Response Criteria for malignant lymphoma. Complete response (CR) as per IWG is complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. Partial response (PR) is a minimum of 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses and no increase in the size of other nodes. Stable disease (SD) is when a participant fails to attain the criteria needed for a CR or PR, but does not fulfill those for PD. PD is any new lesion or increase by >50% of previously involved sites from nadir.
Full Information
NCT ID
NCT00893464
First Posted
May 4, 2009
Last Updated
October 12, 2015
Sponsor
Millennium Pharmaceuticals, Inc.
1. Study Identification
Unique Protocol Identification Number
NCT00893464
Brief Title
A Study of IXAZOMIB in Adult Patients With Lymphoma
Official Title
An Open-Label, Dose-Escalation, Phase 1 Study of IXAZOMIB (MLN9708), A Second-Generation Proteasome Inhibitor, in Adult Patients With Lymphoma
Study Type
Interventional
2. Study Status
Record Verification Date
October 2015
Overall Recruitment Status
Completed
Study Start Date
August 2009 (undefined)
Primary Completion Date
October 2014 (Actual)
Study Completion Date
October 2014 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Millennium Pharmaceuticals, Inc.
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
This study is an open-label, multicenter, phase 1, dose-escalation study of IXAZOMIB in adult patients with lymphoma. This study will be the first to administer IXAZOMIB to patients with lymphoma.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lymphoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
31 (Actual)
8. Arms, Groups, and Interventions
Arm Title
IXAZOMIB
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
IXAZOMIB
Intervention Description
Patients will be administered IXAZOMIB by IV on Days 1, 8, and 15 of a 28-day cycle. The first stage of the study will be initiated at a starting dose of 0.125 mg/m2. Subsequent doses will increase until a maximum tolerated dose (MTD) is established.
Primary Outcome Measure Information:
Title
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Description
An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event.
Time Frame
Baseline up to 30 days after last dose of study drug
Title
Number of Participants Reporting at Least 1 TEAE Related to Laboratory Assessments
Description
The number of participants with any markedly abnormal standard safety laboratory values collected throughout study. Hematology, clinical chemistry and urinalysis were performed. TEAEs related to laboratory assessment observed at any time-points were reported under 3 system organ classes: blood and lymphatic system disorders, metabolism and nutrition disorders, and investigations.
Time Frame
Baseline and Days 1, 8, and 15 of each treatment cycle (up to Cycle 45)
Title
Number of Participants With Clinically Significant Change From Baseline in Vital Signs
Description
Vital signs included body temperature, weight, systolic and diastolic blood pressure and heart rate.
Time Frame
Baseline and Days 1, 8, 15 of each treatment cycle up to 45 treatment cycles
Title
Maximum Tolerated Dose (MTD)
Description
The MTD was defined as the highest dose of ixazomib that generated dose limiting toxicity (DLT) during Cycle 1 in 0 of 3 or 1 of 6 participants. DLT defined as any of the following considered possibly related to therapy by investigator: Grade 4 neutropenia (absolute neutrophil count [ANC] <500 cell per cubic millimeter [cells/mm^3]) for >7 days; Grade 3 neutropenia with fever or infection; Grade 4 thrombocytopenia for >7 days; platelet count <25,000 cells/mm^3; Grade 3 thrombocytopenia with clinically significant bleeding; platelet count <10,000/mm^3; Grade 2 peripheral neuropathy with pain or Grade 3 peripheral neuropathy; >=Grade 3 nausea/emesis, diarrhea controlled by maximal supportive therapy; Grade 3 QTc prolongation>500 millisecond (msec);any >=Grade 3 nonhematologic toxicity except arthralgia/myalgia; <1 week fatigue; delay in the initiation of the subsequent therapy cycle by >=7 days ; other Grade 2 ixazomib-related nonhematologic toxicities requiring therapy discontinuation.
Time Frame
Treatment Cycle 1
Title
Recommended Phase 2 Dose (RP2D)
Description
The RP2D of Ixazomib was determined in Part 1 (dose escalation) on the basis of the totality of safety, tolerability, pharmacokinetics (PK), pharmacodynamic and preliminary efficacy data observed in Cycles 1 and 2 and beyond.
Time Frame
Baseline up to Treatment Cycle 45
Secondary Outcome Measure Information:
Title
C0: Initial Plasma Concentration After Bolus Intravenous Administration
Description
C0 is the plasma drug concentration at time zero following bolus intravenous injection, obtained from the plasma concentration-time curve.
Time Frame
Cycle 1 Days 1 and 15: Predose and at multiple time points (up to 336 hours postdose)
Title
AUC(0-168): Area Under the Plasma Concentration-Time Curve From Time 0 to 168 Hours Postdose for Ixazomib
Description
AUC(0-168) is a measure of the area under the plasma concentration time-curve from time 0 to 168 hours postdose
Time Frame
Cycle 1 Days 1 and 15: Predose and at multiple time points (up to 168 hours postdose)
Title
Terminal Phase Elimination Half-life (T1/2) for Ixazomib
Description
Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.
Time Frame
Cycle 1 Day 15: Predose and at multiple time points (up to 336 hours postdose)
Title
Rac: Accumulation Ratio for Ixazomib
Description
Rac was estimated as the ratio of AUC (0-168) on Day 15 and AUC (0-168) on Day 1. AUC (0-168) is the area under the plasma concentration-time curve from time 0 to 168 hours postdose.
Time Frame
Cycle 1 Days 1 and 15: Predose and at multiple time points (up to 168 hours postdose)
Title
Ae (0-4): Amount of Drug Excreted in Urine From 0 to 4 Hours Postdose
Description
Ae (0-4) is the total amount of drug excreted in the urine from 0 to 4 hours postdose.
Time Frame
Cycle 1, Days 1 and 15: 0 to 4 hours postdose
Title
Fe (0-4): Fraction of Dose Excreted Unchanged in Urine From 0 to 4 Hours Postdose
Description
Fe (0-4) is the fraction of the dose excreted unchanged in the urine from 0 to 4 hours postdose, calculated as percentage of the exact dose administered.
Time Frame
Cycle 1, Days 1 and 15: 0 to 4 hours postdose
Title
CLr: Renal Clearance
Description
CLr is the volume of plasma from which the drug is completely removed by the kidney in a given amount of time, calculated as the amount of drug excreted in the urine divided by the area under the plasma concentration-time curve, expressed in liter per hour (L/hr).
Time Frame
Cycle 1, Days 1 and 15: 0 to 4 hours postdose
Title
Emax: Maximum Observed Effect for Ixazomib
Description
Emax is the maximum inhibition of 20S proteasome activity in whole blood.
Time Frame
Cycle 1 Days 1 and 15: Predose and at multiple time points (up to 168 hours postdose)
Title
TEmax: Time to Maximum Observed Effect (Emax) for Ixazomib
Description
TEmax: Time to reach the maximum observed effect (Emax), equal to time (hours) to Emax.
Time Frame
Cycle 1 Days 1 and 15: Predose and at multiple time points (up to 168 hours postdose)
Title
Overall Best Response
Description
Overall best response is the best response observed for a participant during the study based on International Working Group (IWG) Response Criteria for malignant lymphoma. Complete response (CR) as per IWG is complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. Partial response (PR) is a minimum of 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses and no increase in the size of other nodes. Stable disease (SD) is when a participant fails to attain the criteria needed for a CR or PR, but does not fulfill those for PD. PD is any new lesion or increase by >50% of previously involved sites from nadir.
Time Frame
Baseline up to Cycle 45
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Male or female patients 18 years or older.
Eastern Cooperative Oncology Group performance status 0-2.
Patients must have a confirmed diagnosis of lymphoma that is relapsed and/or refractory after at least 2 prior chemotherapeutic regimens and for which no curative option exists. Patients with Waldenstrom's macroglobulinemia are not eligible for enrollment in this study. Patients with Hodgkin lymphoma are considered eligible for this study.
Suitable venous access for PK and pharmacodynamic evaluations.
Female patients who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or abstain from heterosexual intercourse.
Male patients who agree to to practice 2 effective methods of contraception or abstain from heterosexual intercourse.
Voluntary written consent must be obtained.
Adequate blood and chemistry values during the screening period:
Absolute neutrophil count (ANC) ≥ 1,500/mm3; platelet count ≥ 100,000/mm3.
Total bilirubin must be ≤ 1.5 × the upper limit of the normal range upper limit of normal (ULN).
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) must be ≤ 2.5 × the upper limit of normal (ULN). AST and ALT may be elevated up to 5 times the upper limit of normal if their elevation can be reasonably ascribed to the presence of metastatic disease.
Calculated creatinine clearance ≥ 30 mL/minute.
Exclusion Criteria:
Peripheral neuropathy ≥ Grade 2.
Female patients who are lactating or have a positive serum pregnancy test during the screening period .
Major surgery within 14 days before the first dose of treatment.
Infection requiring systemic antibiotic therapy or other serious infection within 14 days before the first dose of study treatment.
Life-threatening illness unrelated to cancer.
Diarrhea > Grade 1 based on the NCI CTCAE categorization.
Systemic antineoplastic therapy/or radiotherapy within 21 days before the first dose of study treatment.
Systemic treatment with prohibited medications.
Patient has symptomatic brain metastases.
Evidence of current uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure (CHF), angina, or myocardial infarction within the past 6 months.
QTc > 470 milliseconds (msec) on a 12-lead electrocardiogram (ECG) obtained during the screening period.
Known human immunodeficiency virus (HIV), hepatitis B or hepatitis C positive.
Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
Treatment with any investigational products within 28 days before the first dose of study treatment.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Monitor
Organizational Affiliation
Millennium Pharmaceuticals, Inc.
Official's Role
Study Director
Facility Information:
Facility Name
Tower Cancer Research Center
City
Beverly Hills
State/Province
California
ZIP/Postal Code
90211
Country
United States
Facility Name
Rocky Mountain Cancer Center
City
Denver
State/Province
Colorado
ZIP/Postal Code
80218
Country
United States
Facility Name
Kansas University Medical Center
City
Westwood
State/Province
Kansas
ZIP/Postal Code
66160
Country
United States
Facility Name
Cornell University
City
New York City
State/Province
New York
ZIP/Postal Code
10021
Country
United States
Facility Name
Thomas Jefferson University
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19107
Country
United States
Facility Name
University of Wisconsin Madison
City
Madison
State/Province
Wisconsin
ZIP/Postal Code
53792
Country
United States
Facility Name
Jewish General Hospital
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H3T 1E2
Country
Canada
12. IPD Sharing Statement
Learn more about this trial
A Study of IXAZOMIB in Adult Patients With Lymphoma
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