A Study of IXAZOMIB in Adult Patients With Lymphoma

This study has been completed.
Information provided by (Responsible Party):
Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier:
First received: May 4, 2009
Last updated: October 12, 2015
Last verified: October 2015
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.

Condition Intervention Phase
Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open-Label, Dose-Escalation, Phase 1 Study of IXAZOMIB (MLN9708), A Second-Generation Proteasome Inhibitor, in Adult Patients With Lymphoma

Resource links provided by NLM:

Further study details as provided by Millennium Pharmaceuticals, Inc.:

Primary Outcome Measures:
  • Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to 30 days after last dose of study drug ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline and Days 1, 8, and 15 of each treatment cycle (up to Cycle 45) ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline and Days 1, 8, 15 of each treatment cycle up to 45 treatment cycles ] [ Designated as safety issue: Yes ]
    Vital signs included body temperature, weight, systolic and diastolic blood pressure and heart rate.

  • Maximum Tolerated Dose (MTD) [ Time Frame: Treatment Cycle 1 ] [ Designated as safety issue: Yes ]
    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) [ Time Frame: Baseline up to Treatment Cycle 45 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Cycle 1 Days 1 and 15: Predose and at multiple time points (up to 336 hours postdose) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1 Days 1 and 15: Predose and at multiple time points (up to 168 hours postdose) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1 Day 15: Predose and at multiple time points (up to 336 hours postdose) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1 Days 1 and 15: Predose and at multiple time points (up to 168 hours postdose) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1, Days 1 and 15: 0 to 4 hours postdose ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1, Days 1 and 15: 0 to 4 hours postdose ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1, Days 1 and 15: 0 to 4 hours postdose ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1 Days 1 and 15: Predose and at multiple time points (up to 168 hours postdose) ] [ Designated as safety issue: No ]
    Emax is the maximum inhibition of 20S proteasome activity in whole blood.

  • TEmax: Time to Maximum Observed Effect (Emax) for Ixazomib [ Time Frame: Cycle 1 Days 1 and 15: Predose and at multiple time points (up to 168 hours postdose) ] [ Designated as safety issue: No ]
    TEmax: Time to reach the maximum observed effect (Emax), equal to time (hours) to Emax.

  • Overall Best Response [ Time Frame: Baseline up to Cycle 45 ] [ Designated as safety issue: No ]
    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.

Enrollment: 31
Study Start Date: August 2009
Study Completion Date: October 2014
Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: IXAZOMIB Drug: IXAZOMIB
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.


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

Inclusion Criteria:

  1. Male or female patients 18 years or older.
  2. Eastern Cooperative Oncology Group performance status 0-2.
  3. 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.
  4. Suitable venous access for PK and pharmacodynamic evaluations.
  5. 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.

  6. Voluntary written consent must be obtained.
  7. 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:

  1. Peripheral neuropathy ≥ Grade 2.
  2. Female patients who are lactating or have a positive serum pregnancy test during the screening period .
  3. Major surgery within 14 days before the first dose of treatment.
  4. Infection requiring systemic antibiotic therapy or other serious infection within 14 days before the first dose of study treatment.
  5. Life-threatening illness unrelated to cancer.
  6. Diarrhea > Grade 1 based on the NCI CTCAE categorization.
  7. Systemic antineoplastic therapy/or radiotherapy within 21 days before the first dose of study treatment.
  8. Systemic treatment with prohibited medications.
  9. Patient has symptomatic brain metastases.
  10. Evidence of current uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure (CHF), angina, or myocardial infarction within the past 6 months.
  11. QTc > 470 milliseconds (msec) on a 12-lead electrocardiogram (ECG) obtained during the screening period.
  12. Known human immunodeficiency virus (HIV), hepatitis B or hepatitis C positive.
  13. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
  14. Treatment with any investigational products within 28 days before the first dose of study treatment.
  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: NCT00893464

United States, California
Tower Cancer Research Center
Beverly Hills, California, United States, 90211
United States, Colorado
Rocky Mountain Cancer Center
Denver, Colorado, United States, 80218
United States, Kansas
Kansas University Medical Center
Westwood, Kansas, United States, 66160
United States, New York
Cornell University
New York City, New York, United States, 10021
United States, Pennsylvania
Thomas Jefferson University
Philadelphia, Pennsylvania, United States, 19107
United States, Wisconsin
University of Wisconsin Madison
Madison, Wisconsin, United States, 53792
Canada, Quebec
Jewish General Hospital
Montreal, Quebec, Canada, H3T 1E2
Sponsors and Collaborators
Millennium Pharmaceuticals, Inc.
Study Director: Medical Monitor Millennium Pharmaceuticals, Inc.
  More Information

No publications provided

Responsible Party: Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT00893464     History of Changes
Other Study ID Numbers: C16002, U1111-1166-8981
Study First Received: May 4, 2009
Results First Received: October 12, 2015
Last Updated: October 12, 2015
Health Authority: United States: Food and Drug Administration
Canada: Health Canada

Additional relevant MeSH terms:
Immune System Diseases
Immunoproliferative Disorders
Lymphatic Diseases
Lymphoproliferative Disorders
Neoplasms by Histologic Type

ClinicalTrials.gov processed this record on November 25, 2015