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A Phase 1 Study of IXAZOMIB in Adult Patients With Advanced Nonhematologic Malignancies

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00830869
Recruitment Status : Completed
First Posted : January 28, 2009
Results First Posted : September 9, 2019
Last Update Posted : September 9, 2019
Sponsor:
Information provided by (Responsible Party):
Takeda ( Millennium Pharmaceuticals, Inc. )

Brief Summary:
This is an open-label, multicenter, phase 1, dose escalation study of IXAZOMIB. The primary purpose of this study is to determine the safety profile, establish the maximum tolerated dose, and inform the phase 2 dose of IXAZOMIB administered intravenously in participants with nonhematologic malignancies.

Condition or disease Intervention/treatment Phase
Advanced Non-hematologic Malignancies Drug: IXAZOMIB Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 116 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (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 Advanced Nonhematologic Malignancies
Actual Study Start Date : March 2, 2009
Actual Primary Completion Date : April 20, 2012
Actual Study Completion Date : April 20, 2012

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Part 1: Ixazomib 0.125 milligram per square meter (mg/m^2)
Ixazomib (MLN9708) 0.125 mg/m^2, injection, intravenously (IV), once on Day 1, 4, 8 and 11 followed by 10 days of rest in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity during Part 1 of the study.
Drug: IXAZOMIB

All participants will receive IXAZOMIB IV injection on Days 1, 4, 8, and 11 of each treatment cycle followed by a rest period of 10 days.

The first stage of the study will be initiated at a starting dose of 0.125 mg/m^2. Subsequent doses will increase until a maximum tolerated dose (MTD) is established.


Experimental: Part 1: Ixazomib 0.25 mg/m^2
Ixazomib (MLN9708) 0.25 mg/m^2, injection, IV, once on Day 1, 4, 8 and 11 followed by 10 days of rest in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity during Part 1 of the study.
Drug: IXAZOMIB

All participants will receive IXAZOMIB IV injection on Days 1, 4, 8, and 11 of each treatment cycle followed by a rest period of 10 days.

The first stage of the study will be initiated at a starting dose of 0.125 mg/m^2. Subsequent doses will increase until a maximum tolerated dose (MTD) is established.


Experimental: Part 1: Ixazomib 0.5 mg/m^2
Ixazomib (MLN9708) 0.5 mg/m^2, injection, IV, once on Day 1, 4, 8 and 11 followed by 10 days of rest in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity during Part 1 of the study.
Drug: IXAZOMIB

All participants will receive IXAZOMIB IV injection on Days 1, 4, 8, and 11 of each treatment cycle followed by a rest period of 10 days.

The first stage of the study will be initiated at a starting dose of 0.125 mg/m^2. Subsequent doses will increase until a maximum tolerated dose (MTD) is established.


Experimental: Part 1: Ixazomib 1 mg/m^2
Ixazomib (MLN9708) 1 mg/m^2, injection, IV, once on Day 1, 4, 8 and 11 followed by 10 days of rest in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity during Part 1 of the study.
Drug: IXAZOMIB

All participants will receive IXAZOMIB IV injection on Days 1, 4, 8, and 11 of each treatment cycle followed by a rest period of 10 days.

The first stage of the study will be initiated at a starting dose of 0.125 mg/m^2. Subsequent doses will increase until a maximum tolerated dose (MTD) is established.


Experimental: Part 1: Ixazomib 1.33 mg/m^2
Ixazomib (MLN9708) 1.33 mg/m^2, injection, IV, once on Day 1, 4, 8 and 11 followed by 10 days of rest in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity during Part 1 of the study.
Drug: IXAZOMIB

All participants will receive IXAZOMIB IV injection on Days 1, 4, 8, and 11 of each treatment cycle followed by a rest period of 10 days.

The first stage of the study will be initiated at a starting dose of 0.125 mg/m^2. Subsequent doses will increase until a maximum tolerated dose (MTD) is established.


Experimental: Part 1: Ixazomib 1.76 mg/m^2
Ixazomib (MLN9708) 1.76 mg/m^2, injection, IV, once on Day 1, 4, 8 and 11 followed by 10 days of rest in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity during Part 1 of the study.
Drug: IXAZOMIB

All participants will receive IXAZOMIB IV injection on Days 1, 4, 8, and 11 of each treatment cycle followed by a rest period of 10 days.

The first stage of the study will be initiated at a starting dose of 0.125 mg/m^2. Subsequent doses will increase until a maximum tolerated dose (MTD) is established.


Experimental: Part 1: Ixazomib 2.34 mg/m^2
Ixazomib (MLN9708) 2.34 mg/m^2, injection, IV, once on Day 1, 4, 8 and 11 followed by 10 days of rest in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity during Part 1 of the study. Once the MTD will be established, participants with NSCLC, Head and Neck Cancer (H&N), Soft Tissue Sarcoma (STC) or Prostate Cancer (PC) will be included in MTD disease expanded cohort. An additional tumor pharmacodynamics expansion cohort (TPEC) will enroll participants with any type of solid tumor that can be biopsied for tissue analysis before and after treatment with ixazomib.
Drug: IXAZOMIB

All participants will receive IXAZOMIB IV injection on Days 1, 4, 8, and 11 of each treatment cycle followed by a rest period of 10 days.

The first stage of the study will be initiated at a starting dose of 0.125 mg/m^2. Subsequent doses will increase until a maximum tolerated dose (MTD) is established.


Experimental: Part 2:Ixazomib 1.76 mg/m^2-NSCLC
Ixazomib (MLN9708) 1.76 mg/m^2, injection, IV, once on Day 1, 4, 8, and 11 followed by 10 days of rest period in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity in participants with NSCLC during Part 2 of the study.
Drug: IXAZOMIB

All participants will receive IXAZOMIB IV injection on Days 1, 4, 8, and 11 of each treatment cycle followed by a rest period of 10 days.

The first stage of the study will be initiated at a starting dose of 0.125 mg/m^2. Subsequent doses will increase until a maximum tolerated dose (MTD) is established.


Experimental: Part 2: Ixazomib 1.76 mg/m^2-H&N
Ixazomib (MLN9708) 1.76 mg/m^2, injection, IV, once on Day 1, 4, 8, and 11 followed by 10 days of rest period in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity in participants with H&N during Part 2 of the study.
Drug: IXAZOMIB

All participants will receive IXAZOMIB IV injection on Days 1, 4, 8, and 11 of each treatment cycle followed by a rest period of 10 days.

The first stage of the study will be initiated at a starting dose of 0.125 mg/m^2. Subsequent doses will increase until a maximum tolerated dose (MTD) is established.


Experimental: Part 2: Ixazomib 1.76 mg/m^2-STC
Ixazomib (MLN9708) 1.76 mg/m^2, injection, IV, once on Day 1, 4, 8, and 11 followed by 10 days of rest period in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity in participants with STC during Part 2 of the study.
Drug: IXAZOMIB

All participants will receive IXAZOMIB IV injection on Days 1, 4, 8, and 11 of each treatment cycle followed by a rest period of 10 days.

The first stage of the study will be initiated at a starting dose of 0.125 mg/m^2. Subsequent doses will increase until a maximum tolerated dose (MTD) is established.


Experimental: Part 2: Ixazomib 1.76 mg/m^2-PC
Ixazomib (MLN9708) 1.76 mg/m^2, injection, IV, once on Day 1, 4, 8, and 11 followed by 10 days of rest period in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity in participants with PC during Part 2 of the study.
Drug: IXAZOMIB

All participants will receive IXAZOMIB IV injection on Days 1, 4, 8, and 11 of each treatment cycle followed by a rest period of 10 days.

The first stage of the study will be initiated at a starting dose of 0.125 mg/m^2. Subsequent doses will increase until a maximum tolerated dose (MTD) is established.


Experimental: Part 2: Ixazomib 1.76 mg/m^2-TPEC
Ixazomib (MLN9708) 1.76 mg/m^2, injection, IV, once on Day 1, 4, 8, and 11 followed by 10 days of rest period in 21-day treatment cycles for a maximum of 12 cycles, or until progressive disease or unacceptable toxicity in participants with various types of solid tumors suitable for biopsy in tumor pharmacodynamic expansion cohort (TPEC) during Part 2 of the study.
Drug: IXAZOMIB

All participants will receive IXAZOMIB IV injection on Days 1, 4, 8, and 11 of each treatment cycle followed by a rest period of 10 days.

The first stage of the study will be initiated at a starting dose of 0.125 mg/m^2. Subsequent doses will increase until a maximum tolerated dose (MTD) is established.





Primary Outcome Measures :
  1. Part 1: Number of Participants With Dose Limiting Toxicity (DLT) [ Time Frame: Part 1: Cycle 1 Day 1 up to Cycle 1 Day 21 ]
    Toxicity according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 3.0. DLT is any of following related to ixazomib:Grade (GR) 4 neutropenia (absolute neutrophil count<500 cells/cubic meter[cells/mm^3])for>7 days; GR 3 neutropenia with coincident fever and/or infection; GR 4 thrombocytopenia (platelets <25,000 cells/mm3)for>7 days; GR 3 thrombocytopenia with clinically significant bleeding; Platelet count<10,000 cells/mm3; GR 3 peripheral neuropathy;>=GR 3 nausea/emesis in absence of optimal antiemetic therapy; >=GR 3 diarrhoea in absence of optimal supportive therapy;GR 3 QTc prolongation noted on average of 3 electrocardiograms (ECGs);>=GR 3 nonhematological toxicity except GR 3 arthralgia/myalgia or GR 3 fatigue for<1 week; Delay in initiation of subsequent therapy cycle by>7 days due to treatment-related toxicity Other>=GR 2 nonhematological toxicity that opinion of investigator, requires discontinuation of therapy with Ixazomib.

  2. Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Event (SAEs) [ Time Frame: Part 1: Cycle 1 Day 1 up to Cycle 10 Day 41; Part 2: Cycle 1 Day 1 up to Cycle 12 Day 41 ]
  3. Number of Participants With Clinically Significant TEAEs Related to Laboratory Abnormalities [ Time Frame: Day 1 up to 30 days after last dose of study drug (Cycle 12 Day 41) ]
  4. Number of Participants With Clinically Significant Change From Baseline in Vital Signs [ Time Frame: Day 1 up to 30 days after last dose of study drug (Cycle 12 Day 41) ]
    Vital sign measurements included diastolic and systolic blood pressure, heart rate, weight and oral temperature.


Secondary Outcome Measures :
  1. Part 1: AUC (0-72): Area Under the Plasma Concentration-time Curve From Time 0 to 72 Hours Post-dose for Ixazomib [ Time Frame: Part 1: Cycle 1 Days 1 and 11: pre-dose and at multiple time points (up to 72 hours) post-dose ]
    AUC (0-72) is a measure of the area under the plasma concentration-time curve from time 0 to 72 hours post-dose for ixazomib.

  2. Part 1: C0: Initial Plasma Concentration After Bolus Intravenous Administration [ Time Frame: Part 1: Cycle 1 Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose; Cycle 1 Day 11 pre-dose and at multiple time points (up to 264 hours) post-dose ]
    C0 is the plasma drug concentration at time zero following bolus intravenous injection.

  3. Part 1: Rac: Accumulation Ratio for Ixazomib [ Time Frame: Cycle 1 Day 11 pre-dose and at multiple time points (up to 72 hours) post-dose ]
    Rac was estimated as the ratio of AUC (0-72) on Day 11 and AUC (0-72) on Day 1. AUC (0-72) is the area under the plasma concentration-time curve from time 0 to 72 hours post-dose.

  4. Part 1: Terminal Phase Elimination Half-life (T1/2) for Ixazomib [ Time Frame: Part 1: Cycle 1 Day 11 pre-dose and at multiple time points (up to 264 hours) post-dose ]
    T1/2 is the time required for half of the drug to be eliminated from the plasma.

  5. Part 1: E Max: Maximum Observed Effect for Ixazomib [ Time Frame: Part 1: Cycle 1 Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose; Cycle 1 Day 11 pre-dose and at multiple time points (up to 264 hours) post-dose ]
    E max is the maximum inhibition of 20S proteasome activity in whole blood.

  6. Part 1: TEmax: Time to Maximum Observed Effect (Emax) for Ixazomib [ Time Frame: Part 1: Cycle 1 Days 1 and 11 pre-dose and at multiple time points (up to 72 hours) post-dose; Cycle 1 Day 11 pre-dose and at multiple time points (up to 264 hours) post-dose ]
    TEmax is the time to reach the Emax, equal to time (hours) to Emax.

  7. Number of Participants With Best Overall Response [ Time Frame: Day 18 up to Day 21 of each cycle (Part 1: up to Cycle 10; Part 2: up to Cycle 12) ]
    Best overall response for a participant is best observed post-baseline disease response as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 criteria. Complete Response (CR): disappearance of all target lesions, non-target lesions and normalization of tumor marker level. Partial Response (PR): at least 30% decrease in sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the baseline smallest sum of longest diameter; persistence of 1 or more non-target lesion(s) or maintenance of tumor marker level above normal limits. Progressive disease: at least 20% increase in the sum of the longest diameter of target lesions, taking as reference the baseline smallest sum of longest diameter or appearance of 1 or more new lesions or unequivocal progression of existing non-target lesions.

  8. Part 2: Ixazomib Concentration in Postdose Clinical Tumor Samples in Ixazomib 1.76 mg/m^2-TPEC [ Time Frame: Cycle 1 Days 1 and 4: Predose and (from 4-20 hours) post-dose ]
    The average data of Days 1 and 4 of Cycle 1 was reported.

  9. 20S Proteasome Activity of Ixazomib in the Tumor Tissue [ Time Frame: Cycle 1 Days 1 and 4 pre-dose and at multiple time points (up to 2 hours of tumor biopsy) post-dose ]
  10. Expression of Biomarker (ATF-3) in Tumor Tissue [ Time Frame: Cycle 1 Days 1 and 4 pre-dose and at multiple time points (up to 2 hours of tumor biopsy) post-dose ]


Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Each participant must meet all of the following inclusion criteria to be enrolled in the study:

  1. Male or female participants 18 years or older.
  2. Eastern Cooperative Oncology Group performance status 0-2.
  3. A diagnosis of a nonhematologic malignancy for which standard treatment is no longer effective. In the expanded cohort, enrollment will be limited to participants with a diagnosis of NSCLC, H&N cancer (squamous cell cancer), STS, or PC.
  4. Suitable venous access for pharmacokinetic (PK) and pharmacodynamic evaluations.
  5. Female participants who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or abstain from heterosexual intercourse.

    Male participants who agree to practice 2 effective methods of contraception or abstain from heterosexual intercourse.

  6. Voluntary written consent must be obtained.
  7. Adequate clinical laboratory values during the screening period.
  8. In the escalation portion of the study, radiographically or clinically evaluable tumor was required, but measurable disease as defined by response evaluation criteria in solid tumors (RECIST) criteria was not required. In the MTD disease expansion cohorts and the TPEC, clinically measurable disease as defined by RECIST criteria was required for evaluation of NSCLC, H&N cancer, and STS. Prostate specific antigen (PSA) alone was acceptable for evaluation of PC.
  9. For participants in the TPEC, tumor tissue that, in the opinion of the investigator, could have been safely biopsied using a core needle.

Exclusion Criteria:

Participants meeting any of the following exclusion criteria are not to be enrolled in the study:

  1. Peripheral neuropathy greater than or equal to (>=) Grade 2.
  2. Female participants 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 greater than (>) Grade 1 based on the National Cancer Institute Common Terminology .Criteria for Adverse Events (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. Participant has symptomatic brain metastasis.
  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.
  15. For participants in the TPEC and participants in the MTD disease expansion cohorts who gave informed consent to undergo tumor biopsy, ongoing anticoagulant therapy (example, aspirin, clopidogrel [Plavix ®], warfarin, or heparin) that cannot be held to permit tumor biopsy .
  16. Known allergy to boron or excipients.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00830869


Locations
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United States, Florida
H. Lee Moffitt Cancer Center and Research Institute
Tampa, Florida, United States, 33612
United States, Georgia
Emory University
Atlanta, Georgia, United States, 30322
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
United States, North Carolina
Duke University
Durham, North Carolina, United States, 27710
United States, Tennessee
Sarah Cannon Research Institute
Nashville, Tennessee, United States, 37203
United States, Washington
University of Washington- Seattle Cancer Care
Seattle, Washington, United States, 98109
Canada, Ontario
Princess Margaret Hospital
Toronto, Ontario, Canada, M5G 2M9
Sponsors and Collaborators
Millennium Pharmaceuticals, Inc.
Investigators
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Study Director: Medical Monitor Millennium Pharmaceuticals, Inc.
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Responsible Party: Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT00830869    
Other Study ID Numbers: C16001
U1111-1206-2180 ( Other Identifier: WHO )
First Posted: January 28, 2009    Key Record Dates
Results First Posted: September 9, 2019
Last Update Posted: September 9, 2019
Last Verified: July 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Takeda ( Millennium Pharmaceuticals, Inc. ):
Drug therapy
Additional relevant MeSH terms:
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Neoplasms
Ixazomib
Antineoplastic Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action