Antineoplastic Agents

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Anti-Infective Agents

Ixazomib

Proteasome Inhibitors

HIV Protease Inhibitors

Protease Inhibitors

Enzyme Inhibitors

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

IXAZOMIB

Medical Monitor

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.

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

An Open-Label, Dose Escalation, Phase 1 Study of IXAZOMIB (MLN9708), a Second-Generation Proteasome Inhibitor, in Adult Patients With Advanced Nonhematologic Malignancies

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.

Vital sign measurements included diastolic and systolic blood pressure, heart rate, weight and oral temperature.

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.

C0 is the plasma drug concentration at time zero following bolus intravenous injection.

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.

T1/2 is the time required for half of the drug to be eliminated from the plasma.

E max is the maximum inhibition of 20S proteasome activity in whole blood.

TEmax is the time to reach the Emax, equal to time (hours) to Emax.

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.

The average data of Days 1 and 4 of Cycle 1 was reported.

Millennium Pharmaceuticals, Inc.

At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

Ixazomib (MLN9708) 0.125 milligram per square meter (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.

Part 1: Ixazomib 0.125 mg/m^2

Part 1: Ixazomib 0.25 mg/m^2

Part 1: Ixazomib 0.5 mg/m^2

Part 1: Ixazomib 1 mg/m^2

Part 1: Ixazomib 1.33 mg/m^2

Part 1: Ixazomib 1.76 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.

Part 1: Ixazomib 2.34 mg/m^2

Part 2:Ixazomib 1.76 mg/m^2-Non-small Cell Lung Cancer(NSCLC)

Part 2: Ixazomib 1.76 mg/m^2-Head and Neck Cancer (H&N)

Part 2: Ixazomib 1.76 mg/m^2-Soft Tissue Sarcoma (STC)

Part 2: Ixazomib 1.76 mg/m^2-Prostate Cancer (PC)

Part 2: Ixazomib 1.76 mg/m^2-TPEC

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Canada

Region of Enrollment

Height

Weight

Body surface area

The safety population included all participants who received at least 1 dose of ixazomib.

Medical Director

The DLT population included all participants who received all Cycle 1 doses of ixazomib and who had completed Cycle 1. If Cycle 1 was interrupted by a DLT, the participant was included in this population.

Part 1: Number of Participants With Dose Limiting Toxicity (DLT)

TEAEs

SAEs

The safety population included all participants who received at least 1 dose of study drug.

Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Event (SAEs)

Liver function analyses

Renal function analyses

Tissue enzyme analyses notelsewhereclassified(NEC)

Red blood cell analyses

Platelet analyses

Mineral and electrolyte analyses

Metabolism tests NEC

Urinalysis NEC

White blood cell analyses

Thrombocytopenias

Anaemias NEC

Leukopenias NEC

Neutropenias

Leukocytoses NEC

Marrow depression and hypoplastic anaemias

Thrombocytoses

Sodium imbalance

Hyperglycaemic conditions NEC

Potassium imbalance

Calcium metabolism disorders

Magnesium metabolism disorders

Disorders of purine metabolism

Metabolic acidoses (excluding diabetic acidoses)

Phosphorus metabolism disorders

Protein metabolism disorders NEC

Coagulation and bleeding analyses

Number of Participants With Clinically Significant TEAEs Related to Laboratory Abnormalities

Number of Participants With Clinically Significant Change From Baseline in Vital Signs

Cycle 1 Day 1

Cycle 1 Day 11

PK analysis population where data at specified time points was available,defined as participants in dose escalation phase who received protocol-specified dosing in Cycle 1 without dose reductions/interruptions, did not receive excluded concomitant medications in Cycle 1,had sufficient concentration-time data to permit estimation of PK parameters.

Part 1: AUC (0-72): Area Under the Plasma Concentration-time Curve From Time 0 to 72 Hours Post-dose for Ixazomib

PK analysis population where data at specified time points was available, defined as participants in dose escalation phase who received protocol-specified dosing in Cycle 1 without dose reductions/interruptions,did not receive excluded concomitant medications in Cycle 1,had sufficient concentration-time data to permit estimation of PK parameters.

Part 1: C0: Initial Plasma Concentration After Bolus Intravenous Administration

PK analysis population defined as participants in dose escalation phase who received protocol-specified dosing in Cycle 1 without dose reductions/interruptions,did not receive excluded concomitant medications in Cycle 1,had sufficient concentration-time data to permit estimation of PK parameters.

Part 1: Rac: Accumulation Ratio for Ixazomib

Part 1: Terminal Phase Elimination Half-life (T1/2) for Ixazomib

PD analysis population where baseline/post-baseline assessments was available, defined as participants in dose escalation phase who received protocol-specified dosing in Cycle 1 without dose reductions/interruptions,did not receive any excluded concomitant medications in Cycle 1,had sufficient effect-time data to permit estimation of PD parameters.

Part 1: E Max: Maximum Observed Effect for Ixazomib

Part 1: TEmax: Time to Maximum Observed Effect (Emax) for Ixazomib

Progressive disease

The response-evaluable population included all participants who received at least 1 cycle of ixazomib treatment, had measurable disease at baseline, and had at least 1 postbaseline response assessment.

Number of Participants With Best Overall Response

The tumor PK analysis set where Day 1 and 4 assessment were available. The tumor PK and PD analysis population includes all participants who provided a baseline tumor biopsy sample and 1 post-baseline tumor biopsy sample on Day 1 or Day 4.

Spots Global Cancer Trial Database for A Phase 1 Study of IXAZOMIB in Adult Patients With Advanced Nonhematologic Malignancies

Trial Identification

Conditions

Interventions

Study Description

Keywords

Eligibility

Locations

Contact Details

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