A Study of IXAZOMIB in Adult Patients With Lymphoma

Study Overview
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Brief Summary
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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.

Official Title
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An Open-Label, Dose-Escalation, Phase 1 Study of IXAZOMIB (MLN9708), A Second-Generation Proteasome Inhibitor, in Adult Patients With Lymphoma

Conditions
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Lymphoma

Intervention / Treatment
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* Drug: IXAZOMIB


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IXAZOMIB<br> | Drug: IXAZOMIB<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline up to 30 days after last dose of study drug | 
| 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. | Baseline and Days 1, 8, and 15 of each treatment cycle (up to Cycle 45) | 
| 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. | Baseline and Days 1, 8, 15 of each treatment cycle up to 45 treatment cycles | 
| 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. | Treatment Cycle 1 | 
| 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. | Baseline up to Treatment Cycle 45 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Cycle 1 Days 1 and 15: Predose and at multiple time points (up to 336 hours postdose) | 
| 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 | Cycle 1 Days 1 and 15: Predose and at multiple time points (up 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. | Cycle 1 Day 15: Predose and at multiple time points (up to 336 hours postdose) | 
| 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. | Cycle 1 Days 1 and 15: Predose and at multiple time points (up 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. | Cycle 1, Days 1 and 15: 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. | Cycle 1, Days 1 and 15: 0 to 4 hours postdose | 
| 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). | Cycle 1, Days 1 and 15: 0 to 4 hours postdose | 
| Emax: Maximum Observed Effect for Ixazomib | Emax is the maximum inhibition of 20S proteasome activity in whole blood. | Cycle 1 Days 1 and 15: Predose and at multiple time points (up to 168 hours postdose) | 
| TEmax: Time to Maximum Observed Effect (Emax) for Ixazomib | TEmax: Time to reach the maximum observed effect (Emax), equal to time (hours) to Emax. | Cycle 1 Days 1 and 15: Predose and at multiple time points (up to 168 hours postdose) | 
| 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. | Baseline up to Cycle 45 |