A Phase I Study of the Combination of Alsertib (MLN8237) and Brentuximab Vedotin in Relapsed/Refractory CD30-Positive Lymphomas and Solid Malignancies
Overview
- Phase
- Phase 1
- Intervention
- Brentuximab Vedotin
- Conditions
- CD30-positive Lymphoma
- Sponsor
- Eric Bernicker, MD
- Locations
- 1
- Primary Endpoint
- Maximum tolerated dose (MTD)
- Status
- Withdrawn
- Last Updated
- 7 years ago
Overview
Brief Summary
This is an open label phase I trial designed to evaluate the maximum tolerated dose, dose-limiting toxicities, pharmacokinetics, and activity of the combination of alsertib (MLN8237) and brentuximab vedotin in patients with relapsed/refractory CD30-positive lymphomas and solid malignancies. Cohorts of 3-6 patients will receive escalating or de-escalating doses of MLN8237 based on a 3 + 3 design.
Detailed Description
This is an investigator-initiated, open label phase I trial designed to evaluate the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics, and activity of brentuximab vedotin in combination with MLN8237 in patients with relapsed/refractory CD30-positive lymphomas and solid malignancies. Brentuximab vedotin at a fixed dose of 1.8 mg/kg will be administered on Day 1 every three weeks as a 30-minute outpatient intravenous infusion. MLN8237 will be orally administered in two divided doses from Days 1-7. The starting dose (level 0) of MLN8237 will be 60 mg daily given in two divided doses (30 mg qAM, 30 mg qPM).The dose of MLN8237 will be escalated in 20-mg increments up to 100 mg daily and de-escalated in 20-mg decrements to 40 mg daily. The fixed dose of brentuximab vedotin on Day 1 and daily dose of MLN8237 on Day 1-7 will constitute one treatment cycle. If no DLTs are observed in the last study cohort, the cohort will be expanded to include a total of 12 patients. If a de-escalation dose is required because 2 or more patients experience DLTs, the next lower cohort will be studied. If 2 or more patients do not experience DLTs, this dose will be declared the MTD. This cohort will be expanded to include 12 patients in order to study the biological endpoints and clinical benefit of the combination. If at any point during the expansion cohort phase of the trial 33% or more of the patients treated at the MTD/maximum administered dose experience a DLT, accrual of additional patients at this does level will cease and the next lowest dose may be explored.
Investigators
Eric Bernicker, MD
Study Investigator
The Methodist Hospital Research Institute
Eligibility Criteria
Inclusion Criteria
- •Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care;
- •Relapsed or refractory CD30-positive lymphoma such as Hodgkin's and anaplastic large cell lymphoma or CD30-positive cancer such as testicular embryonal carcinoma, cutaneous angiosarcoma, and nasopharyngeal non-keratinizing carcinoma or any CD30-positive solid tumor. CD30 positivity is defined as ≥ 25% CD30 expression by immunohistochemistry. (CD30 analysis will be performed by an in-house CLIA and CAP-accredited laboratory);
- •Male or female patients aged ≥ 18 years;
- •Adequate cardiac function (cardiac ejection fraction of ≥ 45%);
- •Patients must have received at least two prior therapies for CD30-positive lymphoma or solid malignancy;
- •Absolute neutrophil count \> 1500/mm³, platelets \> 100,000/mm³, and hemoglobin \> 8 g/dL. Values must be obtained without the need for myeloid growth factor or platelet transfusion support within 14 days of the first dose of the study treatment; however, erythrocyte growth factor is allowed as per the American Society of Clinical Oncology guidelines;
- •Total bilirubin ≤ 1.5 x upper limit of normal (ULN) and aspartate transaminase (AST) and alanine transaminase (ALT) \< 2.5 x ULN. AST and/or ALT may be up to 5 x ULN if liver metastases are present;
- •Adequate renal function as defined by a serum creatinine of \< 2.0 mg/dL and calculated creatinine clearance of ≥ 30 mL/minute;
- •Eastern Cooperative Oncology Group performance status of 0 to 2;
- •Female patients must be either:
Exclusion Criteria
- •Radiation therapy to more than 25% of the bone marrow. Whole pelvic radiation is considered to be over 25%;
- •Prior allogeneic bone marrow or organ transplantation;
- •Expected survival of less than 4 weeks;
- •Known gastrointestinal (GI) disease or GI procedures that could interfere with the oral absorption of or tolerance to alisertib. Examples include but are not limited to partial gastrectomy, history of small intestine surgery, and celiac disease;
- •Known history of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary disease;
- •Known cerebral or meningeal disease (Hodgkin's lymphoma or any other etiology), including signs or symptoms of progressive multifocal leukoencephalopathy;
- •Symptomatic neurologic disease that compromises normal activities of daily living or requires medication;
- •Requirement for constant or intermittent administration of a proton pump inhibitor, a H2 antagonist, or pancreatic enzymes. Intermittent use of antacids or H2 antagonists is allowed;
- •Systemic infection requiring intravenous antibiotic therapy within 14 days preceding the first dose of the study treatment or other severe viral or bacterial infection;
- •Absolute QT interval of \> 460 msec in the presence of \> 4.0 mEq/L potassium and \> 1.8 mg/dL magnesium;
Arms & Interventions
Alsertib and Brentuximab Vedotin
Brentuximab vedotin at a fixed dose of 1.8 mg/kg will be administered by intravenous infusion on day 1 of every 21-day cycle. MLN8237 at a dose of 60 mg will be orally administered daily in 2 divided doses (30 mg qAM, 30 mg qPM) from days 1 to 7 of each 21-day cycle. MLN8237 dose will be escalated in 20-mg increments to the maximum dose of 100 mg (Level 2) or de-escalated in a 20-mg decrement to the minimum dose of 40 mg (Level -1).
Intervention: Brentuximab Vedotin
Alsertib and Brentuximab Vedotin
Brentuximab vedotin at a fixed dose of 1.8 mg/kg will be administered by intravenous infusion on day 1 of every 21-day cycle. MLN8237 at a dose of 60 mg will be orally administered daily in 2 divided doses (30 mg qAM, 30 mg qPM) from days 1 to 7 of each 21-day cycle. MLN8237 dose will be escalated in 20-mg increments to the maximum dose of 100 mg (Level 2) or de-escalated in a 20-mg decrement to the minimum dose of 40 mg (Level -1).
Intervention: Alsertib
Outcomes
Primary Outcomes
Maximum tolerated dose (MTD)
Time Frame: Approximately 12 weeks
Determine the MTD of the alsertib (MLN8237) and brentuximab vedotin combination in patients with relapsed/refractory CD30-positive lymphomas and solid malignancies.
Secondary Outcomes
- Dose-limiting toxicities (DLTs)(Approximately 12 weeks)
- Recommended phase 2 dose (RP2D)(Approximately 12 weeks)
- Antitumor activity(Approximately 12 weeks)
- Area under the plasma concentration versus time curve(Cycle 1, Day 1 at pre-infusion and 10 min, 24 h, and 48 h post-infusion; trough sample on Cycle 1, Day 8; and Cycle 2, Day 1 at pre-infusion and 12 h and 24 h post-infusion.)