Alsertib (MLN8237) and Brentuximab Vedotin for Relapsed/Refractory CD30-Positive Lymphomas and Solid Malignancies

NCT02780011 | Withdrawn Phase 1 DMC

• 1 other identifier: Pro00012815
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

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.

Conditions

CD30-positive Lymphoma; CD30-positive Solid Tumor

Keywords

CD30+; Relapsed; Refractory; ALCL

Outcome Measures

Primary Outcomes (1)

• Maximum tolerated dose (MTD)

  Determine the MTD of the alsertib (MLN8237) and brentuximab vedotin combination in patients with relapsed/refractory CD30-positive lymphomas and solid malignancies.

  Approximately 12 weeks

Secondary Outcomes (4)

• 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.

Other Outcomes (2)

• H3K activity

  Approximately 12 weeks

• Correlation between CD30 detection method and clinical response

  Approximately 12 weeks

Study Arms (1)

Alsertib and Brentuximab Vedotin

EXPERIMENTAL

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).

Drug: Brentuximab Vedotin; Drug: Alsertib

Interventions

Brentuximab Vedotin DRUG

Antibody-drug conjugate composed of the anti-CD30 chimeric immunoglobulin G1 monoclonal antibody cAC10 and the antimicrotubule drug monomethyl auristatin E connected by a protease-cleavable linker.

Also known as: Adcetris

Alsertib and Brentuximab Vedotin

Alsertib DRUG

Aurora A kinase inhibitor

Also known as: MLN8237

Alsertib and Brentuximab Vedotin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• post-menopausal for at least one year before the screening visit, or
• surgically sterilized, or
• willing to use an acceptable method of birth control (i.e., hormonal contraceptive, intrauterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study;
• Male patients, even if surgically sterilized (i.e., post-vasectomy status), must agree to use an acceptable contraceptive method during the course of the study and for 4 months after the last dose of alisertib.

You may not qualify if:

• 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;
• Myocardial infarction within 6 months prior to enrollment or has New York Heart Association Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any electrocardiogram abnormality at screening has to be documented by the investigator as not medically relevant;
• Female patient who is pregnant or breastfeeding. Confirmation that the subject is not pregnant must be established by a negative serum beta human chorionic gonadotropin pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women;
• Patient has received other investigational drugs within 14 days of enrollment;
• Serious medical or psychiatric illness likely to interfere with participation in this clinical study;
• Other severe acute or chronic medical or psychiatric condition, including uncontrolled diabetes, malabsorption, resection of the pancreas or upper small bowel, requirement for pancreatic enzymes, any condition that would modify small bowel absorption of oral medications, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for enrollment in this study;

Sponsors & Collaborators

• Eric Bernicker, MD: lead
• Millennium Pharmaceuticals, Inc.: collaborator
• The Methodist Hospital Research Institute: collaborator

Study Sites (1)

Houston Methodist Cancer Center

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Recurrence

Interventions

Brentuximab Vedotin; MLN 8237

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Oligopeptides; Peptides; Amino Acids, Peptides, and Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Serum Globulins; Globulins

Study Officials

• Swami Padmanabhan Iyer, MD

  The Methodist Hospital Research Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Study Investigator

Study Record Dates

• First Submitted: February 24, 2016
• First Posted: May 23, 2016
• Study Start: December 1, 2015
• Primary Completion: September 1, 2018
• Study Completion: September 1, 2018
• Last Updated: July 27, 2018

Record last verified: 2018-07

Data Sharing

• IPD Sharing: Will share

Locations

US (1)