Clinical trial NCT01045421: Alisertib in Adults With Nonhematological Malignancies, Followed by Alisertib in Lung, Breast, Head and Neck or Gastroesophageal Malignancies
Official title: A Phase 1 Dose Escalation Study of MLN8237, an Aurora A Kinase Inhibitor, in Adult Patients With Nonhematological Malignancies, Followed by a Phase 2 of MLN8237 in Lung, Breast, Head and Neck, or Gastroesophageal Malignancies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Advanced Nonhematological Malignancies
Non-Small Cell Lung Cancer
Small Cell Lung Cancer
Metastatic Breast Cancer
Head and Neck Squamous Cell Carcinoma
Gastroesophageal Adenocarcinoma
Keywords: NSCLC
SCLC
HNSCC
Lead sponsor: Millennium Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2010-01-11
Enrollment: 273
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is an open-label, multicenter study with a phase 1 dose escalation portion and a 2-stage, phase 2 portion, investigating MLN8237 (alisertib) in patients with advanced nonhematological malignancies.

Detailed description: Following the determination of the Recommended Phase 2 Dose (RP2D) and schedule (Phase 1), 20 response-evaluable patients in each of the 5 tumor indications will be enrolled (Phase 2-Stage 1). An interim analysis will determine which tumor indications will proceed to enroll an additional 25 patients (Phase 2-Stage 2) to further evaluate Overall Response Rate (ORR) and other secondary endpoints.

Eligibility criteria: Inclusion Criteria:

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

* 18 years or older
* Histologically or cytologically confirmed metastatic and/or advanced solid tumor (Phase 1 only)
* Phase 2 requires Non-small cell lung cancer (NSCLC); Small-cell lung cancer; Breast adenocarcinoma (female patients only); Squamous cell cancer of the head and neck (HNSCC); or Gastroesophageal adenocarcinoma
* Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
* 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 practice effective barrier contraception or agree to abstain from heterosexual intercourse
* Voluntary written consent
* Wiling to comply with scheduled visits, treatment plan, laboratory tests and other trial procedures
* Measurable disease (Phase 2 only)

Exclusion Criteria:

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

* Female patients who are pregnant or lactating
* Serious medical or psychiatric illness that could interfere with protocol completion
* Receipt of more than 2 previous cytotoxic chemotherapeutic regimens (4 previous regimens for breast cancer). There is no limit on the number of prior noncytotoxic therapies
* Prior treatment with Aurora A-targeted agents, including MLN8237
* Prior treatment with high-dose chemotherapy
* Prior allogeneic bone marrow or other organ transplant
* Antineoplastic therapy, radiation therapy or any experimental therapy 21 days prior to first dose of MLN8237
* Symptomatic brain metastasis
* Radiotherapy to greater than 25% of bone marrow
* Diagnosis or treatment of another malignancy within 2 years preceding first dose of study drug except nonmelanoma skin cancer or in situ malignancy completely resected
* Myocardial infarction within 6 months of enrollment
* Uncontrolled cardiovascular condition
* Major surgery within 14 days of first dose of MLN8237
* Active infection requiring systemic therapy, or other serious infection
* Inability to swallow oral medication
* Known history of human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C
* Patients requiring full systemic anticoagulation
* History of uncontrolled sleep apnea syndrome
* Treatment with clinically significant enzyme inducers within 14 days prior to the first dose of MLN8237 and during the study

Primary outcomes:
measure: Phase 1: Number of Participants With Dose-Limiting Toxicities (DLTs)
timeFrame: Phase 1: Cycle 1 Day 1 to Cycle 2 Day 21
measure: Phase 2: Percentage of Participants With Objective Response
timeFrame: Baseline until complete response or partial response, assessed every 2 cycles up to end of study (up to 50 cycles)
Secondary outcomes:
measure: Phase 2: Progression-free Survival (PFS)
timeFrame: Baseline until progressive disease, assessed every 2 cycles up to end of study (up to 50 cycles)
measure: Phase 2: Time to Disease Progression (TTP)
timeFrame: Baseline until disease progression, assessed every 2 cycles up to end of study (up to 50 cycles)
measure: Phase 2: Duration of Response (DOR)
timeFrame: Baseline up to Week 50
measure: Phase 2: Number of Participants Reporting One or More Treatment-emergent Adverse Events and Serious Adverse Events
timeFrame: Baseline up to 30 days after the last dose of study drug
measure: Phase 1: Cmax- Maximum Observed Plasma Concentration for Alisertib
timeFrame: Days 1 and 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours post-dose
measure: Phase 1: Tmax- Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib
timeFrame: Days 1 and 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours postdose
measure: Phase 1: AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Alisertib
timeFrame: Days 1 and 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours postdose
measure: Phase 1: Terminal Phase Elimination Half-life (T1/2) for Alisertib
timeFrame: Day 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours postdose
measure: Phase 1: Rac- Accumulation Ratio for Alisertib
timeFrame: Days 1 and 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours postdose
measure: Phase 1: Peak to Trough Ratio for Alisertib
timeFrame: Day 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours postdose
measure: Phase 1: Steady State Oral Clearance (CLss/F) for Alisertib
timeFrame: Day 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours postdose
measure: Phase 2: Relationship Between Clinical Response and Molecular Markers of Response
timeFrame: 12 months
Other outcomes:
Locations:
city: Houston
country: United States
state: Texas
city: Salt Lake City
country: United States
state: Utah
Study officials:
affiliation: Millennium Pharmaceuticals, Inc.
name: Medical Monitor
role: STUDY_DIRECTOR
References:
citation: Melichar B, Adenis A, Lockhart AC, Bennouna J, Dees EC, Kayaleh O, Obermannova R, DeMichele A, Zatloukal P, Zhang B, Ullmann CD, Schusterbauer C. Safety and activity of alisertib, an investigational aurora kinase A inhibitor, in patients with breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous-cell carcinoma, and gastro-oesophageal adenocarcinoma: a five-arm phase 2 study. Lancet Oncol. 2015 Apr;16(4):395-405. doi: 10.1016/S1470-2045(15)70051-3. Epub 2015 Feb 27.
citation: Falchook G, Kurzrock R, Gouw L, Hong D, McGregor KA, Zhou X, Shi H, Fingert H, Sharma S. Investigational Aurora A kinase inhibitor alisertib (MLN8237) as an enteric-coated tablet formulation in non-hematologic malignancies: phase 1 dose-escalation study. Invest New Drugs. 2014 Dec;32(6):1181-7. doi: 10.1007/s10637-014-0121-6. Epub 2014 Jun 1.