Alisertib in Adults With Nonhematological Malignancies, Followed by Alisertib in Lung, Breast, Head and Neck or Gastroesophageal Malignancies

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Advanced Nonhematological Malignancies, Non-Small Cell Lung Cancer, Small Cell Lung Cancer, Metastatic Breast Cancer, Head and Neck Squamous Cell Carcinoma, Gastroesophageal Adenocarcinoma

Intervention / Treatment
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* Drug: MLN8237 (Alisertib)


Participation Criteria
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Eligibility Criteria
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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

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
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MLN8237 (Alisertib)<br>MLN8237 administered as an enteric-coated tablet (ECT) | Drug: MLN8237 (Alisertib)<br>* Phase 1: MLN8237 will be administered orally twice a day on a 7-day dosing schedule Phase 2: MLN8237 will be administered orally at the maximum tolerated dose determined in Phase 1 for 7-days followed by a minimum 14-day rest period.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Number of Participants With Dose-Limiting Toxicities (DLTs) | Toxicity according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0. DLT defined as any of the following considered related to alisertib by investigator: Grade 4 neutropenia (absolute neutrophil count <500 cells/cubic meter [cells/mm^3]) for >7 days; Grade 4 neutropenia with coincident fever; Grade 4 thrombocytopenia (platelets <25,000 cells/mm3) for >7 days; Platelet count <10,000 cells/mm3; Grade 3 thrombocytopenia with clinically significant bleeding; Delay in initiation of the subsequent therapy cycle by >7 days due to treatment-related toxicity; >=Grade 3 nonhematological toxicity except >=Grade 3 nausea/emesis occurred in the absence of optimal antiemetic therapy; >=Grade 3 diarrhea occurred in the absence of optimal supportive therapy with loperamide/comparable antidiarrheal; Grade 3 fatigue for <1 week; Other Grade 3 nonhematological toxicity that could be safely, reliably controlled to <=Grade 2 with appropriate treatment. | Phase 1: Cycle 1 Day 1 to Cycle 2 Day 21 | 
| Phase 2: Percentage of Participants With Objective Response | Percentage of participants with objective response based assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST). CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis less than [<] 10 millimeter [mm]). No new lesions. PR was defined as greater than or equal to (>=) 30 percent (%) decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions. | Baseline until complete response or partial response, assessed every 2 cycles up to end of study (up to 50 cycles) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2: Progression-free Survival (PFS) | PFS was defined as the time from randomization (or the first dose of study treatment for non-randomized studies) to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first. Tumor progression as per RECIST 1.1 was defined as at least 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this included the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of 1or more new lesions is also considered progression. | Baseline until progressive disease, assessed every 2 cycles up to end of study (up to 50 cycles) | 
| Phase 2: Time to Disease Progression (TTP) | Time in days from start of study treatment to first documentation of objective tumor progression. Tumor progression as per RECIST 1.1 was defined as at least 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of 1or more new lesions is also considered progression. | Baseline until disease progression, assessed every 2 cycles up to end of study (up to 50 cycles) | 
| Phase 2: Duration of Response (DOR) | Time in days from the first documentation of objective tumor response to objective tumor progression or death due to any cancer. Duration of tumor response=(the date of the first documentation of objective tumor progression or death due to cancer minus the date of the first CR or PR that was subsequently confirmed plus 1). CR: complete disappearance of all target lesions and non-target disease, except nodal disease; all nodes decreased to normal; no new lesions. PR: >=30% decrease under baseline of the sum of diameters of all target lesions; no unequivocal progression of non-target disease; no new lesions. Tumor progression: >=20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study); absolute increase of >=5 mm; appearance of >=1 new lesions is also considered progression. DOR calculated for the subgroup of participants with objective response. | Baseline up to Week 50 | 
| Phase 2: Number of Participants Reporting One or More Treatment-emergent Adverse Events and Serious Adverse Events | 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 the last dose of study drug | 
| Phase 1: Cmax- Maximum Observed Plasma Concentration for Alisertib | Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. | Days 1 and 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours post-dose | 
| Phase 1: Tmax- Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib | Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax. | Days 1 and 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours postdose | 
| Phase 1: AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Alisertib | Area under the plasma concentration-time curve during a dosing interval, where tau is the length of the dosing interval. | Days 1 and 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours postdose | 
| Phase 1: Terminal Phase Elimination Half-life (T1/2) for Alisertib | Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma. | Day 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours postdose | 
| Phase 1: Rac- Accumulation Ratio for Alisertib | Rac was estimated as a ratio of AUC (0-tau) at Day 7 and AUC (0-tau) at Day 1. Area under the plasma concentration-time curve during a dosing interval, where tau is the length of the dosing interval. | Days 1 and 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours postdose | 
| Phase 1: Peak to Trough Ratio for Alisertib | Peak to trough ratio was estimated as a ratio of Cmax at Day 7 and the minimum observed plasma concentration (Ctrough) of alisertib at Day 7. Cmax is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. Ctrough is the minimum plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. | Day 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours postdose | 
| Phase 1: Steady State Oral Clearance (CLss/F) for Alisertib | CL/F is apparent clearance of the drug from the plasma, calculated as the drug dose divided AUC(0-tau), expressed in liter per hour (L/hr). | Day 7: predose, 30 minutes, 1, 2, 3, 4, 6, 8, and 12 hours postdose | 
| Phase 2: Relationship Between Clinical Response and Molecular Markers of Response | In SCLC,chemo-sensitive/resistant population were analyzed;in breast cancers,ER2 and ER2 status were analyzed.HR+ =estrogen receptor-positive or progesterone receptor-positive. HER+ =human epidermal growth factor receptor 2 (HER2). Triple negative =negative for estrogen receptors, progesterone receptors, and HER2.Clinical response according to RECIST version 1.1. CR:complete disappearance of all target lesions,non-target disease,except nodal disease;all nodes decrease to normal (short axis <10 mm);no new lesions. PR:>=30% decrease under baseline of the sum of diameters of all target lesions (SLD);short axis was used in the sum for target nodes,longest diameter used in the sum for all other target lesions;no unequivocal progression of non-target disease;no new lesions. Progressive Disease (PD): >=20% rise in SLD from the smallest value on study;unequivocal progression of existing non-target lesions. Stable Disease (SD):Neither sufficient shrinkage for PR nor sufficient increase for PD. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NSCLC, SCLC, HNSCC