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A Phase I/II Trial to Assess Safety and Tolerability of an Oral Aurora Kinase A Inhibitor, MLN8237, In Combination With Erlotinib In Patients With Recurrent or Metastatic Non-Small Cell Lung Cancer

Phase 1/Phase 2
18 Years
Open (Enrolling)
Non-small Cell Lung Cancer Metastatic, Non-small Cell Lung Cancer Recurrent

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Trial Information

A Phase I/II Trial to Assess Safety and Tolerability of an Oral Aurora Kinase A Inhibitor, MLN8237, In Combination With Erlotinib In Patients With Recurrent or Metastatic Non-Small Cell Lung Cancer


I. Safety and tolerability of the combination treatment. (Phase I) II. Maximum tolerated
dose (MTD) of MLN8237 (alisertib) when given in combination with standard dose erlotinib
(erlotinib hydrochloride). (Phase I) III. Progression free survival. (Phase II)


I. Pharmacokinetic (PK) parameters of erlotinib and MLN8237, including, but not limited to
maximum concentration of drug (Cmax), time of occurrence for maximum drug concentration
(Tmax), and area under the curve from time zero to the last measurable concentration(AUC0-t

II. Overall response rate (ORR), duration of response (DOR), time to progression (TTP), and
overall survival (OS). (Phase II) III. Adverse events (AEs), serious adverse events (SAEs),
assessments of clinical laboratory values. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of alisertib followed by a phase II study.

Patients receive alisertib orally (PO) twice daily (BID) on days 1-7 and erlotinib
hydrochloride PO once daily (QD) on days 1-21. Courses repeat every 21 days for up to 2
years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years,
every 6 months for 2 years, and then annually thereafter.

Inclusion Criteria:

- Patients with cytologically or histologically confirmed recurrent locally advanced or
metastatic NSCLC have received at least one prior recognized systemic therapy for
therapy for advanced disease, (recognized therapy must include a platinum doublet
unless contraindicated due to organ dysfunction)

- Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1

- Measurable disease by Response Evaluation Criteria in Solid Tumors- (RECIST) 1.1
criteria; previous irradiated tumor is acceptable if there is at least a 20% increase
in the size of the previously irradiated lesion

- Absolute neutrophil count (ANC) >= 1500/mm^3

- Platelets >= 100,000/mm^3

- Hemoglobin (Hgb) >= 9g/dL

- Total bilirubin =< upper limit of normal (ULN)

- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and
serum glutamic pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 1.5 x
ULN; AST and/or ALT may be up to 5 X ULN if with known liver mets

- Adequate renal function as defined by: calculated creatinine clearance must be at
least 40 mL/minute (Cockcroft-Gault)

- Serious, active infections must be controlled; patients may be enrolled while still
on antibiotics as long as clinical signs of active infection are absent

- Previous radiation allowed provided the patient has recovered from the acute and
chronic side effects to =< grade 1 (National Cancer Institute [NCI] Common
Terminology Criteria for Adverse Events v. 4.0 [CTCAE v 4.0])

- Availability of archival diagnostic tissue (paraffin tissue block of resected tumor,
core biopsy, fine needle aspirate cell block, or if block cannot be submitted 20-25
[5 micron] unstained slides cut from a block representative of tumor, is required)

- Able and willing to sign an informed consent and Health Insurance Portability and
Accountability Act (HIPAA) authorization

- Able and willing to swallow and absorb orally administered medications and maintain a
fast as required before and after MLN8237 administration

- Women of childbearing potential (WOCBP) and men who are sexually active, even if
surgically sterilized, with WOCBP must agree to use effective methods of
contraception during active treatment, for the duration of the study, and for 3
months after the completion of the study

Exclusion Criteria

- Prior treatment with an investigational or marketed inhibitor of the epidermal growth
factor receptor (EGFR) pathway or an Aurora Kinase inhibitor

- Patients with mutations in the EGFR gene; the mutational status of all patients will
be determined prior to study entry

- Prior malignancy within the past 3 years other than complete resection of basal or
squamous cell carcinoma of the skin, any in situ malignancy, or low-risk prostate
cancer after curative therapy

- Prior systemic therapy within 14 days of initiating protocol treatment

- Radiation therapy to more than 25% of the bone marrow; whole pelvic radiation is
considered to be over 25%; (ongoing small field radiation therapy for palliation only
is allowed)

- Treatment with clinically significant enzyme inducers, such as the enzyme-inducing
antiepileptic drugs phenytoin, carbamazepine or phenobarbital, or rifampin,
rifabutin, rifapentine or St. John's wort within 14 days prior to the first dose of
MLN8237 and during the study; anticonvulsants at stable doses are allowed

- Treatment with Proton Pump Inhibitor (PPI); patients on PPI therapy prior to
enrollment must stop using the PPI for at least 4 days prior to the first dose of

- Known central nervous system (CNS) disease, except for treated brain metastasis;
treated brain metastases are defined as having no evidence of progression or
hemorrhage after treatment and no ongoing requirement for dexamethasone, as
ascertained by clinical examination and brain imaging (magnetic resonance imaging
[MRI] or computed tomography [CT]) during the screening period; anticonvulsants
(stable doses) are allowed; treatment for brain metastases may include whole brain
radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, linear accelerator [LINAC], or
equivalent) or a combination as deemed appropriate by the treating physician;
patients with CNS metastases treated by neurosurgical resection or brain biopsy
performed < 4 weeks prior to Day 1 will be excluded

- Uncontrolled or unstable medical or psychiatric co-morbidities which would clearly
preclude use of MLN8237 or erlotinib

- Current, recent (within 2 weeks of enrollment of this study), or planned
participation in an experimental drug study

- Unstable angina

- New York Heart Association (NYHA) Grade III or greater congestive heart failure

- History of myocardial infarction within 6 months of enrollment

- Abnormal electrocardiogram (EKG): severe uncontrolled ventricular arrhythmias, or
evidence of acute ischemia or active conduction system abnormalities; prior to study
entry, any EKG abnormality at screening has to be documented by the investigator as
not medically relevant

- Pregnant (positive serum pregnancy test) or breast feeding

- History of any disease that could lead to impaired absorption of drugs

- Known hypersensitivity to any component of the trial agents

- Inability to comply with study and/or follow-up procedures

- Prior allogeneic bone marrow or organ transplantation

- Patient has >= grade 2 (CTCAE v 4.0) peripheral neuropathy within 14 days before

- Known history of uncontrolled sleep apnea syndrome and other conditions according to
enrolling investigator that could result in excessive daytime sleepiness, such as
severe chronic obstructive pulmonary disease; requirement for supplemental oxygen
therapy; or requirement of recurrent thoracentesis to manage pleural effusions

- Known history of human immunodeficiency virus (HIV) infection, hepatitis B, or
hepatitis C; testing is not required in the absence of clinical findings or suspicion

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Safety and tolerability of the combination treatment (Phase I)

Outcome Description:

Toxicity will be evaluated according to the NCI CTCAE, version 4.0.

Outcome Time Frame:

Participants will be followed for the duration of treatment (up to 2 years) through 30 days of completion of treatment

Safety Issue:


Principal Investigator

Hossein Borghaei, DO

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fox Chase Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

October 2011

Completion Date:

November 2013

Related Keywords:

  • Non-small Cell Lung Cancer Metastatic
  • Non-small Cell Lung Cancer Recurrent
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms
  • Neoplasms
  • Neoplasms, Second Primary



Fox Chase Cancer CenterPhiladelphia, Pennsylvania  19111