A study of MLN8237 in patients with solid tumor cancers to find the highest does of MLN8237 followed by further investigation of that dose in cancers of the lung, breast, head and neck or the gastic/oesphagus region.

• Conditions: Phase I portion of the study - Advanced nonhematologic malignancies.Phase II portion of the study - Non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), adenocarcinoma of the esophagus/gastroesophageal junction or stomach, head and neck carcinoma, or adenocarcinoma of the breast.; MedDRA version: 16.0Level: PTClassification code 10041067Term: Small cell lung cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 16.0Level: LLTClassification code 10066354Term: Adenocarcinoma of the gastroesophageal junctionSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 16.0Level: LLTClassification code 10006173Term: Breast adenocarcinomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 16.0Level: PTClassification code 10061873Term: Non-small cell lung cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 16.0Level: PTClassification code 10001150Term: Adenocarcinoma gastricSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 16.0Level: PTClassification code 10067821Term: Head and neck cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2008-006981-27-CZ
• Lead Sponsor: Millennium Pharmaceuticals, Inc

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2010-11-26
• Last Update Posted: 5 August 2014

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 270

Inclusion Criteria

1. Male or female patients 18 years or older.
2. Patients must have a diagnosis of an advanced, unresectable solid tumor that is histologically or cytologically confirmed to be of 1 of the following types, and for which standard curative or life-prolonging treatment does not exist, or is no longer effective or tolerable. Enrollment to the phase 1 portion is not restricted by tumor histology, however, an expansion cohort will include patients with adenocarcinoma of the pancreas, described below. Enrollment to the phase 2 portion requires 1 of the following histologic types:
- Group 1: Non-small cell lung cancer (NSCLC). Including 8 to 10 patients with predominant squamous cell histology, with 6 patients enrolled prior to evaluation for futility.
- Group 2: Small-cell lung cancer, extensive-stage (SCLC). A minimum of 8 and maximum of 12 patients with SCLC and chemotherapyrefractory disease, defined as no response to first-line chemotherapy or relapse within 90 days after completion of first-line chemotherapy.
- Group 3: Invasive adenocarcinoma of the breast (female patients only). Including 8 to 10 patients with disease known to be basal-like intrinsic subtype (also ER, PR, and HER2 negative) and 8 to 10 patients with disease known to be HER2 positive with any ER, PR. For ER, PR, and HER2 negative, the following criteria apply:
- Estrogen receptor (< 10%)
- Progesterone receptor (< 10%)
- HER-2 (negative FISH, IHC 0 - 1+, or IHC 0 - 2+ with negative FISH)
Group 4: Squamous cell cancer of the head and neck cancer (HNSCC). A minimum of 8 and maximum of 12 patients with disease originating in the tonsillar or base of tongue area will be enrolled in the first stage, and this subgroup must have archival tumor available for analysis of HPV16 and HPV18.
- Group 5: Adenocarcinoma of the esophagus, gastroesophageal junction, or stomach.
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
4. Female patients who:
- Are postmenopausal for at least 1 year before the screening visit, OR
- Are surgically sterile, OR
- If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form (ICF) through 30 days after the last dose of study drug, or agree to completely abstain from heterosexual intercourse.
Male patients, even if surgically sterilized (ie, status post-vasectomy), who:
- Agree to practice effective barrier contraception during the entire study treatment period and through 30 days after the last dose of study drug, OR
- Agree to completely abstain from heterosexual intercourse.
5. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
6. Clinical laboratory values as specified below:
- Total bilirubin = 1.5 times the upper limit of normal (ULN).
- Alanine aminotransferase (ALT) and AST must be = 3.0 times the ULN. AST and ALT may be elevated up to 5 times the ULN if the elevation can be reasonably ascribed to their underlying cancer or liver metastases.
- Calculated creatinine clearance = 30 mL/minute.
- Platelet count = 75,000/mm3 without transfusion requirement.
- Absolute neutrophil count (ANC) = 1500/mm3 without the need for growth factor support.
7. Measurable disease as per RECIST, version 1.1 (Only required

Exclusion Criteria

1. Female patients who are lactating or have a positive serum pregnancy test during the screening period.
2. Other severe acute or chronic medical or psychiatric condition, including uncontrolled diabetes, or laboratory abnormality that may increase the risk associated with trial participation or investigational product administration or may interfere with the interpretation of trial results and, in the judgment of the investigator, would make the patient inappropriate for enrollment in this study.
3. Receipt of more than 2 previous cytotoxic chemotherapeutic regimens (4 previous regimens for breast cancer) in the setting of metastatic or recurrent disease, not including regimens used as adjuvant or neo-adjuvant therapies if completed 6 months prior to subsequent chemotherapy. There is no limit on the number of prior noncytotoxic therapies (eg, hormonal, immunological, or biological) that patients may have received. Tyrosine kinase inhibitors (eg, Tarceva® and Iressa®) are considered to be noncytotoxic compounds if their dominant toxicity profile does not include sustained effects on normal proliferating tissues or bone marrow.
4. Prior treatment with Aurora A-targeted agents, including MLN8237.
5. Prior treatment with high-dose chemotherapy, defined as chemotherapy requiring the use of peripheral blood or bone marrow stem cell support for hematopoietic reconstitution.
6. Prior allogeneic bone marrow or other organ transplantation.
7. Systemic antineoplastic treatment within 21 days preceding the first dose of MLN8237. Patients treated with noncytotoxic small molecule drugs (see exclusion criteria in the protocol for examples) must not have received treatment with these drugs for at least 2 weeks before the first dose of MLN8237 is administered. Exceptions requiring a 42-day recovery period from last treatment are listed in the exclusion criteria in the protocol.
-The patient must have recovered (ie, = Grade 1 toxicity or patient’s baseline status,
(except alopecia) from all treatment-related toxicities to be eligible for the study.
8. Radiotherapy to = 25% of bone marrow.
9. Concurrent investigational treatment or treatment with any investigational products within 21 days before the first dose of study drug.
10. Patient has symptomatic brain metastasis. Patients with brain metastases must:
- Have stable neurologic status following local therapy (surgery or radiation) for at least 2 weeks after completion of the definitive therapy, and be without neurologic dysfunction that would confound the evaluation of neurologic and other AEs.
11. Diagnosis of or treatment for another malignancy within 2 years before the first dose of study drug except for nonmelanoma skin cancer that has been completely resected, or any in situ malignancy that has been completely resected.
12. Myocardial infarction within 6 months of enrollment or current history of New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia.
13. Abnormalities on 12-lead electrocardiogram (ECG) considered by the investigator to be clinically significant.
14. Major surgery within 14 days prior to the first dose of study drug treatment.
15. Infection requiring systemic intravenous antibiotic therapy within 14 days preceding the first dose of study drug, or other severe infection.
16. Inability to swallow oral medication or to maintain a fast as

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified