| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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. |
|
| E.1.1.1 | Medical condition in easily understood language |
| MLN 8237 is being developed as a possible treatment for patients with advanced solid tumours ( such as lung cancer, breast cancer etc.) whose disease is no longer responding to standard therapies |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10041067 |
| E.1.2 | Term | Small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066354 |
| E.1.2 | Term | Adenocarcinoma of the gastroesophageal junction |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10006173 |
| E.1.2 | Term | Breast adenocarcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10001150 |
| E.1.2 | Term | Adenocarcinoma gastric |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10067821 |
| E.1.2 | Term | Head and neck cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase 1: The primary objective of the phase 1 portion of this study is to assess the safety and tolerability of MLN8237, formulated as an enteric-coated tablet (ECT), on a 7-day dosing schedule for determining the recommended dose and schedule of MLN8237 to be used in phase 2.
Phase 2: The primary objective of the phase 2 portion of this study is to estimate the antitumor activity of MLN8237 as measured by overall response rate (ORR) in patients with advanced, unresectable nonhematological malignancies (NSCLC, SCLC, adenocarcinoma of the breast, HNSCC, or adenocarcinoma of the esophagus/gastroesophageal junction or stomach). |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the phase 1 portion of this study are:
- To characterize the PK of MLN8237, formulated as ECT (Enteric Coated Tablet), administered on a 7-day dosing schedule.
- To describe any antitumor activity that may be observed with MLN8237 treatment in patients with advanced nonhematological malignancies.
- To determine the RP2D-P (Recommended Phase 2 Dose - Pancreatic) in a subset of patients who meet eligibility criteria for the pancreatic cancer patient cohort.
The secondary objectives of the phase 2 portion of this study are:
- To assess the relationship between clinical response and molecular markers of response.
- To assess additional measures of antitumor activity, including TTP, PFS, and DOR.
- To characterize the safety profile associated with MLN8237. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 for enrollment to the phase 2 part of the study)
8. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.
9. Patients in the pancreatic cancer patient cohort will have the following features:
a) prior history of regional treatment for adenocarcinoma of the pancreas (prior treatment may include pancreatectomy or Whipple surgical procedure, partial [but not total] gastrectomy, or regional radiotherapy); and b) concomitant treatments with pancreatic enzymes and proton pump inhibitor. |
|
| E.4 | Principal 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 required before and after MLN8237 administration.
17. History of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary disease.
18. 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.
19. Patients requiring full systemic anticoagulation (excluding low-dose aspirin, or low-dose anticoagulation to maintain patency of venous access devices). Low molecular weight heparin is allowed if the patient has tolerated treatment with a stable dose and schedule without bleeding complications for more than 1 month.
20. Treatment with clinically significant enzyme inducers (see protocol exclusion criteria for examples) within 14 days prior to the first dose of MLN8237 and during the study.
21. The following eligibility restrictions will apply to patients other than patients enrolled to the pancreatic cancer cohort: malabsorption, resection of pancreas or upper small bowel, requirement for pancreatic enzymes, or any condition that would modify small bowel absorption or oral medications. These exclusion criteria may be modified based on results obtained from evaluation of the pancreatic cancer patient cohort. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1: Primary Endpoint
The primary endpoints for the phase 1 portion of this study include AEs, serious adverse events (SAEs), assessments of clinical and laboratory values, ECGs, and vital sign measurements.
Phase 2: Primary Endpoint
The primary endpoint for the phase 2 portion includes ORR. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After the database is locked to Final Analysis. Final analysis is when the final set of tables, listing and figures are available. Timepoint of evaluation for both endpoints is anticipated to occur March 2014. |
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints for the phase 1 portion of this study include:
PK parameters of MLN8237, including but not limited to, Cmax, Tmax,
and area under the plasma concentration versus time curve zero to the
end of the dosing interval on Days 1 and 7, and terminal half-life on Day
7 for a 7-day BID dosing schedule.
Response, according to RECIST 1.1, in patients with measurable disease.
The secondary endpoints for the phase 2 portion include:
TTP, PFS, and DOR.
AEs, SAEs, assessments of clinical laboratory values, ECGs, and vital
signs measurements. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
After the database is locked to Final Analysis. Final analysis is when the
final set of tables, listing and figures are available. Timepoint of
evaluation for both endpoints is anticipated to occur March 2014. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Czech Republic |
| France |
| Poland |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last patient, last visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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