| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Adenocarcinoma of the breast (Phase 1 only).
Ovarian Cancer, defined to include recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer (Phases 1 and 2). |
|
| E.1.1.1 | Medical condition in easily understood language |
Breast cancer (phase 1 only)
Cancer of the ovary, fallopian tube or the cells lining the abdominal cavity |
|
| 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 | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10058448 |
| E.1.2 | Term | Peritoneal 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 | 14.1 |
| 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 | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061328 |
| E.1.2 | Term | Ovarian epithelial 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 | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10016180 |
| E.1.2 | Term | Fallopian tube 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 Objectives
The primary objectives of phase 1 are as follows:
• To assess the safety and tolerability of alisertib (MLN8237) plus weekly paclitaxel
• To determine the recommended dose and schedule of alisertib and dose of paclitaxel to be used as the combination treatment arm in phase 2
Phase 2: Primary Objective
The primary objective of Phase 2 is as follows:
• To assess progression-free survival (PFS) after treatment with the combination of alisertib 40 mg BID for 3 days on/4 days off, repeated weekly for 3 weeks in a 28-day cycle and weekly paclitaxel 60 mg/m2 on Days 1, 8 and 15 or weekly paclitaxel 80 mg/m2 on Days 1, 8 and 15 of a 28-day cycle alone in patients with recurrent OC, and to compare PFS of the populations enrolled to these 2 treatment arms |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of Phase 1 are:
• To characterize the effect of concomitant administration of alisertib on the pharmacokinetics (PK) of paclitaxel
• To characterize the PK of alisertib administered concomitantly with weekly paclitaxel
• To assess the best overall combined response in patients with recurrent ovarian cancer (OC) or breast cancer
The secondary objectives of Phase 2 are:
• To estimate the overall response rate (ORR), duration of response (DOR), time to disease progression (TTP), and overall survival (OS) associated with alisertib plus weekly paclitaxel and weekly paclitaxel alone in patients with recurrent OC
• To assess the safety and tolerability of alisertib plus weekly paclitaxel
For additional exploratory objectives refer to the protocol
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Female patients 18 years or older.
2. Previously treated, metastatic or locally recurrent malignancy with 1 of the 2 following diagnoses, which has been confirmed histologically or cytologically: a) adenocarcinoma of the breast (phase 1 only); or b) OC, defined to include recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer (phases 1 and 2).
3. Patients with breast cancer must have received prior treatment with at least 1 but no more than 4 prior chemotherapy regimens for locally recurrent or metastatic disease, not including regimens received in the neoadjuvant and/or adjuvant setting.
4. In the phase 1 portion of the study, patients with breast cancer must have measurable disease (per RECIST, version 1.1; see Section 15.3 of the protocol).
5. No antineoplastic therapy or radiotherapy within the 3 weeks before enrollment (2 weeks for regimens with recovery expected within 7 to 14 days). The patient must have recovered (ie, ≤ Grade 1 toxicity or patient’s baseline status, except alopecia) from all treatment related toxicities and must have evidence of PD or persistent disease. The patient must have experienced no more than Grade 2 non-hematologic toxicity attributed to a prior taxane therapy. No hormonal therapy except hormone replacement therapy or birth control medications.
6. ECOG performance status (PS) of 0 or 1 (refer to Section 15.1 of the protocol).
7. Adequate bone marrow function as defined by:
• Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3 (without need for growth factor support)
• Platelet count ≥ 100,000 cells/mm3 (without need for transfusion or growth factor support)
• Hemoglobin level ≥ 9 g/dL
8. Adequate liver function as defined by:
• Bilirubin < 1.5 times the upper limit of normal (ULN)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN (≤ 5 x ULN if due to liver metastases)
• serum albumin greater than the lower limit of normal (LLN)
9. Adequate renal function as defined by:
• Creatinine clearance ≥ 30 mL/minute (can be calculated using serum creatinine value; see Section 15.2 of the protocol)
10. 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 ICF through 30 days after the last dose of study drug, or agree to completely abstain from heterosexual intercourse
11. The patient or the patient’s legal representative is able to provide written informed consent. 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.
12. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
13. Suitable venous access for the study-required blood sampling.
Specific Inclusion Criteria for Patients with Recurrent Ovarian, Fallopian Tube, or Peritoneal Cancer:
14. Prior treatments must have included a platinum and a taxane. The most recent treatment regimen (administered prior to enrollment) need not be a platinum containing or a taxane containing regimen.
• Recurrent disease must be documented within 12 months after discontinuation of platinum therapy, based on RECIST or GCIG CA-125 criteria for disease progression described in item 15 below.
• Patients who previously received weekly taxane are potentially eligible, provided that they did not progress during therapy or within 3 months of completing therapy.
• Patients with platinum-refractory disease, as defined by progression during primary or subsequent platinum-based therapy or persistent radiographic disease after primary or subsequent platinum-based therapy will be included.
15. Patients must have measurable disease in target lesions or assessable disease, and disease progression per RECIST version 1.1 (Section 15.3 of the protocol) or modified GCIG CA 125 criteria (Section 15.4 of the protocol).
• Assessable disease is defined by CA-125 criteria as follows: minimum CA-125 level at the time of entry must have been more than 70 units/mL. This CA-125 level must have at least doubled from baseline to demonstrate evidence of PD from a previous treatment (with the value having been confirmed by at least 2 separate blood samples obtained ≥ 4 weeks apart or other clinical evidence of PD). Patients with CA-125 marker evidence for PD are included only if there is also clinical evidence of PD, eg, CT evidence for PD that is not measurable by RECIST. Radiological evidence of disease does not need to be measurable. Radiological abnormality, persistent after prior therapy, should be confirmed by biopsy to be a viable malignancy in the absence of other clinical or radiological evidence for PD.
|
|
| E.4 | Principal exclusion criteria |
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. Prior treatment with an Aurora A targeted agent (including alisertib).
2. Treatment with clinically significant enzyme inducers within 14 days prior to the first dose of alisertib and during the study. Major prohibited enzyme inducers include the following:
• phenytoin
• carbamazepine
• phenobarbital
• rifampin
• rifabutin
• rifapentine
• St. John's wort
3. Treatment with more than 4 cytotoxic chemotherapy treatment regimens in the metastatic setting. A cytotoxic agent is defined as any agent that targets the genetic, mitotic, and/or metabolic pathways of dividing cells, resulting in toxicity to the bone marrow and/or gastrointestinal mucosa. A chemotherapy regimen is defined as 1 or more agents used continuously or discontinuously (ie, allowing a break or chemotherapy holiday) without the addition of a new agent. A regimen administered pre-operatively and continued after surgery is considered a single regimen. Hormonal therapy is not considered to be a chemotherapy regimen.
• The most recent treatment regimen need not be a platinum-containing or a taxane containing regimen.
• Prior therapy cannot include more than 2 prior taxane-containing regimens.
4. Current use of tamoxifen, thalidomide, or any agent used as maintenance or consolidation therapy for OC.
5. Known hypersensitivity to Cremophor® EL, paclitaxel, or its components.
6. Prior history of ≥ Grade 2 neurotoxicity or any toxicity requiring discontinuation from taxane chemotherapy that is not resolved to ≤ Grade 1.
7. Any comorbid condition or unresolved toxicity that would preclude administration of weekly paclitaxel.
8. Diagnosis of primary CNS malignancy or carcinomatous meningitis.
9. 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.
10. Inability to swallow PO administered medications or to maintain a fast as required before and after alisertib administration.
11. History of hemorrhagic or thrombotic cerebrovascular event in the past 12 months.
12. Surgery within 3 weeks before study enrollment and not fully recovered to baseline or to a stable clinical status.
13. Diagnosis of or treated for another malignancy within 2 years before the first dose or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type, including patients with Stage IA or IB endometrioid carcinomas, are not excluded if they have undergone complete resection.
14. Patients who are lactating or have a positive serum pregnancy test during the screening period.
15. Other severe acute or chronic medical or psychiatric condition, including uncontrolled diabetes, malabsorption, resection of the pancreas or upper small bowel, requirement for pancreatic enzymes, any condition that would modify small bowel absorption of oral medications, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for enrollment in this study.
16. Requirement for constant administration of proton pump inhibitor, H2 antagonist, or pancreatic enzymes. Intermittent uses of antacids or H2 antagonists are allowed as described in Section 6.6 of the protocol.
17. Treatment with any investigational products within 21 days before the first dose of study drug.
18. Prior allogeneic bone marrow or organ transplantation.
19. Systemic infection requiring IV antibiotic therapy within 14 days preceding the first dose of study drug, or other severe infection.
20. 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.
21. Radiotherapy to ≥ 25% of bone marrow (Section 15.5 of the protocol), or whole pelvic radiotherapy.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1: Primary Endpoints
The primary endpoints for the Phase 1 portion of this study include:
• AEs, serious adverse events (SAEs), assessments of clinical and laboratory values, and vital sign measurements with a special attention to hypersensitivity reactions and neurotoxicity from the combination
• Safe doses of MLN8237 and paclitaxel when given in combination
Phase 2: Primary Endpoint
The primary endpoint for the Phase 2 portion of this study includes:
• PFS (Progression-Free Survival) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Ongoing (Safety Assessments)
Every 28 days (PFS) |
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints for the Phase 1 portion of this study include:
• Best overall combined response
• PK parameters of MLN8237, including but not limited to, maximum plasma concentration (Cmax), Tmax, and area under the plasma concentration versus time curve zero to the end of the dosing interval (AUC0-τ)
• PK parameters of paclitaxel, including but not limited to, Cmax, AUC0-tlast, AUC0-∞, and t½, when administered alone and during concomitant administration of MLN8237
The secondary endpoints for the Phase 2 portion of this study include:
• ORR, DOR, TTP, and OS
• AEs, SAEs, assessments of clinical laboratory values, and vital signs measurements |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The PK of paclitaxel will be characterized during Cycle 1 on Day 1 (paclitaxel administered concomitantly with MLN8237) and Cycle 2 on Day 1 (paclitaxel administered alone). Additionally, MLN8237 PK will be assessed during Cycle 1, on Days 1 and 3.
Every 28 days (Response, lab values, vital signs)
Ongoing (Safety Assessments)
|
|
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| 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 | No |
| 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 |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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