| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced, Recurrent, or Persistent Endometrial Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10014735 |
| E.1.2 | Term | Endometrial cancer NOS |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
| To determine if MLN0128 in combination with weekly paclitaxel improves progression-free survival (PFS) compared to weekly paclitaxel alone. |
|
| E.2.2 | Secondary objectives of the trial |
1) To determine if single-agent MLN0128 improves PFS compared to weekly paclitaxel alone.
2) To determine if MLN0128 + MLN1117 improves PFS compared to weekly paclitaxel alone.
3) To assess the safety and tolerability of single-agent MLN0128, MLN0128 in
combination with paclitaxel, and MLN0128 + MLN1117.
4) To evaluate improvement in efficacy measures (endpoints other than PFS) of MLN0128 in combination with weekly paclitaxel, single-agent MLN0128, and MLN0128 +MLN1117 to weekly paclitaxel alone.
5) To collect plasma concentration-time data with sparse pharmacokinetic (PK) sampling to contribute to future population PK analysis.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologic or cytologic diagnosis of endometrial carcinoma (including endometrioid, serous, mixed adenocarcinoma, clear-cell carcinoma, or carcinosarcoma)
2. Evidence that the endometrial cancer is advanced, recurrent, or persistent and has relapsed or is refractory to curative therapy or established treatments.
3. At least 1 prior platinum-based chemotherapeutic regimen, but not more than 2 prior chemotherapeutic regimens, for management of endometrial carcinoma. Prior treatment may include chemotherapy, chemotherapy/radiation therapy, and/or consolidation/maintenance therapy. Chemotherapy administered in conjunction with primary radiation as a radio-sensitized therapy will be considered a systemic chemotherapy regimen.
4. Measureable disease by RECIST 1.1, defined as at least 1 lesion that can be accurately measured in at least 1 dimension (longest diameter to be recorded). Each lesion must be ≥ 10 mm in long axis when measured by CT, MRI, or caliper measurement by clinical exam. Lymph nodes must be ≥ 15 mm in short axis when measured by CT or MRI.
5. Tumor accessible and patient consents to undergo fresh tumor biopsies.
6. Female patients 18 years or older.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
8. 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 1 highly effective method of contraception, and 1 additional effective (barrier) method at the same time, from the time of signing the informed consent through 90 days (or longer, as mandated by local labeling [eg, USPI, SmPC, etc.]) after the last dose of study drug, OR
- Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods] and withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
9. Clinical laboratory values as specified below within 4 weeks before the first dose of study drug:
- Bone marrow reserve consistent with absolute neutrophil count (ANC) ≥ 1500/uL; platelet count ≥ 100,000/uL; glycosylated hemoglobin (HbA1c) < 6.5%.
- Total bilirubin must be less than or equal to 1.5 x times the upper limit of the normal range (ULN).
- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) must be less than or equal to 2.5 the upper limit of the normal range. AST and ALT may be elevated up to 5 times the ULN if their elevation can be reasonably ascribed to the presence of metastatic disease in liver.
- Creatinine clearance ≥ 50 mL/min/1.73 m2 based either on Cockcroft-Gault estimate or based on a 12- or 24-hour urine collection.
- Fasting serum glucose < 130 mg/dL and fasting triglycerides ≤ 300 mg/dL.
10. Ability to swallow oral medications, willingness to perform mucositis prophylaxis, and suitable venous access for the study-required blood sampling.
11. 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. |
|
| E.4 | Principal exclusion criteria |
1. Positive serum pregnancy test during the screening period or a positive urine pregnancy test on Day 1 before first dose of study drug. Women who are lactating and breastfeeding are not eligible.
2. Previous treatment with any weekly taxane regimen.
3. History of severe hypersensitivity reactions to paclitaxel or any of its excipients.
4. Previous treatment with PI3K, AKT, dual PI3K/mTOR inhibitors, TORC1/2 inhibitorsor TORC1 inhibitors.
5. Initiation of treatment with hematopoietic growth factors, transfusions of blood and blood products, or systemic corticosteroids (either IV or oral steroids, excluding inhalers) within 1 week before administration of the first dose of study drug (patients already receiving erythropoietin on a chronic basis for ≥ 4 weeks are eligible).
6. Patients who are taking proton pump inhibitors (PPIs) within 7 days of the first dose of study drug or who require treatment with PPIs throughout the trial or those who are taking H2 receptor antagonists within 24 hours of the first dose of study drug.
7. A prothrombin time (PT) or activated partial thromboplastin time (aPTT) above the ULN or a history of a coagulopathy or bleeding disorder.
8. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection.
9. Sensory or motor neuropathy ≥ Grade 2.
10. Central nervous system (CNS) metastasis, endometrial leiomyosarcoma, or endometrial stromal sarcoma.
11. Manifestations of malabsorption due to prior gastrointestinal surgery, gastrointestinal disease, or for some other reason that may alter the absorption of MLN0128 or MLN1117. In addition, patients with enteric stomata are also excluded.
12. Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active CNS disease, active infection, or any other condition that could compromise participation of the patient in the study.
13. Known human immunodeficiency virus infection.
14. History of any of the following within the last 6 months before administration of the first dose of study drug:
- Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures.
- Ischemic cerebrovascular event, including transient ischemic attack and arteryrevascularization procedures.
- Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation, or ventricular tachycardia).
- Placement of a pacemaker for control of rhythm.
- New York Heart Association Class III or IV heart failure (see Section 14.3).
- Pulmonary embolism.
15. Significant active cardiovascular or pulmonary disease before administration of the first dose of study drug, including:
- Uncontrolled hypertension (ie, either systolic blood pressure >180 mm Hg; diastolic blood pressure > 95 mm Hg).
- Pulmonary hypertension.
- Uncontrolled asthma or oxygen saturation < 90% by arterial blood gas analysis or pulse oximetry on room air.
- Significant valvular disease; severe regurgitation or stenosis by imaging independent of symptom control with medical intervention; or history of valve replacement.
- Medically significant (symptomatic) bradycardia.
- History of arrhythmia requiring an implantable cardiac defibrillator.
- Baseline prolongation of the rate-corrected QT interval (QTc; eg, repeated demonstration of QTc interval > 480 msec, or history of congenital long QT syndrome or torsades de pointes).
16. Diagnosed or treated for another malignancy within 2 years before administration of the first dose of study drug or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
17. Patients with endometrioid histology and histologically confirmed expression of estrogen receptors (ER) and/or progesterone receptors (PgR) who have not received prior endocrine therapy and for whom endocrine therapy is currently indicated. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| progression-free survival (PFS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The total accrual duration will be approximately 24 months, assuming 10% of the patients are enrolled within the first 6 months and 45% of the patients are enrolled within the first 12 months. The final analysis for the primary comparison of PFS between the paclitaxel treatment arm and the paclitaxel + MLN0128 8 mg QD x 3 treatment arm will occur approximately 6 months after the last patient is randomized. |
|
| E.5.2 | Secondary end point(s) |
The number and percentage of patients with TEAEs.
Overall survival (OS).
Time to progression (TTP).
Overall response rate (ORR) (complete response [CR] + partial response [PR]).
Clinical benefit rate (CBR) (CR + PR + stable disease [SD], SD of any duration).
CBR at 16 weeks (CBR-16 is defined as the proportion of patients who achieve CR or partial response of any duration or have SD with a duration of at least 16 weeks). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Overall survival is defined as the time from the date of randomization to the date of death. Overall survival will be analyzed using similar methods as the primary endpoint of PFS. Overall response rate is defined as the proportion of patients who achieve a best response of CR or PR. CBR is defined as the proportion of patients who achieve a best response of CR, PR, or SD. TTP is defined as the time from the date of randomization to the date of first documentation of progression. TTP will be analyzed using similar methods as the primary endpoint of PFS. Duration of SD is defined as the time from the date of randomization to the date of first documentation of disease progression for patients who achieved SD as the best overall response. |
|
| 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 | No |
| 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 | No |
| E.6.10 | Pharmacogenetic | No |
| 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 | 4 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 44 |
| 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 |
| Australia |
| Belgium |
| Canada |
| Germany |
| Italy |
| Netherlands |
| Norway |
| Spain |
| United Kingdom |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 36 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 36 |
Print
