| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| ER+/HER2- Advanced or Metastatic Breast Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced Breast cancer or cancer that has spread |
|
| 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 | 10072737 |
| E.1.2 | Term | Advanced breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| 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 |
Phase 1b
- To evaluate the safety and tolerability of MLN0128 in combination with either exemestane or fulvestrant
Phase 2
- To evaluate the antitumor activity by clinical benefit rate (CBR) at 16 weeks (CBR-16 is defined as the proportion of patients who achieve complete response [CR] or partial response of any duration, or have stable disease [SD] at 16 weeks) of treatment with MLN0128 in combination with either exemestane or fulvestrant |
|
| E.2.2 | Secondary objectives of the trial |
- To further evaluate the antitumor activity of MLN0128 in combination with either exemestane or fulvestrant
- To evaluate the pharmacokinetics of MLN0128 and exemestane when administered in combination and to evaluate the pharmacokinetics of MLN0128 when administered in combination with fulvestrant
- To assess the safety and tolerability of MLN0128 in combination with either exemestane or fulvestrant |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Advanced or metastatic breast cancer.
2. Histological or cytological confirmation of ER+ status (defined as > 1% positive tumor cells), and histological or cytological confirmation of HER2-negative (HER2-) status by local laboratory testing using criteria in the American Society of Oncology (ASCO)/College of American Pathologists (CAP) Clinical Practice Guideline update.
3. Female patients 18 years of age or older who:
- Are postmenopausal for at least 1 year before the Screening visit, where menopause is defined by:
o Age ≥ 55 years and 1 year or more of amenorrhea
o Age < 55 years and 1 year or more of amenorrhea, with an estradiol assay < 20 pg/mL
o Surgical menopause with bilateral oophorectomy
4. Patients who have a history of brain metastasis are eligible for the study provided that all the following criteria are met:
- Brain metastases which have been treated
- No evidence of disease progression for 3 months or hemorrhage after treatment
- Off-treatment with dexamethasone for 4 weeks before administration of the first dose of MLN0128
- No ongoing requirement for dexamethasone or anti-epileptic drugs
5. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 as defined in the protocol
6. Clinical laboratory values as specified below within 4 weeks before the first dose of MLN0128:
- Bone marrow reserve consistent with absolute neutrophil count (ANC) ≥ 1.5 x 109/L; platelet count ≥ 100 x 109/L; hemoglobin ≥ 9 g/dL
- Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN (≤ 5 xULN if liver metastases are present)
- Creatinine clearance ≥ 50 mL/min 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
7. Left ventricular ejection fraction (LVEF) within 5 absolute percentage points of institutional standard of normal as measured by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) within 4 weeks before the first dose of MLN0128 (ie, if the institutional standard of normal is 50%, LVEF may be as low as 45% to be eligible for the study).
8. Able to provide paraffin blocks or a minimum of 10 unstained slides of available archival tumor tissues (paraffin blocks are preferred). If archival tumor tissue is not available, a tumor biopsy may be performed before the patient begins treatment with MLN0128. If fewer than 10 slides are available or the tumor content/area
requirements are not met, study eligibility will be determined upon discussion with the sponsor.
9. Ability to swallow oral medications, willingness to perform mucositis prophylaxis, and suitable venous access for the study-required blood sampling.
10. Voluntary written consent must be given before the 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.
Phase 1b Only:
11. Patients may have SD or disease progression during their most recent treatment with exemestane or fulvestrant, or everolimus in combination with either exemestane (any country) or fulvestrant (US Only). Exemestane or fulvestrant in combination with MLN0128 can also be initiated as a new line of therapy.
Phase 2 Only
12. Measureable disease defined as follows:
- At least 1 extra-osseous lesion that can be accurately measured in at least 1 dimension. The lesion must measure ≥ 20 mm with conventional imaging techniques or ≥ 10 mm with spiral CT or MRI, or
- Bone lesions (lytic or mixed [lytic plus sclerotic]) in the absence of measurable disease as defined above
13. Patients must have had disease progression during treatment with everolimus in combination with either exemestane (any country) or fulvestrant (US only) (duration of treatment ≥ 4 weeks) and must have tolerated everolimus treatment in combination with exemestane (any country) or fulvestrant (US only) adequately according to the treating physician's judgment. Everolimus in combination with exemestane or fulvestrant is not required to be the most recent treatment before enrollment, but progression on the most recent anticancer therapy is required for enrollment. |
|
| E.4 | Principal exclusion criteria |
1. Prior anticancer therapy or other investigational therapy within 2 weeks before administration of the first dose of MLN0128 (except for exemestane or fulvestrant, which should be continued). Treatment with everolimus must be discontinued 2 weeks before administration of the first dose of MLN0128.
2. Chronic concomitant therapy with bisphosphonates or denosumab for the prevention of bone metastases. Concomitant treatment with bisphosphonates is permitted for treatment of osteoporosis or management of existing bone metastases if initiated at least 4 weeks before administration of the first dose of MLN0128.
3. Exclusion criterion 3 was removed as of Protocol Amendment 6.
4. 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 MLN0128 (patients already receiving erythropoietin on a chronic basis for ≥ 4 weeks are eligible).
5. Previous treatment with dual PI3K/mTOR inhibitors or TORC1/2 inhibitors.
6. Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown reason that may alter the absorption of MLN0128.
7. Poorly controlled diabetes mellitus defined as glycosylated hemoglobin (HbA1c) > 7%; patients with a history of transient glucose intolerance due to corticosteroid administration may be enrolled in this study if all other inclusion/exclusion criteria are met.
8. Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active central nervous system disease, active infection, or any other condition that could compromise participation of the patient in the study.
9. Known human immunodeficiency virus infection.
10. History of any of the following within the last 6 months before administration of the first dose of MLN0128:
- Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures
- Ischemic cerebrovascular event, including transient ischemic attack and artery revascularization 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
- Pulmonary embolism
11. Significant active cardiovascular or pulmonary disease before administration of the first dose of MLN0128, including:
- Uncontrolled hypertension (ie, 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 ms, or history of congenital long QT syndrome, or torsades de pointes)
12. Diagnosed or treated for another malignancy within 2 years before administration of the first dose of MLN0128 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 are not excluded if they have undergone complete resection.
13. More than 3 prior chemotherapy regimens for locally advanced or metastatic disease. (Phase 1b Only)
14. More than 1 prior chemotherapy regimen for locally advanced or metastatic disease. (Phase 2 Only) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1b
- Adverse events, SAEs, assessments of clinical laboratory values, vital sign measurements, physical examination findings, and electrocardiograms (ECGs)
Phase 2
- CBR-16 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1b
AEs:
From first dose to 30 days post last dose
SAEs:
From ICF signature to 30 days post last dose
Lab values:
Screening; Cycle 1 & 2 D1, D15; Cycle 3 & above D1 plus EOT
Vital signs & Physical Exam:
Screening; Cycle 1 & 2 D1, D15; Cycle 3 & above D1 plus EOT
ECGs:
Screening; Cycle 1 D1 (0.5 pre dose, 2 & 4 hrs post dose) & D15 (0.5 pre dose & 2 hrs post dose); Cycle 2 D1 (0.5 pre dose & 2 hrs post dose; EOT
Phase 2
CBR-16:
Week 16 of treatment |
|
| E.5.2 | Secondary end point(s) |
- Clinical benefit rate at 24 weeks (CBR-24 is defined as the proportion of patients who achieve CR or partial response of any duration or have SD at 24 weeks)
- Overall response rate (ORR; defined as best response of CR or partial response)
- Progression-free survival
- Overall survival (OS)
- Change in tumor size from baseline
- Steady-state PK parameters of MLN0128 and exemestane including, but not limited to, single-dose maximum (peak) concentration (Cmax), Tmax, area under the plasma concentration versus time curve from zero to 24 hours (AUC24h), area under the plasma concentration versus time curve from zero to the last measurable concentration (AUCt), and t1/2
- Adverse events, SAEs, assessments of clinical laboratory values, vital sign measurements, physical examination findings, and ECGs |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
CBR-24: Week 24 of treatment
ORR; PFS; OS & Change in tumor size: D28 Cycle 1 then D28 every 2 cycles from C2 through C6 and then D28 every 3 cycles; PFS&OS Q3mo after EOT
D1, Any time during the Cycle 2 D15 visit, with the 2nd sample to be collected 1 hr after first.
PD activity: screening, Cycle 1 D15; EOT (for responders who relapse)
AEs: From first dose to 30 days post last dose
SAEs: From ICF to 30 days post last dose
Lab values, Vital signs & Physical Exam: Screening; Cycle 1 & 2 D1, D15; Cycle 3+ D1 plus EOT
ECGs: Screening; Cycle 1 D1 (0.5 pre dose, 2 & 4 hrs post dose) & D15 (0.5 predose & 2 hrs postdose); Cycle 2 D1 (0.5 predose & 2 hrs
postdose; EOT
|
|
| 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 | No |
| 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 | No |
| 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 | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 |
| Belgium |
| France |
| 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
|
| The study will be terminated 6 months after the last patient completes an EOT study 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 | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
