| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| metastatic clear-cell renal cell carcinoma (mccRCC) |
|
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10050018 |
| E.1.2 | Term | Renal cancer metastatic |
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10038407 |
| E.1.2 | Term | Renal cell 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 |
The primary objectives of the study are:
To compare the efficacy of single-agent MLN0128 versus single-agent everolimus in patients
with mccRCC.
To compare the efficacy of the combination of MLN0128+MLN1117 versus single-agent
everolimus in patients with mccRCC. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are:
To assess the safety and tolerability of MLN0128 and MLN0128+MLN1117.
To compare the efficacy of the combination of MLN0128+MLN1117 versus single-agent
MLN0128 in patients with mccRCC.
To evaluate the efficacy (endpoints other than PFS; ie, overall survival [OS],
time-to-progression [TTP], objective response rate [ORR], and clinical benefit rate [CBR])
among the 3 treatment groups.
To collect plasma concentration-time data with sparse PK sampling to contribute to future
population PK analysis |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Each patient must meet all of the following inclusion criteria to be enrolled in the study.
1. Male or female patients aged 18 years or older.
2. Histologically confirmed renal cell carcinoma with a clear-cell component.
3. Evidence that the renal cell carcinoma is advanced or metastatic.
4. Radiologic evidence of progressive disease (according to RECIST Version 1.1) either during or within 6 months after stopping their most recent systemic therapy for RCC before enrollment into this study.
5. At least 1 prior line of VEGF-targeted therapy, but not more than 4 total prior lines of systemic therapy. Exposure to more than 1 line of VEGF-targeted therapy is acceptable. Patients may also have received prior therapies with interferon, IL-2, anti-PD1 antibodies, cabozantinib, or other experimental agents, but not prior therapy with any agent that targets PI3K, AKT, or mTOR.
6. Karnofsky Performance Status (KPS) ≥70% (refer to Appendix D).
7. Life expectancy of ≥3 months.
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 (See Appendix E), 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 patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
Male patients, even if surgically sterilized (ie, status postvasectomy), who:
Agree to practice highly effective barrier contraception during the entire study treatment period and through 120 days after the last dose of study drug (or longer, as mandated by local labeling [eg, USPI, SmPC, etc]), OR
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the female partner], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
Agree not to donate sperm during the course of this study or within 120 days after receiving their last dose of study drug.
9. Suitable venous access for the study-required blood sampling.
10. Screening clinical laboratory values as specified below:
Absolute neutrophil count 2000/L and platelet count 100,000/L.
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 2.5the upper limit of normal (ULN).
Total bilirubin 1.5ULN.
Estimated creatinine clearance by Cockcroft-Gault ≥40 mL/min/1.73m2 (see Appendix F).
Glycosylated hemoglobin (HbA1c) <7.0%, fasting serum glucose 130 mg/dL, and fasting triglycerides 300 mg/dL.
11. At least 14 days since the end of prior systemic VEGF-targeted treatment (ie, sunitinib,pazopanib, axitinib, or sorafenib), radiotherapy, or surgical procedure with resolution of all treatment-related toxicity (except alopecia and hypothyroidism) either to Grade 0 or 1 (NCI CTCAE Version 4.03) or to Baseline.
12. At least 21 days since the last dose of bevacizumab, other antibody, or interferon.
13. 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 |
Patients meeting any of the following exclusion criteria are not to be enrolled in the study.
1. Central nervous system (CNS) metastasis.
2. Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active CNS disease, active infection, or any other condition that might compromise the patient’s participation in the study.
3. Known human immunodeficiency virus infection.
4. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection.
5. Manifestations of malabsorption due to prior GI surgery, GI disease, or for an unknown reason that may alter the absorption of everolimus, MLN0128, or MLN1117. In addition, patients with enteric stomata are excluded.
6. Women who are either breast feeding or pregnant.
7. 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 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 (see Appendix G). Pulmonary embolism.
8. Significant active cardiovascular or pulmonary disease including:
Uncontrolled hypertension (ie, either systolic blood pressure >160 mm Hg or diastolic blood pressure >95 mm Hg). Use of anti-hypertensive agents to control hypertension before Cycle 1 Day 1 is allowed.
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).
9. 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 nonmelanoma skin cancer, superficial bladder cancer, very low risk prostate on observation, or carcinoma in situ of any type are not excluded if they have
undergone complete resection.
10. Prior therapy with agents that target PI3K, AKT, or mTOR. Patients with known hypersensitivity to everolimus or rapamycin derivatives are also excluded.
11. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to this protocol.
12. Patients who have taken a PPI within 3 days before receiving the first dose of study drug. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is PFS (progression-free survival) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Time from date of randomization to disease progression or death, whichever occurs first, assessed until post treatment follow up of last patient. (For a patient whose disease has not progressed and is last known to be alive, PFS will be censored at the last response assessment that is SD or better).
The final analysis for the pair-wise comparisons of PFS between single-agent MLN0128
and everolimus and between the combination of MLN0128+MLN1117 and everolimus will occur
approximately 6 months after the last patient is randomized. |
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints are:
1) The number and percentage of patients with treatment-emergent adverse events.
2) Overall survival (OS).
3)Time-to-progression (TTP).
4) Objective response rate (ORR; defined as complete response [CR]+partial response [PR] per
Response Evaluation Criteria in Solid Tumors [RECIST] Version 1.1).
5)Clinical benefit rate (CBR; defined as CR+PR+stable disease) with SD of any duration, and
CBR with SD duration of at least 4 months. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Serious adverse events will be reported from signing of the informed consent form through 30 days after the last dose of study drug
2) OS is defined as the time from the date of randomization to the date of death, assessed until post treatment follow up.
3) TTP is defined as the time from the date of randomization to the date of first documentation of progression. For apatient whose disease has not progressed, TTP will be censored at the last response assessment that is SD or better. TPP will be assessed at day 28 of Cycle 2, Day 28 cycle 4, day 28 of cycle 5 and beyond up to 24 months
5) CR,PR and SD will be assessed at day 28 of Cycle 2, Day 28 cycle 4, day 28 of cycle 5 and beyond up to 24 months
|
|
| 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 | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| potential crossover treatment for patients initially randomized to the single-agent everolimus arm A |
|
| 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 | 3 |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 53 |
| 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 |
| Canada |
| France |
| Hungary |
| Italy |
| Russian Federation |
| 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
|
| The study will be closed when the last patient discontinues study treatment. |
|
| 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 | 33 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 35 |
| E.8.9.2 | In all countries concerned by the trial days | 25 |
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