E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
non-small cell lung cancer (NSCLC) |
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E.1.1.1 | Medical condition in easily understood language |
non-small cell lung cancer (NSCLC) |
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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 | 18.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10059515 |
E.1.2 | Term | Non-small cell lung cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 2: To evaluate progression-free survival (PFS) as the primary efficacy measure of MLN1117 plus docetaxel versus docetaxel alone in patients with advanced NSCLC |
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E.2.2 | Secondary objectives of the trial |
PHASE 2:
- To evaluate the safety and tolerability of MLN1117 plus docetaxel administered to patients with NSCLC
- To evaluate the PK of MLN1117 when administered with docetaxel
- To evaluate additional efficacy measures, such as response rate (RR), disease control rate, response duration, time to progression (TTP), and OS, of MLN1117 plus docetaxel versus docetaxel alone in patients with NSCLC
- To evaluate PFS and additional efficacy measures of MLN1117 plus docetaxel versus docetaxel alone in different populations of patients with NSCLC, such as patients with squamous NSCLC versus nonsquamous NSCLC, and patients with
squamous NSCLC with or without PIK3CA mutation and/or amplification (MUT/AMP) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Has a histologically and/or cytologically confirmed diagnosis of NSCLC (squamous or nonsquamous).
•For Phase 2, has a diagnosis of mixed squamous and nonsquamous (or adenosquamous) NSLC.
•Has locally advanced or metastatic disease (Stage IIIb or Stage IV) with radiographically or clinically evaluable lesions.
•Has experienced failure of at least 1 prior chemotherapy regimen.
•For Phase 2, has received 1 prior platinum-based chemotherapy regimen (excluding a docetaxel-containing regimen) for advanced or metastatic (Stage IIIb or Stage IV) disease followed by documented progressive disease.
•For Phase 1b, has experienced failure of multiple lines of prior chemotherapy.
•For Phase 2, has archived or fresh tumor biopsy samples obtained during screening sufficient for genotyping.
•Has adequate organ function, before the first dose of study drug.
•Has Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
•Female participants who are postmenopausal for at least 1 year before the screening visit or are surgically sterile, or are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 30 days after the last dose of study drug, or agree to practice true abstinence.
•Male participants agree to practice effective barrier contraception during the entire study treatment period and through 120 days after the last dose of study drug, or agree to practice true abstinence.
•Has suitable venous access for the study-required blood sampling.
•Has recovered (ie, <= Grade 1 toxicity or eligibility per this protocol is met) from the reversible effects of prior anticancer therapy.
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E.4 | Principal exclusion criteria |
•Previous treatment with a PI3K or AKT inhibitor.
•Prior cancer therapy or other investigational therapy within 2 weeks before the first administration of study drug or failed to recover from the reversible effects of prior anticancer therapies. For prior therapies with a half-life longer than 3 days, the interval must be at least 28 days before the first administration of study drug, and the patient must have documented progressive disease.
•Has poorly controlled diabetes mellitus defined as HbA1c > 6.5%.
•Has taken strong inhibitors or strong inducers of CYP3A4 within 14 days before the first dose of study drug.
•Has taken histamine-H2 receptor antagonists and/or neutralizing antacids within 24 hours before the first administration of study drug.
•Has taken proton pump inhibitors within 7 days before the first administration of study drug.
•Has any clinically significant co-morbidities.
•Has acute myocardial infarction within 6 months before starting study drug, current or history of New York Heart Association Class III or IV heart failure, Evidence of current uncontrolled cardiovascular conditions including cardiac arrhythmias, angina, pulmonary hypertension, or ECG evidence of acute ischemia or active conduction system abnormalities, Fridericia's corrected QT interval > 475 milliseconds (msec) (males) or > 450 msec (females) on a 12-lead ECG during the Screening period, or abnormalities on 12-lead ECG including, but not limited to, changes in rhythm and intervals that in the opinion of the investigator are considered to be clinically significant.
•Has known, previously diagnosed human immunodeficiency virus infection or active chronic hepatitis B or C.
•Has brain metastasis, except for those patients who have completed definitive therapy, are not on steroids, have a stable neurologic status for at least 2 weeks after completion of the definitive therapy and steroids, and do not have neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
•Has active secondary malignancy that requires treatment.
•Has any serious medical or psychiatric illness, including drug or alcohol abuse.
•Male participants who intend to donate sperm during the course of this study or 120 days after receiving their last dose of study drug.
•Female participants who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period or a positive urine pregnancy test on Day 1 before administration of the first dose of study drug |
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E.5 End points |
E.5.1 | Primary end point(s) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
DLTs, MTD, and RP2D may occur at any time.
PFS data will be collected during the posttreatment follow-up period of up to 6 months after the last dose of study drug
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E.5.2 | Secondary end point(s) |
Endpoints for phase 2
- Safety:
o Vital signs
o Physical examination findings
o 12-lead ECG
o Clinical laboratory test results
o AEs and SAEs
- Response rate (complete response [CR] + partial response [PR]), disease control rate (CR + PR + stable disease [SD]), duration of response (DOR), and TTP
- Overall Survival
- MLN1117 plasma concentrations when administered 1 day after docetaxel
- Exploratory endpoints
o Correlation between PIK3CA and/or other mutations detected in circulating tumor DNA and tumor tissue DNA
o Correlation between the amount of and allelic frequencies of PIK3CA and/or othermutations detected in circulating tumor DNA and clinical response
o Genetic polymorphisms in genes encoding drug metabolizing enzymes and/or transporters on the PK of MLN1117 and/or in genes related to clinical response and/or study drug-related toxicity
o HRQOL, physical functioning, and other effects of the disease and/or therapy as measured by the PRO instruments the EORTC QLQ-C30(1, 2) and the EORTC QLQLC-13(3) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Any time during phase II of the study |
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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 | No |
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 | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | 7 |
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 | 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 |
Italy |
Netherlands |
Spain |
United Kingdom |
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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
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The study will be terminated 6 months after the last patient completes an EOT study visit |
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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 | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |