E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
ALK-mutated Non-small cell lung cancer |
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E.1.1.1 | Medical condition in easily understood language |
ALK-mutated Non-small cell lung cancer |
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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 | 16.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061873 |
E.1.2 | Term | Non-small cell lung cancer |
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 |
The primary objectives for Part 1 of the study are as follows:
-To determine the RP2D of RO5424802 to be used in Part 2 of the study
-To evaluate the safety and tolerability of 600-mg and 900-mg doses of RO5424802 administered twice daily to patients with locally advanced or metastatic NSCLC who have ALK rearrangement and in whom prior crizotinib therapy has failed
-To characterize DLTs, if any, associated with RO5424802 after 21 days of
treatment when administered twice daily at 600- and 900-mg doses to patients with locally advanced or metastatic NSCLC who have ALK re-arrangement and in whom prior crizotinib therapy has failed
-To characterize the PK of RO5424802
The primary efficacy objectives for Part 2 study are as follows:
•To evaluate efficacy of RO5424802 by objective response rate (ORR) as per central independent radiological review committee (IRC) using RECIST criteria version 1.1 in the overall population. |
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E.2.2 | Secondary objectives of the trial |
•To evaluate efficacy of RO5424802 by objective response rate (ORR) as
per central IRC using RECIST criteria version 1.1 in patients without
prior exposure of cytotoxic chemotherapy treatment(s)
•To evaluate efficacy of RO5424802 by ORR per investigator review of
radiographs using RECIST 1.1
•To evaluate disease control rate (DCR) of RO5424802 based on IRC and
investigator review of radiographs |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Drug Drug Interaction Study (DDI) with Midazolan
Version & Date: The DDI substudy is included in the main protocol Version 4 Dated 19 November 13.
14 ALK-positive patients from sites capable of performing intensive PK assessments will receive a single oral 2-mg dose of MDZ on Day -1 (day preceding start of RO5424802 dosing on Day 1) and Day 21 of cycle 1 for evaluation of the effect of multiple oral dosing of RO5424802 on CYP3A activity using MDZ as an in vivo probe substrate. Serial PK collections will be conducted following the single doses of MDZ. Patients who enroll into and complete the Midazolam substudy will continue to be treated until progression, following the Part 2 Schedule of Assessments , starting at cycle 2. |
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E.3 | Principal inclusion criteria |
1.Patients with locally advanced (AJCC stage IIIB) not amenable to curative therapy) or metastatic AJCC stage IV
2.NSCLC2.Male or female ≥18 years old
3.Life expectancy, in the opinion of the investigator, of at least 12 weeks
4.ECOG Performance Status of 0>2
5.Histologically confirmed NSCLC
6.Documented ALK rearrangement based on an FDA approved test
7.Prior treatment with crizotinib and progression based on RECIST criteria version 1.1. Patients need to have a minimum 1-week wash-out period between the last dose of crizotinib and the first dose of study treatment (for patients enrolled in the midazolam substudy). Patients can either be chemotherapynaïve or have received at least one line of platinum-based chemotherapy for locally advanced or metastatic disease
8- Specific Inclusion Criteria Specific to Midazolam DDI Substudy Patients
· Patients with measurable or non-measurable disease
· Patients will require a minimum 2-week washout from crizotinib or other tyrosine kinase inhibitor prior to the dose of midazolam on Day -1
· Liver function tests at baseline (AST, ALT, and bilirubin) within normal limits (WNL) |
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E.4 | Principal exclusion criteria |
1.Receipt of any other ALK inhibitors in addition to crizotinib
2.Receipt of any prior cytotoxic chemotherapy for ALK-positive NSCLC within 4 weeks prior to the first dose of study treatment. Patients who received crizotinib or other tyrosine kinase inhibitors need to have a minimum 1-week wash-out period before the first dose of study treatment
3.A previous malignancy within the past 3 years (other than curatively treated basal cell carcinoma of the skin, early gastrointestinal cancer by endoscopic resection, in situ carcinoma of the cervix or any cured cancer that is considered to have no impact on PFS and OS for the current NSCLC)
4.Active or uncontrolled infectious diseases requiring treatment
5.NCI CTCAE (version 4.03) Grade 3 or higher toxicities due to prior therapy that has not shown improvement and are considered to interfere with current study medication.
6.History of organ transplant
7.Co-administration of anti-cancer therapies other than those administered in this study.
8 Specific Exclusion Criteria Specific to Midazolam DDI Substudy Patients
· Patients without a minimum of 2-week washout from crizotinib or other tyrosine kinase inhibitor prior to the dose of midazolam on Day -1
· History of hypersensitivity to midazolam or benzodiazepines or any contraindications to midazolam use including acute narrow angle glaucoma, myasthenia gravis, sleep apnea syndrome, etc. (see midazolam prescribing information: Roxane Laboratorie, 2007)
· Consumption of any CYP3A modulating agents including herbal supplements or foods (e.g. grapefruit, pomelo, star fruit or Seville orange containing products) within 2 weeks or 5 half-lives (whichever is longer) before the first dose of midazolam treatment and during the evaluation of the DDI (at least up to Day 22 of Cycle 1)
· Consumption of any concomitant medication with a reported serious drug interaction or which is contraindicated with midazolam within 2 weeks or 5 half-lives (whichever is longer) before the first dose of midazolam |
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E.5 End points |
E.5.1 | Primary end point(s) |
Part 1 – Determination of a Phase II recommended dose – Dose Escalation Study
•Incidence of DLTs by NCI CTCAE v4.03 grade and associated dose of RO5424802 (600 and 900 mg BID)
Part 2 – Evaluation of Safety and Efficacy of RO5424802 in ALK-positive NSCLC Patients with ALK Rearrangements.
•Objective tumor response rate (PR and CR) as assessed by an independent radiological review committee using RECIST v1.1
•Objective responses must be confirmed ≥28 days after initial response; [Primary in the “all patients” and “patients who have received at least one line of platinum-based cytotoxic chemotherapy” groups |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• To evaluate efficacy of RO5424802 by ORR per investigator review of radiographs using RECIST 1.1
• To evaluate disease control rate (DCR) of RO5424802 based on IRC and investigator review of radiographs
• To assess duration of response (DOR) in patients treated with RO5424802 based on IRC and investigator review of radiographs
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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 | 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) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
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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.8.2.4 | 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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
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 |
Denmark |
France |
Italy |
Luxembourg |
Netherlands |
Sweden |
Australia |
Germany |
Hong Kong |
Spain |
Russian Federation |
Singapore |
Taiwan |
United Kingdom |
United States |
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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 end of the study is defined as the date when the last patient, last visit (LPLV) occurs. As patients will be offered continued treatment beyond progression with RO5424802 alone or in combination with erlotinib depending on their EGFR status and whether the treating physicians consider that the patient is still benefiting from RO5424802 treatment, LPLV is expected to occur when the last patient has either died or is lost to follow-up.
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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 | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |