| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| ALK positive Non-Small cell lung cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Anaplastic lymphoma kinase (ALK) positive Non-Small Cell Lung Cancer (NSCLC) is a distinct subset of lung cancer which is characterized by a specific genetic change in the ALK gene. |
|
| 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 | 19.0 |
| 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) |
|
| 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:
-To determine the recommended Phase II dose of RO5424802 to be used in Part 2 of the study
-To evaluate the safety and tolerability of 600mg and 900mg doses of RO5424802 administered twice daily to subjects with locally advanced or metastatic NSCLC who have ALK rearrangement and in whom prior crizotinib therapy has failed
-To characterize dose-limiting toxicities, if any, associated with RO5424802 after 21 days of treatment when administered twice daily at 600- and 900mg doses to subjects with locally advanced or metastatic NSCLC who have ALK re-arrangement and in whom prior crizotinib therapy has failed
-To characterize the pharmacokinetics of RO5424802
The primary efficacy objectives for Part 2:
•To evaluate efficacy of RO5424802 by objective response rate (ORR) as per central independent radiological review committee (IRC) using Response Evaluation Criteria in Soid Tumors (RECIST) criteria version 1.1 in the overall population. |
|
| E.2.2 | Secondary objectives of the trial |
-To evaluate efficacy of RO5424802 by ORR as per central IRC using RECIST criteria version 1.1 in subjects 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 (IIRR)
-To assess duration of response (DOR) in subjects treated with RO5424802 based on IIRR
-To evaluate the progression-free survival (PFS) in subjects treated with RO5424802 based on IIRR
-To evaluate central nervous system (CNS) ORR in subjects with CNS metastases who have measurable disease in the CNS at baseline, based on IRC review of radiographs (IRR)
-To assess CNS DOR in subjects who have a CNS Objective Response based on IRR
-To assess CNS progression rates (CPR) at 3, 6, 9 and 12 months based on cumulative incidence by IRR
-To assess overall survival (OS) |
|
| 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 6 Dated 14 April 2016.
Up to 14 ALK-positive patients from sites capable of performing intensive PK assessments will receive a single oral 2-mg dose of DZ 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 eligible for the midazolam substudy should have failed a prior treatment with an ALK inhibitor (approved or experimental), with or without prior treatment with chemotherapy. 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. |
|
| E.3 | Principal inclusion criteria |
-Patients with locally advanced (AJCC stage IIIB) not amenable to curative therapy or metastatic (AJCC stage IV) NSCLC
-Male or female ≥18 years old
-Life expectancy, in the opinion of the investigator, of at least 12 weeks
-Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2
-Histologically confirmed NSCLC
-Documented ALK rearrangement based on a Food and Drug Administration (FDA) approved test
-Prior treatment with crizotinib and progression based on RECIST criteria version 1.1. Subjects 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). Subjects can either be chemotherapynaïve or have received at least one line of
platinum-based chemotherapy for locally advanced or metastatic disease
-Adequate hematologic function
-Adequate hepatic function
-Adequate renal function
-Recovery from effects of any major surgery or significant traumatic injury at least 28 days before the first dose of study treatment
-Subjects with brain or leptomeningeal metastases are allowed on study if they have previously been treated with Whole brain radiotherapy (WBRT) or gamma-knife radiosurgery. Subjects must have completed treatment, be clinically stable and have discontinued the use of corticosteroids for this indication for>=2 weeks. If not previously treated with WBRT or gamma-knife radiosurgery, subjects must have been asymptomatic without neurological signs and clinically stable for >=2 weeks without steroid treatment prior to first dose
-Measurable disease (by RECIST criteria version 1.1) prior to the first dose of study treatment
-Negative pregnancy test within 10 days of first dose for women of child bearing potential
-For women of childbearing potential: agreement to remain abstinent or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 3 months after the last dose of study drug
-For men: agreement to use a barrier method of contraception during the treatment period and for at least 3 months after the last dose
Specific Inclusion Criteria Specific to Midazolam DDI Substudy subjects
-Subjects with measurable or non-measurable disease
-Subjects 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) |
|
| 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.National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (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. Baseline QTc >470 ms, or baseline symptomatic bradycardia <45 beats per minute
9. Known HIV positivity or AIDS-related illness
10. Any significant concomitant disease
11. Administration of strong/ potent CYP3A inhibitors or inducers within 14 days prior to first administration of study drug
12. History of hypersensitivity to any of the additives in the RO5424802 formulation
13. Any clinically significant concomitant disease
14. Any psychological, familial, sociological or geographical condition
Specific Exclusion Criteria Specific to Midazolam DDI Substudy Subjects
· 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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1
1. Determination of a Phase II recommended dose
2. Incidence of DLTs by NCI CTCAE v4.03 grade and associated dose of RO5424802 (600 and 900 mg twice a day [BID])
3. Plasma PK analysis for RO5424802
Part 2
4. Objective tumor response rate (ORR) (Partial response [PR] and Complete response [CR]) as assessed by an independent radiological review committee using RECIST v1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part 1
1-2. Up to 21 days of cycle 1
3. Day (D) 1, D8, D15 and D21 of Cycle (C) 1; D1 of C2, C3, C4 and C5; Completion/Early Termination Visit (C/ETV), 28D (+/-3 days) after the last dose of study drug
Part 2
4. Approximately 24 months |
|
| E.5.2 | Secondary end point(s) |
1. ORR (PR and CR) as assessed by IRC using RECIST v1.1 in subjects without prior exposure of cytotoxic chemotherapy treatment(s)
2. ORR (PR and CR) as assessed by the investigator using RECIST v1.1
3. Disease control rate based on IIRR
4. Duration of Response based on IIRR
5. Progression Free Survival based on IIRR
6. CNS Objective Response Rate in subjects with measurable disease in the CNS metastasis as assessed by IRC
7. Duration of CNS Response as assessed by IRC
8. CNS progression rate as assessed by IRC
9. Overall Survival |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-7. Approximately 24 months
8. At 3, 6, 9 and 12 months
9. Approximately 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 | 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 |
|
| 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 |
|
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| 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 |
| Australia |
| Belgium |
| Denmark |
| France |
| Germany |
| Hong Kong |
| Italy |
| Luxembourg |
| Netherlands |
| Russian Federation |
| Singapore |
| Spain |
| Sweden |
| Taiwan |
| 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 final analysis will take place once all patients have been followed for a minimum of 16 weeks, i.e. two tumor assessments in order that any observed CR or PR can be confirmed, unless they progressed or withdrew sooner.The end of the study is defined as the date at which the last data point required for a statistical analysis of overall survival is received. The final analysis for survival will occur when approximately 50% of patients have died. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| 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 | 4 |
| 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 |
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