Safety and efficacy study of RO5424802 in subjects with non-small cell lung cancer with ALK mutation that did not respond or stop responding to crizotinib.

• Register: EUCTR
• Last refreshed on: 9 October 2017
• Main ID: EUCTR2012-004455-36-DK
• Date of registration: 28/05/2013
• Prospective Registration: Yes
• Primary sponsor: F. Hoffmann-La Roche Ltd
• Public title: Safety and efficacy study of RO5424802 in subjects with non-small cell lung cancer with ALK mutation that did not respond or stop responding to crizotinib.
• Scientific title: AN OPEN-LABEL, NON-RANDOMIZED, MULTICENTER PHASE I/II TRIAL OF RO5424802 GIVEN ORALLY TO NON - SMALL CELL LUNG CANCER PATIENTS WHO HAVE ALK MUTATION AND FAILED CRIZOTINIB TREATMENT
• Date of first enrolment: 28/05/2013
• Target sample size: 130
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012-004455-36
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Belgium, Canada, Denmark, France, Germany, Italy, Luxembourg, Netherlands, Russian Federation, Spain, Sweden, United Kingdom, United States

Contacts

• Name: Trial Information Support Line-TISL
• Affiliation: F. Hoffmann-La Roche Ltd

• Name: Trial Information Support Line-TISL
• Affiliation: F. Hoffmann-La Roche Ltd

Key inclusion & exclusion criteria

Inclusion criteria:
-Patients with locally advanced (AJCC stage IIIB) not amenable to curative therapy or metastatic (AJCC stage IV) NSCLC
-NSCLC2.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)
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 112
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 18

Exclusion criteria:
-Receipt of any other ALK inhibitors in addition to crizotinib
-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
-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)
-Active or uncontrolled infectious diseases requiring treatment
-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
-History of organ transplant
-Co-administration of anti-cancer therapies other than those administered in this study
-Baseline QTc >470 ms, or baseline symptomatic bradycardia <45 beats per minute -Known HIV positivity or AIDS-related illness
-Any significant concomitant disease
-Administration of strong/ potent CYP3A inhibitors or inducers within 14 days prior to first administration of study drug
-History of hypersensitivity to any of the additives in the RO5424802 formulation
-Any clinically significant concomitant disease
-Any psychological, familial, sociological or geographical condition

Specific Exclusion Criteria Specific to Midazolam DDI Substudy subjects
-Subjects 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


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

ALK positive Non-Small cell lung cancer
MedDRA version: 19.0 Level: PT Classification code 10061873 Term: Non-small cell lung cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Product Name: ALK Inhibitor
Product Code: RO5424802
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Alectinib
Current Sponsor code: RO5424802/F03
Other descriptive name: ALK Inhibitor
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 150-

Trade Name: Tarceva
Product Name: Tarceva
Product Code: RO0508231/V05
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Erlotinib
CAS Number: 183321-74-6
Current Sponsor code: RO0508231/V05
Other descriptive name: erlotinib hydrochloride
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 25-

Trade Name: Tarceva
Product Name: Tarceva
Product Code: RO0508231/V02
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: ERLOTINIB
CAS Number: 183321-74-6
Current Sponsor code: RO05508231/V02
Other descriptive name: erlotinib hydrochloride
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-

Trade Name: Tarceva
Product Name: Tarceva
Product Code: RO0508231/V03
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: ERLOTINIB
CAS Number: 183321-74-6
Current Sponsor code: RO0508231/V03
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 150-

Primary Outcome(s)

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

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

Secondary Objective: -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)

Main Objective: The primary objectives for Part 1:
-To determine the recommende 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 900-mg doses to subjects with locally advanced or metastatic NSCLC who have ALK rearrangement 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 Responce Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.1 in the overall population

Secondary Outcome(s)

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

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

Secondary ID(s)

2012-004455-36-SE

NP28673

Source(s) of Monetary Support

F. Hoffmann-La Roche Ltd