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

Study Objectives

The safety objectives for this study are as follows:
• To evaluate the safety profile of RO5424802 using the National Cancer Institute
Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03
• To assess the effect of RO5424802 on cardiac repolarization (QTc)
The primary objectives of efficacy for this study are as follows:
• To evaluate efficacy of RO5424802 by objective response rate (ORR) as per
independent radiological review committee (IRC) using RECIST criteria version
1.1 in the overall population [with and without prior exposure of cytotoxic
chemotherapy treatment(s)]
• To evaluate efficacy of RO5424802 by objective response rate (ORR) as per
independent radiological review committee (IRC) using RECIST criteria version
1.1 in patients with prior exposure of cytotoxic chemotherapy treatment(s)
The secondary efficacy objectives for this study are as follows:
• To evaluate efficacy of RO5424802 by objective response rate (ORR) as per
independent radiological review committee (IRC) using RECIST criteria version
1.1 in patients without prior exposure of cytotoxic chemotherapy treatment(s)

Participation conditions

Inclusion criteria

Patients must meet the following criteria for study entry:
1. Patients with locally advanced or metastatic NSCLC (stage IIIB or stage IV by
AJCC 7th)
2. 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 with the last dose of crizotinib being within 60 days from the first dose of
study treatment. Patients can either be chemotherapy-naïve or have received at
least one line of platinum-based chemotherapy
8. Adequate hematologic function:
Platelet count ≥100×109/L
Absolute neutrophil count ≥1,500/μL
Hemoglobin ≥9 g/dL
9. Adequate hepatic function:
ALT (SGPT) and AST (SGOT) ≤ 2.5 × ULN (≤5 × ULN for patients with
concurrent liver metastases)
Bilirubin ≤2 mg/dL
10. Adequate renal function:
Serum creatinine ≤2 × ULN or calculated creatinine clearance of
≥60 mL/min (Cockroft and Gault formula)
11. Recovery from effects of any major surgery or significant traumatic injury at least
28 days before the first dose of study treatment
12. Patients with brain or leptomeningeal metastases are allowed on study if the
lesions are asymptomatic without neurological signs and clinically stable for at
least 2 weeks without steroid treatment. Patients who do not meet these criteria
are not eligible for the study. However, they can be re-screened after completing
WBRT or gamma-knife treatment. They must have completed any corticosteroid
therapy ≥2 weeks prior to the first dose of study treatment
13. Measurable disease (by RECIST criteria version 1.1) prior to the the first dose of
study treatment.
14. Negative serum pregnancy test within 10 days prior to commencement of dosing
in pre-menopausal women. Women may be included if they are either surgically
sterile or have been menopausal for ≥1 year
15. For women who are not postmenopausal (12 months of amenorrhea) or
surgically sterile (absence of ovaries and/or uterus): agreement to use two
adequate methods of contraception, including at least one method with a failure
rate of <1% per year (e.g., hormonal implants, combined oral contraceptives,
vasectomized partner), during the treatment period and for at least 3 months
after the last dose of study treatment
16. For men: agreement to use a barrier method of contraception during the
treatment period and for at least 40 days after the last dose of study treatment
17. Signed written Institutional Review Board (IRB)/Ethical Committee (EC) approved
informed consent form, prior to performing any study-related procedures

Exclusion criteria

Patients who meet any of the following criteria will be excluded from study entry:
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. Baseline QTc >470 ms, or baseline symptomatic bradycardia <45 beats per
minute
9. Pregnant or lactating women
10. Known HIV positivity or AIDS-related illness
11. Any significant concomitant disease determined by the investigator to be
potentially aggravated by the investigational drug

Centre Hospitalier de Luxembourg