EUCROSS: European Trial on Crizotinib in ROS1 Translocated Lung Cancer

EUCROSS is a phase II trial to evaluate the efficacy and safety of crizotinib in patients with adenocarcinoma of the lung harbouring ROS1 translocations. In individual treatment attempts and an ongoing phase I trial crizotinib has shown remarkable effects on this selected subgroup of lung cancer patients. Crizotinib is a tyrosine kinase inhibitor, blocking the catalytic activity of rearranged ALK and ROS1 as well as MET. The patients eligible for the trial will be treated with 250mg crizotinib twice-daily. Tumor response to treatment will be assessed every 6 weeks by CT or MRI scans. In case of progression treatment beyond may be conducted if clinically indicated. To identify mechanisms of resistance to crizotinib treatment, an optional re-biopsy may be performed in these cases and fresh frozen tumor material will analyzed at the University of Cologne.

Inclusion criteria

• Patients with adenocarcinoma of the lung that is locally advanced or metastatic independent from the number of prior lines of therapy, i.e. including non-pretreated patients (UICC stage IIIB or IV)
• Positive for ROS1 translocation by central FISH-testing
• Ability to swallow pills
• Age > 18 years
• ECOG performance status 0 to 2
• Life expectancy of at least 12 weeks
• Disease measurable per Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1)
• Any prior treatment (chemotherapy, radiation or surgery) must have been completed at least 2 weeks prior to initiation of study medication
• Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 14 days prior to screening:
• Hemoglobin ≥ 8.0 g/dL
• Absolute neutrophil count (ANC) ≥ 1,000 /mm3
• Platelet count ≥ 50 000/µL
• Total bilirubin ≤ 2 x upper limit of normal (ULN)
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (AP) ≤ 2,5 x ULN or ≤ 5 x ULN in case of liver involvement
• PT-INR/PTT ≤ 1.5 x ULN
• Serum creatinine ≤ 2 times ULN
• Calculated creatinine clearance (CLcr) ≥ 40 ml/min (Cockcroft-Gault formula)
• Written informed consent
• Negative serum pregnancy test within 3 days prior to start of dosing premenopausal women. Women of non-childbearing potential may be included without serum pregnancy test if they are either surgically sterile or have been postmenopausal for ≥ 1 year.

Fertile men and women must have an effective method of contraception during treatment and for at least 3 months after completion of treatment as directed by their physician. Effective methods of contraception result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly (for example implants, injectables, combined oral contraception or intra-uterine devices). At the discretion of the investigator, acceptable methods of contraception may include total abstinence where lifestyle of the patient ensures compliance (Periodic abstinence and withdrawal are not acceptable methods of contraception).

Exclusion criteria

• Previous treatment with specific ALK or ROS1 inhibitors
• Current treatment within another therapeutic clinical trial
• Other history of ongoing malignancy that would potentially interfere with the interpretation of efficacy (early stage or chronic disease is allowed if not requiring active therapy or intervention and being under control)
• Pregnancy or breastfeeding
• Use of drugs or foods that are known potent CYP3A4 inhibitors, including but not limited to atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole and grapefruit or grapefruit juice
• Use of drugs that are known potent CYP3A4 inducers, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John's wort
• Use of drugs that are CYP3A4 substrates with narrow therapeutic indices, including but not limited to dihydroergotamine, ergotamine, pimozide, astemizole, cisapride, and terfenadine
• Active CNS metastases. Patients with brain metastasis are eligible if asymptomatic for ≥ 14 days before starting study medication and off corticosteroids.
• History of or known carcinomatous meningitis or leptomeningeal disease
• Known diagnosis of HIV, active hepatitis B and/or C (testing is not mandatory)
• Any person being in an institution on assignment of the respective authority against his/her own will
• Any medical, mental or psychological condition which in the opinion of the investigator would not permit the patient to complete the study or understand the patient information
• Ongoing cardiac dysrhythmias of CTCAE grade ≥2, uncontrolled atrial fibrillation of any grade or QTcF interval > 470ms
• Patients with known interstitial fibrosis or interstitial lung disease
• Any of the following within 3 months prior to first crizotinib administration:

Myocardial infarction, severe/unstable angina, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack