EUCROSS: European Trial on Crizotinib in ROS1 Translocated Lung Cancer

Study Overview
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Brief Summary
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EUCROSS is a phase II trial to evaluate the efficacy and safety of crizotinib in patients with adenocarcinoma of the lung harbouring ROS1 translocations. Patients will be treated with 250mg crizotinib bid until progression or intolerable toxicity.

Detailed Description
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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.

Official Title
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EUCROSS: A Phase II Trial to Evaluate Efficacy and Safety of Crizotinib Treatment in Advanced Adenocarcinoma of the Lung Harbouring ROS1 Translocations

Conditions
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Lung Cancer, Adenocarcinoma, NSCLC

Intervention / Treatment
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* Drug: Crizotinib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Crizotinib<br>Patients are treated in this single-arm trial with oral crizotinib 250 mg b.i.d.. Treatment dose will be adjusted according to the protocol if indicated. Treatment will be conducted until disease progression or beyond disease progression according to the protocol if clinically indicated. | Drug: Crizotinib<br>* 250mg crizotinib bid until end of treatment<br>* Other names: Xalkori;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR); evaluation criteria: investigator assessed RECIST v.1.1 analysis | CT/MRI scans will be performed to evaluate the efficacy of crizotinib treatment in advanced adenocarcinoma of the lung harbouring ROS1 fusion genes (primary outcome measure: objective response rate (ORR) according to RECIST v.1.1) | From time of beginning of treatment until the documention of response according to RECIST v1.1 (expected average 12 months) . | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) according to RECIST v1.1; evaluation criteria: investigator assessed RECIST v.1.1 analysis | CT/MRI scans will be performed to assess the PFS during treatment period. | From time of beginning of treatment until the first documented event of progression according to RECIST v1.1 (expected average 12 months). | 
| Overall Survival (OS); evaluation criteria: investigator assessed RECIST v.1.1 analysis | OS will be assessed by telephone calls every 3 months after the safety follow-up visit. | From beginning to end of study (Last subject last visit (LSLV)) (up to approximately 24 months). | 
| Duration of Response (DR); evaluation criteria: investigator assessed RECIST v.1.1 analysis | CT/MRI scans will be performed to asses the DR. | From time of beginning of treatment until the documention of progression according to RECIST v1.1 (expected average 12 months). | 
| Time to Tumor Response; evaluation criteria: investigator assessed RECIST v.1.1 analysis | CT/MRI scans will be performed to assess the Time to Tumor Response. | From time of beginning of treatment until the first documented event of response according to RECIST v1.1 (expected average 3 months). | 
| Disease Control Rate (DCR); evaluation criteria: investigator assessed RECIST v.1.1 analysis | CT/MRI scans will be performed at weeks 6, 12, 24 to assess the DCR. | From beginning of treatment to week 6, 12 and 24 according to RECIST v1.1 (expected average 3 months). | 
| Safety/Adverse Events and tolerability in all patients treated with crizotinib assessed by number and severity of adverse events as recorded on the case report form, vital signs, laboratory variables, physical examination, electrocardiogram and RECIST1.1 | Safety and tolerability will be assessed on every study visit and for 28 days after end of treatment. | From beginning of treatment until 28 days post treatment (expected average 12 months). | 
| Patient Reported Outcomes (PRO) (EORTC QLQ-C30, EORTC QLQ-LC13) | Patient reported outcomes (PRO) of health-related quality of life (HRQoL), disease/treatment related symptoms of lung cancer and general health status | Questionnaires (EORTC QLQ-LC13, EORTC QLQ-C30) completed at baseline and every 4 weeks from beginning of treatment until end of study. | 
| To evaluate the efficacy of crizotinib treatment in the patient subgroup with ROS1 translocation confirmed by the CAGE technology regarding the objective response rate (ORR) (evaluation criteria: investigator assessed RECIST v1.1) | CT/MRI scans will be performed to evaluate the efficacy of crizotinib treatment in advanced adenocarcinoma of the lung harbouring ROS1 fusion genes as confirmed by CAGE sequencing | From time of beginning of treatment until the documention of response according to RECIST v1.1 (expected average 12 months) . | 
| Objective Response Rate (ORR), Overall Survival (OS), Progression Free Survival (PFS), Duration of Response (DR), Time to Tumor Response, Disease Control Rate (DCR); evaluation criteria: RECIST v1.1 by independent radiologic review | CT/MRI scans will be performed to evaluate the efficacy of crizotinib treatment | From time of beginning of treatment until the documention of response according to RECIST v1.1 (expected average 12 months) . | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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lung cancer, adenocarcinoma, NSCLC, ROS1, ROS1 translocation, crizotinib, phase II