Clinical trial NCT02183870: EUCROSS: European Trial on Crizotinib in ROS1 Translocated Lung Cancer
Official title: EUCROSS: A Phase II Trial to Evaluate Efficacy and Safety of Crizotinib Treatment in Advanced Adenocarcinoma of the Lung Harbouring ROS1 Translocations
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Lung Cancer
Adenocarcinoma
NSCLC
Keywords: lung cancer
adenocarcinoma
NSCLC
ROS1
ROS1 translocation
crizotinib
phase II
Lead sponsor: University of Cologne
Sponsor class: OTHER
Collaborators: name: Spanish Lung Cancer Group
name: Pfizer
First posted: 2014-07-08
Enrollment: 34
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Objective Response Rate (ORR); evaluation criteria: investigator assessed RECIST v.1.1 analysis
timeFrame: From time of beginning of treatment until the documention of response according to RECIST v1.1 (expected average 12 months) .
Secondary outcomes:
measure: Progression Free Survival (PFS) according to RECIST v1.1; evaluation criteria: investigator assessed RECIST v.1.1 analysis
timeFrame: From time of beginning of treatment until the first documented event of progression according to RECIST v1.1 (expected average 12 months).
measure: Overall Survival (OS); evaluation criteria: investigator assessed RECIST v.1.1 analysis
timeFrame: From beginning to end of study (Last subject last visit (LSLV)) (up to approximately 24 months).
measure: Duration of Response (DR); evaluation criteria: investigator assessed RECIST v.1.1 analysis
timeFrame: From time of beginning of treatment until the documention of progression according to RECIST v1.1 (expected average 12 months).
measure: Time to Tumor Response; evaluation criteria: investigator assessed RECIST v.1.1 analysis
timeFrame: From time of beginning of treatment until the first documented event of response according to RECIST v1.1 (expected average 3 months).
measure: Disease Control Rate (DCR); evaluation criteria: investigator assessed RECIST v.1.1 analysis
timeFrame: From beginning of treatment to week 6, 12 and 24 according to RECIST v1.1 (expected average 3 months).
measure: 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
timeFrame: From beginning of treatment until 28 days post treatment (expected average 12 months).
measure: Patient Reported Outcomes (PRO) (EORTC QLQ-C30, EORTC QLQ-LC13)
timeFrame: Questionnaires (EORTC QLQ-LC13, EORTC QLQ-C30) completed at baseline and every 4 weeks from beginning of treatment until end of study.
measure: 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)
timeFrame: From time of beginning of treatment until the documention of response according to RECIST v1.1 (expected average 12 months) .
measure: 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
timeFrame: From time of beginning of treatment until the documention of response according to RECIST v1.1 (expected average 12 months) .
Other outcomes:
measure: Characterization of ROS1 fusion gene on a genomic level by CAGE Technology to identify the exact break-apart point as well as the involved fusion genes.
timeFrame: From beginning of screening of first patient to screening of last patient (expected average 24 months).
measure: Characterization of molecular and genetic mechanisms of resistance to crizotinib treatment in patients showing disease progression.
timeFrame: At time of disease progression (expected average 12 months).
Locations:
city: Heidelberg
country: Germany
facility: Thoraxklinik Heidelberg
state: Baden-Würtemberg
city: Frankfurt a.M.
country: Germany
facility: Universitätsklinikum Frankfurt - Medizinische Klinik II
state: Hessen
city: Großhansdorf
country: Germany
facility: LungenClinic Großhansdorf
state: Schleswig-Holstein
city: Berlin
country: Germany
facility: Evangelische Lungenklinik Berlin
city: Cologne
country: Germany
facility: University of Cologne / LCGC
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen
city: A Coruna
country: Spain
facility: Maria Rosaria Garcia Campelo
city: Alicante
country: Spain
facility: CEIC Hospital General Universitario de Alicante
city: Barcelona
country: Spain
facility: CEIC Hopsital Vall d'Hebron
city: Barcelona
country: Spain
facility: Institut Catala D'Oncologia
city: Las Palmas de Gran Canaria
country: Spain
facility: Hospital Universitario Materno-Infantil de Canarias
city: Madrid
country: Spain
facility: CEIC Área 2 - Hospital Universitario de La Princesa
city: Majadahonda
country: Spain
facility: CEIC Área 6 - Hospital Universitario Puerta de Hierro de Majadahonda
city: Malaga
country: Spain
facility: CEIC Malaga Nordeste - Hospital Regional Universitario Carlos Haya
city: Palma de Mallorca
country: Spain
facility: Hospital Son Llatzer
city: Sevilla
country: Spain
facility: CEIC Hospital Universitario Virgen del Rocio
city: Valencia
country: Spain
facility: CEIC Hospital Clínico Universitario de Valencia
city: Basel
country: Switzerland
facility: Universitätsspital Basel
Study officials:
affiliation: Uniklinik Köln, Department I for Internal Medicine, LCGC
name: Juergen Wolf, Prof. Dr. med.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bos M, Gardizi M, Schildhaus HU, Heukamp LC, Geist T, Kaminsky B, Zander T, Nogova L, Scheffler M, Dietlein M, Kobe C, Holstein A, Maintz D, Buttner R, Wolf J. Complete metabolic response in a patient with repeatedly relapsed non-small cell lung cancer harboring ROS1 gene rearrangement after treatment with crizotinib. Lung Cancer. 2013 Jul;81(1):142-3. doi: 10.1016/j.lungcan.2013.02.018. Epub 2013 Apr 1.
citation: Takeuchi K, Soda M, Togashi Y, Suzuki R, Sakata S, Hatano S, Asaka R, Hamanaka W, Ninomiya H, Uehara H, Lim Choi Y, Satoh Y, Okumura S, Nakagawa K, Mano H, Ishikawa Y. RET, ROS1 and ALK fusions in lung cancer. Nat Med. 2012 Feb 12;18(3):378-81. doi: 10.1038/nm.2658.