EUCROSS: European Trial on Crizotinib in ROS1 Translocated Lung Cancer

Lung Cancer Clinical Trial

— EUCROSS  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02183870
• Other study ID #: EUCROSS
• Secondary ID: 2013-002737-38DR
• Status: Completed
• Phase: Phase 2
• Start date: May 2014
• Est. completion date: February 29, 2020

Study information

• Verified date: June 2022
• Source: University of Cologne
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 34
• Est. completion date: February 29, 2020
• Est. primary completion date: July 24, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Adenocarcinoma
• Lung Cancer
• Lung Neoplasms
• NSCLC

Intervention

Drug:
• Crizotinib
250mg crizotinib bid until end of treatment

Locations

Country	Name	City	State
Germany	Evangelische Lungenklinik Berlin	Berlin
Germany	University of Cologne / LCGC	Cologne
Germany	Universitätsklinikum Frankfurt - Medizinische Klinik II	Frankfurt a.M.	Hessen
Germany	LungenClinic Großhansdorf	Großhansdorf	Schleswig-Holstein
Germany	Thoraxklinik Heidelberg	Heidelberg	Baden-Würtemberg
Germany	Universitätsklinikum Tübingen	Tübingen
Spain	Maria Rosaria Garcia Campelo	A Coruna
Spain	CEIC Hospital General Universitario de Alicante	Alicante
Spain	CEIC Hopsital Vall d'Hebron	Barcelona
Spain	Institut Catala D'Oncologia	Barcelona
Spain	Hospital Universitario Materno-Infantil de Canarias	Las Palmas de Gran Canaria
Spain	CEIC Área 2 - Hospital Universitario de La Princesa	Madrid
Spain	CEIC Área 6 - Hospital Universitario Puerta de Hierro de Majadahonda	Majadahonda
Spain	CEIC Malaga Nordeste - Hospital Regional Universitario Carlos Haya	Malaga
Spain	Hospital Son Llatzer	Palma de Mallorca
Spain	CEIC Hospital Universitario Virgen del Rocio	Sevilla
Spain	CEIC Hospital Clínico Universitario de Valencia	Valencia
Switzerland	Universitätsspital Basel	Basel

Sponsors (3)

Lead Sponsor	Collaborator
University of Cologne	Pfizer, Spanish Lung Cancer Group

Countries where clinical trial is conducted

Germany,  Spain,  Switzerland, 

References & Publications (2)

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, Büttner 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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.	CAGE technology (Cap Analysis of Gene Expression) is an RNA based sequencing technology to identify the exact break-apart point as well as the fusion genes.	From beginning of screening of first patient to screening of last patient (expected average 24 months).
Other	Characterization of molecular and genetic mechanisms of resistance to crizotinib treatment in patients showing disease progression.	Mechanisms of resistance to crizotinib will be analysed by molecular pathologic analyses, e.g. NGS and FISH.	At time of disease progression (expected average 12 months).
Primary	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	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).
Secondary	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).
Secondary	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).
Secondary	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).
Secondary	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).
Secondary	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).
Secondary	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.
Secondary	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) .
Secondary	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) .