EUCROSS: European Trial on Crizotinib in ROS1 Translocated Lung Cancer

Sponsor

University of Cologne (Other)

Overall Status

Completed

CT.gov ID

NCT02183870

Collaborator

Spanish Lung Cancer Group (Other), Pfizer (Industry)

Enrollment

Locations

Arm

Duration (Months)

1.9

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Lung Cancer Adenocarcinoma NSCLC	Drug: Crizotinib	Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

34 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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 Start Date :

May 1, 2014

Actual Primary Completion Date :

Jul 24, 2018

Actual Study Completion Date :

Feb 29, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Crizotinib 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 250mg crizotinib bid until end of treatment Other Names: Xalkori

Arm

Intervention/Treatment

Experimental: Crizotinib

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

250mg crizotinib bid until end of treatment

Other Names:

Xalkori

Outcome Measures

Primary Outcome Measures

Objective Response Rate (ORR); evaluation criteria: investigator assessed RECIST v.1.1 analysis [From time of beginning of treatment until the documention of response according to RECIST v1.1 (expected average 12 months) .]
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)

Secondary Outcome Measures

Progression Free Survival (PFS) according to RECIST v1.1; evaluation criteria: investigator assessed RECIST v.1.1 analysis [From time of beginning of treatment until the first documented event of progression according to RECIST v1.1 (expected average 12 months).]
CT/MRI scans will be performed to assess the PFS during treatment period.
Overall Survival (OS); evaluation criteria: investigator assessed RECIST v.1.1 analysis [From beginning to end of study (Last subject last visit (LSLV)) (up to approximately 24 months).]
OS will be assessed by telephone calls every 3 months after the safety follow-up visit.
Duration of Response (DR); evaluation criteria: investigator assessed RECIST v.1.1 analysis [From time of beginning of treatment until the documention of progression according to RECIST v1.1 (expected average 12 months).]
CT/MRI scans will be performed to asses the DR.
Time to Tumor Response; evaluation criteria: investigator assessed RECIST v.1.1 analysis [From time of beginning of treatment until the first documented event of response according to RECIST v1.1 (expected average 3 months).]
CT/MRI scans will be performed to assess the Time to Tumor Response.
Disease Control Rate (DCR); evaluation criteria: investigator assessed RECIST v.1.1 analysis [From beginning of treatment to week 6, 12 and 24 according to RECIST v1.1 (expected average 3 months).]
CT/MRI scans will be performed at weeks 6, 12, 24 to assess the DCR.
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 [From beginning of treatment until 28 days post treatment (expected average 12 months).]
Safety and tolerability will be assessed on every study visit and for 28 days after end of treatment.
Patient Reported Outcomes (PRO) (EORTC QLQ-C30, EORTC QLQ-LC13) [Questionnaires (EORTC QLQ-LC13, EORTC QLQ-C30) completed at baseline and every 4 weeks from beginning of treatment until end of study.]
Patient reported outcomes (PRO) of health-related quality of life (HRQoL), disease/treatment related symptoms of lung cancer and general health status
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) [From time of beginning of treatment until the documention of response according to RECIST v1.1 (expected average 12 months) .]
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
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 [From time of beginning of treatment until the documention of response according to RECIST v1.1 (expected average 12 months) .]
CT/MRI scans will be performed to evaluate the efficacy of crizotinib treatment

Other Outcome Measures

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. [From beginning of screening of first patient to screening of last patient (expected average 24 months).]
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.
Characterization of molecular and genetic mechanisms of resistance to crizotinib treatment in patients showing disease progression. [At time of disease progression (expected average 12 months).]
Mechanisms of resistance to crizotinib will be analysed by molecular pathologic analyses, e.g. NGS and FISH.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Thoraxklinik Heidelberg	Heidelberg	Baden-Würtemberg	Germany	69126
2	Universitätsklinikum Frankfurt - Medizinische Klinik II	Frankfurt a.M.	Hessen	Germany	60590
3	LungenClinic Großhansdorf	Großhansdorf	Schleswig-Holstein	Germany	22927
4	Evangelische Lungenklinik Berlin	Berlin		Germany	13125
5	University of Cologne / LCGC	Cologne		Germany	50937
6	Universitätsklinikum Tübingen	Tübingen		Germany
7	Maria Rosaria Garcia Campelo	A Coruna		Spain
8	CEIC Hospital General Universitario de Alicante	Alicante		Spain
9	CEIC Hopsital Vall d'Hebron	Barcelona		Spain
10	Institut Catala D'Oncologia	Barcelona		Spain
11	Hospital Universitario Materno-Infantil de Canarias	Las Palmas de Gran Canaria		Spain
12	CEIC Área 2 - Hospital Universitario de La Princesa	Madrid		Spain
13	CEIC Área 6 - Hospital Universitario Puerta de Hierro de Majadahonda	Majadahonda		Spain
14	CEIC Malaga Nordeste - Hospital Regional Universitario Carlos Haya	Malaga		Spain
15	Hospital Son Llatzer	Palma de Mallorca		Spain
16	CEIC Hospital Universitario Virgen del Rocio	Sevilla		Spain
17	CEIC Hospital Clínico Universitario de Valencia	Valencia		Spain
18	Universitätsspital Basel	Basel		Switzerland