E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adult patients with either firstly diagnosed or relapsed advanced adenocarcinoma of the lung harbouring ROS1 translocation |
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E.1.1.1 | Medical condition in easily understood language |
Advanced stage lung cancer harbouring ROS1 translocations |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025032 |
E.1.2 | Term | Lung adenocarcinoma NOS |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate efficacy of crizotinib treatment in advanced adenocarcinoma of the lung harbouring ROS1 fusion genes (primary endpoint: objective response rate (ORR) according to RECIST v.1.1) |
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E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of crizotinib monotherapy (secondary endpoints: overall survival (OS), progression free survival (PFS), duration of response (DR), time to tumor response, disease control rate (DCR))
To evaluate safety and tolerability of crizotinib monotherapy
To characterize ROS1 fusion genes on a genomical level
To characterize tumors becoming resistant to crizotinib (whole genome sequencing)
To assess patient reported outcomes (PRO) of health-related quality of life (HRQoL), disease/treatment related symptoms of lung cancer,
and general health status
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 result of ROS1 translocation by central FISH-testing is mandatory.
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 (CRCL) ≥ 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 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).
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E.4 | Principal 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 carinomatous 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
History of extensive disseminated/bilateral or known presence of interstitial fibrosis or interstitial lung disease of any grade, including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, and pulmonary fibrosis, but not history of prior, radiation pneumonitis.
Any of the following within 3 months prior to first crizotinib administration:
Myocardial infarction, severe/unstable angina, symptomatic congestive heart failure, coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack
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E.5 End points |
E.5.1 | Primary end point(s) |
Objective response rate defined as complete and partial responses according to RECIST v.1.1. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
ORR will be evaluated after 6, 12, 18 - every 6 weeks - of treatment |
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E.5.2 | Secondary end point(s) |
Median overall survival (OS), median progression free survival (PFS), median duration of response (DR), median time to tumor response, disease control rate (DCR) at 6, 12 and 24 weeks
Type, incidence, severity, seriousness and relationship to study medications of adverse events according to NIH CTCAE v4.0
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
DCR will be evaluated at 6, 12, 18 (every 6) weeks |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Germany |
Netherlands |
Spain |
Switzerland |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |