C34
Conditions
Interventions
Group 1: Crizotinib 250 mg BID p.o. + 150 mg Cobicistat QD p.o. for 14 days
Group 2: Crizotinib 250 mg BID p.o. + Itraconazole 200 mg QD p.o. for 14 days
Sponsors
Ruprecht-Karls University Heidelberg (Medical Faculty)University Hospital Heidelberg represented in law by its commercial directorDipl.-Volksw. Irmtraut Gürkan.
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Inclusion criteria
Inclusion criteria: 1. Histologically or cytologically confirmed diagnosis of non-small cell lung cancer (NSCLC) that is Anaplastic Lymphocyte Kinase (ALK) positive as assessed by a Immunohistochemistry (IHC) (D5F3 by Ventana/Roche tissue diagnostics, Switzerland or 5A4 by Novocastra, UK) reverse transcriptase polymerase chain reaction (rtPCR), fluorescence in-situ hybdridisation (FISH); or that is ROS1 positve as assessed by next generation sequencing or FISH. 2. Treatment with crizotinib 250 mg p.o. BID for at least 14 days by standard of care 3. Crizotinib plasma trough concentractions (Cmin) < 310 ng/ml at screening visit 4. Male or female aged =18 years 5. Life expectancy of at least 12 weeks 6. ECOG Performance Score of 0-2 7. Adequate renal, hematologic, and liver function 8. Patients must have recovered from effects of any major surgery or significant traumatic injury at least 28 days before the first dose of study treatment 9. Prior brain or leptomeningeal metastases allowed if asymptomatic (e.g., diagnosed incidentally at study baseline). Prior radiation treatment must be completed at least 14 days before enrolment and patients must be clinically stable. 10. Use of highly effective contraception (failure rate of less than 1% per year when used consistently and correctly) as defined in appendix 8 during the intake of crizotinib and at least 90 days after the last dose of crizotinib. 11. Ability to understand and willingness to comply with study interventions and restrictions. 12. Voluntarily signed informed consent after full explanation of the study to the patient.
Exclusion criteria
Exclusion criteria: Patient characteristics: 1. National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (version 4.03) Grade 3 or higher toxicities due to any prior therapy (e.g., radiotherapy) (excluding alopecia), which have not shown improvement and are strictly considered to interfere with current study medication 2. Patients with baseline QTcF >470 ms at screening 3. Patients with symptomatic bradycardia (defined as a heart rate 2.5-fold ULN (> 5-fold ULN in presence of hepatic metasases) 5. Estimates glomerular filtration rate (eGFR) according to the Cockcroft and Gould-formula of =30 ml/min. If GFR was determined with 24h collection urine, then GFR supercedes the eGFR-value. 6. Hemoglobin < 10.0 g/dL, white blood cell count < 3.0 /nL, platelets < 75 /nL, absolute neutrophil count < 1.5/nL 7. Contraindication against crizotinib as stated in the german Xalkori® drug label with exception of the drug combinations investigated in this protocol. 8. Known intolerance of crizotinib or midazolam or any additives as listed in the german Xalkori® and Dormicum® V drug labels. 9. Any clinically significant (history of) disease or condition that whose presence or treatment could interfere with the conduct of the study or the absorption of oral medications or that would, in the opinion of the Principal Investigator, pose an unacceptable risk to the patient in this study 10. Pregnant or breast-feeding women Concomittant medication 11. Current co-administration of anti-cancer therapies other than crizotinib. 12. Exposure with strong/potent cytochrome P450 (CYP) 3A inhibitors or inducers within 14 days prior to the first dose until the end of study treatment (See Appendix 6) Exposure with any drug with a known risk of TdP according to Arizona CERT within 14 days prior to the first dose of itraconazole until the end of study treatment (See Appendix 7) 13. Exposure with any drug that is primarily eliminated through CYP3A4 and has a narrow therapeutic index (see list in Appendix 6) Only for participants in Phase A (Crizotinib – cobicistat arm): 14. Contraindication against cobicistat as stated in the german Tybost® drug label with exception of the drug combinations investigated in this protocol. · Exposure with any drug listed in Appendix 4: Drugs that should not be combined with Tybost®. · Hypersensitivity against cobicistat or against any of the excipients of Tybost® film tablets (silicon dioxide; Croscarmellose sodium; magnesium stearate; microcrystalline cellulose Sunset yellow FCF, aluminum salt ( E110 ); Macrogol 3350 ( E1521 ); Polyvinyl alcohol, (partially hydrolyzed) (E1203); Talc ( E553b ); Titanium dioxide (E171 ); Iron (III ) hydroxide Only for participants in Phase B (Crizotinib – itraconazole arm): 15. Contraindication against itraconazole as stated in the german Sempera® drug label with exception of the drug combinations investigated in this protocol. · Hereditary fructose intolerance, glucose-galactose-malabsorption, saccharase-isomaltase deficieny · Exposure with any drug listed in Appendix 5: that should not be combined with Sempera®. · Hypersensitivity to itraconazole or any excipients of ‘Sempera® 100 mg Hartkapsel’ (Sucrose, cornstarch, Glucosesirup (Ph. Eur.), Hypromellose, Macrogol (20 000), gelatine, titanium
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Geometric mean ratio (90% confidence interval) of crizotinib AUC0-t and during, cobicistat (itraconazole) treatment. | — |
Secondary
| Measure | Time frame |
|---|---|
| Pharmacokinetics · AUC0-t, Cmax,ss , Cmin,ss , CL/F, t1/2, Vss, kel of crizotinib before and during, cobicistat (itraconazole) treatment. · AUC0-8, AUC0-t, Cmax, CL/F, Tmax t1/2 Vd, Vss of midazolam before and during, cobicistat (itraconazole) treatment. · CYP3A activity measured as estimated oral metabolic midazolam clearance. · From all screened patients: correlation of CYFRA 21-1 with Cmin, ss. Pharmacodynamics · HR before and during, cobicistat (itraconazole) treatment. · QTcF before and during, cobicistat (itraconazole) treatment. · Safety and tolerability of crizotinib pharmacoenhancement with cobicistat (itraconazole) · Biomarkers (CYFRA 21-1, CEA, and exploratory lncRNAs) and treatment. Pharmacogenomics · From all screened patients: correlat kinetics. | — |
Countries
Germany
Contacts
Public ContactFarastuk Bozorgmehr
Abt. Onkologie der ThoraxtumorenThoraxklinik
Outcome results
None listed