Trial document




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  DRKS00012360

Trial Description

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Title

Pharmacokinetic Enhancement of Crizotinib plasma
concentrations with Cobicistat or Itraconazole in Anaplastic
Lymphoma Kinase positive advanced Non-Small Cell Lung
Cancer Patients

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Trial Acronym

PrECIsioN

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URL of the Trial

[---]*

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Brief Summary in Lay Language

This study investigates the possibility to increase blood levels of the drug crizotinib in patients with lung cancer whose trough levels are below average by adding cobicistat or itraconazole.

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Brief Summary in Scientific Language

This study explores the possibility of pharmacoenhancement in patients with ALK pos. NSCLC treated with crizotinib with either cobicistat or itraconazole.

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Organizational Data

  •   DRKS00012360
  •   2017/04/21
  •   [---]*
  •   yes
  •   Approved
  •   AFmu-047/2017, Ethik-Kommission I der Medizinischen Fakultät Heidelberg
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Secondary IDs

  •   2016-002187-14 
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Health Condition or Problem studied

  •   C34 -  Malignant neoplasm of bronchus and lung
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Interventions/Observational Groups

  •   Crizotinib 250 mg BID p.o. + 150 mg Cobicistat QD p.o. for 14 days
  •   Crizotinib 250 mg BID p.o. + Itraconazole 200 mg QD p.o. for 14 days
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Characteristics

  •   Interventional
  •   [---]*
  •   Other
  •   Open (masking not used)
  •   [---]*
  •   Other
  •   Other
  •   Other
  •   I
  •   Yes
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Primary Outcome

Geometric mean ratio (90% confidence interval) of crizotinib AUC0-τ and during, cobicistat
(itraconazole) treatment.

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Secondary Outcome

Pharmacokinetics
· AUC0-τ, Cmax,ss , Cmin,ss , CL/F, t1/2, Vss, kel of crizotinib before and during, cobicistat (itraconazole)
treatment.
· AUC0-∞, AUC0-τ, 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.

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
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Recruitment

  •   Actual
  •   2017/07/13
  •   16
  •   Monocenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional 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.

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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 < 60 bpm
associated with dizziness, or syncope, or seizures, or unexplained loss of
conciousness) or heart rate < 50 bpm at screening
4. ASAT and / or ALAT > 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 dioxide (E 171), Indigo carmine (E
132), erythrosine (E 127)).
· Signs of ventricular dysfunction (e.g. decompensation of heart failure) or
history of heart failure.

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Addresses

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    • Ruprecht-Karls University Heidelberg (Medical Faculty)University Hospital Heidelberg represented in law by its commercial directorDipl.-Volksw. Irmtraut Gürkan.
    • Im Neuenheimer Feld 672
    • 69120  Heidelberg
    • Germany
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    • Abt. Klinische Pharmakologie und PharmakoepidemiologieMedizinische Klinik
    • Mr.  Prof. Dr. med.  Walter  Haefeli 
    • Im Neuenheimer Feld 410
    • 69120  Heidelberg
    • Germany
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    • Abt. Onkologie der ThoraxtumorenThoraxklinik
    • Ms.  Dr.  Farastuk  Bozorgmehr 
    • Röntgen Str.1
    • 69126  Heidelberg
    • Germany
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Sources of Monetary or Material Support

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    • Abt. Klinische Pharmakologie und PharmakoepidemiologieMedizinische Klinik
    • Mr.  Prof. Dr. med.  Walter  Haefeli 
    • Im Neuenheimer Feld 410
    • 69120  Heidelberg
    • Germany
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Status

  •   Enrolling by invitation
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Trial Publications, Results and other Documents

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* This entry means the parameter is not applicable or has not been set.