Pharmacokinetic Enhancement of Crizotinib plasmaconcentrations with Cobicistat or Itraconazole in AnaplasticLymphoma Kinase positive advanced Non-Small Cell LungCancer Patients - PrECIsio
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 1
研究概览
简要总结
The inhibitor of anaplastic lymphoma kinase (ALK) crizotinib significantly increases survival in patients with ALK-positive non-small cell lung cancer (NSCLC). When evaluating crizotinib pharmacokinetics (PKs) in patients taking the standard flat oral dose of 250 mg b.i.d., interindividual PK variability is substantial and patient survival is lower in the quartile with the lowest steady-state trough plasma concentrations (Cmin,ss ), suggesting that concentrations should be monitored and doses individualized. We investigated whether the CYP3A inhibitor cobicistat increases Cmin,ss of the CYP3A substrate crizotinib in patients with low exposure. Patients with ALK-positive NSCLC of our outpatient clinic treated with crizotinib were enrolled in a phase I trial (EudraCT 2016-002187-14, DRKS00012360) if crizotinib Cmin,ss was below 310 ng/mL and treated with cobicistat for 14 days. Crizotinib plasma concentration profiles were established before and after a 14-day co-administration of cobicistat to construct the area under the plasma concentration-time curve in the dosing interval from zero to 12 hours (AUC0-12 ). Patients were also monitored for adverse events by physical examination, laboratory tests, and 12-lead echocardiogram. Enrolment was prematurely stopped because of the approval of alectinib, a next-generation ALK-inhibitor with superior efficacy. In the only patient enrolled, cobicistat increased Cmin,ss from 158 ng/mL (before cobicistat) to 308 ng/mL (day 8) and 417 ng/mL (day 14 on cobicistat), concurrently the AUC0-12 increased by 78% from 2,210 ng/mLh to 3,925 ng/mLh. Neither safety signals nor serious adverse events occurred. Pharmacoenhancement with cobicistat as an alternative for dose individualisation for patients with NSCLC with low crizotinib exposure appears to be safe and is cost-effective and feasible.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non-randomized controlled study
- 盲法
- Open (masking not used)
入排标准
- 年龄范围
- 18 Years 至 one（—）
- 性别
- All
入选标准
- •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
- •2. Treatment with crizotinib 250 mg p.o. BID for at least 14 days by standard of
- •3. Crizotinib plasma trough concentractions (Cmin) < 310 ng/ml at screening
- •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
- •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
- •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.
排除标准
- •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
- •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
- •· Hereditary fructose intolerance, glucose-galactose-malabsorption,
- •saccharase-isomaltase deficieny
- •· Exposure with any drug listed in Appendix 5: that should not be
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