Sorafenib Administered Using a High-dose, Pulsatile Regimen: a Phase I Exposure Escalation Study

NCT02636426 | Completed Phase 1 DMC

• 1 other identifier: 2015.224
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

Brief Summary

Sorafenib is an oral anticancer drug and inhibits multiple protein kinases important for tumor growth and metastases, including VEGFR, PDGFR, and RAF kinases. In daily clinical practice it is currently used at a dose of 400 mg twice daily in a continuous schedule. In this phase I study patients will be treated with a new dosing schedule of sorafenib: i.e. a high-dose, pulsatile schedule. The tolerability and safety of this new schedule is examined in exposure escalation cohorts based on a target plasma AUC0-12h (area under the curve). Exposure escalation cohorts are used instead of conventional dose escalation cohorts because the effect of a drug is dependent of its AUC levels and large differences in plasma sorafenib AUC0-12h have previously been shown between patients treated at the same dose level. Using pharmacokinetic monitoring, the sorafenib dose will be adjusted to a target plasma AUC0-12h. The escalation cohorts consist of 3-6 patients per exposure level starting with a target plasma sorafenib AUC0-12h level of 25-50 mg/L/h. After the determination of the maximum tolerated AUC0-12h, 10 additional patients will be entered into an expansion cohort. In the expansion cohort the patients will be treated with a weekly pulse of sorafenib at the maximum tolerated AUC0-12h for further assessment of safety and preliminary exploration of efficacy.

Conditions

Neoplasms

Keywords

phase I study; sorafenib; high-dose schedule; pharmacokinetics; drug monitoring

Outcome Measures

Primary Outcomes (1)

• To determine the maximum tolerated plasma AUC0-12h of high-dose, pulsatile sorafenib

  Toxicity is graded according to National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0.

  The exposure limiting toxicity period is within the first 42 days from the start of treatment. The maximum tolerated AUC0-12h of sorafenib is determined after completion of the escalation part of the study. It is expected to be completed within one year.

Secondary Outcomes (8)

• AUC0-12h of sorafenib and its primary active metabolite pyridine-N-oxide (escalation cohorts)

  Pharmacokinetics analysis is performed during the first three treatment cycles (i.e. day 1, 8 en 15).

• Cmax of sorafenib and its primary active metabolite pyridine-N-oxide (escalation cohorts)

  Pharmacokinetics analysis is performed during the first three treatment cycles (i.e. day 1, 8 en 15).

• Tmax of sorafenib and its primary active metabolite pyridine-N-oxide (escalation cohorts)

  Pharmacokinetics analysis is performed during the first three treatment cycles (i.e. day 1, 8 en 15).

• T1/2 of sorafenib and its primary active metabolite pyridine-N-oxide (escalation cohorts)

  Pharmacokinetics analysis is performed during the first three treatment cycles (i.e. day 1, 8 en 15).

• Recommended phase II dose

  This depends on the maximum tolerated AUC0-12h of sorafenib. The maximum tolerated AUC0-12h of sorafenib is determined after completion of the escalation part of the study. It is expected to be completed within one year.

Study Arms (1)

sorafenib

EXPERIMENTAL

In this phase I study patients are treated with high-dose, pulsatile sorafenib in escalating AUC0-12h cohorts.

Drug: sorafenib

Interventions

sorafenib DRUG

In new dosing schedule of sorafenib is investigated in this study: high-dose, pulsatile sorafenib

Also known as: Nexavar

sorafenib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histological or cytological documentation of incurable locally advanced or metastatic solid malignancy for which no standard therapy exists.
• Patients eligible for the expansion cohort must be willing to undergo tumor and skin biopsies, while tumor and skin biopsies are optional for patients enrolled in the escalation cohort. Primary tumor or metastatic site must be accessible for biopsy. Bone metastases are excluded as a biopsy site.
• Evaluable disease by RECIST version 1.1. criteria (see appendix III; at least 1 target or non-target lesion for the dose escalation cohorts; at least 1 target lesion the for dose expansion cohorts).
• Patients must have documented radiographic or clinical progressive disease.
• Age ≥ 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1 (appendix IV).
• Normal 12-lead ECG (clinically insignificant abnormalities permitted), and left ventricular ejection fraction (LVEF) \> 50% evaluated by multigated acquisition scan (MUGA) or echocardiogram.
• Normal or regulated thyroid function - supplementation or blocking drugs permitted.
• Urine analysis: no clinically significant abnormalities.
• Albumin higher than 25 g/L.
• Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 14 days prior to screening:
• Hemoglobin ≥ 5,6 mmol/L
• Absolute neutrophil count (ANC) ≥ 1,5 x 10\*9/l
• Platelet count ≥ 100 x 10\*9/l
• Total bilirubin ≤ 1.5 times the upper limit of normal (ULN). Patients with known Gilbert's disease who have serum bilirubin ≤ 3x ULN may be enrolled.

You may not qualify if:

• Evidence of a significant uncontrolled concomitant disease, such as cardiovascular disease (including stroke, New York Heart Association Class III or IV cardiac disease or myocardial infarction within 6 months prior to screening, unstable arrhythmia, clinically significant valvular heart disease and unstable angina); nervous system, pulmonary (including obstructive pulmonary disease and history of symptomatic bronchospasm), renal, hepatic, endocrine, or gastrointestinal disorders; or a serious non-healing wound or fracture.
• Prior radiotherapy in the abdominal or thoracic area or in \> 3 vertebrae in the spine (if long interval since previous radiotherapy or radiotherapy in ≤ 3 vertebrae, eligibility will be decided on an individual basis by the primary investigator).
• Poorly controlled hypertension despite adequate blood pressure medication. Blood pressure must be ≤ 160/95 mmHg at the time of screening on a stable antihypertensive regimen. Blood pressure must be stable on at least 2 separate measurements.
• Seizure disorders requiring anticonvulsant therapy.
• Major surgery, other than diagnostic surgery, within 4 weeks prior to day 1, without complete recovery.
• Known active bacterial, viral, fungal, mycobacterial, or other infection (including HIV and atypical mycobacterial disease, but excluding fungal infection of the nail beds).
• Known hypersensitivity to sorafenib or to its excipients.
• Presence of any significant central nervous system or psychiatric disorder(s) that would interfere with the patient's compliance.
• Drug or alcohol abuse.
• Any evidence of a disease or condition that might affect compliance with the protocol or interpretation of the study results or render the patient at high risk from treatment complications.
• Unwillingness or inability to comply with study and follow-up procedures.
• Chemotherapy, radiotherapy, or biologic therapy within the previous 4 weeks; Nitrosoureas or mitomycin C within the previous 6 weeks; Investigational agents within the previous 4 weeks.
• Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis.
• Untreated or active central nervous system (CNS) metastases (progressing or requiring anticonvulsants or corticosteroids for symptomatic control).
• Patients with a history of treated CNS metastases are eligible, provided that all of the following criteria are met:

Sponsors & Collaborators

• Amsterdam UMC, location VUmc: lead

Study Sites (1)

VU University Medical Center

Amsterdam, North Holland, 1081 HV, Netherlands

Location

Related Publications (4)

• Strumberg D, Richly H, Hilger RA, Schleucher N, Korfee S, Tewes M, Faghih M, Brendel E, Voliotis D, Haase CG, Schwartz B, Awada A, Voigtmann R, Scheulen ME, Seeber S. Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J Clin Oncol. 2005 Feb 10;23(5):965-72. doi: 10.1200/JCO.2005.06.124. Epub 2004 Dec 21.

  PMID: 15613696 BACKGROUND

• Pecuchet N, Lebbe C, Mir O, Billemont B, Blanchet B, Franck N, Viguier M, Coriat R, Tod M, Avril MF, Goldwasser F. Sorafenib in advanced melanoma: a critical role for pharmacokinetics? Br J Cancer. 2012 Jul 24;107(3):455-61. doi: 10.1038/bjc.2012.287. Epub 2012 Jul 5.

  PMID: 22767146 BACKGROUND

• Wang X, Zhang L, Goldberg SN, Bhasin M, Brown V, Alsop DC, Signoretti S, Mier JW, Atkins MB, Bhatt RS. High dose intermittent sorafenib shows improved efficacy over conventional continuous dose in renal cell carcinoma. J Transl Med. 2011 Dec 21;9:220. doi: 10.1186/1479-5876-9-220.

  PMID: 22188900 BACKGROUND

• Honeywell R, Yarzadah K, Giovannetti E, Losekoot N, Smit EF, Walraven M, Lind JS, Tibaldi C, Verheul HM, Peters GJ. Simple and selective method for the determination of various tyrosine kinase inhibitors used in the clinical setting by liquid chromatography tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2010 May 1;878(15-16):1059-68. doi: 10.1016/j.jchromb.2010.03.010. Epub 2010 Mar 15.

  PMID: 20382575 BACKGROUND

MeSH Terms

Conditions

Neoplasms

Interventions

Sorafenib

Intervention Hierarchy (Ancestors)

Phenylurea Compounds; Urea; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring

Study Officials

• Henk MW Verheul, MD PhD

  Amsterdam UMC, location VUmc

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr. MD PhD

Study Record Dates

• First Submitted: December 2, 2015
• First Posted: December 21, 2015
• Study Start: September 1, 2015
• Primary Completion: December 27, 2017
• Study Completion: December 27, 2017
• Last Updated: October 22, 2018

Record last verified: 2018-10

Locations

NL (1)