Dose-escalation Study to Assess Selumetinib Safety, Tolerability and PK

NCT01960374 | Completed Phase 1

• 1 other identifier: D1532C00086
• Study Type: interventional
• Target: 117
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of the study is to assess the safety, tolerability and PK of selumetinib (AZD6244; ARRY-142886) (Hyd-Sulfate) in healthy male Japanese and non-Japanese Asian volunteers following administration of a single dose. Standard safety assessments including ECGs, vital signs, blood/urine safety tests, PK samples and monitoring of adverse events and an optional exploratory pharmacogenetics will be performed.

Conditions

Healthy Volunteers Pharmacokinetic Study

Keywords

RAS or RAF oncogenes, Inhibition of MEK pathway, inhibition cancer cell proliferation promising anti-cancer therapeutic strategy.

Outcome Measures

Primary Outcomes (3)

• Pharmacokinetics of selumetinib by assessment of maximum plasma selumetinib concentration (Cmax)

  Rate and extent of absorption of selumetinib following oral doses of selumetinib by assessment of maximum plasma selumetinib concentration (Cmax). Metabolite to parent drug ratios will be calculated for the primary PK parameters AUC and Cmax, and AUC (0-t) if applicable.

  Plasma will be collected at the following time points pre-dose then 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36 and 48 hours post dose

• Pharmacokinetics of selumetinib by assessment of area under the plasma concentration time curve from zero to infinity (AUC)

  Rate and extent of absorption of selumetinib following oral doses of selumetinib by assessment of area under the plasma concentration time curve from zero to infinity (AUC). Metabolite to parent drug ratios will be calculated for the primary PK parameters AUC and Cmax, and AUC (0-t) if applicable.

  Plasma will be collected at the following time points pre-dose then 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36 and 48 hours post dose

• Pharmacokinetics of selumetinib by assessment of area under the plasma concentration time curve from zero to the last measurable time point, AUC0-t, if AUC is not adequately measurable

  Rate and extent of absorption of selumetinib following oral doses of selumetinib by assessment of area under the plasma concentration time curve from zero to the last measurable time point, AUC0-t, if AUC is not adequately measurable. Metabolite to parent drug ratios will be calculated for the primary PK parameters AUC and Cmax, and AUC (0-t) if applicable.

  Plasma will be collected at the following time points pre-dose then 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36 and 48 hours post dose

Secondary Outcomes (16)

• Assessment of the Safety and Tolerability of Selumetinib by collection of adverse event reports

  All AEs will be collected from Day -1, throughout the treatment periods, and including the follow-up period, assessed after minimum of 7 days. SAEs will be recorded from the time of informed consent.

• Pharmacogenetics

  Optional exploratory sample for pharmacogenetics can be taken any time between Day 1 and Day 3 after dosing.

• Determine safety and tolerability of selumetinib by assessment of 12 lead electrocardiograms

  Triplicate 12-lead ECG evaluated at screening & admission. Single 12-lead paper ECGs will follow all dECGs. Digital ECGs will be taken on Day 1 & Day 2 (pre-dose, 1.5h, 2.5h, 4h, 6h, 24h, 48h (pECG only)) & at follow up, at least 7 days after dose.

• Determine safety and tolerability of selumetinib by physical examination

  At screening and follow up (at least 7 days after dose) full physical examination will be performed. On admission and discharge (day 3) from the CPU a brief physical examination will be performed.

• Determine safety and tolerability of selumetinib by assessment of vital signs

  Supine blood pressure and pulse and oral body temperature will be evaluated at screening and admission, Day 1 (at pre-dose, 1.5h and 6h), Day 2, Day 3 and at follow up at follow up, at least 7 days after dose.

Study Arms (2)

Japanese Arm

EXPERIMENTAL

3 cohorts of 9 subjects. Each cohort will receive oral 25 mg, 50 mg (anticipated) or 75 mg (anticipated) selumetinib (AZD6244; ARRY-142886) (Hyd-Sulfate).

Drug: Selumetinib

Non-Japanese Asian Arm

EXPERIMENTAL

3 cohorts of 9 subjects. Each cohort will receive oral 25 mg, 50 mg (anticipated) or 75 mg (anticipated) selumetinib (AZD6244; ARRY-142886) (Hyd-Sulfate).

Drug: Selumetinib

Interventions

Selumetinib DRUG

1, 2 or 3 x 25 mg selumetinib (AZD6244; ARRY-142886) (Hyd-Sulfate) capsule administered orally as a single dose on Day 1 of the study (total dose 25 mg, 50 mg and 75 mg respectively) with 240 ml of water at room temperature.

Also known as: (AZD6244; ARRY-142886) (Hyd-Sulfate)

Japanese Arm; Non-Japanese Asian Arm

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Provision of signed and dated, written informed consent prior to any study-specific procedures.
• Non-smokers for at least three months prior to drug administration.
• Healthy male volunteers aged 18 to 55 years with suitable veins for cannulation or repeated venipunctures.
• Subjects included will be either healthy first generation Japanese, or healthy first generation non-Japanese Asian (e.g. Korean, Chinese).
• Japanese subjects must meet the following requirements in order to participate in the study:
• Subject was born in Japan, Parents and grandparents (both maternal and paternal) are Japanese
• Subject is in possession of a valid Japanese passport, Expatriate of Japan for not longer than 5 years.
• Non-Japanese Asian subjects must meet the following requirements in order to participate in the study:
• Subject was born in an Asian country other than Japan, (such as Korea, China, Taiwan etc but not India), Parents and grandparents (both maternal and paternal) are non-Japanese Asian
• Subject is in possession of a valid passport from their country of origin, Expatriate of their country of origin for not longer than 5 years;
• Have a BMI between 18 and 30 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg, inclusive.
• Must use acceptable methods of contraception if the male subject's partner could become pregnant from the time of the first administration of treatment or study medication until 3 months following administration of the last treatment or dose of study medication.

You may not qualify if:

• History of any clinically important disease or disorder which, in the opinion of the investigator, may either put the volunteer at risk because of participation in the study, or influence the results or the volunteer's ability to participate in the study
• History or presence of gastrointestinal, hepatic, or renal disease or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
• Any clinically important illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP.
• Any clinically significant abnormalities in clinical chemistry, haematology, or urinalysis results, as judged by the Investigator.
• Any positive result on screening for serum hepatitis B surface antigen (HbsAg), anti hepatitis core antibody (anti HBc Ig G \[and anti HBc IgM if IgG is positive\], hepatitis C antibodies (anti HCV), and HIV 1 and 2 antibodies (anti HIV 1/2).
• Abnormal vital signs, after 10 minutes supine rest.
• Current or past history of central serous retinopathy or retinal vein thrombosis, intraocular pressure greater than 21 mmHg or uncontrolled glaucoma.
• Known or suspected history of drug abuse, as judged by the Investigator.
• History of alcohol abuse or excessive intake of alcohol, as judged by the Investigator.
• Positive screen for drugs of abuse or cotinine (nicotine) or positive screen for alcohol at screening or on admission to the study centre on Day -1.
• History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, as judged by the Investigator, or history of hypersensitivity to drugs with a similar chemical structure or class to selumetinib.
• Excessive intake of caffeine-containing drinks or food eg, coffee, tea, chocolate, Red Bull, or cola (more than 6 units of caffeine per day).
• Use of drugs with enzyme-inducing properties such as St John's Wort within 3 weeks prior to the first administration of IP.
• Use of any prescribed or non prescribed medication including antacids, analgesics other than paracetamol/acetaminophen 1 g 4 times a day for occasional use, herbal remedies, vitamins, and minerals during the 2 weeks or five half-lives of the compound, whichever is longer, prior to the first administration of IP.
• Any intake of grapefruit, grapefruit juice, Seville oranges, Seville orange marmalade, or other products containing grapefruit or Seville oranges within 7 days of the first admission on Day -1.Plasma donation within 1 month of screening or any blood donation/blood loss greater than 500 mL during the 3 months prior to screening.

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (1)

Research Site

London, United Kingdom

Location

MeSH Terms

Interventions

AZD 6244

Study Officials

• Ian C Smith, MD

  AstraZeneca UK, MSD

  STUDY CHAIR

• Ulrike Lorch, MD

  Richmond Pharmacology Ltd, UK

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: HEALTH SERVICES RESEARCH
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 9, 2013
• First Posted: October 10, 2013
• Study Start: October 1, 2013
• Primary Completion: May 1, 2014
• Study Completion: May 1, 2014
• Last Updated: June 2, 2014

Record last verified: 2014-05

Locations

GB (1)