Assess Safety & Efficacy of Selumetinib When Given in Combination With Standard First Line Treatment for Advanced Non-small Cell Lung Cancer (SELECT-3)

A Phase I, Open Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of Selumetinib (AZD6244; ARRY-142886) in Combination With First Line Chemotherapy Regimens in Patients With Non-Small Cell Lung Cancer (NSCLC)

This is a Phase I, open label multicentre study of selumetinib administered orally in combination with first line chemotherapy regimens to patients with advanced/metastatic NSCLC. The study has been designed to allow an investigation of the optimal dose of selumetinib in combination with various standard first line double-platinum chemotherapy regimens. Initial assessment will be based on tolerability of selumetinib in combination with one or more selected regimens that are considered to be tolerated also being assessed for preliminary evidence of activity.

This study is a dose finding and optional cohort expansion; In addition all patients will be assessed for anti-cancer efficacy of the combination of selumetinib and chemotherapy.

Study Overview

• Status: Completed
• Conditions: Locally Advanced or Metastatic NSCL Cancer Stage IIIB IV
• Intervention / Treatment: Drug: selumetinib; Drug: gemcitabine; Drug: cisplatin; Drug: carboplatin; Drug: pemetrexed

Detailed Description

A Phase I, Open Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of Selumetinib (AZD6244; ARRY-142886) in Combination with First Line Chemotherapy Regimens in Patients with Non-Small Cell Lung Cancer (NSCLC)

• Study Type: Interventional
• Enrollment (Actual): 55
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Glasgow, United Kingdom, G12 0YN
    • Research Site
  • London, United Kingdom, W1G 6AD
    • Research Site
  • Manchester, United Kingdom, M20 4BX
    • Research Site
  • Newcastle upon Tyne, United Kingdom, NE7 7DN
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Provision of signed, written and dated consent prior to any study specific procedures
• Male or female, aged 18 years or older
• Histological or cytological confirmation of locally advanced or metastatic NSCLC (IIIB-IV)
• Female patients must not be breast-feeding and have a negative pregnancy test prior to start of dosing or must have evidence of non-child-bearing potential
• Patients must be eligible to receive treatment with the platinum doublet combination with which selumetinib is being combined and in accordance with the local product information

Exclusion Criteria:

• Prior chemotherapy or other systemic anti-cancer treatment for advanced NSCLC.
• Prior surgery or radiotherapy within 6 months or palliative radiotherapy within 4 weeks of start of study treatment.
• Female patients who are breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control
• Another primary malignancy within 5 years of starting study treatment, except for adequately treated basal or squamous cell carcinoma of the skin or cancer of the cervix in situ.
• As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases, active bleeding diatheses, renal transplant, or active infection

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Selumetinib+standard chemotherapy; Selumetinib plus gemcitabine; or pemetrexed and cisplatin or carboplatin

Drug: selumetinib; 2 x 25mg capsules bd continuously in cohort 1 (with gemcitabine and cisplatin). If tolerated - next cohort 3 x 25mg capsules bd continuously. if higher doses are explored, required number of capsules will be provided. Option to administer on D2-19 of each 21 day cycle if required to assess tolerability of combinations with chemotherapy; Drug: gemcitabine; 1250 mg/m2 iv on Day 1 and 8 of each 21 day cycle. If combination not tolerated, option to give 1000 mg/m2 iv on Day 1 and Day 8 of each 21 day cycle; Drug: cisplatin; 75 mg/m2 iv on Day 1 of each 21 day cycle. If combination not tolerated, option to give 50 mg/m2 iv on Day 1 or 25mg/m2 iv on Day 1 and Day 8 of each 21 day cycle; Drug: carboplatin; If it is not possible to identify a tolerable combination of selumetinib, gemcitabine and cisplatin, cisplatin may be replaced with carboplatin (AUC5) iv on Day 1 of each 21 day cycle; Drug: pemetrexed; Gemcitabine may be replaced with pemetrexed 500 mg/m2 iv on Day 1 of each 21 day cycle.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose Limiting Toxicity (DLT) Events in Chemotherapy in Combination With Selumetinib	Any toxicity not attributable to the disease or disease-related processess under investigation, considered related to the combination of chemotherapy plus selumetinib, which occurs within the timeframe and is dose limiting	The first dose on Cycle 1 Day 1 up to the time before dosing on Cycle 2 Day 1, assessed up to 3 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best Objective Response	The best response a patient has had during their time in the study up until RECIST progression or last valuable assessment in the absence of RECIST progression. Per Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for a Partial Response nor sufficient increase to qualify for Progressive Disease (PD); Progressive Disease (PD), >=20% increase in the sum of the longest diameter of target lesions, the sum must also demonstrate an absolute increase of >=5mm; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm	Screening, week 6 and week 12
Percentage Change From Baseline at 6 Weeks in Target Lesion Size	The percentage change in the sum of the diameters of target lesions	Week 6
Best Percentage Change From Baseline in Target Lesion Size	The best percentage change in tumour size a patient has had during their time in the study up until RECIST progression or last valuable assessment in the absence of RECIST progression. Percentage change was derived at each visit by the percentage change in the sum of the diameters of target lesions	Screening, week 6 and week 12
Objective Response Rate (ORR)	The number of patients who had at least 1 confirmed visit response of Complete Response (CR) or Partial Response (PR) prior to any evidence of progression. Per Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm; Objective Response Rate (ORR) = CR + PR	Up until progression or last evaluable assessment in the absence of progression, up to 9 months
AUC (0-tau)	Area under the concentration time curve (AUC) over a dosing interval at steady state (0-tau)	Cycle 2 Day1, pre-dose, 0.5, 1, 1.5, 2, 4, 8, 10 hours post dose
Cmax,ss	Maximum plasma concentration at steady state	Cycle 2 Day1, pre-dose, 0.5, 1, 1.5, 2, 4, 8, 10 hours post dose
Tmax,ss	Time to reach maximum plasma concentration at steady state	Cycle 2 Day1, pre-dose, 0.5, 1, 1.5, 2, 4, 8, 10 hours post dose
CL/F	Apparent oral plasma clearance	Cycle 2 Day1, pre-dose, 0.5, 1, 1.5, 2, 4, 8, 10 hours post dose

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Study Director: Gabriella Mariani, MD, AstraZeneca UK, MSD; Principal Investigator: Emma Dean, BMEDSCI, BM, BS, PHD, The Christie NHS Foundation Trust, UK; Principal Investigator: Fiona Blackhall, PhD, FRCP, The Christie NHS Foundation Trust Clinical Trials Unit; UK

Publications and helpful links

Helpful Links

• D1532C00070revisedCSP-2_Redacted

Study record dates

Study Major Dates

• Study Start (Actual): April 4, 2013
• Primary Completion (Actual): January 4, 2016
• Study Completion (Actual): January 4, 2016

Study Registration Dates

• First Submitted: March 8, 2013
• First Submitted That Met QC Criteria: March 11, 2013
• First Posted (Estimate): March 12, 2013

Study Record Updates

• Last Update Posted (Actual): March 13, 2018
• Last Update Submitted That Met QC Criteria: March 12, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: metastatic,; Non Small Cell Lung Cancer,; MEK1/2 inhibitor,; first line treatment for Non Small Cell Lung Cancer
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Folic Acid Antagonists; Gemcitabine; Carboplatin; Cisplatin; Pemetrexed
• Other Study ID Numbers: D1532C00070; EudraCT number: 2012-005202-22