Ph II Trial of Carboplatin and Pemetrexed With or Without AZD1775 for Untreated Lung Cancer

A Phase II Study of AZD1775 Plus Pemetrexed and Carboplatin Followed by a Randomised Comparison of Pemetrexed and Carboplatin With or Without AZD1775 in Patients With Previously Untreated Stage IV Non-Squamous Non-Small-Cell Lung Cancer

The aim of this study is to combine AZD1775 with standard front-line chemotherapy in subjects with advanced NSCLC.

Study Overview

• Status: Terminated
• Conditions: Previously Untreated Stage IV Non-Squamous Non Small Cell Lung Cancer
• Intervention / Treatment: Drug: AZD1775; Drug: pemetrexed; Drug: carboplatin; Drug: AZD1775 Matching Placebo

Detailed Description

This is a randomised, phase II trial comparing AZD1775 plus pemetrexed and carboplatin followed by maintenance AZD1775 and pemetrexed versus pemetrexed and carboplatin followed by maintenance pemetrexed in patients with previously untreated metastatic non-squamous NSCLC with TP53 mutations. The primary endpoint of the trial is assessment of progression-free survival (PFS).

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Englewood, Colorado, United States
      • Research Site
  • Florida
    • Fort Myers, Florida, United States
      • Research Site
    • Orlando, Florida, United States
      • Research Site
  • Illinois
    • Peoria, Illinois, United States
      • Research Site
  • Indiana
    • Fort Wayne, Indiana, United States
      • Research Site
  • Kansas
    • Wichita, Kansas, United States
      • Research Site
  • Ohio
    • Cincinnati, Ohio, United States
      • Research Site
  • Tennessee
    • Nashville, Tennessee, United States
      • Research Site

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria

• Provision of informed consent prior to any study specific procedures
• Histologic or cytologic diagnosis of advanced NSCLC, Recurrent or Stage IV disease (according to American Joint Committee on Cancer (AJCC) staging system, v7.0).
• No prior chemotherapy for locally advanced or metastatic disease
• Subjects with a known EGFR mutation must have received previous treatment with an EGFR tyrosine kinase inhibitor; and subjects with a known ALK translocation must have received previous treatment with an ALK inhibitor.
• No prior radiation therapy to the whole pelvis or to ≥25% of the total bone marrow area.
• At least one measurable lesion according to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1
• Mandatory availability of tumour tissue (archival or fresh if archival is not available) for TP53 determination.
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 or 1.
• Absolute neutrophil count (ANC) ≥1500/μL
• Hemoglobin (Hgb) ≥10 g/dL
• Platelets ≥100,000/μL
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST), ≤3.0 x the upper limit of normal (ULN); 5 x ULN if known hepatic metastases
• Total bilirubin ≤1.5 x ULN, unless secondary to Gilbert's disease
• Serum creatinine ≤1.5 x ULN and a calculate creatinine clearance (CrCl) ≥45 mL/min by the Cockcroft-Gault method
• Ability to swallow oral medication
• Fertile male subjects willing to use at least one medically acceptable form of birth control for the duration of the study and for 2 weeks after treatment stops
• Female subjects who are not of childbearing potential and fertile female subjects of childbearing potential who agree to use adequate contraceptive measures who are not breastfeeding, and who have a negative serum or urine pregnancy test within 72 hours prior to start of study treatment
• Predicted life expectancy ≥12 weeks
• Must be ≥18 years of age
• Willingness and ability to comply with study and follow-up procedures
• Ability to understand the nature of this trial and give written informed consent Exclusion criteria
• Use of a study drug ≤21 days or 5 half-lives (whichever is shorter) prior to the first dose of AZD1775
• Major surgical procedures ≤28 days of beginning AZD1775, or minor surgical procedures ≤7 days
• Known central nervous system (CNS) disease
• Subject has had prescription or non-prescription drugs or other products (i.e. grapefruit juice) known to be sensitive CYP3A4 substrates
• Any known hypersensitivity or contraindication to the components of study treatment
• Any of the following cardiac diseases currently or within the last 6 months as defined by New York Heart Association ([NYHA] Appendix G) ≥ Class 2
• Corrected QT interval (QTc) >470 msec (as calculated by Fridericia correction formula) at study entry or congenital long QT syndrome.
• Pregnant or lactating
• Any serious, active underlying medical condition that would impair the ability of the subjects to receive study treatment
• Unable or unwilling to take folic acid or vitamin B12
• Presence of other active cancers, or history of treatment for invasive cancer ≤3 years
• Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AZD1775 + carboplatin + pemetrexed; Randomised: AZD1775 + pemetrexed + carboplatin followed by maintenance AZD1775 + pemetrexed versus pemetrexed and carboplatin followed by maintenance pemetrexed.	Drug: AZD1775; AZD1775 is a highly selective, adenosine-triphosphate (ATP) competitive, small molecule inhibitor of the WEE 1 kinase that sensitizes tumor cells to cytotoxic agents and is being developed for the treatment of advanced solid tumors and p53 pathway deficient malignancies; Other Names: MK-1775; Drug: pemetrexed; This drug is a part of a general group of chemotherapy drugs called anti-metabolites. It prevents cells from using folate to make DNA and RNA. Because cancer cells need these substances to make new cells, this drug helps to stop the growth of cancer cells.; Drug: carboplatin; This drug is a platinum chemotherapy drug that acts like an alkylating agent. It stops the growth of cancer cells, causing the cells to die.
Experimental: Placebo + carboplatin + pemetrexed; Randomised: AZD1775 + pemetrexed + carboplatin followed by maintenance AZD1775 + pemetrexed versus pemetrexed and carboplatin followed by maintenance pemetrexed.	Drug: pemetrexed; This drug is a part of a general group of chemotherapy drugs called anti-metabolites. It prevents cells from using folate to make DNA and RNA. Because cancer cells need these substances to make new cells, this drug helps to stop the growth of cancer cells.; Drug: carboplatin; This drug is a platinum chemotherapy drug that acts like an alkylating agent. It stops the growth of cancer cells, causing the cells to die.; Drug: AZD1775 Matching Placebo; AZD1775 is a highly selective, adenosine-triphosphate (ATP) competitive, small molecule inhibitor of the WEE 1 kinase that sensitizes tumor cells to cytotoxic agents and is being developed for the treatment of advanced solid tumors and p53 pathway deficient malignancies

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival	Progression free survival is defined as the time from randomisation until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the subject withdraws from randomised therapy or receives another anti-cancer therapy prior to progression.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess the Objective Response Rates in Each Arm	The objective response rate is defined as the number of the subjects with a confirmed best overall response of CR or PR divided by the number of subjects in the Full Analysis Set (FAS) for whom measureable disease is present at baseline	Up to a maximum of 4 treatment cycles (treatment cycles will be repeated every 21 days)
Assess the Disease Control Rate in Each Treatment Arm	the disease control rate is defined as the percentage of FAS subjects with a best overall response of CR, PR or SD).	Up to a maximum of 4 treatment cycles (treatment cycles will be repeated every 21 days)
Assess the Duration of Response in Each Treatment Arm	Duration of response is defined as the time from the date of first documented response until the date of documented progression or any cause death.	Up to a maximum of 4 treatment cycles (treatment cycles will be repeated every 21 days)
Assess Overall Survival in Each Treatment Arm	Overall survival is defined as the time from the date of randomization until death due to any cause.	Up to a maximum of 4 treatment cycles (treatment cycles will be repeated every 21 days)

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Principal Investigator: David R Spigel, MD, SCRI Development Innovations, LLC

Study record dates

Study Major Dates

• Study Start: March 1, 2014
• Primary Completion (Actual): June 1, 2015
• Study Completion (Actual): June 1, 2015

Study Registration Dates

• First Submitted: March 6, 2014
• First Submitted That Met QC Criteria: March 12, 2014
• First Posted (Estimate): March 14, 2014

Study Record Updates

• Last Update Posted (Actual): March 29, 2017
• Last Update Submitted That Met QC Criteria: February 10, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: Stage IV 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; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Folic Acid Antagonists; Carboplatin; Pemetrexed; Adavosertib
• Other Study ID Numbers: D6011C00002