Trial design

The trial consists of a series of parallel, multi-centre, single arm, phase II trial arms, each testing an experimental targeted drug in a population stratified by multiple pre-specified actionable target putative biomarkers, using a Bayesian adaptive umbrella design. The trial also includes an arm for the population with no actionable genetic change who will be treated with a sequential pipeline of drugs.

Trial Objectives

The primary objective is to evaluate whether there is a signal of activity in each drug-(putative)biomarker cohort separately. A Bayesian adaptive umbrella design is adopted to achieve this objective.

A secondary objective of the trial is to provide the opportunity for industrial partners to test novel agents in the cohort of patients who are not positive for any of the actionable targets in the trial, referred to as the no actionable genetic change arm. In particular, if interim analysis shows significant activity for one of the targeted drugs in a targeted group then it may be relevant to assess the putative biomarker specificity of this drug by including it as a treatment option for the no actionable genetic change arm. Such an assessment could be important to inform the design of future trials for that drug. During the course of the trial, any drugs that are selected for allocation to the no actionable genetic change arm will be included in a pipeline of options that become available sequentially. The first drug to be tested in this arm is durvalumab (Cohort NA1). No comparison whatsoever will be made between any agents tested in the no actionable genetic change arm.

Circulating tumour DNA (ctDNA) samples and whole blood germline DNA samples are being collected from all trial patients. Optional research biopsies may also be collected prior to the patient starting treatment, or post-treatment discontinuation. These are in order to:

  • Collect tissue linked to clinical outcome data for future exploratory analysis to investigate the molecular genotype of tumours in responding versus non-responding patients and to further develop the clinical diagnostic test necessary to support further investigation of the agent in the relevant molecularly-defined group.
  • Identify predictive biomarkers for activity of the various drugs used in the various molecular cohorts.
  • Determine the mechanisms of resistance to the target therapies utilised.

 

Treatment arms

The below trial arms and cohorts are currently open to recruitment: 

Trial arms and cohorts currently open to recruitment
 ArmInvestigational Medicinal Products Cohort Number NSCLC HistologyMolecular Cohort
B Vistusertib  – MTORC-1/2 Inhibitor B2 NSCLC STK11/LKB1 mutation or homozygous deletion
C Palbociclib – CDK-4/6 Inhibitor C1 SCC p16 (CDKN2A) loss of function with proficient Rb
    C3 NSCLC CDK4 amplification with proficient Rb
    C4 NSCLC CCND1 amplification with proficient Rb
    C5 NSCLC
  • STK11/LKB1 mutation or homozygous deletion, or TSC1/2 mutation AND
  • Activated KRAS/MAPK pathway i.e. concomitant KRAS, NRAS or NF1 mutation AND
  • Proficient Rb (no loss of Rb function either by mutation or deletion)
D Crizotinib – ALK Inhibitor D1 NSCLC MET amplification
    D3 NSCLC MET exon 14 skipping (splice mutation or deletion)
E Selumetinib – MEK Inhibitor & Docetaxel  E1  SCC  NF1 mutation 
    E2  ADC or NOS NSCLC NF1 mutation
    E3  NSCLC NRAS mutation
J AZD6738 – ATR inhibitor & Durvalumab – PD-L1 Inhibitor J1 NSCLC
  • KRAS mutation
  • STK11/LKB1 successful test result
    NAJ  NSCLC  No actionable genetic change for other trial arms

The following trial Arms and Cohorts are now closed to recruitment:

Trial arms and cohorts closed to recruitment
 ArmInvestigational Medicinal Products Cohort Number NSCLC HistologyMolecular Cohort
A AZD4547 – FGFR Inhibitor A1 NSCLC FGFR2/3 mutation
B Vistusertib  – MTORC-1/2 Inhibitor B1 NSCLC TSC1/2 mutation
C Palbociclib – CDK-4/6 Inhibitor C2 ADC or NOS NSCLC p16 (CDKN2A) loss of function with proficient Rb
    C6 NSCLC

KRAS mutation with proficient Rb

(No concomitant STK11/LKB1 mutation or deletion, no PIK3CA mutation or amplification, no PTEN mutation or homozygous deletion, no AKT mutation, no EGFR mutation, no FGFR2/3 mutation, no TSC1/2 mutation, and no HER2 mutation)

D Crizotinib – ALK Inhibitor D2 NSCLC ROS1 gene fusions
F AZD5363 - AKT Inhibitor F1 SCC PIK3CA mutation & no KRAS, NF1, NRAS, HRAS or BRAF aberrations
    F2 SCC PIK3CA amplification & no KRAS, NF1, NRAS, HRAS or BRAF aberrations
    F3 NSCLC

PIK3CA mutation or PIK3CA amplification & no KRAS, NF1, NRAS, HRAS or BRAF aberrations (ADC or NOS NSCLC)

PTEN mutation or PTEN loss & no KRAS, NF1, NRAS, HRAS or BRAF aberrations (ADC or NOS NSCLC)

AKT mutation & no KRAS, NF1, NRAS, HRAS or BRAF aberrations (NSCLC)

    F4 SCC PTEN loss or PTEN mutation & no KRAS, NF1, NRAS, HRAS or BRAF aberrations
G Osimertinib – EGFR mutation positive T790M+ Inhibitor G1 NSCLC EGFR mutation & T790M mutation
H Sitravatinib – VEGFR inhibitor H1 NSCLC RET rearrangements
NA Durvalumab – PD-L1 Inhibitor NA1 NSCLC No actionable genetic change for other trial arms