Deciphering Antitumour Response and Resistance With INtratumour Heterogeneity — DARWINII  

Non-small Cell Lung Cancer Clinical Trial

Official title: Deciphering Antitumour Response and Resistance With INtratumour Heterogeneity - DARWINII

Status Active, not recruiting

Clinical Trial Summary

DARWIN II is a multi-arm non-randomised phase II trial, Eligible patient will be those who relapse with NSCLC (clinical trials.gov ref. NCT02183883). .

The trial will investigate assess if intra-tumour heterogeneity (clonal vs subclonal actionable mutation) is associated with PFS.

Patients without an actionable mutation will receive MPDL3280A (atezolizumab), a monoclonal antibody targeting anti-PDL1, as monotherapy or in combination with chemotherapy, The options for combination therapy will vary depending on the histology of the NSCLC (i.e. non-squamous or squamous).

Patients with BRAFV600 mutations, HER2 Amplification, ALK/RET gene rearrangements will be enrolled into arms treating with vemurafenib, trastuzumab emtansine and alectinib respectively.

DARWIN II will include extensive exploratory biomarker analysis to investigate a number of genomic and immune markers that may predict response to MPDL3280A (atezolizumab) and help guide future clinical trial design.

Clinical Trial Description

DARWIN II is an exploratory phase II study examining the role of intra-tumour heterogeneity and predicted neo-antigens on the anti-tumour activity of anti-PDL1 immunotherapy.

It will examine how clonal dominance and intratumour heterogeneity influence outcomes after treatment, offering a unique opportunity to decipher mechanisms of resistance to immunotherapy with anti-PDL1. These data will help improve future study design by developing greater understanding of patient selection for immunotherapies in patients with NSCLC. The relationship between intratumour heterogeneity and cfDNA/CTCs will also be explored in DARWIN II, which may develop tools for patient selection and monitoring to be examined further in future studies. Results from DARWIN II will help to identify a biomarker for anti-PD-L1 therapy which could be used for patient stratification in future phase III trials of molecules targeting this T-cell inhibitory checkpoint. DARWIN II will also provide preliminary data on efficacy of MPDL3280A, which could be used to design randomised studies.

This is a multicentre non-randomised phase II study based on patients with relapsed NSCLC, who have provided a biopsy sample at the time of relapse.

The study arms:

• Arm 1: Patients without an actionable mutation - MPDL3280A (atezolizumab) monotherapy or in combination with chemptherapy

• Arm 2: BRAFV600 - vemurafenib

• Arm 3: ALK/RET gene rearrangement - alectinib

• Arm 4: HER2 Amplification - trastuzumab emtansine

Arms 2-4 are closed to further recruitment as of 25th May 2021. ;

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Non-small Cell Lung Cancer

• NCT number: NCT02314481
• Study type: Interventional
• Source: University College, London
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: May 12, 2017
• Completion date: May 2026