Deciphering Antitumour Response and Resistance With INtratumour Heterogeneity (DARWINII)
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|ClinicalTrials.gov Identifier: NCT02314481|
Recruitment Status : Recruiting
First Posted : December 11, 2014
Last Update Posted : June 11, 2020
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). Patients must have at least two tissue/DNA samples of their disease available for sequencing.
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.
|Condition or disease||Intervention/treatment||Phase|
|Non-small Cell Lung Cancer||Drug: MPDL3280A Drug: Vemurafenib Drug: Alectinib Drug: Trastuzumab emtansine||Phase 2|
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
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||119 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Deciphering Antitumour Response and Resistance With INtratumour Heterogeneity - DARWINII|
|Actual Study Start Date :||May 12, 2017|
|Estimated Primary Completion Date :||November 2024|
|Estimated Study Completion Date :||November 2025|
Experimental: No actionable mutation - MPDL3280A
MPDL3280A 1200mg IV infusion - 3 weekly for 24 cycles monotherapy
Or in combination with chemotherapy:
Until progression, unacceptable toxicity or completion of a total of 24 cycles.
Intravenous (IV) infusion, as monotherapy of in combination with chemotherapy
Other Name: Atezolizumab
Experimental: BRAF V600 - vemurafenib
Vemurafenib 960mg twice daily until PD
Film coated tablet
Other Name: Zelboraf
Experimental: ALK/RET gene rearrangement - alectinib
Alectinib 600mg twice daily until PD
Other Name: Alecensa
Experimental: HER2 amplification - T-DM1
Trastuzumab emtansine (T-DM1) 3.6mg/kg - 3 weekly until PD IV infusion
Drug: Trastuzumab emtansine
Powder for concentrate for solution for infusion
- Progression free survival (PFS) [ Time Frame: From date of registration until the date of first documented progression or death (whichever occurs first), assessed up to 84 months ]Defined as the period between the date of registration to the date of subsequent progression or death (whichever occurs first)
- Objective response rate [ Time Frame: From date of registration until last CT scan, assessed up to 84 months ]Investigator-assessed according to RECISTv1.1 and irRC (Arm 1 only)
- Overall survival [ Time Frame: From date of registration until death date, assessed up to 84 months ]Time to event outcomes
- ProgressionT [ Time Frame: From date registration until progression, , assessed up to 84 months ]ime to event outcomes
- Duration of response [ Time Frame: Period between first complete response or partial response until the first date recurrence or progressive disease, assessed up to 84 months ]Period between first complete response or partial response until the first date recurrence or progressive disease, assessed up to 84 months
- Toxicity - Dose reductions, interruptions, modifications and exposure [ Time Frame: From date of regsitration until end of treatment, assessed up to 84 months ]Dose reductions, interruptions, modifications and exposure
- Exploratory assessments [ Time Frame: Assessed at end of trial, at approximately 84 months ]Interrogation of recurrence and progression biopsies to decipher the molecular basis for resistance in combination with analyses of CTCs/cfDNA as well as CT imaging heterogeneity analyses
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02314481
|Contact: Kitty Chan||020 7679 email@example.com|
|Contact: Abby Sharp||020 7679 firstname.lastname@example.org|
|Univeristy College London Hospital||Recruiting|
|London, United Kingdom|
|Contact: Amy Smith|
|Principal Investigator:||Charles Swanton||UCL|