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 1) without an actionable mutation will receive MPDL3280A (atezolizumab), a
monoclonal antibody targeting anti-PDL1.
Patients with BRAFV600 mutations, HER2 Amplification, ALK/RET gene rearrangements will be
enrolled into arms treating with vemurafenib, trastuzumab emtansine and alectinib
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.
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)
- Arm 2: BRAFV600 - vemurafenib
- Arm 3: ALK/RET gene rearrangement - alectinib
- Arm 4: HER2 Amplification - trastuzumab emtansine
- Multi-region sequencing data of the primary tumour available. Non-TRACERx patients
must have at least two tissue/DNA samples of their disease available. Non-TRACERx
patients may be recruited pending UCL GCLP MiSeq or equivalent NGS panel if EGFR
sensitising mutations and ALK fusions have been excluded (according to local testing
- Subjects must be willing to have a biopsy of relapsed disease. Consent for this biopsy
will be obtained within the TRACERx study (TRACERx patients) or using the DARWIN2
'trial entry tissue sample' consent form (non-TRACERx patients). Procurement of the
biopsy sample is not necessary at the time of registration to the DARWIN2 trial.
However, patients must undergo a biopsy prior to commencement of any trial treatment
within DARWIN2. If a patient does not have a biopsy at recurrence then in exceptional
circumstances the patient may still be eligible to join DARWIN2. Site must contact the
CTC to discuss. There will be no other exceptions to the eligibility requirements at
the time of registration
- Arm 1: Absence of any actionable mutation
- Arm 2: Presence of BRAFV600 mutation
- Arm 3: Presence of ALK/RET gene fusion and ALK IHC+
- Arm 4: Presence of HER2 amplification and HER2 IHC 3+ only.
- Absence of sensitizing EGFR mutation (tested according to local protocol). Exception
will be made for patients with sensitizing EGFR mutations who have radiological
defined progression following treatment with an EGFR TKi during DARWIN1 or off study
e.g. standard of care (if agreed following prior discussion with the CI, UCL CTC)
- Written Informed consent for DARWIN2.
- ECOG PS 0-2 for arms 1-3, ECOG PS 0-1 for arm 4.
- Measurable disease by RECIST v1.1. Patients without measurable disease may be eligible
following discussion with the CI and UCL CTC but will not count towards the primary
- At least 18 years of age.
- Anticipated life expectancy of at least three months.
- Able to swallow and retain oral medication for arms 2 & 3.
- Adequate organ function
- Women with child-bearing potential, or men who are able to father a child, must be
willing to practice highly effective methods of birth control during the trial and for
7 months after the end of treatment.
- Women of childbearing potential must have a negative pregnancy test within 14 days
before the first dose of trial medication.
- Suitable for radical radiotherapy.
- Palliative radiotherapy within 1 week prior to registration.
- Patients with current or pre-existing interstitial lung disease
- Patients with pre-existing autoimmune disease (some exceptions allowed).
- Known hypersensitivity to study IMP or to any of the excipients
- Inability to understand or to comply with the requirements of the trial, trial
protocol or to provide informed consent.
- Anti-cancer therapy including chemotherapy, radiation therapy (7 days if palliative
radiotherapy), immunotherapy (except for atezolizumab), biologic therapy, or major
surgery within 14 days prior to registration.
- Known human immunodeficiency virus (HIV), Hepatitis B Virus (HBV), Hepatitis C Virus
(HCV) or syphilis infection. Subjects with evidence of hepatitis B virus clearance may
- History of other malignancy; Exception: (a) Subjects who have been successfully
treated and are disease-free for 3 years, (b) a history of completely resected
non-melanoma skin cancer, (c) successfully treated in situ carcinoma, (d) CLL in
stable remission, or (e) indolent prostate cancer requiring no or only anti-hormonal
therapy with histologically confirmed tumour lesions that can be clearly
differentiated from lung cancer target and non-target lesions are eligible.
- Patients with symptomatic brain metastases.
- Severe symptomatic arrhythmias (excluding atrial fibrillation)
- The following cardiac abnormalities:
- Corrected QT (QTc) interval ≥480 msecs (Arms 2, 3 and 4 only)
- Arm 4: LVEF <50%
- History of acute coronary syndromes (including unstable angina) within the past 6
- Coronary angioplasty, or stenting within the past 24 weeks
- Class III, or IV heart failure as defined by the New York Heart Association
(NYHA) functional classification system
- History of known arrhythmias (except sinus arrhythmia) within the past 6 months
- History of myocardial infarction within the past 6 months
- Uncontrolled medical conditions (i.e., diabetes mellitus, hypertension etc),
psychological, familial, sociological, or geographical conditions that do not permit
compliance with the protocol; or unwillingness or inability to follow the procedures
required in the protocol.
- Pregnant, lactating or actively breastfeeding females.
- Arm 1: Treatment with systemic corticosteroids or other systemic immunosuppressive
medications (including but not limited to prednisone, dexamethasone (>2mg),
cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti−tumor necrosis
factor (TNF) agents) within 2 weeks prior to registration, or anticipated requirement
for systemic immunosuppressive medications during the trial.
- Patients who have received acute, low-dose, systemic immunosuppressant
medications (e.g. a one-time dose of dexamethasone for nausea) may be enrolled in
the trial after discussion with UCL CTC.
- The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone)
- Low-dose supplemental corticosteroids for adrenocortical insufficiency are
- Doses of ≤2mg dexamethasone or equivalent (e.g. ≤12.5mg prednisolone) are
- Arm 2: Previous BRAF inhibitor therapy
- Arms 2, 3 and 4: Patients taking medicines known to prolong QT interval 2 weeks prior
to registration. Use also not permitted while on trial