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 either 1) without an actionable mutation and PDL1 positive or 2)
without an actionable mutation and PDL1 negative following first line cytotoxic
chemotherapy - MPDL3280A
- 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
- Subjects must be willing to have a biopsy of relapsed disease. Consent will be
obtained through the TRACERx study. (TRACERx patients) or using the DARWIN2 trial
entry biopsy consent form (non-TRACERx patients). Procurement of the biopsy sample is
not necessary at the time of trial registration. However, patients must undergo a
biopsy prior to commencement of any trial treatment.
- Absence of any actionable mutation and PDL1 positive. OR
- Absence of any actionable mutation and PDL1 negative following first line
- Arm2: Presence of BRAFV600 mutation
- Arm3: Presence of ALK/RET gene fusion and ALK IHC+/RET FISH
- Arm4: Presence of HER2 amplification and HER2 IHC2+/3+
- Absence of sensitising EGFR mutation (tested according to local protocol). The only
exception will be patients who progress on DARWIN1 or on EGFR TKi off-study (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.
- No previous chemotherapy the advanced setting (exception if PDL1 negative an received
first line cytotoxic chemotherapy)
- Measurable disease by RECIST v1.1. See Appendix 4
- 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 as defined by the following baseline values:
- Absolute neutrophil count (ANC) ≥1.5x10^9/L
- Platelets ≥100x10^9/L
- Serum bilirubin ≤1.5 x upper limit of normal (ULN). (In case of Gilberts
syndrome discuss with TMG)
- Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) ≤3xULN or ≤5x
ULN if liver metastases are present).
- Creatinine clearance must be >30mL/min calculated or measured.
- Women with child-bearing potential, or men who are able to father a child, must be
willing to practice acceptable 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, immunotherapy,
biologic therapy, or major surgery within 14 days prior registration.
- Treatment with systemic corticosteroids or other systemic immunosuppressive
medications (including but not limited to prednisone, dexamethasone,
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 enroled in the trial after discussion with
CTC. The use of inhaled corticosteroids and mineralocorticoids (e.g.,
fludrocortisone) is allowed. Low-dose supplemental corticosteroids for adrenocortical
insufficiency are allowed).
- 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 be enrolled.
- 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.
- The following cardiac abnormalities:
- Corrected QT (QTc) interval ≥480 msecs
- Arm 4: LVEF <50%
- History of acute coronary syndromes (including unstable angina) within the past
- 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
- Patients taking medicines known to prolong QT interval 2 weeks prior to registration.
Use also not permitted while on trial
- Arm 3 - Use of potent inhibitors and inducers of CYP3A, 2 weeks or 5 half-lives
(whichever is longer) prior to registration. Use also not permitted while on trial.
- Uncontrolled medical conditions (i.e., diabetes mellitus, hypertension, uncorrectable
electrolyte abnormalities (including magnesium 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
- Pregnant, lactating or actively breastfeeding females