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.
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
Inclusion Criteria:
- Multi-region sequencing data of the primary tumour available. Non-TRACERx patients
must have two tissue/DNA samples of their disease. Non-TRACERx patients may be
recruited to ARM1 pending UCL GCLP MiSeq or equivalent NGS panel if EGFR sensitising
mutations and ALK fusions have been excluded (according to local testing procedures).
Patients with confirmed ALK aberration by local testing are eligible for ARM 3
providing they have two tissue/DNA samples of their Disease. Central testing for ALK
will be performed separately. Patients with a confirmed BRAFV600 mutation by local
testing or other non TRACERx NGS panel are eligible for ARM2, providing they have two
tissue/DNA samples of their Disease. Central testing for BRAFV600 will be performed
separately. Patients with squamous cell carcinoma do not require local testing for
EGFR sensitising mutations and ALK fusions prior to inclusion for the trial.
- 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 tissue sample' 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. 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
- ECOG PS 0-1 for MPDL3280A in combination with chemotherapy
- ECOG PS 0-2 for MPDL3280A monotherapy.
- Ability to avoid ibuprofen 2 days before, the day of, and 2 days following
administration of Pemetrexed (combination therapy involving pemetrexed only)
- Ability to take folic acid, Vitamin B12, and dexamethasone according to protocol
(combination therapy involving pemetrexed only):
- Arm 2: Presence of BRAFV600 mutation
- ECOG PS 0-2 for arm 2
- Arm 3: Presence of ALK/RET gene fusion and ALK IHC+/RET FISH
- ECOG PS 0-2 for arm 3
- Arm 4: Presence of HER2 amplification and HER2 IHC 3+ only
- ECOG PS 0-1 for arm 4.
- 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 e.g.
standard of care (if agreed following prior discussion with the CI & UCL CTC), or
patients with squamous cell carcinoma
- Written Informed consent for DARWIN2.
- 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 PFS
primary endpoint. 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) ≥1.5x109/L
- Platelets ≥100x109/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 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.
Exclusion Criteria:
- Suitable for radical radiotherapy.
- Palliative radiotherapy within 1 week prior to registration.
- Patients with current or pre-existing interstitial lung disease.
- Patients with active 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 (palliative dose within
7 days), immunotherapy (other than MPDL3280A (Atezolizumab) for Arm 1), biologic
therapy, or major surgery within 14 days prior 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
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.
- Severe symptomatic arrhythmias (excluding atrial fibrillation)
- The following cardiac abnormalities:
- Corrected QT (QTc) interval ≥480 msecs (Arm 2)
- Arm 4: LVEF <50%
- History of acute coronary syndromes (including unstable angina) within the past 6
months
- 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 and atrial fibrillation)
within the past 3 months
- History of myocardial infarction within the past 3 months
- 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
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) 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 CTC.
- The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone)
is allowed.
- Low-dose supplemental corticosteroids for adrenocortical insufficiency are
allowed. Doses of ≤2mg dexamethasone or equivalent (e.g. ≤12.5mg prednisolone)
are allowed.
- Arm 1 (combination therapy involving pemetrexed only): Presence of third space fluid
which cannot be controlled by drainage before or during initiation of pemetrexed
therapy
- Arm 1 (combination therapy involving pemetrexed only):
- Bilirubin >1.5 times the upper limit of normal
- Transaminases >3.0 times the upper limit of normal (ULN), except in presence of
known hepatic metastasis, wherein may be up to 5 times the ULN
- Arm 1: Patients cannot receive MPDL3280A (Atezolizumab) monotherapy if their immediate
previous line of treatment has contained immunotherapy targeting PDL1 or PD1 with or
without chemotherapy, see Appendix 6 (3).
- Arm 1: Patients cannot receive MPDL3280A (Atezolizumab) in combination with
chemotherapy if their immediate previous line of treatment has contained immunotherapy
targeting the PDL1 or PD1 given in combination with chemotherapy, see Appendix 6 (3).
- Arm 2: Previous BRAF inhibitor therapy.
- Arm 2: Patients taking medicines known to prolong QT interval 2 weeks prior to
registration. Use also not permitted while on trial
