Patient case: 64-year-old female with melanoma; genetic feature: BRAF (E586K)

Clinical trial: Deciphering Antitumour Response and Resistance With INtratumour Heterogeneity

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). 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 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.

Detailed 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)
  -  Arm 2: BRAFV600 - vemurafenib
  -  Arm 3: ALK/RET gene rearrangement - alectinib
  -  Arm 4: HER2 Amplification - trastuzumab emtansine

Eligibility: Inclusion Criteria:
  -  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 procedures).
  -  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 PFS endpoint.
  -  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.
  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 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 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 (Arms 2, 3 and 4 only)
  -  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) 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) 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 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

Relevance to patient case: not relevant