Clinical Trials /

Deciphering Antitumour Response and Resistance With INtratumour Heterogeneity

NCT02314481

Description:

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.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Deciphering Antitumour Response and Resistance With INtratumour Heterogeneity
  • Official Title: Deciphering Antitumour Response and Resistance With INtratumour Heterogeneity - DARWIN II

Clinical Trial IDs

  • ORG STUDY ID: 14/0274
  • NCT ID: NCT02314481

Conditions

  • Non-small Cell Lung Cancer

Interventions

DrugSynonymsArms
MPDL3280ANo actionable mutation - MPDL3280A
VemurafenibZelborafBRAF V600 - vemurafenib
AlectinibALK/RET gene rearrangement - alectinib
Trastuzumab emtansineT-DM1, KadcylaHER2 amplification - T-DM1

Purpose

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), The trial will investigate assess if intra-tumour heterogeneity (clonal vs subclonal actionable mutation) is associated with PFS. Patients 1) without an actionable mutation and PDL1 positive or 2) without an actionable mutation and PDL1 negative following first line cytotoxic chemotherapy, will receive MPDL3280A 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 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 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
    

Trial Arms

NameTypeDescriptionInterventions
No actionable mutation - MPDL3280AExperimentalMPDL3280A 1200mg - 3 weekly for 16 cycles
  • MPDL3280A
BRAF V600 - vemurafenibExperimentalVemurafenib 960mg twice daily until PD
  • Vemurafenib
ALK/RET gene rearrangement - alectinibExperimentalAlectinib 600mg twice daily until PD
  • Alectinib
HER2 amplification - T-DM1ExperimentalTrastuzumab emtansine (T-DM1) 3.6mg/kg - 3 weekly until PD
  • Trastuzumab emtansine

Eligibility Criteria

        Inclusion Criteria:

          -  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.

          -  Arm1:

               -  Absence of any actionable mutation and PDL1 positive. OR

               -  Absence of any actionable mutation and PDL1 negative following first line
                  cytotoxic chemotherapy

               -  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.

        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, 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
                  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

          -  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
             protocol.

          -  Pregnant, lactating or actively breastfeeding females
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression free survival (PFS), defined as the period between the date of registration to the date of subsequent progression or death (whichever occurs first).
Time Frame:From date of registration until the date of first documented progression or death (whichever occurs first), assessed up to 84 months
Safety Issue:
Description:

Secondary Outcome Measures

Measure:ORR, Investigator-assessed according to RECISTv1.1 and irRC (Arm 1 only)
Time Frame:From date of registration until last CT scan, assessed up to 84 months
Safety Issue:
Description:
Measure:Time to event outcomes - overall survival
Time Frame:From date of registration until death date, assessed up to 84 months
Safety Issue:
Description:
Measure:Time to event outcomes - progression
Time Frame:From date registration until progression, , assessed up to 84 months
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure:Toxicity, including dose reductions, interruptions, modifications and exposure
Time Frame:From date of regsitration until end of treatment, assessed up to 84 months
Safety Issue:
Description:
Measure:Exploratory assessments include 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.
Time Frame:Assessed at end of trial, at approximately 84 months
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University College, London

Trial Keywords

  • NSCLC
  • Clonal dominance
  • Clonal evolution
  • Intratumour heterogeneity
  • Genomic instability
  • Drug resistance
  • Immunotherapy
  • PDL1
  • BRAF V600
  • ALK
  • RET
  • HER2 amplification
  • MPDL3280A
  • Vemurafenib
  • Alectinib
  • T-DM1
  • Trastuzumab emtansine
  • TRACERX

Last Updated

May 16, 2017