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
MPDL3280AAtezolizumabNo actionable mutation - MPDL3280A
VemurafenibZelborafBRAF V600 - vemurafenib
AlectinibAlecensaALK/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). 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
    

Trial Arms

NameTypeDescriptionInterventions
No actionable mutation - MPDL3280AExperimentalMPDL3280A 1200mg - 3 weekly for 24 cycles IV infusion
  • 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 IV infusion
  • Trastuzumab emtansine

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression free survival (PFS)
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:Defined as the period between the date of registration to the date of subsequent progression or death (whichever occurs first)

Secondary Outcome Measures

Measure:Objective response rate
Time Frame:From date of registration until last CT scan, assessed up to 84 months
Safety Issue:
Description:Investigator-assessed according to RECISTv1.1 and irRC (Arm 1 only)
Measure:Overall survival
Time Frame:From date of registration until death date, assessed up to 84 months
Safety Issue:
Description:Time to event outcomes
Measure:ProgressionT
Time Frame:From date registration until progression, , assessed up to 84 months
Safety Issue:
Description:ime to event outcomes
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:Period between first complete response or partial response until the first date recurrence or progressive disease, assessed up to 84 months
Measure:Toxicity - Dose reductions, interruptions, modifications and exposure
Time Frame:From date of regsitration until end of treatment, assessed up to 84 months
Safety Issue:
Description:Dose reductions, interruptions, modifications and exposure
Measure:Exploratory assessments
Time Frame:Assessed at end of trial, at approximately 84 months
Safety Issue:
Description: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

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

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