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Deciphering Antitumour Response and Resistance With INtratumour Heterogeneity (DARWIN II)

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ClinicalTrials.gov Identifier: NCT02314481
Recruitment Status : Recruiting
First Posted : December 11, 2014
Last Update Posted : February 1, 2019
Sponsor:
Collaborator:
Hoffmann-La Roche
Information provided by (Responsible Party):
University College, London

Tracking Information
First Submitted Date  ICMJE December 5, 2014
First Posted Date  ICMJE December 11, 2014
Last Update Posted Date February 1, 2019
Actual Study Start Date  ICMJE May 12, 2017
Estimated Primary Completion Date January 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 30, 2018)
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 ]
Defined as the period between the date of registration to the date of subsequent progression or death (whichever occurs first)
Original Primary Outcome Measures  ICMJE
 (submitted: December 8, 2014)
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 ]
Change History Complete list of historical versions of study NCT02314481 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 30, 2018)
  • Objective response rate [ Time Frame: From date of registration until last CT scan, assessed up to 84 months ]
    Investigator-assessed according to RECISTv1.1 and irRC (Arm 1 only)
  • Overall survival [ Time Frame: From date of registration until death date, assessed up to 84 months ]
    Time to event outcomes
  • ProgressionT [ Time Frame: From date registration until progression, , assessed up to 84 months ]
    ime to event outcomes
  • 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 ]
    Period between first complete response or partial response until the first date recurrence or progressive disease, assessed up to 84 months
  • Toxicity - Dose reductions, interruptions, modifications and exposure [ Time Frame: From date of regsitration until end of treatment, assessed up to 84 months ]
    Dose reductions, interruptions, modifications and exposure
  • Exploratory assessments [ Time Frame: Assessed at end of trial, at approximately 84 months ]
    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
Original Secondary Outcome Measures  ICMJE
 (submitted: December 8, 2014)
  • 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 ]
  • Time to event outcomes - overall survival [ Time Frame: From date of registration until death date, assessed up to 84 months ]
  • Time to event outcomes - progression [ Time Frame: From date registration until progression, , assessed up to 84 months ]
  • 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 ]
  • Toxicity, including dose reductions, interruptions, modifications and exposure [ Time Frame: From date of regsitration until end of treatment, assessed up to 84 months ]
  • 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 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Deciphering Antitumour Response and Resistance With INtratumour Heterogeneity
Official Title  ICMJE Deciphering Antitumour Response and Resistance With INtratumour Heterogeneity - DARWIN II
Brief 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
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Non-small Cell Lung Cancer
Intervention  ICMJE
  • Drug: MPDL3280A
    Intravenous (IV) infusion
    Other Name: Atezolizumab
  • Drug: Vemurafenib
    Film coated tablet
    Other Name: Zelboraf
  • Drug: Alectinib
    capsule
    Other Name: Alecensa
  • Drug: Trastuzumab emtansine
    Powder for concentrate for solution for infusion
    Other Names:
    • T-DM1
    • Kadcyla
Study Arms  ICMJE
  • Experimental: No actionable mutation - MPDL3280A
    MPDL3280A 1200mg - 3 weekly for 24 cycles IV infusion
    Intervention: Drug: MPDL3280A
  • Experimental: BRAF V600 - vemurafenib
    Vemurafenib 960mg twice daily until PD
    Intervention: Drug: Vemurafenib
  • Experimental: ALK/RET gene rearrangement - alectinib
    Alectinib 600mg twice daily until PD
    Intervention: Drug: Alectinib
  • Experimental: HER2 amplification - T-DM1
    Trastuzumab emtansine (T-DM1) 3.6mg/kg - 3 weekly until PD IV infusion
    Intervention: Drug: Trastuzumab emtansine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 8, 2016)
119
Original Estimated Enrollment  ICMJE
 (submitted: December 8, 2014)
157
Estimated Study Completion Date  ICMJE January 2023
Estimated Primary Completion Date January 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Kitty Chan 020 7679 9237 ctc.darwin2@ucl.ac.uk
Contact: Yenting Ngai 020 7679 9747 ctc.darwin2@ucl.ac.uk
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02314481
Other Study ID Numbers  ICMJE 14/0274
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University College, London
Study Sponsor  ICMJE University College, London
Collaborators  ICMJE Hoffmann-La Roche
Investigators  ICMJE
Principal Investigator: Charles Swanton UCL
PRS Account University College, London
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP