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Deciphering Antitumour Response and Resistance With INtratumour Heterogeneity (DARWINII)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02314481
Recruitment Status : Recruiting
First Posted : December 11, 2014
Last Update Posted : June 11, 2020
Sponsor:
Collaborator:
Hoffmann-La Roche
Information provided by (Responsible Party):
University College, London

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 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.


Condition or disease Intervention/treatment Phase
Non-small Cell Lung Cancer Drug: MPDL3280A Drug: Vemurafenib Drug: Alectinib Drug: Trastuzumab emtansine Phase 2

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) monotherapy or in combination with chemptherapy
  • Arm 2: BRAFV600 - vemurafenib
  • Arm 3: ALK/RET gene rearrangement - alectinib
  • Arm 4: HER2 Amplification - trastuzumab emtansine

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 119 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Deciphering Antitumour Response and Resistance With INtratumour Heterogeneity - DARWINII
Actual Study Start Date : May 12, 2017
Estimated Primary Completion Date : November 2024
Estimated Study Completion Date : November 2025

Resource links provided by the National Library of Medicine

Drug Information available for: Vemurafenib

Arm Intervention/treatment
Experimental: No actionable mutation - MPDL3280A

MPDL3280A 1200mg IV infusion - 3 weekly for 24 cycles monotherapy

Or in combination with chemotherapy:

  • For non-squamous: Cisplatin or Carboplatin plus pemetrexed & MPDL3280A - 3 weekly for 4 cycles followed by MPDL3280A and pemetrexed 3 weekly for 20 cycles
  • For squamous: Carboplatin plus paclitaxel & MPDL3280A - 3 weekly for 4 cycles followed by MPDL3280A 3 weekly for 20 cycles

Until progression, unacceptable toxicity or completion of a total of 24 cycles.

Drug: MPDL3280A
Intravenous (IV) infusion, as monotherapy of in combination with chemotherapy
Other Name: Atezolizumab

Experimental: BRAF V600 - vemurafenib
Vemurafenib 960mg twice daily until PD
Drug: Vemurafenib
Film coated tablet
Other Name: Zelboraf

Experimental: ALK/RET gene rearrangement - alectinib
Alectinib 600mg twice daily until PD
Drug: Alectinib
capsule
Other Name: Alecensa

Experimental: HER2 amplification - T-DM1
Trastuzumab emtansine (T-DM1) 3.6mg/kg - 3 weekly until PD IV infusion
Drug: Trastuzumab emtansine
Powder for concentrate for solution for infusion
Other Names:
  • T-DM1
  • Kadcyla




Primary Outcome Measures :
  1. 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)


Secondary Outcome Measures :
  1. 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)

  2. Overall survival [ Time Frame: From date of registration until death date, assessed up to 84 months ]
    Time to event outcomes

  3. ProgressionT [ Time Frame: From date registration until progression, , assessed up to 84 months ]
    ime to event outcomes

  4. 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

  5. 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

  6. 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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02314481


Contacts
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Contact: Kitty Chan 020 7679 9237 ctc.darwin2@ucl.ac.uk
Contact: Abby Sharp 020 7679 9688 ctc.darwin2@ucl.ac.uk

Locations
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United Kingdom
Univeristy College London Hospital Recruiting
London, United Kingdom
Contact: Amy Smith         
Sponsors and Collaborators
University College, London
Hoffmann-La Roche
Investigators
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Principal Investigator: Charles Swanton UCL
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Responsible Party: University College, London
ClinicalTrials.gov Identifier: NCT02314481    
Other Study ID Numbers: 14/0274
First Posted: December 11, 2014    Key Record Dates
Last Update Posted: June 11, 2020
Last Verified: March 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University College, London:
Alectinib
NSCLC
Clonal dominance
Clonal evolution
Intratumour heterogeneity
Genomic instability
Drug resistance
Immunotherapy
PDL1
BRAF V600
ALK
RET
HER2 amplification
MPDL3280A
Vemurafenib
T-DM1
Trastuzumab emtansine
TRACERX
Additional relevant MeSH terms:
Layout table for MeSH terms
Carcinoma, Non-Small-Cell Lung
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Trastuzumab
Ado-trastuzumab emtansine
Atezolizumab
Vemurafenib
Maytansine
Antineoplastic Agents, Immunological
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators