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Non-small Cell Lung CancerPhase 2DARWINIINCT02314481

Deciphering Antitumour Response and Resistance With INtratumour Heterogeneity

A Phase 2 study testing MPDL3280A, Vemurafenib and Alectinib in people with Non-small Cell Lung Cancer, run by University College, London at 1 site in United Kingdom.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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). . The trial will investigate assess if intra-tumour heterogeneity (clonal vs subclonal actionable mutation) is associated with PFS. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Non-small Cell Lung Cancer
What is being tested?
MPDL3280A, Vemurafenib and Alectinib
Could I receive a placebo?
No, everyone receives an active treatment
How many people
50 participants
Where
1 siteUnited Kingdom
Study dates
12 May 2017to 30 Nov 2025
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • TRACERx Patients
  • Multi-region sequencing data of the primary tumour available.
  • TRACERx patients should be approached for a biopsy of the active locally advanced or metastatic disease but this is not mandated for DARWIN2 trial inclusion. Consent for this biopsy will be obtained within the TRACERx study.
  • Non-TRACERx patients
  • Minimum requirement:
  • Fresh frozen biopsy of active locally advanced or metastatic disease OR at least two FFPE regions from primary tumour available
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  • Optimal Tissue availability:
  • Multi-region tissue of the primary tumour available (FFPE or fresh frozen) AND a fresh frozen biopsy of active locally advanced or metastatic disease
  • OR One archival biopsy tissue sample (FFPE or fresh frozen)/pre-extracted DNA sample AND one fresh frozen biopsy of active locally advanced or metastatic disease
  • OR Two fresh biopsies of active locally advanced or metastatic disease that are spatially separated e.g. one lymph node biopsy AND one lung biopsy.
  • Consent for the biopsy(ies) of the active locally advanced or metastatic disease for non-TRACERx patients must be taken using the DARWIN2 'trial entry tissue sample' consent form.
  • 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
  • Absence of ALK fusions (tested according to local protocol) except for patient being considered for arm 3. Patients with squamous cell carcinoma do not require local testing for EGFR sensitising mutations and ALK fusions prior to inclusion for the trial.
  • 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 registration.

Who cannot join

  • 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.
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  • 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

Trial locations and contacts

1 site in 1 country.

United Kingdom1 site

  • Univeristy College London Hospital

    London

Other trials in United Kingdom

About this study

Official title: Deciphering Antitumour Response and Resistance With INtratumour Heterogeneity - DARWINII

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.

Read more

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.

Read the 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

Arms 2-4 are closed to further recruitment as of 25th May 2021.

Being tested
MPDL3280A, Vemurafenib, Alectinib, Trastuzumab emtansine
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
Medical subject headings
Carcinoma, Non-Small-Cell Lung, Genomic Instability

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • MPDL3280ADrug

    Also called Atezolizumab

    Intravenous (IV) infusion, as monotherapy of in combination with chemotherapy

  • VemurafenibDrug

    Also called Zelboraf

    Film coated tablet

  • AlectinibDrug

    Also called Alecensa

    capsule

  • Trastuzumab emtansineDrug

    Also called T-DM1, Kadcyla

    Powder for concentrate for solution for infusion

Study groups in NCT02314481
Study groupRoleWhat they receive
No actionable mutation - MPDL3280AExperimentalMPDL3280A 1200mg IV infusion - 3 weekly until progression or unacceptable toxicity. 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 until progression or unacceptable toxicity or completion of a total of 35 cycles. MPDL3280A will then continue 3 weekly until progression or unacceptable toxicity. * For squamous: Carboplatin plus paclitaxel \& MPDL3280A - 3 weekly for 4 cycles followed by MPDL3280A 3 weekly until progression or unacceptable toxicity.
Receives: Drug: MPDL3280A
BRAF V600 - vemurafenibExperimentalVemurafenib 960mg twice daily until PD
Receives: Drug: Vemurafenib
ALK/RET gene rearrangement - alectinibExperimentalAlectinib 600mg twice daily until PD
Receives: Drug: Alectinib
HER2 amplification - T-DM1ExperimentalTrastuzumab emtansine (T-DM1) 3.6mg/kg - 3 weekly until PD IV infusion
Receives: Drug: Trastuzumab emtansine

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Progression free survival (PFS)

    Defined as the period between the date of registration to the date of subsequent progression or death (whichever occurs first)

    Measured: From date of registration until the date of first documented progression or death (whichever occurs first), assessed up to 84 months

  2. Overall survival

    Time to event outcomes

    Measured: From date of registration until death date, assessed up to 84 months

Secondary outcomes (5)

  1. Objective response rate

    Investigator-assessed according to RECISTv1.1 and irRC (Arm 1 only)

    Measured: From date of registration until last CT scan, assessed up to 84 months

  2. Progression

    ime to event outcomes

    Measured: From date registration until progression, , assessed up to 84 months

  3. Duration of response

    Period between first complete response or partial response until the first date recurrence or progressive disease, assessed up to 84 months

    Measured: Period between first complete response or partial response until the first date recurrence or progressive disease, assessed up to 84 months

  4. Toxicity - Dose reductions, interruptions, modifications and exposure

    Dose reductions, interruptions, modifications and exposure

    Measured: From date of regsitration until end of treatment, assessed up to 84 months

  5. Exploratory assessments

    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

    Measured: Assessed at end of trial, at approximately 84 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted11 Dec 2014 (estimated)
  2. Study start12 May 2017
  3. Primary completion30 Nov 2025
  4. Study completion30 Nov 2025

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
50 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02314481
Sponsor's protocol ID
14/0274
Acronym
DARWINII
Status last verified
Apr 2026
First submitted
5 Dec 2014
Last updated
4 May 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing MPDL3280A, Vemurafenib and Alectinib in people with Non-small Cell Lung Cancer, run by University College, London at 1 site in United Kingdom.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 37 inclusion and 33 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 4 May 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome 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). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02314481.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 May 2026.

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