Deciphering Antitumour Response and Resistance With INtratumour Heterogeneity

NCT02314481 | Completed Phase 2 DMC

• 1 other identifier: 14/0274
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

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). . 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.

Conditions

Non-small Cell Lung Cancer

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

Outcome Measures

Primary Outcomes (2)

• Progression free survival (PFS)

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

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

• Overall survival

  Time to event outcomes

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

Secondary Outcomes (5)

• Objective response rate

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

• Progression

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

• Duration of response

  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

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

• Exploratory assessments

  Assessed at end of trial, at approximately 84 months

Study Arms (4)

No actionable mutation - MPDL3280A

EXPERIMENTAL

MPDL3280A 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.

Drug: MPDL3280A

BRAF V600 - vemurafenib

EXPERIMENTAL

Vemurafenib 960mg twice daily until PD

Drug: Vemurafenib

ALK/RET gene rearrangement - alectinib

EXPERIMENTAL

Alectinib 600mg twice daily until PD

Drug: Alectinib

HER2 amplification - T-DM1

EXPERIMENTAL

Trastuzumab emtansine (T-DM1) 3.6mg/kg - 3 weekly until PD IV infusion

Drug: Trastuzumab emtansine

Interventions

MPDL3280A DRUG

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

Also known as: Atezolizumab

No actionable mutation - MPDL3280A

Vemurafenib DRUG

Film coated tablet

Also known as: Zelboraf

BRAF V600 - vemurafenib

Alectinib DRUG

capsule

Also known as: Alecensa

ALK/RET gene rearrangement - alectinib

Trastuzumab emtansine DRUG

Powder for concentrate for solution for infusion

Also known as: T-DM1, Kadcyla

HER2 amplification - T-DM1

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• TRACERx Patients
• Multi-region sequencing data of the primary tumour available.
• 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
• 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):

You may not qualify if:

• 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

Sponsors & Collaborators

• University College, London: lead
• Hoffmann-La Roche: collaborator

Study Sites (1)

Univeristy College London Hospital

London, United Kingdom

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Genomic Instability

Interventions

atezolizumab; Vemurafenib; alectinib; Ado-Trastuzumab Emtansine

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Maytansine; Macrolides; Lactones; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Trastuzumab; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Charles Swanton

  UCL

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 5, 2014
• First Posted: December 11, 2014
• Study Start: May 12, 2017
• Primary Completion: November 30, 2025
• Study Completion: November 30, 2025
• Last Updated: May 4, 2026

Record last verified: 2026-04

Locations

GB (1)