Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Afatinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Afatinib, tablet, 40mg, 30mg, 20mg, OD, taken until progression, unacceptable toxicity, intercurrent illness, patient/clinician decision

40mg, 30mg, 20mg, OD, taken until progression, unacceptable toxicity, intercurrent illness, patient/clinician decision.

EGFR positive mutation patients only: dose escalation to a maximum of 50 mg/day may be considered in patients who tolerate a 40 mg/day dose (i.e. absence of diarrhoea, skin rash, stomatitis, and other adverse reactions with CTCAE Grade \> 1) in the first 3 weeks. The dose should not be escalated in any patients with a prior dose reduction. The maximum daily dose for EGFR mutation positive patients is 50 mg.

Martin Forster

To assess if targeting activating EGFR and HER2 mutations in Non-Small Cell Lung Cancer (NSCLC) is more effective when these mutations are truncal dominant mutations (≥50%), as opposed to non-dominant (≥5 to \<50%) or low frequency mutations (\<5%).

This trial will be available to patients registered to the TRACERx study (NCT01888601), or non-TRACERx patients who have two archival tissue/DNA samples who are willing to have a biopsy of their relapsed disease.

Increasing evidence suggests that clonal dominance of the drug target should be considered when stratifying therapeutics in solid tumours. It is likely that intratumour heterogeneity and cancer subclonal diversity may contribute to the high failure rate of oncology drugs relative to other medical specialties where drugs are applied to stable somatic genomes rather than unstable genomes found in cancer populations. In addition, increasing evidence in NSCLC and other solid tumours suggests that the selection of resistant subclones during the disease course is responsible for the acquisition of drug resistance and therapeutic failure. Finally, spatial separation of cancer subclones within the same tumour is likely to contribute to the difficulties associated with cancer biomarker validation.

"Actionable mutations" may not be optimally actionable if they are present at one site of disease or within a minority tumour subclone. Such minority subclones are likely to contribute to intratumour heterogeneity and discordant results when interpreting multiple biopsies from the same tumour. Our work in NSCLC, renal cancers and glioblastomas is demonstrating that such subclones, carrying potentially targetable events, may be spatially separated within the same tumour or between primary and metastatic sites. This has been demonstrated in the context of EGFR somatic mutations that may be heterogeneous in up to 25-30% of patients, present at one site of disease but not another. The impact of such actionable driver heterogeneity on treatment response, drug resistance and outcome is currently unclear and is the subject of investigation within this protocol; DARWIN1 will assess the impact of EGFR activating mutation and HER2 mutation heterogeneity on progression free survival outcomes in advanced NSCLC treated with the EGFR tyrosine kinase inhibitor, afatinib.

Deciphering Afatinib Response and Resistance With INtratumour Heterogeneity

From date of registration until the date of the last documented progression or date of death from any cause, whichever comes first, assessed up to 60 months.

From date of registration until the date of death from any cause assessed up to 60 months.

From date of registration until the date of the last documented progression assessed up to 60 month.

From date of registration until the date of the last documented response assessed up to 60 months.

Adverse events, including any dose reductions, interruptions and modifications from date of registration up until 60 months.

Boehringer Ingelheim

University College, London

Symptoms and General Pathology

Rare Diseases

Genomic Instability

Myotonic Dystrophy Type 1

Pharmaceutical Solutions

Anti-Arrhythmia Agents

Vasodilator Agents

Analgesics

Trastuzumab

Paclitaxel

Carboplatin

Pemetrexed

Albumin-Bound Paclitaxel

Cisplatin

Immunomodulating Agents

Atezolizumab

Alectinib

Ado-Trastuzumab Emtansine

Vemurafenib

Adenosine

Maytansine

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Tubulin Modulators

Antimitotic Agents

Immunotoxins

Immunoconjugates

Immunologic Factors

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.

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

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

MPDL3280A

Powder for concentrate for solution for infusion

Trastuzumab emtansine

Charles Swanton

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.

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.

Deciphering Antitumour Response and Resistance With INtratumour Heterogeneity

Deciphering Antitumour Response and Resistance With INtratumour Heterogeneity - DARWINII

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

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

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

Dose reductions, interruptions, modifications and exposure

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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Deciphering Afatinib Response and Resistance With INtratumour Heterogeneity	NCT02183883	Non-small Cell ...	Afatinib	18 Years -	University College, London
Deciphering Antitumour Response and Resistance With INtratumour Heterogeneity	NCT02314481	Non-small Cell ...	MPDL3280A Vemurafenib Alectinib Trastuzumab emt...	18 Years -	University College, London

Spots Global Cancer Trial Database for clonal dominance