Clinical Trials /

Osimertinib and Bevacizumab Versus Osimertinib Alone as Second-line Treatment in Stage IIIb-IVb NSCLC With Confirmed EGFRm and T790M (BOOSTER)

NCT03133546

Description:

BOOSTER is a randomised, controlled, phase II trial comparing osimertinib and bevacizumab versus osimertinib alone as second-line treatment in patients with stage IIIb-IVb non-small cell lung carcinoma (NSCLC) harbouring activating EGFR (exon 19 deletion or L858R) and T790M resistance mutation.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
  • Squamous Cell Lung Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Osimertinib and Bevacizumab Versus Osimertinib Alone as Second-line Treatment in Stage IIIb-IVb NSCLC With Confirmed EGFRm and T790M (BOOSTER)
  • Official Title: A Randomised Phase II Trial of Osimertinib and Bevacizumab Versus Osimertinib Alone as Second-line Treatment in Stage IIIb-IVb NSCLC With Confirmed EGFRm and T790M

Clinical Trial IDs

  • ORG STUDY ID: ETOP 10-16
  • SECONDARY ID: 2016-002029-12
  • SECONDARY ID: ESR-15-11666
  • SECONDARY ID: MO39447
  • NCT ID: NCT03133546

Conditions

  • Non Small Cell Lung Cancer Metastatic

Interventions

DrugSynonymsArms
OsimertinibTagrissoOsimertinib plus Bevacizumab
BevacizumabAvastinOsimertinib plus Bevacizumab

Purpose

BOOSTER is a randomised, controlled, phase II trial comparing osimertinib and bevacizumab versus osimertinib alone as second-line treatment in patients with stage IIIb-IVb non-small cell lung carcinoma (NSCLC) harbouring activating EGFR (exon 19 deletion or L858R) and T790M resistance mutation.

Detailed Description

      Lung cancer has been the most common carcinoma in the world for several decades. Non-small
      cell lung carcinoma (NSCLC) represents approximately 80-85% of all lung cancers. At the time
      of diagnosis approximately 70% of NSCLC patients already have advanced or metastatic disease
      not amenable to surgical resection. A significant percentage of early stage NSCLC patients
      who have undergone surgery subsequently develop distant recurrence.

      First-generation EGFR tyrosine kinase inhibitors (TKIs) provide significant clinical benefit
      in patients with advanced EGFR-mutant (EGFRm) non-small cell lung carcinoma (NSCLC). However,
      all patients ultimately develop disease progression, driven - as the most prevalent
      identified biological mechanism - by the acquisition of a second T790M EGFR TKI resistance
      mutation.

      Osimertinib (AZD9291) is a novel oral, potent, and selective third-generation irreversible
      inhibitor of both EGFRm-sensitizing and T790M resistance mutants. This
      mono-anilino-pyrimidine compound is structurally distinct from other third-generation EGFR
      TKIs and offers a pharmacologically differentiated profile from earlier first and second
      generation EGFR TKIs.

      Osimertinib is being evaluated in several prospective clinical trials, notably in frontline
      treatment, in the adjuvant setting, and in combination with later lines in EGFRm positive
      advanced disease. Combination treatments that target both tumour cells and tumour
      microenvironment (such as angiogenesis) may be a promising strategy for further improving
      efficacy outcomes in patients with EGFRm NSCLC following progression on EGFR TKI therapy and
      other lines of therapy. There is thus a considerable unmet clinical need for novel
      therapeutic options that can further extend the efficacy of targeted agents such as EGFR
      TKIs, across all lines of therapy.

      Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that binds to and inhibits
      the interaction of VEGF-A to its receptors (Flt-1 and KDR) on the surface of endothelial
      cells. The interaction of VEGF with its receptors leads to endothelial cell proliferation and
      new blood vessel formation in in vitro models of angiogenesis. Neutralising the biological
      activity of VEGF regresses the vascularisation of tumours, normalises remaining tumour
      vasculature, and inhibits the formation of new tumour vasculature, thereby inhibiting tumour
      growth. Bevacizumab is indicated for the first-line treatment of unresectable, locally
      advanced, recurrent or metastatic non-squamous NSCLC in combination with carboplatin and
      paclitaxel.

      Osimertinib monotherapy, at the dose to be evaluated in this trial, has shown consistent and
      high objective response rates in the target patient population.

      Anti-angiogenic agents targeting the VEGF/VEGFR signalling pathway have been shown to provide
      additional efficacy when used in combination with first-line platinum-based chemotherapy in
      several trials in non-squamous NSCLC or in combination with erlotinib as first line therapy
      in EGFRm positive NSCLC patients. The combination of osimertinib plus an anti-angiogenic
      agent such as bevacizumab may provide a wider activity against tumours that have developed
      resistance to EGFR TKI agents by blocking the dual pathways of proliferative signalling and
      antigenic signalling. Preclinical studies suggested that patients on lower doses of EGFR TKI
      tend to develop treatment resistance earlier than those who receive higher doses. Therefore
      the combination may also delay the development of subsequent resistance as the preclinical
      studies suggested anti-angiogenic agents may increase intratumoural uptake of anti-cancer
      drugs by changing tumour vessel physiology.

      Efficacy and safety data from the osimertinib monotherapy studies have shown promising
      efficacy and an acceptable safety profile at the recommended dose of 80 mg once daily. The
      combination of osimertinib with bevacizumab may have the potential to provide additional
      clinical benefit in terms of increased and/or prolonged disease control and a delay in the
      emergence of resistance in patients with advanced EGFRm NSCLC who have progressed following a
      prior EGFR TKI agent, compared against the current standard of care (chemotherapy or another
      EGFR TKI) or monotherapy of any of the individual agents.
    

Trial Arms

NameTypeDescriptionInterventions
Osimertinib plus BevacizumabExperimentalPatients will receive treatment with osimertinib and bevacizumab until disease progression, lack of tolerability or the patient declines further treatment. Treatment may also continue beyond progression for as long as the patient may still derive benefit.
  • Osimertinib
  • Bevacizumab
Osimertinib aloneActive ComparatorPatients will receive treatment with osimertinib until disease progression, lack of tolerability or the patient declines further treatment. Treatment may also continue beyond progression for as long as the patient may still derive benefit.
  • Osimertinib

Eligibility Criteria

        Inclusion Criteria:

          -  Patients (male/female) must be >18 years of age.

          -  Patients diagnosed with NSCLC, stage IIIb/IIIc (not amenable to radical therapy) or
             IVa/IVb according to 8th TNM classification, after progression following prior EGFR
             TKI therapy (erlotinib, gefitinib, dacomitinib or afatinib) as the most recent
             treatment regimen;

          -  Pathological diagnosis of predominantly non-squamous NSCLC;

          -  Maximum one line of previous platinum based chemotherapy;

          -  Histological or cytological confirmation of EGFRm (exon 19 deletion or exon 21L858R);

          -  Locally confirmed T790M mutation determined from biopsy (preferred) or on circulating
             tumour DNA, documented in tissue, plasma or serum after disease progression on the
             most recent treatment regimen;

          -  Plasma, serum, and tumour (preferred) tissue or cytology (if biopsy was taken and FFPE
             tumor material is not yet fully depleted) after disease progression on the most recent
             EGFR TKI treatment available for central confirmation of T790M;

          -  Measurable or evaluable disease according to RECIST 1.1;

          -  Adequate haematological, renal and liver function;

          -  World Health Organization (WHO) performance status 0-2.

        Exclusion Criteria:

          -  Patients with mixed NSCLC with predominantly squamous cell cancer, or with any small
             cell lung cancer (SCLC) component;

          -  Symptomatic or active central nervous system metastases, as indicated by progressive
             growth or increasing need of steroids.

          -  Patients currently receiving medications or herbal supplements known to be potent
             CYP3A4 inducers;

          -  Patients with any unresolved toxicities from prior therapy greater than CTCAE V 4.0
             grade 1 (exception: alopecia & grade 2, prior platinuma-therapy related neuropathy)

          -  Previous treatment with osimertinib and/or bevacizumab;
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression Free Survival (PFS)
Time Frame:PFS will be measured from date of patient enrolment until documented progression, or death, if progression is not documented, evaluated up to 48 months from enrolment of the first patient and compared between treatment arms.
Safety Issue:
Description:PFS in patients with locally advanced or metastatic NSCLC will be assessed according to RECIST 1.1 criteria.The two treatment arms will be compared using the Kaplan-Meier method.

Secondary Outcome Measures

Measure:Objective Response Rate (ORR)
Time Frame:ORR will be evaluated from date of patient enrolment until termination of trial treatment across all assessment timepoints, evaluated up to 48 months from enrolment of the first patient and compared between treatment arms.
Safety Issue:
Description:ORR, defined as the percentage of patients reaching a complete or partial response, based on evaluation using RECIST 1.1 criteria and disease control rate.
Measure:Disease Control
Time Frame:Evaluated across all assessment timepoints from date of patient enrolment to termination of trial treatment, evaluated up to 48 months from enrolment of the first patient and compared between treatment arms.
Safety Issue:
Description:Disease control, defined as complete or partial response, or disease stabilisation confirmed at subsequent radiological assessment.
Measure:Adverse Events
Time Frame:From date of signature of informed consent until 30 days after all trial treatment discontinuation, for a maximum of 48 months from enrolment of the first patient
Safety Issue:
Description:Adverse events, graded by CTCAE 4.0, will be recorded from date of signature of informed consent until 30 days after all trial treatment discontinuation.
Measure:Overall Survival (OS)
Time Frame:Evaluated from date of enrolment until death from any cause, assessed at 48 months from enrolment of the first patient.
Safety Issue:
Description:Defined as the time from date of randomisation until death from any cause.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:European Thoracic Oncology Platform

Trial Keywords

  • NSCLC
  • EGFR
  • TKI
  • EGFRm
  • T790M

Last Updated

February 19, 2018