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A Platform Study of Novel Agents in Combination With Radiotherapy in NSCLC

ConditionNon Small Cell Lung Cancer
Trial statusRecruiting
Trial phasePhase 1
Trial typeInterventional
Biological sexAll
Age18+
SponsorUniversity of Leeds

About this trial

CONCORDE is a multi-institution, multi-arm, Phase IB study that will determine the recommended phase II dose (RP2D) and safety profiles of different DNA damage repair inhibitors (DDRis) when given in an open label fashion in combination with fixed dose curative intent radiotherapy (RT) in patients with stage IIB/IIIA/IIIB NSCLC, followed by up to 12 months of consolidation durvalumab immunotherapy in selected study arms. The RP2D will be evaluated by incorporating the number of observed dose limiting toxicities (DLTs) into a time to event continuous reassessment method (TiTE- CRM) model within each of the experimental arms. TiTE-CRM is used here to take into account longer-term toxicities up to 13.5 months post start of radiotherapy and use these to inform dose escalation decision making.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

Histologically or cytologically confirmed NSCLC (patients where the local MDT agree the diagnosis is NSCLC after review of the available pathology and imaging at MDT can be enrolled after discussion with the CI).

Not suitable for concurrent chemoradiotherapy/surgery due to tumour or patient factors

Stage IIB and III (TNM 8th Edition).

Planned to receive RT at curative intent doses (i.e., 60Gy) as part of treatment plan (either with or without induction chemotherapy).

Disqualifiers

Mixed non-small cell and small cell tumours.

Confirmed progressive disease during induction chemotherapy.

Participation in a study of an investigational agent or using an investigational device within 4 weeks prior to the anticipated start of treatment.

Current or previous malignant disease which may impact on a patient's estimated life expectancy (other than NSCLC).

Trial design

Design model

Parallel

Treatments tested in this trial

  • Radiotherapy

    Radiation

    Administered as 30 fractions of 2Gy. Total 60 60Gy. Administered once daily monday to friday.

  • Olaparib Oral Tablet [Lynparza]

    Drug

    Oral tablet

  • AZD1390

    Drug

    Oral tablet

  • Ceralasertib

    Drug

    Oral Tablet

  • AZD5305

    Drug

    Oral Tablet

  • Durvalumab

    Drug

    1500mg iv infusion

Treatment groups

200 Participants
are divided into 7 treatment groups

7

Treatment groups

See each treatment group below.

Group A: Radiotherapy onlyActive comparator 1 intervention
Group B: Olaparib + radiotherapyExperimental treatment 2 interventions
Group C: AZD1390 + radiotherapyExperimental treatment 2 interventions
Group D: Ceralasertib (AZD6738) + radiotherapy + Consolidation durvalumabExperimental treatment 3 interventions
Group E: AZD5305 + radiotherapy + Consolidation durvalumabExperimental treatment 3 interventions
Group F: RT + consolidation durvalumabActive comparator 2 interventions
Group G: Arm D - did not proceedExperimental treatment 1 intervention

Trial outcomes

Primary outcomes

1

Dose limiting Toxicities

Dose-limiting toxicities (DLTs), within 13.5 months of starting radiotherapy, in order to establish the Recommended Phase II Dose (RP2D) of each DDRi-RT combination.

Time frame
13.5 months after start of radiotherapy

Secondary outcomes

1

Safety and toxicity

Safety will be reported based on the occurrence of SAEs, SARs and SUSARs. Toxicity will be reported based on adverse events, as graded by CTCAE V5.0, and determined by routine clinical assessments at each centre.

Time frame
2 years after end of RT
2

Treatment compliance

Treatment compliance will be measured by overall radiotherapy treatment time and delays, omissions and reductions to treatment doses (both DDRi and RT).

Time frame
End of trial treatment (DDRi and RT)
3

Best overall response

Best overall response will be measured as the best response (complete response, partial response or stable disease) recorded until disease progression, reported up to 2 years post-RT. This will be assessed using RECIST 1.1

Time frame
2 years after end of RT
4

Disease control

This will be assessed using the Green Criteria. Disease Control includes either the complete disappearance of all evidence of malignant disease or residual radiographic abnormalities assessed by chest CT scan at 3 and 6 months after completion of RT, which then remains stable for an additional 6 months or more and which then qualifies as controlled local disease.

Time frame
2 years after end of RT

Other outcomes

1

Assessment of mutations in components of DDR pathway in archival tumour and cfDNA prior to therapy

Exploratory endpoint

Time frame
2 years after end of RT
2

Assessment of T cells within the archival tumour specimens

Exploratory endpoint

Time frame
2 years after end of RT
3

Changes in cfDNA during and following treatment with DDRi-RT compared to RT alone.

Exploratory endpoint

Time frame
2 years after end of RT
4

Changes in circulating biomarkers of cardiac and respiratory toxicity during and following treatment with DDRi-RT compared to RT alone.

Exploratory endpoint

Time frame
3 months post end of RT

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

University of Leeds

Lead sponsor

University of Manchester

Collaborator

Newcastle University

Collaborator

University of Oxford

Collaborator

The Leeds Teaching Hospitals NHS Trust

Collaborator

Beatson West of Scotland Cancer Centre

Collaborator

University of Glasgow

Collaborator

Velindre NHS Trust

Collaborator

University College London Hospitals

Collaborator

Queen's University, Belfast

Collaborator

University of Sheffield

Collaborator

Source ClinicalTrials.gov
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