Trial Title:
A Platform Study of Novel Agents in Combination With Radiotherapy in NSCLC
NCT ID:
NCT04550104
Condition:
Non Small Cell Lung Cancer
Conditions: Official terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Durvalumab
Olaparib
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Intervention model description:
The trial is designed as a randomised Phase I dose escalation platform study, using the
TiTE CRM design to find the RP2D of each DDRi with RT combination. At the time of patient
identification the treating centre will be informed of the allocated study arm following
a pre-specified prioritisation schedule. Consenting participants will be randomised
between DDRi with RT or RT only. Patients are not randomised between experimental arms
nor will endpoints be compared between experimental arms. RT only participants will be
pooled across the platform to provide contemporary data on toxicity.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Radiation
Intervention name:
Radiotherapy
Description:
Administered as 30 fractions of 2Gy. Total 60 60Gy. Administered once daily monday to
friday.
Arm group label:
AZD1390 + radiotherapy
Arm group label:
AZD5305 + radiotherapy + Consolidation durvalumab
Arm group label:
Arm D - did not proceed
Arm group label:
Ceralasertib (AZD6738) + radiotherapy + Consolidation durvalumab
Arm group label:
Olaparib + radiotherapy
Arm group label:
RT + consolidation durvalumab
Arm group label:
Radiotherapy only
Intervention type:
Drug
Intervention name:
Olaparib Oral Tablet [Lynparza]
Description:
Oral tablet
Arm group label:
Olaparib + radiotherapy
Other name:
AZD2281
Intervention type:
Drug
Intervention name:
AZD1390
Description:
Oral tablet
Arm group label:
AZD1390 + radiotherapy
Intervention type:
Drug
Intervention name:
Ceralasertib
Description:
Oral Tablet
Arm group label:
Ceralasertib (AZD6738) + radiotherapy + Consolidation durvalumab
Other name:
AZD6738
Intervention type:
Drug
Intervention name:
AZD5305
Description:
Oral Tablet
Arm group label:
AZD5305 + radiotherapy + Consolidation durvalumab
Intervention type:
Drug
Intervention name:
Durvalumab
Description:
1500mg iv infusion
Arm group label:
AZD5305 + radiotherapy + Consolidation durvalumab
Arm group label:
Ceralasertib (AZD6738) + radiotherapy + Consolidation durvalumab
Arm group label:
RT + consolidation durvalumab
Summary:
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.
Detailed description:
Radiotherapy is an effective treatment for patients with non-small cell lung cancer
(NSCLC) that has not spread beyond the chest area. Radiotherapy is used as a curative
treatment but unfortunately for most patients the cancer can return. Radiotherapy kills
cells by damaging their DNA. Cells have the ability to repair that damage, especially the
cells of normal tissue. If DNA repair can be prevented radiotherapy should be more
effective causing the cancer cells to die.
The study will use new drugs that affect how cells repair DNA damage, called DNA damage
response inhibitors (DDRi). These will be given together with radiotherapy to hopefully
improve the effectiveness of radiotherapy, followed by up to 12 months of durvalumab
immunotherapy in selected study arms to develop the trial in line with the standard of
care for NSCLC. The study will try to find out the most effective and safe dose of this
combination treatment. This will be a clinical trial where patients due to have
radiotherapy, with the hope of successful treatment that could lead to cure from their
cancer or extension of life, will be offered entry onto the study. All patients will
receive their radiotherapy, with 3 out of every 4 people also receiving a single DDRi
drug alongside this. Both patients and study doctors will know prior to the start of the
actual treatment whether a DDRi will be given, and if so which one; no placebos will be
used. The patients will be followed closely to check for side effects and to assess how
their cancer is responding to treatment. Blood samples will be taken to monitor treatment
progress and to try to predict which patients are most likely to benefit from this type
of combined treatment.
Criteria for eligibility:
Criteria:
Core Inclusion Criteria (Radiation Phase)
1. 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).
2. Not suitable for concurrent chemoradiotherapy/surgery due to tumour or patient
factors
3. Stage IIB and III (TNM 8th Edition).
4. Planned to receive RT at curative intent doses (i.e., 60Gy) as part of treatment
plan (either with or without induction chemotherapy).
5. Patient considered suitable for radical RT by the local lung cancer
multidisciplinary team and a clinical oncologist.
6. If chemotherapy has been given previously, the maximum interval between the last day
of chemotherapy and the start of RT <10 weeks.
7. Age ≥18
8. Life expectancy estimated to be greater than 6 months.
9. Karnofsky Performance status ≥70.
10. MRC dyspnoea score <3.
11. Forced expiratory volume in one second (FEV1) ≥35% predicted and diffusing capacity
of the lungs for carbon monoxide (DLCO or TLCO) ≥35% predicted.
12. Patient must be fully informed about the study and have signed the informed consent
form.
13. Patient must be willing and able to comply with the protocol, have mental capacity
and (if relevant) use effective contraception throughout treatment and for 4 months
for women of childbearing potential, and 6 months for men after treatment
completion. Treatment is defined as including the last dose of durvalumab or DDRi in
the consolidation phase.
14. Adequate organ function as defined in master protocol.
15. Patient has a body weight of >30kg.
Core Exclusion Criteria (Radiation Phase)
1. Mixed non-small cell and small cell tumours.
2. Confirmed progressive disease during induction chemotherapy.
3. Participation in a study of an investigational agent or using an investigational
device within 4 weeks prior to the anticipated start of treatment.
4. Current or previous malignant disease which may impact on a patient's estimated life
expectancy (other than NSCLC).
5. History of interstitial pneumonitis.
6. Prior thoracic radiotherapy.
7. Prior treatment with pneumotoxic drugs, e.g. busulfan, bleomycin, within the past
year. If prior therapy in lifetime, then exclude if history of pulmonary toxicities
from administration. Patients who have received treatment with nitrosoureas (e.g.,
carmustine, lomustine) in the year before study entry without experiencing lung
toxicity are allowed on study.
8. Mean resting corrected QT interval (QTcF) >470 msec obtained from 3
electrocardiograms.
9. Received a prior autologous or allogeneic organ or tissue transplantation.
10. Patients unable to swallow orally administered medications or chronic
gastrointestinal (GI) disease likely to interfere with absorption of IMP in the
opinion of the treating investigator (e.g. malabsorption syndrome, resection of the
small bowel, poorly controlled inflammatory bowel disease etc.).
11. Grade 2 or higher peripheral sensory neuropathy.
12. Known positive test for human immunodeficiency virus, active hepatitis B or C
infection.
13. Positive pregnancy test (at eligibility assessment for women of childbearing
potential) or breast-feeding women.
14. Patients with persistent toxicities (>CTCAE grade 2) caused by previous cancer
therapy, excluding alopecia.
15. Patients with myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or with
features suggestive of MDS/AML.
16. Major surgery within 2 weeks of confirmation of eligibility.
17. Patients considered a poor medical risk by the investigator due to a serious,
uncontrolled medical disorder, non-malignant system disease or active uncontrolled
infection. Examples include, but are not limited to, uncontrolled ventricular
arrhythmia, uncontrolled hypertension, uncontrolled atrial fibrillation, active
bleeding, recent (within 3 months) myocardial infarction, major seizure, active
COVID-19, any psychiatric disorder that prohibits obtaining informed consent.
18. Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease (e.g., ulcerative colitis or Crohn's disease), systemic
lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with
polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.
19. Exclusions as described in the relevant study arm protocol. Patients ineligible for
a particular study arm may be considered for entry into an alternative study arm if
an appropriate slot is available and they meet all the inclusion and exclusion
criteria for that arm. This will need to be discussed with CTRU and the patient will
be required to reconsent using the appropriate study arm PIS/ICF.
Core Inclusion Criteria (Consolidation Phase)
1. A minimum of 4 and a maximum of 8 weeks* have elapsed following completion of RT
2. Any toxicities from RT have resolved to grade 1. If patient has pneumonitis
following RT treatment, this must be asymptomatic (grade 1). If pneumonitis is ≥2 or
requiring steroids, then participant is not eligible
3. Karnofsky Performance status ≥70
4. The laboratory requirements set out in Table 1 of the master protocol are met
5. Patient has no known hypersensitivity to the excipients of durvalumab
6. Patient has body weight of >30kg *Investigators should ideally aim to start
consolidation treatment within 6 weeks, following the receipt of the CT scan results
to rule out progression.
Core Exclusion Criteria (Consolidation Phase)
1. Progressive disease during RT or at the end of RT treatment response assessment.
2. Participant declines treatment in the consolidation phase.
3. Patients who have received prior anti-PD-1 or anti PD-L1 treatment.
4. Major surgery within 4 weeks of confirmation of eligibility for consolidation phase.
5. Current or prior use of immunosuppressive medication within 14 days before the first
dose of durvalumab.
6. Patients considered a poor medical risk by the investigator due to a serious,
uncontrolled medical disorder, non-malignant system disease, active GI infection or
active uncontrolled infection.
7. Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease e.g., colitis or Crohn's disease), systemic lupus
erythematosus, Sarcoidosis syndrome, or Wegener syndrome granulomatosis with
polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc).
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Belfast City Hospital
Address:
City:
Belfast
Country:
United Kingdom
Status:
Recruiting
Contact:
Email:
CTRU_CONCORDE@leeds.ac.uk
Investigator:
Last name:
Jonathan McAleese
Email:
Principal Investigator
Facility:
Name:
Addenbrooke's Hospital
Address:
City:
Cambridge
Country:
United Kingdom
Status:
Recruiting
Contact:
Email:
CTRU_CONCORDE@leeds.ac.uk
Investigator:
Last name:
Huiqi Yang
Email:
Principal Investigator
Facility:
Name:
Velindre Cancer Centre
Address:
City:
Cardiff
Country:
United Kingdom
Status:
Recruiting
Contact:
Email:
CTRU_CONCORDE@leeds.ac.uk
Investigator:
Last name:
Paul Shaw
Email:
Principal Investigator
Facility:
Name:
The Royal Marsden Hospital Chelsea
Address:
City:
Chelsea
Country:
United Kingdom
Status:
Recruiting
Contact:
Email:
CTRU_CONCORDE@leeds.ac.uk
Investigator:
Last name:
Merina Ahmed
Email:
Principal Investigator
Facility:
Name:
Western General Hospital
Address:
City:
Edinburgh
Country:
United Kingdom
Status:
Recruiting
Contact:
Email:
CTRU_CONCORDE@leeds.ac.uk
Investigator:
Last name:
Stephen Harrow
Email:
Principal Investigator
Facility:
Name:
St James's University Hospital
Address:
City:
Leeds
Country:
United Kingdom
Status:
Recruiting
Contact:
Email:
CTRU_CONCORDE@leeds.ac.uk
Investigator:
Last name:
Kevin Franks
Email:
Principal Investigator
Facility:
Name:
University College Hospital London
Address:
City:
London
Country:
United Kingdom
Status:
Recruiting
Contact:
Email:
CTRU_CONCORDE@leeds.ac.uk
Investigator:
Last name:
Crispin Hiley
Email:
Principal Investigator
Facility:
Name:
The Christie NHS Foundation Trust
Address:
City:
Manchester
Country:
United Kingdom
Status:
Recruiting
Contact:
Email:
CTRU_CONCORDE@leeds.ac.uk
Investigator:
Last name:
Corinne Faivre-Finn
Email:
Principal Investigator
Investigator:
Last name:
Clara Chan
Email:
Principal Investigator
Facility:
Name:
Freeman Hospital, Newcastle upon Tyne Hospitals NHS Trust
Address:
City:
Newcastle Upon Tyne
Country:
United Kingdom
Status:
Recruiting
Contact:
Last name:
Alastair Greystoke
Email:
ctru_leeds@leeds.ac.uk
Investigator:
Last name:
Adam Hassani
Email:
Principal Investigator
Facility:
Name:
Weston Park Hospital
Address:
City:
Sheffield
Country:
United Kingdom
Status:
Recruiting
Contact:
Email:
CTRU_CONCORDE@leeds.ac.uk
Investigator:
Last name:
Matthew Hatton
Email:
Principal Investigator
Facility:
Name:
The Royal Marsden Sutton
Address:
City:
Sutton
Country:
United Kingdom
Status:
Recruiting
Contact:
Email:
CTRU_CONCORDE@leeds.ac.uk
Investigator:
Last name:
Merina Ahmed
Email:
Principal Investigator
Start date:
March 17, 2021
Completion date:
March 2028
Lead sponsor:
Agency:
University of Leeds
Agency class:
Other
Collaborator:
Agency:
University of Manchester
Agency class:
Other
Collaborator:
Agency:
Newcastle University
Agency class:
Other
Collaborator:
Agency:
University of Oxford
Agency class:
Other
Collaborator:
Agency:
The Leeds Teaching Hospitals NHS Trust
Agency class:
Other
Collaborator:
Agency:
Beatson West of Scotland Cancer Centre
Agency class:
Other
Collaborator:
Agency:
University of Glasgow
Agency class:
Other
Collaborator:
Agency:
Velindre NHS Trust
Agency class:
Other
Collaborator:
Agency:
University College London Hospitals
Agency class:
Other
Collaborator:
Agency:
Queen's University, Belfast
Agency class:
Other
Collaborator:
Agency:
University of Sheffield
Agency class:
Other
Source:
University of Leeds
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT04550104
