Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Breast Diseases

Skin Diseases

Antineoplastic Agents

All Drugs and Chemicals

Pembrolizumab

Olaparib

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

All eligible participants according to the definition of cohorts 1-3 will receive pembrolizumab i.v. 200 mg q3w in combination with olaparib tablets 300 mg twice daily (total dose 600 mg per day).

The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). Based on the totality of data generated in the Keytruda development program, 200 mg Q3W is the appropriate dose of pembrolizumab for adults across all indications and regardless of tumor type.

Pembrolizumab Injection [Keytruda]

All patients will receive olaparib treatment as an addition to pembrolizumab. The dose of olaparib used in this study is 300 mg twice daily (total daily dose of 600 mg) which is the currently approved dose.

Olaparib Oral Tablet [Lynparza]

Peter A. Fasching, MD, Prof.

This study will examine the combination of pembrolizumab and olaparib in three populations.

* Cohort 1: aBC patients with a germline mutation in BRCA1 or BRCA2,
* cohort 2: aBC patients with a germline mutation in one of the moderate penetrance homologous repair genes (ATM, BARD1, CHEK2, FANCC, PALB2, RAD51C, RAD51D, SLX4, XRCC2), and
* cohort 3: aBC patients with a HRD as assessed by whole genome sequencing.

This is a multicenter, prospective, phase II, one-arm, three-cohort, open-label study of pembrolizumab in combination with olaparib in patients with advanced HER2 negative breast cancer who have either

* a deleterious germline mutation in BRCA1/2 irrespective of tumor HRD status (Cohort 1),
* or a deleterious germline mutation in ATM, BARD1, CHEK2, FANCC, PALB2, RAD51C, RAD51D, SLX4, XRCC2 irrespective of tumor HRD status (Cohort 2),
* or a centrally confirmed high tumor HRD status, but no deleterious germline mutation in BRCA1/2, ATM, BARD1, CHEK2, FANCC, PALB2, RAD51C, RAD51D, SLX4, XRCC2 (Cohort 3). HRD assessment needs to be performed on a tumor biopsy not more than 12 months before study entry.

All eligible participants according to the definition of cohorts 1-3 will receive pembrolizumab i.v. 200 mg q3w in combination with olaparib tablets 300 mg twice daily (total dose 600 mg per day).

Study medication will be withdrawn/ended in case of onset of unacceptable toxicities, progression, withdrawal of consent, death, or end of study, whichever occurs first. Safety follow-up is planned for 90 days after the last application of study medication. Participants will be followed for survival for a maximum of 18 months after therapy start.

Comprehensive Analysis of Predictors of the Treatment With Pembrolizumab and Olaparib in Patients With Unresectable or Metastatic HER2 Negative Breast Cancer and a Deleterious Germline Mutation or a Homologous Recombination Deficiency (COMPRENDO

A Phase II Open-Label Study for the Comprehensive Analysis of Predictors of the Treatment With Pembrolizumab and Olaparib in Patients With Unresectable or Metastatic HER2 Negative Breast Cancer and a Deleterious Germline Mutation in BRCA1/2, ATM, BARD1, CHEK2, FANCC, PALB2, RAD51C, RAD51D, SLX4, XRCC2 or a Homologous Recombination Deficiency

Overall response rate (ORR) is defined as the number of participants with a confirmed best response of complete response (CR) or partial response (PR) per RECIST v1.1.

DOR is defined as the time between the date of first response (CR or PR) to the date of first tumor progression per RECIST v1.1.

PFS is defined as the time between the date of study entry and the first date of progression or death due to any cause, whichever occurs first

OS is defined as the time between the date of study entry and the date of death due to any cause

Incidence of adverse events (AEs) and serious adverse events (SAEs), incidence of deaths, and incidence of abnormalities in the laboratory diagnostics

Merck Sharp & Dohme LLC

Institut fuer Frauengesundheit

Respiratory Tract (Lung and Bronchial) Diseases

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Durvalumab

This study arm will include up to 12 months of consolidation durvalumab for eligible participants following the completion of radiotherapy +/- DDRi.

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

Radiotherapy

AZD1390

Ceralasertib

AZD5305

Jamie B Oughton, MPhil

Jonathan McAleese

Huiqi Yang

Paul Shaw

Merina Ahmed

Stephen Harrow

Kevin Franks

Crispin Hiley

Corinne Faivre-Finn

Clara Chan

Alastair Greystoke

Adam Hassani

Matthew Hatton

Alastair Greystoke, MB ChB, MSc, PhD

Corinne Faivre-Finn, MD, PhD

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.

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.

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.

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

A Platform Study of DNA Damage Response Inhibitors in Combination With Conventional Radiotherapy in Non Small Cell Lung Cancer

De-identified individual participant data datasets generated and/or analysed during the current study will be available upon request from the Clinical Trials Research Unit, University of Leeds. Data will be made available at the end of the trial. Data will remain available from then on for as long as CTRU retains the data.

CTRU makes data available by a 'controlled access' approach. Data will only be released for legitimate secondary research purposes, where the Chief Investigator, Sponsor and CTRU agree that the proposed use has scientific value and will be carried out to a high standard (in terms of scientific rigour and information governance and security), and that there are resources available to satisfy the request. Data will only be released in line with participants' consent, all applicable laws relating to data protection and confidentiality, and any contractual obligations to which the CTRU is subject.

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.

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.

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

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

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.

Participants who have not progressed at the time of analysis will be censored at the last date they were known to be alive and progression free

Participants who have not died at the time of analysis will be censored at the last date they were known to be alive

Health Related Quality of Life will be determined using EORTC QLQ-C30, IL-73 and IL-74

Objective response rate (ORR) is defined as the proportion of patients who have a partial or complete response to therapy. The proportion of patients with evaluable scans that achieve at least a partial response, as defined by RECIST v1.1(31), will be presented with 95% confidence intervals.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Comprehensive Analysis of Predictors of the Treatment With Pembrolizumab and Olaparib in Patients With Unresectable or Metastatic HER2 Negative Breast Cancer and a Deleterious Germline Mutation or a Homologous Recombination Deficiency (COMPRENDO	NCT05033756	Malignant Neopl... Breast Cancer	Pembrolizumab I... Olaparib Oral T...	18 Years -	Institut fuer Frauengesundheit
A Platform Study of Novel Agents in Combination With Radiotherapy in NSCLC	NCT04550104	Non Small Cell ...	Radiotherapy Olaparib Oral T... AZD1390 Ceralasertib AZD5305 Durvalumab	18 Years -	University of Leeds
A Platform Study of Novel Agents in Combination With Radiotherapy in NSCLC	NCT04550104	Non Small Cell ...	Radiotherapy Olaparib Oral T... AZD1390 Ceralasertib AZD5305 Durvalumab	18 Years -	University of Leeds
A Platform Study of Novel Agents in Combination With Radiotherapy in NSCLC	NCT04550104	Non Small Cell ...	Radiotherapy Olaparib Oral T... AZD1390 Ceralasertib AZD5305 Durvalumab	18 Years -	University of Leeds
A Platform Study of Novel Agents in Combination With Radiotherapy in NSCLC	NCT04550104	Non Small Cell ...	Radiotherapy Olaparib Oral T... AZD1390 Ceralasertib AZD5305 Durvalumab	18 Years -	University of Leeds

Spots Global Cancer Trial Database for olaparib oral tablet [lynparza]