Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Immune System Diseases

Breast Neoplasms

Triple Negative Breast Neoplasms

Hypersensitivity

Breast Diseases

Skin Diseases

Antineoplastic Agents

All Drugs and Chemicals

Durvalumab

Olaparib

Poly(ADP-ribose) Polymerase Inhibitors

Antineoplastic Agents, Immunological

Enzyme Inhibitors

Twice daily oral Olaparib 300mg alone as maintenance therapy until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.

Twice daily oral olaparib plus intravenous Durvalumab every 4 weeks as maintenance therapy until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.

Olaparib Oral Product

olaparib 300mg twice daily plus intravenous durvalumab every 28 days

Olaparib Oral Product in combination with Durvalumab

Sarah Sammons, MD

This is a randomized, international, multicenter, Phase II study designed to explore the efficacy of olaparib or olaparib in combination with durvalumab in platinum-treated mTNBC. The primary objectives are to explore olaparib or olaparib in combination with durvalumab as maintenance therapy following clinical benefit with platinum-based therapy in subjects with mTNBC.

Subjects suitable for enrollment into this trial are adult subjects with histologically documented triple negative adenocarcinoma of the breast that is inoperable, locally advanced, or metastatic, and is not amenable to resection with curative intent, and who have received at least 4 cycles of platinum-based chemotherapy in the 1st or 2nd line setting AND derived clinical benefit (CR / PR / SD) per RECIST 1.1 with platinum-based therapy as determined by the treating physician.

Eligible subjects will be randomized to either olaparib or olaparib in combination with durvalumab. Study treatment will continue until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination. Upon treatment discontinuation, subjects will be followed every 2 months for survival.

Although randomization will be used to allocate subjects to either the olaparib or olaparib in combination with durvalumab arm, no comparisons between treatment regimens are planned. The purpose of randomization was to reduce bias due to subject selection into either treatment arm.

Phase II Multicenter Study of Durvalumab and Olaparib in Platinum tReated Advanced Triple Negative Breast Cancer (DORA)

Phase II Multicenter Study of Durvalumab and Olaparib in Platinum tReated Advanced Triple Negative Breast Cancer

PFS, defined as the time from randomization to the first occurrence of disease progression or death from any cause on study for olaparib alone. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Death on study is defined as death from any cause within 30 days of the last dose of study treatment regimen. Reported as events (disease progression or death) per month.

PFS, as defined as the time from randomization to the first occurrence of disease progression (as determined using RECIST v1.1 criteria and assessed by the investigator) or death from any cause on study for olaparib in combination with durvalumab. Death on study is defined as death from any cause within 30 days of the last dose of study treatment regimen. Reported as (disease progression or death) events per month.

To determine the efficacy of maintenance olaparib following platinum based chemotherapy as assessed by overall survival (OS).

To determine the efficacy of maintenance olaparib in combination with durvalumab following platinum based chemotherapy as assessed by overall survival (OS).

To determine the efficacy of maintenance olaparib following platinum-based chemotherapy as assessed by overall response rate (ORR) based on RECIST 1.1 (Response Evaluation Criteria In Solid Tumors Criteria). Per RECIST v1.1 for target lesions and assessed by CT or MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

To determine the efficacy of maintenance olaparib in combination with durvalumab following platinum-based chemotherapy as assessed by overall response rate (ORR) based on RECIST 1.1 (Response Evaluation Criteria In Solid Tumors Criteria). Per RECIST v1.1 for target lesions and assessed by CT or MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

To determine the efficacy of maintenance olaparib following platinum-based chemotherapy as assessed by clinical benefit rate (CBR) based on RECIST 1.1 (Response Evaluation Criteria In Solid Tumors Criteria). Per RECIST v1.1 for target lesions and assessed by CT or MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease (PD); Clinical Benefit (CB) = CR + PR + SD for \>= 24 weeks.

To determine the efficacy of maintenance olaparib in combination with durvalumab following platinum-based chemotherapy as assessed by clinical benefit rate (CBR) based on RECIST 1.1 (Response Evaluation Criteria In Solid Tumors Criteria). Per RECIST v1.1 for target lesions and assessed by CT or MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease (PD); Clinical Benefit (CB) = CR + PR + SD for \>= 24 weeks.

AstraZeneca

Duke University

Assistant Professor of Medicine

Twice daily oral Olaparib 300mg alone as maintenance therapy until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.

Olaparib Oral Product: olaparib 300mg twice daily

A - Olaparib Alone

Twice daily oral olaparib plus intravenous Durvalumab every 4 weeks as maintenance therapy until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.

Olaparib Oral Product in combination with Durvalumab: olaparib 300mg twice daily plus intravenous durvalumab every 28 days

B - Olaparib Plus Durvalumab

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Senior Biostatistician

Assumed median PFS = 2.0 months as historical control, transformed to rate of 0.35/month

Intent To Treat population. Only applies to the "olaparib alone" arm.

Efficacy of Olaparib Alone as Assessed by PFS (Progression-free Survival) Reported as Events Per Month

Intent to Treat population. Only applies to the "olaparib plus durvalumab" arm.

Efficacy of Olaparib in Combination With Durvalumab as Assessed by PFS (Progression-free Survival)

Only applies to the "olaparib alone" arm.

Overall Survival (Olaparib Alone)

Only applies to the "olaparib plus durvalumab" arm.

Overall Survival (Olaparib in Combination With Durvalumab)

Overall Response Rate (ORR) as Measured by Number of Participants Achieving Complete Response (CR) or Partial Response (PR) as Defined by RECIST 1.1 (Olaparib Alone)

Overall Response Rate (ORR) as Measured by Number of Participants Achieving Complete Response (CR) or Partial Response (PR) as Defined by RECIST 1.1 (Olaparib in Combination With Durvalumab)

Clinical Benefit Rate (CBR) as Measured by the Number of Participants Achieving Complete Response (CR), Partial Response (PR) or Stable Disease for ≥ 24 Weeks (SD) as Defined by RECIST 1.1. (Olaparib Alone)

Clinical Benefit Rate (CBR) as Measured by the Number of Participants Achieving Complete Response (CR), Partial Response (PR) or Stable Disease for ≥ 24 Weeks (SD) as Defined by RECIST 1.1. (Olaparib in Combination With Durvalumab)

Overall Study

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Rare Diseases

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Endocrine Gland Neoplasms

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Genital Neoplasms, Female

Urogenital Neoplasms

Endocrine System Diseases

Gonadal Disorders

Ovarian Cancer

Ovarian Epithelial Cancer

Olaparib Maintenace Treatment after first line platium based chemotherapy in BRCA wilde-type ovarian cancer patients

Clorinda Schettino, MD

Sandro Pignata, MD

Emanuela Rossi, MD

Saverio Cinieri, MD

Sandro Pignata, MD, PhD

Domenico Sergi, MD

Antonella Savarese, MD

This trial is a multicenter, prospective, phase II single arm, open-label trial in which patients with newly diagnosed advanced epithelial ovarian, primitive peritoneal, and fallopian tube cancer BRCA wild type, in partial or complete response to first line platinum-based chemotherapy, receive Olaparib maintenance therapy (300 mg, tablets formulation twice daily).

MITO 35a: Olaparib Maintenance Therapy in Newly Diagnosed BRCA Wild-type Advanced Ovarian, Fallopian Tube and Primitive Peritoneal Cancer

MITO 35a: A Multicenter, Prospective, Single Arm Trial of Olaparib Maintenance Therapy in Newly Diagnosed BRCA Wildtype Advanced Ovarian, Fallopian Tube and Primitive Peritoneal Cancer

PFS as defined by the Investigator using RECIST 1.1 as the time frame from enrollment to progression or death for any cause.

PFS2 as defined by the Investigator using RECIST 1.1, as the time frame from enrollment to the second progression or death for any cause after subsequent treatment.

OS is defined as the time elapsed from randomization to death due to any cause

Number of participants with treatment-related side effects graded according to Common Criteria for Adverse Events (CTCAE) version 5.0

National Cancer Institute, Naples

Symptoms and General Pathology

Recurrence

Patients, irrespective of BRCA status, will be treated with olaparib tablet 300 mg bid

ex vivo functional assay (RAD51 assay also known as Repair Capacity (RECAP) assay ) to test homologous recombination deficiencie (HRD) in viable tumor tissue

Functional RAD51 assay

Judith Kroep, MD, PhD

Maaike Vreeswijk, PhD

Hilde Jalving, MD PhD

J R Kroep, MD PhD

M Vreeswijk, PhD

Ingrid Boere, MD PhD

PARP inhibitors are most effective in homologous recombinant (HR) deficient tumors. There are clear indications that besides BRCA1 or BRCA2 mutated EOC, there is an additional group of EOC having deficiencies in HR (i.e. BRCAness) that might benefit from treatment with PARP inhibitors. Assessment of HR in high grade EOC might therefore serve as a better predictive biomarker and allow the identification of a larger group of patients that could benefit most from platinum based chemotherapy and maintenance treatment with a PARP inhibitor. We recently developed a robust ex vivo functional assay (RAD51 assay;) to test HR in viable tumor tissue. In the proposed study, we will evaluate whether the RAD51 assay predicts sensitivity to therapy with olaparib, in patients with recurrent EOC. With the RAD51 assay we aim to identify a larger number of patients who will benefit from treatment with the PARP inhibitor olaparib than patients with a germline or somatic BRCA mutation only. Furthermore, we aim to identify molecular markers (including genomic markers) that are associated with the outcome of the RAD51 assay. Finally, we will explore whether these molecular markers can be measured in liquid biopsies by analysing ctDNA.

Epithelial ovarian cancer (EOC) often presents at an advanced stage, and harbours an unfavourable prognosis. Standard of care includes complete or optimal debulking surgery and chemotherapy, however, most patients experience recurrent disease. Recurrences are often treated with additional chemotherapy, and for selected patients, treatment with PARP inhibitors may be an option. Patients with platinum sensitive recurrent epithelial ovarian cancer (EOC) and a germ-line or somatic BRCA1 or BRCA2 mutation, who are in response to platinum based chemotherapy are currently eligible for maintenance treatment with the Poly (ADP-ribose) polymerase (PARP) inhibitor olaparib after chemotherapy. Germline (11-15%) or somatically acquired (6-7%) BRCA1 and BRCA2 mutations lead to deficiency in homologous recombination (HR) and subsequent less effective DNA repair. PARP inhibitors are most effective in HR deficient tumors. There are clear indications that besides BRCA1 or BRCA2 mutated EOC, there is an additional group of EOC (\~15-30%) having deficiencies in HR (i.e. BRCAness) that might benefit from treatment with PARP inhibitors (Mukhopadhyay, Cancer Res 2012; Konstantinopolos, Cancer Discovery 2015; Telli, Clin Cancer Res 2016). Assessment of HR in high grade EOC might therefore serve as a better predictive biomarker and allow the identification of a larger group of patients that could benefit most from platinum based chemotherapy and maintenance treatment with a PARP inhibitor. We recently developed a robust ex vivo functional assay (RAD51 assay;) to test HR in viable tumor tissue (Naipal, Clin. Cancer Res., 2014). It is still unknown however, whether the outcome of the RAD51 assay reliably predicts the sensitivity to platinum-based chemotherapy or PARP inhibitors. In the proposed study, we will therefore evaluate whether the RAD51 assay predicts sensitivity to therapy with olaparib, in patients with recurrent EOC. With the RAD51 assay we aim to identify a larger number of patients who will benefit from treatment with the PARP inhibitor olaparib than patients with a germline or somatic BRCA mutation only. Furthermore, we aim to identify molecular markers (including genomic markers) that are associated with the outcome of the RAD51 assay. Finally, we will explore whether these molecular markers can be measured in liquid biopsies by analysing ctDNA.

prospective, Dutch, multicenter, single arm phase II study

Functional Analysis of BRCAness

Correlation Between Homologous Recombination Deficiency and Response to Olaparib in Patients With Recurrent Epithelial Ovarian Cancer (EOC)

molecular marker analysis BRCA/HRD (ctDNA in blood), using NGS and digital PCR analyses

The primary endpoint is the RR, defined as the best overall response (partial response and/or complete response) according to RECIST1.1 for both the HR proficient and HR deficient group as determined by the RAD51 assay.

time from start of maintenance olaparib to the date of first documented disease progression or death from any cause, whichever occurs first, of olaparib for the BRCA1 or BRCA2 mutant (germline or somatic) HR deficient group, the non BRCA mutant HR deficient group and the HR proficient group

time from start olaparib to death (any cause).

Percentage of informative RAD51 test results in tumor biopsies and/or ascites

Identify loss of function mutations in genes involved in HR as part of the molecular analysis in the HR proficient and HR deficient group as determined by the RAD51 assay.

Safety and adverse events (AE) of Common Terminology Criteria for Adverse Events version 4.03 (CTCAE) grade 3\>5.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase II Multicenter Study of Durvalumab and Olaparib in Platinum tReated Advanced Triple Negative Breast Cancer (DORA)	NCT03167619	Triple Negative...	Olaparib Oral P... Olaparib Oral P...	21 Years -	Duke University
MITO 35a: Olaparib Maintenance Therapy in Newly Diagnosed BRCA Wild-type Advanced Ovarian, Fallopian Tube and Primitive Peritoneal Cancer	NCT05233982	Ovarian Cancer	Olaparib Oral P...	18 Years -	National Cancer Institute, Naples
Functional Analysis of BRCAness	NCT04780945	Ovarian Neoplas... Homologous Reco... BRCA1 Mutation BRCA2 Mutation	Functional RAD5... Olaparib Oral P...	18 Years -	Leiden University Medical Center

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