Durvalumab and Olaparib in Metastatic or Recurrent Endometrial Cancer (DOMEC)

• ClinicalTrials.gov Identifier: NCT03951415
• Recruitment Status: Unknown
• First Posted: May 15, 2019
• Last Update Posted: April 1, 2021
• Sponsor: Leiden University Medical Center
• Collaborators: Amsterdam University Medical Center; Erasmus Medical Center; Maastricht University Medical Center; The Netherlands Cancer Institute; Radboud University Medical Center; University Medical Center Groningen; UMC Utrecht; AstraZeneca
• Information provided by (Responsible Party): J.R. Kroep, Leiden University Medical Center

Study Description

Brief Summary:

The DOMEC trial is designed as a Dutch Gynecological Oncology Group (DGOG), prospective, multi-center, phase II study for 55 patients with advanced (recurrent, refractory or metastatic) endometrial cancer or carcinosarcoma of the uterus to investigate the efficacy of the combination therapy of olaparib tablets and durvalumab IV.

Condition or disease	Intervention/treatment	Phase
Endometrial Neoplasms; Uterine Neoplasms; Endometrium Cancer	Drug: PARP inhibitor and Anti-PD-L1	Phase 2

Detailed Description:

The prognosis of recurrent or persistent endometrial carcinoma not amenable to local therapy is poor. First line therapy exists of platinum-based chemotherapy or hormonal therapy. No standard subsequent-line therapy has been described.The combination of Poly(ADP-ribose) polymerases (PARP) inhibition and Programmed death-ligand 1 (PD-L1) blocking has great potential in the treatment of recurrent endometrial cancer. The DOMEC trial is designed to investigate this treatment combination among all molecular subgroups.

The DOMEC trial is designed as a DGOG, prospective, multi-center, phase II study for 55 patients with advanced (recurrent, refractory or metastatic) endometrial cancer, including carcinosarcoma of the uterus. Patients must have had one prior platinum-based chemotherapeutic regimen or not be able/willing to get chemotherapy. The aim is to investigate the efficacy of the combination therapy of olaparib tablets 300mg twice daily orally and durvalumab 1500mg by IV infusion every 4 weeks in terms of progression free survival. Secondary objectives are to investigate objective response rate, overall survival, safety and predictive biomarkers.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 55 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Durvalumab and Olaparib in Metastatic or Recurrent Endometrial Cancer
• Actual Study Start Date: July 8, 2019
• Estimated Primary Completion Date: August 1, 2021
• Estimated Study Completion Date: August 1, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: PARP inhibitor and Anti-PD-L1; olaparib tablets 300mg twice daily orally and durvalumab 1500mg by IV infusion every 4 weeks	Drug: PARP inhibitor and Anti-PD-L1; olaparib tablets 300mg twice daily orally and durvalumab 1500mg by IV infusion every 4 weeks; Other Names: olaparib; durvalumab; PARP inhibitor; Anti-PD-L1 Monoclonal Antibody

Outcome Measures

Primary Outcome Measures :

1. Progression free survival (PFS) [ Time Frame: 6 months ]
   PFS will be counted from the date of registration until the first observation of radiological progressive disease according to RECIST 1.1 criteria or death due to any cause, whichever occurred first.

Secondary Outcome Measures :

1. Objective response rate (ORR) [ Time Frame: 12 weeks ]
   according to RECIST 1.1 criteria
2. Overall survival (OS) [ Time Frame: Through study completion, up to 36 months ]
   OS will be determined from the date of registration until death from any cause.
3. Adverse events [ Time Frame: Through study completion, up to 36 months ]
   Assessed by NCI Common Terminology Criteria for adverse Events (CTCAE) version 5.0
4. Predictive biomarkers in tumor biopsy [ Time Frame: At baseline ]
   MMRd/POLE, HR status, quantification of CD3,CD4,CD8,CD103,CD161,PD-1,LAG3,CTLA-4,NKG2A,GOXp3 positieve T cells, NK cells, percentage PD-L1 on myeloid cells/tumorcells, quantification of myeloid cell infiltration (CD68,CD14,CD33,CD163) in tumor biopsies.

Other Outcome Measures:

1. Functional HRD assay (optional) [ Time Frame: At baseline ]
   Extra biopsy
2. Immunological effects of PARP-1 inhibition (optional) [ Time Frame: Change From Baseline to 6 weeks and 12 weeks ]
   Tests for T cell and APC functionality measured by the measurement of recall antigen responses and mixed lymphocyte cultures, respectively, the levels of regulatory T cells, activation markers on T cells and DC).
3. Predictive biomarkers for PD-L1 blocking in blood (optional) [ Time Frame: Change From Baseline to 6 weeks and 12 weeks ]
   e.g. monocyticMDSC levels, DC levels, inhibitory marker expression, neutrophil-to-lymphocyte ratio, absolute lymphocyte count, T-cell reactivity during PD-L1 blocking, T-cell cytokine expression after SEB activation

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion criteria:

• Written informed consent
• Age > 18 years old
• Histologically confirmed diagnosis of endometrial cancer or carcinosarcoma of the endometrium.
• Metastatic disease or locally advanced tumor not amenable to local therapy.
• Documented progressive disease before enrolment.
• Measurable lesions outside irradiated field or progressive measurable lesions in irradiated area
• Not eligible for hormonal therapy (because of negative hormone receptor/poor differentiation, or after failure of hormonal therapy).
• Previous failure of chemotherapy, or refusal to undergo chemotherapy or chemo-naive patients not suitable for chemotherapy.
• WHO performance 0-1

• Adequate organ system function as measured within 28 days prior to administration of study treatment, as defined below:

  • Haemoglobin ≥ 10.0 g/dL, with no blood transfusion in the past 28 days.
  • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
  • Platelet count ≥ 100 x 109/L
  • Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (not applicable to Gilbert's syndrome)
  • Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) ≤ 2.5 x ULN unless liver metastases are present in which case they must be ≤ 5x ULN
  • Patients must have creatinine clearance estimated of ≥51 mL/min estimated using the Cockcroft-Gault equation or 24 hr urine clearance.
• Life expectancy of at least 16 weeks.
• Measurable disease as defined by RECIST 1.1 criteria
• Able to swallow and retain oral medication.
• A female is eligible to enter and participate in this study if there is:

Exclusion criteria:

• Participation in another clinical study with an investigational product during the last month or previous enrolment in the present study.
• Any previous treatment with PARP inhibitor, including olaparib and/or any previous treatment with a PD1 or PD-L1 inhibitor
• History of another primary malignancy except for malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of investigational product and of low potential risk for recurrence or adequately treated non-melanoma skin cancer, lentigo maligna or carcinoma in situ.
• History of leptomeningeal carcinomatosis, symptomatic uncontrolled brain metastases (≤2mg/ day corticosteroids started ≥4 weeks prior to treatment is accepted) and spinal cord compression (unless received definitive treatment and clinically stable for 28 days) .
• Resting ECG with QTc > 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome
• Concomitant use of known strong or moderate CYP3A inhibitors and inducers.
• Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
• Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab (except intranasal and inhaled corticosteroids or systemic prednisone ≤ 10 mg/day)
• Major surgery ≤2 weeks of starting study treatment
• History of active primary immunodeficiency
• Active or prior documented autoimmune or inflammatory disorders, with exception of: vitiligo or alopecia, hypothyroidism stable on hormone replacement, any chronic skin condition that does not require systemic therapy, celiac disease controlled by diet alone
• Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
• Active infection including tuberculosis, hepatitis B/C and HIV
• Patients with an expected or known hypersensitivity to olaparib or durvalumab or any of the excipients of the products.
• Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT).
• Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.
• Pregnancy or breastfeeding

Contacts and Locations

Locations

Netherlands

Amsterdam UMC, AMC

Amsterdam, Netherlands, 1105 AZ

NKI-AVL

Amsterdam, Netherlands

Universitair Medisch Centrum Groningen

Groningen, Netherlands

Leiden University Medical Center

Leiden, Netherlands, 2300RC

Academisch Ziekenhuis Maastricht

Maastricht, Netherlands

RadboudMC

Nijmegen, Netherlands

Erasmus MC

Rotterdam, Netherlands

Universitair Medisch Centrum Utrecht

Utrecht, Netherlands

Sponsors and Collaborators

Leiden University Medical Center

Amsterdam University Medical Center

Erasmus Medical Center

Maastricht University Medical Center

The Netherlands Cancer Institute

Radboud University Medical Center

University Medical Center Groningen

UMC Utrecht

AstraZeneca

More Information

• Responsible Party: J.R. Kroep, Principal Investigator, Leiden University Medical Center
• ClinicalTrials.gov Identifier: NCT03951415
• Other Study ID Numbers: DOMEC
• First Posted: May 15, 2019
• Last Update Posted: April 1, 2021
• Last Verified: March 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by J.R. Kroep, Leiden University Medical Center:

Poly (ADP-ribose) Polymerase Inhibitors; Antibodies, Monoclonal; Checkpoint Inhibitors; olaparib; durvalumab; Anti-PD-L1

Additional relevant MeSH terms:

Neoplasms; Endometrial Neoplasms; Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Durvalumab; Olaparib; Poly(ADP-ribose) Polymerase Inhibitors; Antineoplastic Agents, Immunological; Antineoplastic Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action