DOMEC: Durvalumab and Olaparib in Metastatic or Recurrent Endometrial Cancer

Sponsor

Leiden University Medical Center (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03951415

Collaborator

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) (Other), Erasmus Medical Center (Other), Maastricht University Medical Center (Other), The Netherlands Cancer Institute (Other), Radboud University Medical Center (Other), University Medical Center Groningen (Other), UMC Utrecht (Other), AstraZeneca (Industry)

Enrollment

Locations

Arm

24.8

Anticipated Duration (Months)

6.9

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

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

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 :

Jul 8, 2019

Anticipated Primary Completion Date :

Aug 1, 2021

Anticipated Study Completion Date :

Aug 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

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

Progression free survival (PFS) [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

Objective response rate (ORR) [12 weeks]
according to RECIST 1.1 criteria
Overall survival (OS) [Through study completion, up to 36 months]
OS will be determined from the date of registration until death from any cause.
Adverse events [Through study completion, up to 36 months]
Assessed by NCI Common Terminology Criteria for adverse Events (CTCAE) version 5.0
Predictive biomarkers in tumor biopsy [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

Functional HRD assay (optional) [At baseline]
Extra biopsy
Immunological effects of PARP-1 inhibition (optional) [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).
Predictive biomarkers for PD-L1 blocking in blood (optional) [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

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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

	Site	City	Country	Postal Code
1	Amsterdam UMC, AMC	Amsterdam	Netherlands	1105 AZ
2	NKI-AVL	Amsterdam	Netherlands
3	Universitair Medisch Centrum Groningen	Groningen	Netherlands
4	Leiden University Medical Center	Leiden	Netherlands	2300RC
5	Academisch Ziekenhuis Maastricht	Maastricht	Netherlands
6	RadboudMC	Nijmegen	Netherlands
7	Erasmus MC	Rotterdam	Netherlands
8	Universitair Medisch Centrum Utrecht	Utrecht	Netherlands