DOMEC - phase II trial of Durvalumab (MEDI4736) and Olaparib in Metastatic/recurrent Endometrial Cancer, a DGOG trial

Phase 2

Recruiting

Conditions: Endometrial cancer inclusive carcinosarcoma of the endometrium
10027476

Registration Number: NL-OMON49312

Lead Sponsor: Academisch Medisch Centrum

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Recruiting

Sex: Not specified

Target Recruitment: 55

Inclusion Criteria

1. Must provide written informed consent prior to performance of study-specific
procedures or
assessments, and must be willing to comply with treatment and follow-up
assessments.
2. Age > 18 years old
3. Histologically confirmed diagnosis of endometrial cancer or carcinosarcoma
of the endometrium. Besides central revision, a tumor block or 20 slides are
asked for TR.
4. Metastatic disease or locally advanced tumor not amenable to local therapy.
5. Documented progressive disease before enrolment.
6. Measurable lesions outside irradiated field or progressive measurable
lesions in irradiated area
7. Not eligible for hormonal therapy (because of negative hormone receptor/poor
differentiation, or after failure of hormonal therapy).
8. Previous failure of chemotherapy, or refusal to undergo chemotherapy or
chemo-naive patients not suitable for chemotherapy.
9. WHO performance 0-1
10. 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 :
11. Expected adequacy of follow-up
12. Life expectancy of at least 16 weeks.
13. Measurable disease as defined by RECIST 1.1 criteria
14. Able to swallow and retain oral medication.
15. Body weight > 30 kg

Exclusion Criteria

1. Participation in another clinical study with an investigational product
during the last month or
previous enrolment in the present study.
2. Any previous treatment with PARP inhibitor, including olaparib and/or any
previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab.
3. History of another primary malignancy that could conceivably be active
evaluated by the study physician. except for Examples include, but are not
limited to:
* Malignancy treated with curative intent and with no known active disease >=5
years before the first dose of IP and of low potential risk for recurrence.
* Adequately treated non-melanoma skin cancer or lentigo maligna without
evidence of disease
* Adequately treated carcinoma in situ without evidence of disease.
4. History of leptomeningeal carcinomatosis. Patients with symptomatic
uncontrolled brain metastases. A scan to confirm the absence of brain
metastases is not required. The patient can receive a stable dose of
corticosteroids (maximum 2 mg/day) before and during the study as long as these
were started at least 4 weeks prior to treatment. Patients with spinal cord
compression unless considered to have received definitive treatment for this
and evidence of clinically stable disease for 28 days.
5. Resting ECG with QTc > 470 msec on 2 or more time points within a 24 hour
period or family history of long QT syndrome
6. Concomitant use of known strong CYP3A inhibitors (eg. itraconazole,
telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or
cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or
moderate CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem,
fluconazole, verapamil). The required washout period prior to starting olaparib
is 2 weeks.
7. Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin,
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John*s
Wort ) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The
required washout period prior to starting olaparib is 5 weeks for enzalutamide
or phenobarbital and 3 weeks for other agents.
8. 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
* Patients with Grade >=2 neuropathy will be evaluated on a case-by-case basis
after consultation with the Study Physician.
* Patients with irreversible toxicity not reasonably expected to be exacerbated
by treatment with durvalumab and olaparib may be included only after
consultation with the Study Physician.
9. Current or prior use of immunosuppressive medication within 14 days before
the first dose of durvalumab, with the exceptions of intranasal and inhaled
corticosteroids or systemic corticosteroids at physiological doses, which are
not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid.
10. Major surgery within 2 weeks of starting study treatment and patients must
have recovered from any effects of any major surgery.
11. Patients considered a poor medical risk due to a serious, uncontrolled
medical disorder, non-malignant systemic disease or active, uncontrolled
infection. Examples include, but are not limited to, uncontrolled ventricular

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>Primary study outcome:<br /><br>To determine the efficacy, in terms of the meadian progression-free survival<br /><br>using CT scans using RECIST 1.1.</p><br>

Secondary Outcome Measures

Name	Time	Method
<p>Secondary:<br />- Best objective response rate (ORR), progression free survival (PFS) at 6<br />months, overall survival (OS) using CT scan evaluation using RECIST 1.1.<br />- Toxicity using NCI-CTCAE version 5.0<br />- Explorative analysis for predictive biomarkers (eg MMRd/POLE, HR status,<br />quantification of CD3,CD4,CD8,<br />CD103,CD161,PD-1,LAG3,CTLA-4,NKG2A,FOXp3 positive T cells, NK cells, percentage<br />PDL1 on myeloid cells/tumor cells, quantification of myeloid cell infiltration<br />(CD68,CD14,CD33,CD163)) in tumor biopsies.</p>