Endometrial cancer inclusive carcinosarcoma of the endometrium
Conditions
Interventions
Patients will be treated with 2 experimental agents: olaparib (2x/day oral) and
durvalumab (1x/4 weeks iv).
Patients wil continue durvalumab infusions als long as the disease is stable or
in regress
Sponsors
Academisch Medisch Centrum
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
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 =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
Exclusion criteria: 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary study outcome: To determine the efficacy, in terms of the meadian progression-free survival using CT scans using RECIST 1.1. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary: - Best objective response rate (ORR), progression free survival (PFS) at 6 months, overall survival (OS) using CT scan evaluation using RECIST 1.1. - Toxicity using NCI-CTCAE version 5.0 - Explorative analysis for predictive biomarkers (eg MMRd/POLE, HR status, quantification of CD3,CD4,CD8, CD103,CD161,PD-1,LAG3,CTLA-4,NKG2A,FOXp3 positive T cells, NK cells, percentage PDL1 on myeloid cells/tumor cells, quantification of myeloid cell infiltration (CD68,CD14,CD33,CD163)) in tumor biopsies. | — |
Countries
Netherlands
Outcome results
None listed