| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| advanced endometrial cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| advanced endometrial cancer |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To determine the efficacy, in terms of the progression-free survival, in patients with recurrent or metastatic endometrial cancer receiving treatment with durvalumab and olaparib
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| E.2.2 | Secondary objectives of the trial |
- Objective response rate (ORR), progression free survival (PFS) at 6 months, overall survival (OS)
- Toxicity
- 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.
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Optional:
- Baseline HRD assay (Rad51)
- Immunomonitoring (venous bloodsamples bloodsamples 50 cc at 3 different time points)
- Explorative analysis for the immunological effects of PARP-1 inhibition and predictive biomarkers for PD-L1 blocking in blood.
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| E.3 | Principal 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 or cytologically 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)
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
16. A female is eligible to enter and participate in this study if there is:
Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients*.
Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
- Women <50 years of age would be considered post-menopausal if they have been amenorrheic for > 12 months following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
- Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). |
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| E.4 | Principal exclusion criteria |
1. another investigational product during the last month.
2. Any previous treatment with PARP inhibitor and/or any previous treatment with a PD1 or PD-L1 inhibitor.
3. History of another primary malignancy that could conceivably be active evaluated by the study physician.
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 or moderate CYP3A inhibitors. The required washout period prior to starting olaparib is 2 weeks.
7. Concomitant use of known strong or moderate CYP3A inducers. 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 arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent.
12. History of active primary immunodeficiency
13. Active or prior documented autoimmune or inflammatory disorders, diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:
Patients with vitiligo or alopecia
Patients with hypothyroidism stable on hormone replacement
Any chronic skin condition that does not require systemic therapy
Patients without active disease in the last 5 years may be included but only after consultation with the study physician
Patients with celiac disease controlled by diet alone
14. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
15. Active infection including tuberculosis, hepatitis B , hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
16. Patients with a known hypersensitivity to olaparib or durvalumab or any of the excipients of the products.
17. Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT).
18. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.
19. Female patients who are pregnant or breastfeeding or patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| To determine the efficacy, in terms of the median progression-free survival using CT scans using RECIST 1.1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Best objective response rate (ORR), progression free survival (PFS) at 6 months, overall survival (OS) using CT scan evaluation using RECIST 1.1.
2. Toxicity using NCI-CTCAE version 5.0
3. 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. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
ad 1) at disease progression, and in case of mortality
ad 2) at disease progression
ad 3) at baseline and during therapy |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 30 |
| E.8.9.1 | In the Member State concerned days | |
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