| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Primary uterine cancer characterized with dMMR | | Primair endometriumcarcinoom met dMMR | |
| E.1.1.1 | Medical condition in easily understood language | | Primary uterine cancer characterized by high mutational load | | Primaire baarmoeder kanker gekenmerkt door hoog aantal mutaties | |
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial | | The primary objective of this phase 2 trial is to establish the fraction of patients that achieve a major pathologic response (MPR) after 9 cycles of pembrolizumab, with the ultimate aim of informing a follow-up randomized trial. MPR was chosen as primary endpoint to align with ongoing randomized phase 3 ICB trials on neo-adjuvant vs. adjuvant treatment in other tumor types (e.g. the NADINA trial in melanoma; NCT04949113). | | Het primaire doel van deze fase 2 studie is om vast te stellen welke fractie patiënten een majeure pathologische response (MPR) bereiken na 9 cycli pembrolizumab, met als ultiem doel een follow-up randomized controlled trial studie uit te voeren. MPR is gekozen als primair eindpunt in lijn met reeds gestarte gerandomiseerde fase 3 ICI studies waarin neo-adjuvante vs. adjuvante behandeling vergeleken wordt in andere tumortypes (bijv. de NADINA studie bij melanomen; NCT4949113) | |
| E.2.2 | Secondary objectives of the trial | 1. To establish the objective response rate by radiologic assessment using MRI and RECIST 1.1.
2. To establish recurrence free survival (RFS) defined as the number of patients alive without any progress or recurrence at 2 years from disease diagnosis.
3. To assess safety and tolearbility of 9 cycles of neo-adjuvant pembrolizumab in the treatment of MMRd UC.
| 1. Het verkrijgen van een objective responsie waarde door radiologische beoordeling middels MRI en recist 1.1.
2. Bepalen van de recidief vrije overleving welke wordt gedefinieerd als het aantal patiënten zonder recidief 2 jaar na de diagnose.
3. Bepalen van Veiligheid en verdraagzaamheid van 9 kuren neo-adjuvante pembrolizumab bij de behandeling van MMRd endometrium carcinoom.
| |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | -Female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed primary diagnosis of G3/CC
MMRd uterine cancer who are intended to be treated with hysterectomy.
-A female participant is eligible to participate if she is not pregnant, not breastfeeding, is not a woman of childbearing potential (WOCBP) or agrees to
follow contraceptive guidance during the treatment period and at least until standard-of-care hysterectomy.
-The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
| - Vrouwelijke deelneemster, ouder dan 18 jaar, met histologisch bevestigde G3/CC MMRd baarmoederkanker waarbij het behandeldoel een
hysterectomie is.
- De deelneemster is niet vruchtbaar of stemt er mee in anticonceptie te gebruiken tijdens de studie
- De deelneemster geeft schriftelijk toestemming voor deelname aan de studie.
| |
| E.4 | Principal exclusion criteria | -A WOCBP who has a positive serum pregnancy test at screening.
-Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
-Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks [could consider shorter interval for kinase inhibitors or other short half-life drugs] prior to allocation.
-Has received prior radiotherapy within 2 weeks of start of study treatment or radition-related toxicities requiring corticosteroids. Note: Two weeks or fewer of palliative radiotherapy for non-CNS disease with a 1-week washout is permitted.
-Has received a live vaccine or live-attenuated vaccine within 30 days before to the first dose of study intervention. Administration of killed vaccines and Covid vaccines is allowed.
-Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.
-Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
-Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
-Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
-Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
-Has active autoimmune disease that has required systemic treatment in the past 2 years except replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid).
-Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
-Has an active infection requiring systemic therapy.
-Has a known history of Human Immunodeficiency Virus (HIV). Note: No HIV testing is required unless mandated by local health authority.
-Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
-Has not adequately recovered from major surgery or has ongoing surgical complications.
-Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
-Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
-Is pregnant or breastfeeding, or expecting to conceive within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.
| - Een positieve serum zwangerschapstest tijdens de screening
- Eerdere behandeling met anti-PD-1, anti-PD-L1, anti-PD-L2 of andere T-cel remmer
- Behandeling met systemische anti-kanker therapie 4 weken voor aanvang van de studie
- Radiotherapie 2 weken voor aanvang van de studie
- Levende vaccinatie ontvangen 30 dagen voor de eerste toediening van studiemedicatie
- Deelname aan een andere studie of eerdere deelname aan een studie met studiemedicatie tot 4 weken voor start studiemedicatie.
- Immuun gecompromitteerden of behandeling met chronische systemische steroïden
- Een andere bekende maligniteit waarvoor actieve behandeling noodzakelijk was in de afgelopen 3 jaar
- Actieve metastase in het centrale zenuwstelsel
- Ernstige hypersensitiviteit (> graad 3) tegen pembrolizumab
- actieve auto-immuun ziekte waarvoor behandeling heeft plaatsgevonden in de afgelopen 2 jaar
- Voorgeschiedenis met pneumonitis waarvoor steroïden behandeling nodig was
- Actieve infectie waarvoor systemische therapie nodig is
- HIV
- Hepatitis B of C
- Voorgeschiedenis of huidige conditie die volgens de onderzoeker de studie kan beïnvloeden
- Bekende psychiatrische stoornis of middelenmisbruik
- Zwangerschap of borstvoeding
| |
| E.5 End points |
| E.5.1 | Primary end point(s) | The main study endpoint is the fraction of patients that achieve a MPR. that the study is considered positive if neo-adjuvant pembrolizumab induces MPRs in at least 74% of patients.
| Het belangrijkste studie eindpunt is de fractie patiënten die een MPR behaald. De studie is geslaagd wanneer neo-adjuvante pembrolizumab in 74% van de patiënten een MPR geeft.
| |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | | Two independent pathologists will evaluate the collected tumor material after planned surgery to assess the major pathological response (MPR). Hematoxylin and eosin staining on endometrium tissue collected during surgery will be assessed by an experienced pathologist for the evidence of necrosis and/or viable tumor cells. | | Twee onafhankelijke pathologen zullen het verzamelde tumorweefsel evalueren na de geplande operatie om de MPR te bepalen. Hemotoxyline en eosine kleuring op endometrium weefsel zal geanalyzeerd worden om te kijken naar onder andere necrose en vitale tumorcellen. | |
| E.5.2 | Secondary end point(s) | 1.The objective response rate of the tumor determined by radiologic assessment using MRI and RECIST1.1.
2.Recurrence-free survival 2 years from disease diagnosis.
3.The safety and tolerability of 9 cycles of neo-adjuvant pembrolizumab in the treatment of MMRd UC.
| 1. Het verkrijgen van een objective responsie waarde door radiologische beoordeling middels MRI en recist 1.1.
2. Bepalen van de recidief vrije overleving welke wordt gedefinieerd als het aantal patiënten zonder recidief 2 jaar na de diagnose.
3. Bepalen van Veiligheid en verdraagzaamheid van 9 kuren neo-adjuvante pembrolizumab bij de behandeling van MMRd endometrium carcinoom. | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | 1. In order to establish the objective response rate (ORR), MRI will be performed at baseline (week 4) and will be compared to MRI performed after the second, fourth, sixth and ninth cycle of pembrolizumab (weeks 11, 17, 23 and 32, respectively). Tumor response will be classified according to RECIST 1.1.
2. Recurrence free survival will be assessed at the 2-year mark from initial disease diagnosis.
3. All AEs will be followed until they have abated, or until a stable situation has been reached.
All AEs from the first study treatment to 30 days after the surgery will be documented. AEs occurring later than this must only be documented if a relationship to the study drug is suspected.
| 1. Om een objective response rate (OOR) te kunnen bepalen, zal er een baseline MRI worden verricht en nadien zal deze vergeleken worden met een MRI na 2, 4, 6 en 9 kuren pembrolizumab (weken 11, 17, 23 en 32, respectievelijk). Tumor respons zal worden geclassificeerd volgens RECIST 1.1.
2. Recidief vrije overleving zal worden onderzocht 2 jaar na de initiële diagnose.
3. Alle AEs worden gevolgd tot ze zijn opgelost of tot een stabiele situatie is bereikt. Alle AEs van de eerste studie behandeling tot 30 dagen na de operatie worden gedocumenteerd. AEs die nadien voorkomen worden alleen gedocumenteerd als er een waarschijnlijke relatie is tot het studie medicijn. | |
| 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 | No |
| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 | The trial involves single site in the Member State concerned | Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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 | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
