PAM

Neo-adjuvant Pembrolizumab in dMMR/ POLE-EDM uterine cancer patients: a feasibility study

Protocolnummer:2
EudraCT nummer:2018-001816-31
METc nummer:METc 2019/490
Onderzoekscode:

Samenvatting

The study aims to establish proof-of-concept for use of immune checkpoint blockade (ICB) as novel neo-adjuvant therapy in patients with Uterine Cancer (UC) characterized by either MisMatch Repair deficiency (dMMR) or mutations in the exonuclease (proofreading) domain of DNA polymerase epsilon (POLE-EDM).

This window-of-opportunity study of ICB in primary dMMR UC (n=10) and primary POLE-EDM UC (n=10) patients. ICB (pembrolizumab; anti-PD1) will be administered in two cycles of 3 weeks between diagnosis and standard-of-care hysterectomy. Tumor responses to pembrolizumab will be assessed 3 weeks after the second cycle of pembrolizumab by a pathologist (primary endpoint) and MRI (secondary endpoint). Peripheral blood and tumor samples will be used to evaluate immune responses.

Follow-up: Adverse events will be followed up to 6 months after the final pembrolizumab administration. Outside the study protocol patients will be followed-up according to standard-of-care guidelines for uterine cancer and/or treatment with pembrolizumab for safety. Patients will be asked to participate in follow-up of disease progression outside of the study.

Inclusiecriteria

  • Female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed primary diagnosis of dMMR/POLE-EDM uterine cancer who are intended to be treated with hysterectomy will be enrolled in this study.
  • Have measurable disease based on RECIST 1.1 on MRI.
  • 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 the contraceptive guidance in section 5.2 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.

Exclusiecriteria

  • A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation.  If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  • 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.
    • Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible.
    • Note: If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.
  • Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
  • Has received a live vaccine within 30 days prior to the first dose of study drug.  Examples of live vaccines include, but are not limited to, the following:  measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine.  Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
  • Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.
    • Note:  Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
  • 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 (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  • 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 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.

Studiecoördinator

Arts-onderzoeker S.T. Paijens & A.L. Eerkens
Afdeling Obstetrie & Gynaecologie
Tel.: +316 25649882 (Onderzoeks telefoon O&G)
E-mail: s.t.paijens@umcg.nl & a.l.eerkens@umcg.nl

Prof. Dr. A.K.L. Reyners
Afdeling Medische Oncologie
Tel.: 050 3612821 (secretariaat Oncologie)
E-mail: a.k.l.reyners@umcg.nl