Neo-adjuvant Pembrolizumab in dMMR/ POLE-EDM Uterine Cancer Patients: a Feasibility Study

NCT04262089 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: PAM-UMCG-001
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

In this feasibility study the investigators intend to treat patients with high mutational uterine cancer with two cycles immune checkpoint inhibition before standard-of-care hysterectomy.

Conditions

Uterine Cancer

Keywords

Uterine cancer; dMMR; POLE-EDM; neo-adjuvant; pembrolizumab

Outcome Measures

Primary Outcomes (3)

• The primary objective is to characterize pathologic responses (necrosis/viable tumor cells) in uterine cancer patients treated with neo-adjuvant pembrolizumab

  Hematoxylin and eosin staining on endometrium tissue collected during standard-of-care hysterectomy will be assessed by an experienced pathologist for evidence of necrosis and/or viable tumor cells

  Tumor tissue is collected during standard of care hysterectomy (up to 6-10 weeks after baseline)

• The primary objective is to characterize pathologic responses (Degree of immune infiltration) in uterine cancer patients treated with neo-adjuvant pembrolizumab

  Hematoxylin and eosin staining on endometrium tissue collected during standard-of-care hysterectomy will be assessed by an experienced pathologist for degree of immune infiltration.

  Tumor tissue is collected during standard of care hysterectomy (week 6-10 after baseline)

• The primary objective is to characterize pathologic responses (Degrees of inflammation, fibrosis, and mucin) in uterine cancer patients treated with neo-adjuvant pembrolizumab

  Hematoxylin and eosin staining on endometrium tissue collected during standard-of-care hysterectomy will be assessed by an experienced pathologist for degrees of inflammation, fibrosis, and mucin, consistent with an ongoing immune response.

  Tumor tissue is collected during standard of care hysterectomy (week 6-10 after baseline)

Secondary Outcomes (1)

• Radiologic response

  MRI is scheduled before start study drug (week 1) and after final study drug ( 6-10 weeks after baseline)

Other Outcomes (4)

• Systemic immune response using an IFN-y-ELISPOT to screen for the presence of antigen-specific T-cell responses to mutation associated neo antigens

  At 6 timepoints through the study up to 32 weeks.

• Safety (adverse events)

  Through study completion, an average of 32 weeks.

• Feasibility (surgical delays due to study treatment)

  Up to planned hysterectomy (6-10 weeks after baseline)

Study Arms (2)

primary dMMR uterine cancer patients

EXPERIMENTAL

primary dMMR uterine cancer patients

Drug: Pembrolizumab (Keytruda)

primary POLE-EDM uterine cancer patients

EXPERIMENTAL

primary POLE-EDM uterine cancer patients

Drug: Pembrolizumab (Keytruda)

Interventions

Pembrolizumab (Keytruda) DRUG

Pembrolizumab (Keytruda), 200mg IV Q3W for a total of 2 administrations per patient, integrated into standard-of-care protocol prior to surgery. Based on the well-established time lines, the interval between diagnosis and standard of care hysterectomy is sufficient to treat patients with two cycles of pembrolizumab without interfering with standard of care.

primary POLE-EDM uterine cancer patients; primary dMMR uterine cancer patients

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• University Medical Center Groningen: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (1)

Universitair Medisch Centrum Groningen

Groningen, 9713 GZ, Netherlands

Location

Related Publications (1)

• Eerkens AL, Brummel K, Vledder A, Paijens ST, Requesens M, Loiero D, van Rooij N, Plat A, Haan FJ, Klok P, Yigit R, Roelofsen T, de Lange NM, Klomp R, Church D, Ter Elst A, Wardenaar R, Spierings D, Foijer F, Koelzer VH, Bosse T, Bart J, Jalving M, Reyners AKL, de Bruyn M, Nijman HW. Neoadjuvant immune checkpoint blockade in women with mismatch repair deficient endometrial cancer: a phase I study. Nat Commun. 2024 Sep 3;15(1):7695. doi: 10.1038/s41467-024-52098-8.

  PMID: 39227583 DERIVED

MeSH Terms

Conditions

Uterine Neoplasms

Interventions

pembrolizumab

Condition Hierarchy (Ancestors)

Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases

Study Officials

• Hans W Nijman, Prof. Dr.

  University Medical Center Groningen, UMCG

  PRINCIPAL INVESTIGATOR

• An KL Reyners, Prof. Dr.

  University Medical Center Groningen, UMCG

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: A window-of-opportunity study of ICB in primary dMMR UC (n=10) and primary POLE-EDM UC (n=10) patients.

Study Record Dates

• First Submitted: January 28, 2020
• First Posted: February 10, 2020
• Study Start: November 1, 2020
• Primary Completion: April 17, 2023
• Study Completion: November 1, 2023
• Last Updated: December 5, 2023

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)