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

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.

Study Overview

• Status: Completed
• Conditions: Uterine Cancer
• Intervention / Treatment: Drug: Pembrolizumab (Keytruda)

Detailed Description

Objective:

The investigators aim to establish proof-of-concept for use of immune checkpoint blockade (ICB) as novel neo-adjuvant therapy in (deficient mismatch repair) dMMR and (Polymerase ε mutation)POLE-EDM uterine cancer (UC). When ICB proves to be feasible as defined in the primary endpoint, a follow-up with a larger multicenter studies to determine clinical efficacy, such as postponing standard-of-care surgery or randomized studies to standard-of-care.

Study design:

The investigators planned a 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).After treatment with immun checkpoint blockade a hysterectomy will take place (standard-of care). Peripheral blood and tumor samples will be used to evaluate immune responses.

Study population:

Primary dMMR/ POLE-EDM UC patients of any stage and/or grade who are intended to be treated with a hysterectomy recruited from the North-Netherlands oncological region.

Intervention: Pembrolizumab, 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.

Main study endpoints:

The primary endpoint is the response rate of the tumor assessed by pathology in uterine cancer patients treated with neo-adjuvant pembrolizumab. The secondary endpoint is the objective response rate of the tumor by MRI using RECIST. Exploratory objectives are immunogenicity, safety and the value of a pipelle biopsy as a predictor for response.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • Universitair Medisch Centrum Groningen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 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

Exclusion Criteria:

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: primary dMMR uterine cancer patients	Drug: Pembrolizumab (Keytruda); 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.
Experimental: primary POLE-EDM uterine cancer patients	Drug: Pembrolizumab (Keytruda); 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Radiologic response	To assess the objective response rate of the tumor by MRI using RECIST1.1 in uterine cancer patients treated with 2 cycles neo-adjuvant pembrolizumab	MRI is scheduled before start study drug (week 1) and after final study drug ( 6-10 weeks after baseline)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Systemic immune response using an IFN-y-ELISPOT to screen for the presence of antigen-specific T-cell responses to mutation associated neo antigens	Collection of PBMC (60mL blood by vena puncture) before, during and after treatment to assess antigen specific T cell responses to mutation-associated neo-antigens	At 6 timepoints through the study up to 32 weeks.
Safety (adverse events)	Adverse events will be documented according CTCAE.	Through study completion, an average of 32 weeks.
Feasibility (surgical delays due to study treatment)	The number of treatment-related surgical postponements will be counted to assess feasibility.	Up to planned hysterectomy (6-10 weeks after baseline)
Predictive value of pipelle biopsy	In order to assess the correlation of pathological response seen in the biopsy and the surgical specimen. A pipelle biopsy will be obtained during surgery and assess as the tumor specimen from hysterectomy in the primary endpoint.	An additional pipelle biopsy is obtained before start of the hysterectomy (6-10 weeks after baseline).

Collaborators and Investigators

• Sponsor: University Medical Center Groningen
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Hans W Nijman, Prof. dr., University Medical Center Groningen, UMCG; Principal Investigator: An KL Reyners, Prof. Dr., University Medical Center Groningen, UMCG

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2020
• Primary Completion (Actual): April 17, 2023
• Study Completion (Actual): November 1, 2023

Study Registration Dates

• First Submitted: January 28, 2020
• First Submitted That Met QC Criteria: February 5, 2020
• First Posted (Actual): February 10, 2020

Study Record Updates

• Last Update Posted (Actual): December 5, 2023
• Last Update Submitted That Met QC Criteria: December 4, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: pembrolizumab; neo-adjuvant; Uterine cancer; dMMR; POLE-EDM
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Female; Uterine Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Uterine Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Pembrolizumab
• Other Study ID Numbers: PAM-UMCG-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes