A Study of Pembrolizumab on the Tumoral Immunoprofile of Gynecologic Cancers

• ClinicalTrials.gov Identifier: NCT02728830
• Recruitment Status: Active, not recruiting
• First Posted: April 5, 2016
• Results First Posted: July 9, 2020
• Last Update Posted: February 23, 2021
• Sponsor: AA Secord
• Collaborator: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): AA Secord, Duke University

Study Description

Brief Summary:

The ultimate goal of the study is to identify potential biomarkers, immune gene expression signatures, and co-stimulatory pathways that may be used to understand the effect of immune checkpoint inhibitors on gynecologic cancers.

Condition or disease	Intervention/treatment	Phase
Gynecologic Neoplasms; Epithelial Ovarian Cancer; Uterine Endometrial Cancer; Fallopian Tube Cancer; Peritoneal Cancer	Drug: Pembrolizumab	Early Phase 1

Detailed Description:

Epithelial gynecologic malignancies are tumors of müllerian origin, which include ovarian, endometrial, fallopian tube, and primary peritoneal cancers, and account for >70,000 new diagnoses and >22,000 deaths per year in the United States alone. Treatment typically consists of a thorough cytoreductive and staging surgery in combination with platinum/taxane chemotherapy. Newer approaches adding anti-angiogenic therapies to chemotherapy have resulted in moderate improvements in recurrence free survival. However, despite these aggressive treatments, the majority of women with advanced stage at diagnosis will experience relapse. Unfortunately, relapsed disease is incurable and women ultimately die of their disease despite maximal efforts at cancer control using subsequent chemotherapy or targeted agents. There has been significant interest in incorporating immune checkpoint therapies in the treatment of gynecologic malignancies, especially given the durable remissions associated with these therapies in the treatment of melanoma and early indications of durable responses in recurrent ovarian cancer. At this time, little is known about whether or how to combine chemotherapy, anti-angiogenic therapies, and immunologic therapies for maximal benefit. Understanding the tumor microenvironment, particularly immune and angiogenic factors that contribute to tumor survival, as well as the changes that occur in response to immunotherapy is critical to identify favorable biomarker profiles which could lead to improved prognostic outcomes and inform the development and sequencing of therapies to maximize benefit.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 39 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot Study Investigating the Effect of Pembrolizumab on the Tumoral Immunoprofile of Gynecologic Cancers of Mullerian Origin
• Study Start Date: June 2016
• Actual Primary Completion Date: January 2019
• Estimated Study Completion Date: December 2021

Arms and Interventions

Arm

Intervention/treatment

Experimental: Pembrolizumab; Subjects will receive one dose of 200mg pembrolizumab by IV 14-21 days prior to surgery. Subjects will undergo standard surgical cytoreductive surgery as deemed appropriate by their gynecologic oncologist, followed by standard adjuvant chemotherapy for their cancer as deemed appropriate by their treating physician. If subject's disease does not get worse following standard of care chemotherapy, they will receive pembrolizumab in the maintenance setting every three weeks for up to a year. If subject's disease returns after completing a year of pembrolizumab and they have not had adverse reactions to pembrolizumab they may be eligible to continue receiving pembrolizumab for an additional year in the second course phase.

Drug: Pembrolizumab; Pembrolizumab 200mg IV; Other Name: Keytruda

Outcome Measures

Primary Outcome Measures :

1. Change in Tumor Immune Infiltrates as Measured by PD-L1 Modified H-Score [ Time Frame: Baseline and 14-21 Days ]

   This outcome measures the change in tumor immune infiltrates post-pembrolizumab versus pre-pembrolizumab as measured by the PD-L1 Modified H-score.

   Histological score (H-score) is a score that is comprised of intensity and percentage of staining and is used for assessing amount of protein (in this case PD-L1) present in a tissue sample. H-score is determined by adding of the percentages of cell staining at each intensity level multiplied by the membrane intensity of staining (0 (no staining), 1+ (weak staining), 2+ (medium staining), 3+(strong staining)).

   The H-score has a range of 0 to 300. Lower H-scores represent lower expression of PD-L1 in the tumor sample, while higher scores represent stronger expression of PD-L1 in the tumor samples.

Secondary Outcome Measures :

1. Toxicity Profile: Frequency and Severity of Adverse Events as Assessed by CTCAE [ Time Frame: 18 months ]
   Frequency and severity of adverse events associated with pembrolizumab when given to patients with newly diagnosed gynecologic cancers of müllerian origin prior to standard surgical therapy and as maintenance therapy after completion of chemotherapy. All events experienced within the AE reporting time frame deemed probably, possibly, or definitely related to study drug above the reporting threshold of 4%. Categorized by grade and frequency, defined using CTCAE 4.0 event name and grading.

Other Outcome Measures:

1. Exploratory: Changes in Tumoral and Circulating Blood Immunoprofile [ Time Frame: Baseline and 14-21 Days ]
   To characterize changes in the tumoral and circulating blood immunoprofile after administration of pembrolizumab. Levels of immune and inflammatory mediators, profile of tumor immune infiltrates, and the expression of PD-L1 in pre-administration samples will be compared to post-administration surgical resection (including ascites) samples.
2. Exploratory: Changes in Tumoral and Circulating Blood Immunoprofile for Those Who Enroll in Second Course Phase at Time of Recurrence [ Time Frame: 18 months ]
   To evaluate changes in the tumoral and circulating blood immunoprofile at time of recurrence. Levels of immune and inflammatory mediators, profile of tumor immune infiltrates, and the expression of PD-L1 in samples at time of recurrence will be compared to pre-administration and surgical samples.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Have histologically or cytologically confirmed gynecologic tumor of müllerian origin, specifically epithelial ovarian, fallopian tube, primary peritoneal, or uterine endometrial cancer.
2. Have disease amenable to surgical resection.
3. Be willing and able to provide written informed consent for the trial.
4. Be at least 18 years of age on day of signing informed consent.
5. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement of the investigator.
6. Have a performance status of 0 or 1 on the ECOG Performance Scale.
7. Demonstrate adequate organ function as defined below. All screening labs should be performed within 10 days of study drug administration:

7a. ANC ≥ 1,500/mcL

7b. Platelets ≥ 100,000/mcL

7c. Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L without transfusion or EPO dependency (within 7 days of assessment)

7d. Serum creatinine ≤ 1.5 times the upper limit of normal or calculated creatinine clearance ≥ 60 mL/min for subject with creatinine levels > 1.5 times institutional upper limit of normal

7e. Serum total bilirubin ≤ 1.5 times the upper limit of normal or direct bilirubin ≤ the upper limit of normal with total bilirubin levels > 1.5 times upper limit of normal

7f. AST and ALT ≤ 2.5 times the upper limit of normal or ≤ 5 times the upper limit of normal for subjects with liver metastases

7g. Albumin > 2.5 mg/dL

7h. International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 times the upper limit of normal unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

7i. Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 times the upper limit of normal unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

8. Female subjects of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

9. Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity until planned hysterectomy/oophorectomy. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.

Exclusion Criteria:

1. Is currently participating and receiving a study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the study drug administration.
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to study drug administration.
3. Has a known history of active TB (Bacillus Tuberculosis)
4. Hypersensitivity to pembrolizumab or any of its excipients.
5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.

6. Has received prior chemotherapy, targeted small molecule therapy, or radiation therapy for the current gynecologic malignancy.

   NOTE: Subjects who have received treatment for a prior unrelated malignancy must have recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.

   NOTE: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.

7. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cervical cancer.
8. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to study drug administration and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to study drug administration. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
9. 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.
10. Has known history of, or any evidence of active, non-infectious pneumonitis.
11. Has an active infection requiring systemic therapy.
12. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
13. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
14. Is pregnant or breastfeeding.
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
18. Has received a live vaccine within 30 days of planned start of study therapy. NOTE: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

Contacts and Locations

Locations

United States, North Carolina

Duke Cancer Institute

Durham, North Carolina, United States, 27710

Sponsors and Collaborators

AA Secord

Merck Sharp & Dohme LLC

Investigators

• Principal Investigator: Angeles A Secord, MD; Duke University

  Study Documents (Full-Text)

Documents provided by AA Secord, Duke University:

Study Protocol and Statistical Analysis Plan  [PDF] October 17, 2019

More Information

• Responsible Party: AA Secord, Professor of Obstetrics & Gynecology, Duke University
• ClinicalTrials.gov Identifier: NCT02728830
• Other Study ID Numbers: Pro00068544
• First Posted: April 5, 2016
• Results First Posted: July 9, 2020
• Last Update Posted: February 23, 2021
• Last Verified: February 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by AA Secord, Duke University:

gynecologic cancers; mullerian cancers; tumoral immunoprofile

Additional relevant MeSH terms:

Endometrial Neoplasms; Fallopian Tube Neoplasms; Carcinoma, Ovarian Epithelial; Genital Neoplasms, Female; Ovarian Neoplasms; Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Ovarian Diseases; Adnexal Diseases; Urogenital Neoplasms; Endocrine System Diseases; Gonadal Disorders; Uterine Neoplasms; Uterine Diseases; Fallopian Tube Diseases; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Pembrolizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents