Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

All Conditions

Rare Diseases

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Endometrial Neoplasms

Fallopian Tube Neoplasms

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Genital Neoplasms, Female

Urogenital Neoplasms

Uterine Neoplasms

Uterine Diseases

Fallopian Tube Diseases

Ovarian Cancer

Ovarian Epithelial Cancer

Fallopian Tube Cancer

Angeles A Secord, MD

The investigators propose to collect biologic samples (i.e. tumor tissue, ascites, and/or blood), from patients undergoing standard of care therapy for a gynecologic malignancy. To detect changes in the immune response following chemotherapy, collection of biologic samples will occur at baseline and at the time of surgery following chemotherapy.

This is a single-institution, non-interventional prospective observational study allowing for specimen and data collection. All participants will receive standard of care surgery and chemotherapy, determined by the gynecologic oncologist and per institutional protocols. Patients with a presumed diagnosis of an eligible gynecologic malignancy (epithelial ovarian, fallopian tube, primary peritoneal, or uterine endometrial cancer) who are being considered for neoadjuvant chemotherapy prior to confirmatory biopsy will be given the option to enroll on this study.

Patients will undergo standard biopsy or endometrial curettage to confirm diagnosis. Additional tumor tissue for research purposes will be collected at the time of biopsy (if safely available). Patients who are undergoing diagnostic or therapeutic paracentesis will have the option to consent to allow excess ascites to be evaluated in this research protocol. Additionally, a research blood sample will be collected on the same day as the biopsy/curettage.

After confirmation of diagnosis, chemotherapy administration will proceed per standard institutional protocol and surgical planning will be performed by the treating gynecologic oncologist. Excess tumor tissue and ascites from the cytoreductive surgery will be collected for immune profiling. An additional vial of blood for research will be collected within 3 days prior to surgery. Post-surgical treatment and chemotherapy will proceed per standard procedures. After completion of post-surgical adjuvant therapy, an additional vial of blood for research will be collected (at next scheduled clinic visit).

1. Blood (30ml) on the day of biopsy
2. Additional tissue at time of clinical biopsy (if it is safe for additional tissue to be collected during this time beyond what is clinically indicated, an effort will be made to do so. All biopsy tissue collected will be sent to pathology, including any additional tissue. Tissue remaining after pathology has performed their clinical care requirements will be collected) OR Collection of excess tissue at time of clinical biopsy (if it is unsafe for additional tissue to be collected, only tissue in excess of what is what pathology uses will be collected)
3. Excess ascites at time of paracentesis (if performed for diagnostic/therapeutic purposes)
4. Additional blood (30ml) within 3 days of surgery
5. Excess tumor tissue and ascites at the time of cytoreductive surgery
6. Blood (30ml) at the next scheduled visit after completion of post-surgical adjuvant therapy.

A Pilot Study Investigating the Effect of Chemotherapy on the Tumoral Immunoprofile of Gynecologic Cancers

To assess changes in the immune response through the characterization of tumor infiltrating lymphocytes (TILs) after administration of chemotherapy. Biomarker testing is for the purpose of biological research and is not intended to test or develop an in-vitro diagnostic test.

To assess changes in immune response through the characterization of inflammatory mediators after administration of chemotherapy. Biomarker testing is for the purpose of biological research and is not intended to test or develop an in-vitro diagnostic test.

To assess changes in the immune response through the characterization of tumor expression of PD-L1 after administration of chemotherapy. Identify immune signatures/biomarkers that predict treatment outcomes. Biomarker testing is for the purpose of biological research and is not intended to test or develop an in-vitro diagnostic test.

To assess changes in HLA-type after administration of chemotherapy. Identify immune signatures/biomarkers that predict treatment outcomes. Biomarker testing is for the purpose of biological research and is not intended to test or develop an in-vitro diagnostic test.

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Duke University

Carcinoma

Endocrine Gland Neoplasms

Ovarian Diseases

Endocrine System Diseases

Gonadal Disorders

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Antineoplastic Agents

All Drugs and Chemicals

Pembrolizumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

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.

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.

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.

A Study of Pembrolizumab on the Tumoral Immunoprofile of Gynecologic Cancers

A Pilot Study Investigating the Effect of Pembrolizumab on the Tumoral Immunoprofile of Gynecologic Cancers of Mullerian Origin

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.

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.

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.

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.

Merck Sharp & Dohme LLC

AA Secord

Professor of Obstetrics & Gynecology

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.

Pembrolizumab: Pembrolizumab 200mg IV

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Primary Tumor Site

Histologic Subtype

Tumor Grade at Diagnosis

This measure is the stage of the cancer as determined by the FIGO (International Federation of Gynecology and Obstetrics) system.

Stage I is the least severe, where the tumor is restricted to the organ of origin.

Stage II involves invasion of surrounding organs or tissue. Stage III involves spread to the distant lymph nodes or tissue within the pelvis.

Stage IV involves distant metastasis beyond the peritoneal cavity.

FIGO Stage of Cancer at Diagnosis

The Eastern Cooperative Oncology Group Performance Status (ECOG) is a way for physicians to track changes in a subject's level of functioning on a 5 point scale. An ECOG score of 0 is a subject who is fully active and able to carry on all pre-disease performance without restriction. An ECOG score of 1 is restricted in physically strenuous activity but ambulatory and able to carry out work of light or sedentary nature (e.g. light house work). The higher the score, the more restricted in level of function and capability of self-care

Eastern Cooperative Oncology Group Performance Status

This measure depicts that amount of residual disease that was left at the time of surgery completion. Optimal R0 notes that no residual disease was left after surgery. Optimal R1 notes that less than 1cm of residual disease remained. Suboptimal debulking notes that macroscopic residual disease was left at the end of surgery.

Debulking Surgery

Analysis was conducted only on subjects who completed the study.

Dr. Angeles Alvarez Secord

Eleven subjects had adequate matched pre- and post- treatment tissue samples for analysis for tumor immune infiltrates.

Change in Tumor Immune Infiltrates as Measured by PD-L1 Modified H-Score

Anemia, Grade 1

Neutropenia, Grade 2

Thrombocytopenia, Grade 1

Abdominal pain, Grade 1

Abdominal pain, Grade 2

ALT elevation, Grade 1

ALT elevation, Grade 2

ALT elevation, Grade 3

AST elevation, Grade 1

AST elevation, Grade 2

AST elevation, Grade 3

ALK phosphatase elevation, Grade 1

ALK phosphatase elevation, Grade 2

Arthralgia, Grade 1

Anorexia, Grade 1

Anorexia, Grade 2

Back pain, Grade 1

Bloating, Grade 1

Bloating, Grade 2

Constipation, Grade 1

Constipation, Grade 2

Diarrhea, Grade 1

Diarrhea, Grade 2

Diarrhea, Grade 3

Dyspnea, Grade 2

Edema, Grade 1

Fatigue, Grade 1

Fatigue, Grade 2

Headache, Grade 1

Hypertension, Grade 1

Hypertension, Grade 2

Hypertension, Grade 3

Hypoalbuminemia, Grade 1

Hypomagnesemia, Grade 1

Hypomagnesemia, Grade 2

Hyponatremia, Grade 1

Hyponatremia, Grade 3

Nausea, Grade 1

Nausea, Grade 2

Proteinuria, Grade 1

Proteinuria, Grade 2

Proteinuria, Grade 3

Vomiting, Grade 1

Weight loss, Grade 1

Toxicity Profile: Frequency and Severity of Adverse Events as Assessed by CTCAE

CXCL10 Fold Change, Pre to Post Pembro

IFN-Gamma Fold Change, Pre to Post Pembro

IL12p70 Fold Change, Pre to Post Pembro

IL1b Fold Change, Pre to Post Pembro

IL2ra Fold Change, Pre to Post Pembro

IL6 Fold Change, Pre to Post Pembro

TNF-Alpha Fold Change, Pre to Post Pembro

Thirteen participants had pre and post samples available for analysis

Exploratory: Changes in Tumoral and Circulating Blood Immunoprofile

No enrolled subjects qualified for the second course phase

Exploratory: Changes in Tumoral and Circulating Blood Immunoprofile for Those Who Enroll in Second Course Phase at Time of Recurrence

Overall Study

Uterine Cervical Neoplasms

Central Nervous System Depressants

Analgesics

Anti-Inflammatory Agents

Antirheumatic Agents

Anesthetics

Morphine

Anti-Inflammatory Agents, Non-Steroidal

Narcotics

Analgesics, Opioid

Analgesics, Non-Narcotic

Patients undergoing standard anesthesia and standard exploratory laparotomy. Treatment will be per your surgeon's routine standards.

Protocol for "rapid recovery laparotomy" procedure involves pre-operative counseling, the use of regional anesthesia (spinal or epidural pain management rather than intravenous narcotics), post-operative use of non-steroidal anti-inflammatory drugs, early eating after surgery, early walking, and certain goals for discharge from the hospital.

Exploratory surgery for gynecologic diagnosis.Involves pre-operative counseling, the use of regional anesthesia (spinal or epidural pain management rather than intravenous narcotics), early eating after surgery, early walking, and certain goals for discharge from the hospital

Laparotomy

given for pain management after surgery per physician orders

intravenous narcotics

standard anesthesia

regional anesthesia

Non-steroidal anti-inflammatory drugs

Peter Argenta, M.D.

Over 600,000 hysterectomies are performed annually in the United States. Despite increasing use of less invasive approaches, the majority of hysterectomies are still performed via traditional laparotomy, which can be associated with generally slower recovery and longer lengths of post-operative hospitalization. Rapid Recovery Protocols (RRP) seek to optimize post-surgical morbidity outcomes by returning a patient to normal physiology as quickly as possible following surgery.

Subjects will be randomly assigned to one of two groups: Rapid recovery protocol (regional anesthesia, pain control options with emphasis on nonsteroidal anti-inflammatory drugs (NSAIDS) over narcotic pain medications, early ambulation, and early enteral feeding) or standard of care (traditional laparatomy and supportive care).

Implementation of a Rapid Recovery Program in Gynecologic Oncology Surgery: A Pilot Study

Length of hospital stay for patients undergoing laparotomy on the gynecologic oncology service measured as whole days from the day of surgery until discharge

Total daily narcotic pain medication used by patients. Narcotic use was standardized by conversion to morphine equivalents using the methods of Korff et al.

Secondary outcome is to determine if rapid recovery can improve Visual Analogue Scale (VAS) for pain assessment. VAS scales are a horizontal line 100 mm in length with the left end labeled 'No pain' and the right end labeled 'Very severe pain'. The subject marks a point on the line that represents their perception of their current state. VAS score is determined by measuring the distance (mm) from the left end of the line to the point on the line marked by the subject. The range of possible values for this pain score is 0 to 100 mm.

Masonic Cancer Center, University of Minnesota

Patients undergoing standard anesthesia and standard exploratory laparotomy. Treatment will be per your surgeon's routine standards.

Laparotomy: Exploratory surgery for gynecologic diagnosis.Involves pre-operative counseling, the use of regional anesthesia (spinal or epidural pain management rather than intravenous narcotics), early eating after surgery, early walking, and certain goals for discharge from the hospital

intravenous narcotics: given for pain management after surgery per physician orders

standard anesthesia: inhalant or intravenous during surgery

Control Group (Standard Laparotomy)

Protocol for "rapid recovery laparotomy" procedure involves pre-operative counseling, the use of regional anesthesia (spinal or epidural pain management rather than intravenous narcotics), post-operative use of non-steroidal anti-inflammatory drugs, early eating after surgery, early walking, and certain goals for discharge from the hospital.

Laparotomy: Exploratory surgery for gynecologic diagnosis.Involves pre-operative counseling, the use of regional anesthesia (spinal or epidural pain management rather than intravenous narcotics), early eating after surgery, early walking, and certain goals for discharge from the hospital

regional anesthesia: given by spinal or epidural infusion

Non-steroidal anti-inflammatory drugs: given for pain management after surgery

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Pilot Study Investigating the Effect of Chemotherapy on the Tumoral Immunoprofile of Gynecologic Cancers	NCT02824328	Ovarian Cancer Fallopian Tube ... Peritoneal Canc... Uterine Endomet...		18 Years -	Duke University
A Pilot Study Investigating the Effect of Chemotherapy on the Tumoral Immunoprofile of Gynecologic Cancers	NCT02824328	Ovarian Cancer Fallopian Tube ... Peritoneal Canc... Uterine Endomet...		18 Years -	Duke University
A Study of Pembrolizumab on the Tumoral Immunoprofile of Gynecologic Cancers	NCT02728830	Gynecologic Neo... Epithelial Ovar... Uterine Endomet... Fallopian Tube ... Peritoneal Canc...	Pembrolizumab	18 Years -	Duke University
Implementation of a Rapid Recovery Program in Gynecologic Oncology Surgery: A Pilot Study	NCT01705288	Cervical Cancer Uterine Endomet... Ovarian Cancer	Laparotomy intravenous nar... standard anesth... regional anesth... Non-steroidal a...	19 Years -	Masonic Cancer Center, University of Minnesota

Spots Global Cancer Trial Database for uterine endometrial cancer