Pembrolizumab, Carboplatin, and Paclitaxel in Treating Patients With Stage III-IV Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

NCT02520154CompletedPHASE2INTERVENTIONAL

Summary

Key Facts

Lead Sponsor

M.D. Anderson Cancer Center

Enrollment

31

Start Date

2016-07-05

Completion Date

2025-05-22

Study Type

INTERVENTIONAL

Official Title

Matched Paired Pharmacodynamics and Feasibility Study of Pembrolizumab in Combination With Chemotherapy in Frontline Ovarian Cancer

Interventions

CarboplatinLaboratory Biomarker AnalysisPaclitaxelPembrolizumabPharmacological Study

Conditions

Stage III Fallopian Tube Cancer AJCC v7Stage III Ovarian Cancer AJCC v6 and v7Stage III Primary Peritoneal Cancer AJCC v7Stage IIIA Fallopian Tube Cancer AJCC v7Stage IIIA Ovarian Cancer AJCC v6 and v7Stage IIIA Primary Peritoneal Cancer AJCC v7Stage IIIB Fallopian Tube Cancer AJCC v7Stage IIIB Ovarian Cancer AJCC v6 and v7Stage IIIB Primary Peritoneal Cancer AJCC v7Stage IIIC Fallopian Tube Cancer AJCC v7Stage IIIC Ovarian Cancer AJCC v6 and v7Stage IIIC Primary Peritoneal Cancer AJCC v7Stage IV Fallopian Tube Cancer AJCC v6 and v7Stage IV Ovarian Cancer AJCC v6 and v7Stage IV Primary Peritoneal Cancer AJCC v7

Eligibility

Age Range

18 Years+

Sex

FEMALE

Inclusion Criteria:

* Signed, written informed consent
* Histology showing high-grade epithelial non-mucinous ovarian, primary peritoneal, or fallopian tube cancer
* No more than 4 prior cycles of chemotherapy for primary advanced (stage III or IV) epithelial ovarian, primary peritoneal, or fallopian tube cancer
* No prior treatment involving irradiation, hormonal therapy, immunotherapy, investigational therapy, and/or other concurrent agents or therapies for ovarian cancer
* A disposition to neoadjuvant chemotherapy with planned interval tumor reductive surgery after 4 complete cycles of treatment
* Planned dose-dense chemotherapy with combination carboplatin and paclitaxel given intravenously
* Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

  * Measurable disease is defined at least one lesion that can be accurately measured in at least one dimension (longest dimension to be recorded); each "target" lesion must be \>= 20 mm when measured by conventional techniques, including palpation, plain x-ray, computed tomography (CT), and magnetic resonance imaging (MRI), or \>= 10 mm when measured by spiral CT
  * Patients with non-measurable but evaluable solid tumors may be deemed eligible contingent upon principal investigator (PI) review
* Peripheral neuropathy grade 0 or 1 by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
* Tissue from an archival tissue sample or fresh tissue obtained from a core or excisional biopsy of a tumor lesion
* Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
* Absolute neutrophil count (ANC) \>= 1,500 /mcL
* Platelets \>= 100,000/mcL
* Hemoglobin (Hgb) \>= 9 g/dL or \>= 5.6 mmol/L
* Creatinine clearance \>= 60 mL/min for subject with creatinine levels \> 1.5 x institutional upper limit of normal (ULN)
* Total bilirubin =\< 1.5 x ULN OR direct bilirubin =\< ULN for subjects with total bilirubin levels \> 1.5 ULN
* Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x ULN OR =\< 5 x ULN for subjects with liver metastases
* International normalized ratio (INR)/prothrombin time (PT) =\< 1.5 x ULN (unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time \[PTT\] is within therapeutic range of intended use of anticoagulants)
* PTT =\< 1.5 x ULN (unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants)
* Women of child-bearing potential (intact uterus) should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 1 year; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
* Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 1 year; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
* Pre-treatment fresh frozen tissue available for research purposes; this tissue can be collected from preoperative laparoscopy, other diagnostic biopsy, or a research-specific biopsy
* Signed informed consent on protocol LAB02-188

Exclusion Criteria:

* Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment
* Histology showing mucinous or low grade epithelial ovarian carcinoma
* History of another primary malignancy except for:

  * Malignancy treated with curative intent and with no known active disease \>= 5 years before the first dose of study drug and or low potential risk for recurrence
  * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
  * Adequately treated carcinoma in situ without evidence of disease e.g., cervical cancer in situ
  * Concomitant stage 1A/B, grade 1-2 endometrioid endometrial cancer as allowable contemporary tumor
* 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 the first dose of study treatment 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 treatment
* Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
* Patients with ovarian cancer not medically fit for diagnostic laparoscopy prior to initiation of therapy
* Patients with any evidence of severe or uncontrolled systemic disease (e.g. severe hepatic impairment, interstitial lung disease \[bilateral, diffuse, parenchymal lung disease\], uncontrolled chronic renal disease \[glomerulonephritis, nephritic syndrome, Fanconi syndrome or renal tubular acidosis\]), or current unstable or uncompensated respiratory or cardiac conditions, or uncontrolled hypertension blood pressure \>= 140/90, active bleeding diatheses or active infection
* Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment
* Has had a prior monoclonal antibody 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
* Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =\< grade 1 or at baseline) from adverse events due to a previously administered agent; Note: subjects with =\< grade 2 neuropathy are an exception to this criterion and may qualify for the study; Note: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
* No active autoimmune disease that has required systemic treatment in past two years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc) is not considered a form of systemic treatment
* Has evidence of interstitial lung disease or active, non-infectious pneumonitis
* Has an active infection requiring systemic therapy
* 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 study
* Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the pre-screening or screening visit through 120 days after the last dose of study treatment
* Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
* Has known active hepatitis B (e.g., hepatitis B surface antigen \[HBsAg\] reactive) or hepatitis C (e.g., hepatitis C virus \[HCV\] ribonucleic acid \[RNA\] \[qualitative\] is detected)
* Has received a live vaccine within 30 days prior to the first dose of study treatment
* Patients with tuberculosis
* Patients with known hypersensitivity to pembrolizumab or any of its excipients
* Patients receiving concurrent additional biologic therapy
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to carboplatin, paclitaxel not responsive to traditional desensitization procedures
* Patient that is not able to understand or to comply with the study instructions and requirements or has a history of non-compliance to the medical regimen

Outcome Measures

Primary Outcomes

To Evaluate Progression-free Survival of Paclitaxel/Carboplatin and Pembrolizumab in Patients With Advanced Stage, Metastatic Ovarian Cancer Undergoing NACT

PFS was defined from the start of neoadjuvant therapy until the date of disease progression or death, whichever occurred first. Disease progression was evaluated using RECIST v1.1 guidelines. Patients who were alive without disease progression were censored at their last evaluation date or until withdrawal of consent. Patients who were removed off protocol for reasons other than disease progression, death, treatment toxicity, or withdrawal of consent were censored at the start date of their non-protocol treatment. Feasibility was defined as the ability to complete all planned 3 cycles of adjuvant carboplatin, paclitaxel, and pembrolizumab.

Time frame: Up to 3 years

Secondary Outcomes

To Describe the Feasibility of Combination Therapy and Maintenance Pembrolizumab in This Population

Pembrolizumab with chemotherapy was feasible and resulted in PFS within the historical range for this EOC population.

Time frame: Up to 3 years

To Evaluate the Safety of Combination and Maintenance Pembrolizumab

Toxicity was evaluated via grading and recording treatment-related adverse events (TRAE) according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.

Time frame: up to 3 years

Locations

M D Anderson Cancer Center, Houston, United States

MD Anderson in Katy, Houston, United States

MD Anderson League City, Nassau Bay, United States

MD Anderson in Sugar Land, Sugar Land, United States

MD Anderson in The Woodlands, The Woodlands, United States

Linked Papers

2024-08-15

Pembrolizumab plus chemotherapy in frontline treatment of advanced ovarian cancer: Clinical and translational results from a phase 2 trial

The efficacy and feasibility of pembrolizumab combined with chemotherapy in frontline management of advanced high-grade epithelial ovarian cancer (EOC) is unknown. Additionally, modification of the tumor microenvironment following neoadjuvant therapy is not well understood. In this single-arm phase 2 trial (this study was registered at ClinicalTrials.gov: NCT02520154), eligible patients received up to 4 cycles of neoadjuvant chemotherapy followed by interval cytoreduction, 3 cycles of adjuvant intravenous carboplatin/weekly paclitaxel/pembrolizumab, and finally maintenance pembrolizumab until progression or toxicity (maximum 20 cycles). The primary endpoint was progression-free survival (PFS). Secondary endpoints included feasibility, toxicity, and overall survival (OS). PD-L1 staining, multiplex immunofluorescence staining, RNA sequencing, reverse-phase protein array analyses were performed on pre- and post-chemotherapy samples. Thirty-one eligible patients were enrolled. Median PFS and OS was 14.88 (95% CI 12.39-23.00) and 57.43 months (95% CI 30.88-not reached), respectively. Among those with PD-L1 combined positive score (CPS) ≥10, the median PFS and OS were not reached compared to those with CPS <10 (10.50 and 30.90 months, respectively). Feasibility was met, with all patients completing their planned adjuvant cycles. Treatment discontinuation due to immune-related toxicity occurred in 6 patients (20%). Chemotherapy resulted in an infiltration of anti-tumor immune cells in the tumor microenvironment. Samples of patients with the best PFS demonstrated increased expression of NF-κB, TGF-β, and β-catenin signaling. Pembrolizumab with chemotherapy was feasible and resulted in PFS within the historical range for this EOC population. Patients with CPS ≥10 may benefit more from this regimen, and future studies should investigate this potential biomarker. This investigator-initiated trial was funded by Merck.

Linked Investigators