Cisplatin, Radiation Therapy, and Pembrolizumab in Treating Patients with Stage IB2-IIB or IIIB-IVA Cervical Cancer
This randomized phase II trial studies the side effects of cisplatin, radiation therapy, and pembrolizumab in treating patients with stage IB2IIB or IIIB-IVA cervical cancer. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays or other sources to kill tumor cells and shrink tumors. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Giving cisplatin, radiation therapy, and pembrolizumab may work better in treating patients with cervical cancer.
- Histologically confirmed cervical cancer * Histologically confirmed invasive squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix, stages IB, IIA, IIB, IIIB, and IVA; stage IB1 with positive pelvic or para-aortic nodes based on magnetic resonance imaging (MRI) is also eligible * No evidence of distant metastases (based on PET/CT done within 4 weeks of start of treatment) * Recurrent cervical cancer is not eligible
- Be willing and able to provide written informed consent for the trial
- Have a performance status of 0-2 on the Eastern Cooperative Oncology Group (ECOG) performance scale
- Absolute neutrophil count (ANC) >= 1,500 /mcL (performed within 14 days of treatment initiation)
- Platelets >= 100,000 / mcL (performed within 14 days of treatment initiation)
- Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN (performed within 14 days of treatment initiation)
- Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (performed within 14 days of treatment initiation)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases (performed within 14 days of treatment initiation)
- Albumin >= 2.5 mg/dL (performed within 14 days of treatment initiation)
- International normalized ratio (INR) or 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 (performed within 14 days of treatment initiation)
- Activated partial thromboplastin time (aPTT) =< 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 (performed within 14 days of treatment initiation)
- Female subject 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
- 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, or until they are no longer of child bearing potential
- Has history of malignancy within the prior 5 years; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy
- Has a diagnosis of immunodeficiency
- Has a known history of: i) human immunodeficiency virus (HIV) (HIV 1/2 antibodies); ii) hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative]); iii) active tuberculosis (TB) (Bacillus tuberculosis); or iv) inflammatory bowel disease
- Hypersensitivity to pembrolizumab 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 known history of, or any evidence of active, non-infectious pneumonitis
- Has an active infection requiring systemic therapy
- 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 trial 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 trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
- 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
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
- A serious uncontrolled medical disorder that in the opinion of the Investigator would impair the ability of the subject to receive protocol therapy
- Has had prior radiation for other diagnoses to the expected treatment field
- Has had prior radiation, chemotherapy, targeted therapy, or investigational therapy for cervical cancer * Note: if subject received major surgery for reason other than cervical cancer, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting treatment
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
- Within 7 days prior to the planned start of study treatment: * Is receiving systemic steroid therapy or any other form of immunosuppressive therapy
- Within 30 days prior to the planned start of study treatment: * Has received a live vaccine; examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, Bacillus Calmette–Guerin (BCG), and typhoid vaccine; 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 * Has participated in a study of an investigational agent and received study therapy or used an investigational device
- Is unable or unwilling to participate in a study related procedure
- Is pregnant or breastfeeding, or expecting to conceive children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of pembrolizumab
Locations & Contacts
Contact: Jennifer Michalle Scalici
Contact: Deborah Kay Armstrong
Contact: Julie Kristina Schwarz
Contact: Erin K. Crane
Contact: Katherine Marie Moxley
Contact: George Larry Maxwell
Contact: Linda Rosenbaum Duska
Contact: Sarah Madhu Temkin
Trial Objectives and Outline
I. To estimate the immunologic effects, as assessed in the tumor and peripheral blood mononuclear cells (PBMC), of both sequential and concurrent administration of pembrolizumab to chemoradiation treatment (CRT).
II. To determine the safety of concurrent chemoradiation in combination with pembrolizumab for the treatment of locally advanced cervical cancer.
I. To estimate rates of complete metabolic response on positron emission tomography (PET)/computed tomography (CT) imaging obtained 12 weeks after CRT.
II. To estimate rates of distant metastasis as the first site of recurrence for patients.
III. To estimate the influence of concurrent and consolidative pembrolizumab (MK-3475) on levels of plasminogen activator inhibitor-1 (PAI-1), a marker of immunosuppressive transforming growth factor (TGF)-beta (B).
IV. To estimate the influence of concurrent and consolidative MK-3475 on levels of IDO, an enzyme that depletes tryptophan, which is essential for T-cell function.
V. To estimate the influence of concurrent and consolidative MK-3475 on levels of major histocompatibility complex (MHC) class I (CD8+ T cell ligand) and MICA (natural killer [NK] ligand), as measured by MHC.
VI. To estimate the progression free survival (PFS) in subjects with locally advanced cervical cancer treated with sequential and concurrent administration of pembrolizumab in relation to CRT.
VII. To estimate the overall survival (OS) in subjects with locally advanced cervical cancer treated with sequential and concurrent administration of pembrolizumab in relation to CRT.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive cisplatin intravenously (IV) over 1 hour once weekly for 5-6 weeks and radiation therapy for 5-8 weeks comprising intensity modulated radiation therapy (IMRT) over 25 fractions and high-dose rate (HDR) brachytherapy over 4-6 fractions as per standard of care. Beginning week 9, patients receive pembrolizumab IV over 30 minutes every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive cisplatin and radiation therapy as in Arm I concurrently with pembrolizumab IV over 30 minutes every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 35 days and then annually for 5 years.
Trial Phase & Type
University of Virginia Cancer Center
Linda Rosenbaum Duska
Secondary IDs NCI-2016-00806, 17801
Clinicaltrials.gov ID NCT02635360