Balstilimab Versus Investigator Choice Chemotherapy in Patients With Recurrent Cervical Cancer (BRAVA)

Inclusion Criteria:

1. Voluntarily agree to participate by giving written informed consent.
2. ≥ 18 years of age.
3. Diagnosis and prior systemic treatment:
4. Has recurrent or metastatic cervical cancer (SCC, AC, or ASC histology) and hasexperienced disease progression during or after treatment with a standardplatinum based therapy with or without bevacizumab.
5. Has received at least 1 prior systemic therapy regimen for recurrent, persistent,and/or metastatic cervical cancer. Note: Chemotherapy administered in the adjuvant or neoadjuvant setting, or incombination with radiation therapy, should not be counted as a prior systemic therapyregimen for recurrent, persistent, and/or metastatic cervical cancer.
6. Measurable disease - based on Investigator assessment. a. Radiological evidence of measurable disease on imaging based on RECIST v1.1 Note:Patients must have at least 1 "target lesion" to be used to assess response, asdefined by RECIST v1.1. Tumors within a previously irradiated field will be designatedas "non target" lesions unless progression is documented, or a biopsy is obtained toconfirm persistence at least 90 days following completion of radiation therapy.
7. Has a life expectancy of at least 3 months and an ECOG performance status of 0 or 1.
8. Patients must have sufficient and adequate formalin-fixed tumor tissue sampleavailable that is not older than 3 years; otherwise, a fresh biopsy is required.Archival tissue or fresh biopsy must be from a site not previously irradiated.
9. Has adequate organ function as indicated by the following laboratory values:
10. Adequate hematological function defined by absolute neutrophil count ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L, and stable hemoglobin ≥ 8 g/dL (withouttransfusions within 1 week before first dose).
11. Adequate hepatic function based by a total bilirubin level ≤ 1.5 × the upperlimit of normal (ULN), aspartate aminotransferase (AST) level ≤ 2.5 × ULN,alanine aminotransferase (ALT) level ≤ 2.5 × ULN, alkaline phosphatase (ALP) ≤ 2.5 × ULN, and albumin ≥ 3.0 mg/dL. In the case of hepatic metastases, < 5 × ULNfor AST/ALT and ALP.
12. Adequate renal function defined as calculated creatinine clearance > 40 mL/min ora serum creatinine < 1.5 × ULN, per institutional standards (creatinine clearanceshould be calculated per institutional standards).
13. Adequate coagulation defined by international normalized ratio or prothrombintime ≤ 1.5 × institutional upper limit of normal IULN unless the patient isreceiving anticoagulant therapy) and activated partial thromboplastin time ≤ 1.5 × IULN (unless the patient is receiving anticoagulant therapy).
14. Normal thyroid function (thyroid stimulating hormone) whether or not the patientis on supplemental thyroid hormone.
15. Has no history of another primary malignancy except:
16. Malignancy treated with curative intent and with no known active disease ≥ 5years before the first dose of study drug and of low potential risk forrecurrence.
17. Adequately treated non-melanoma skin cancer or lentigo maligna without evidenceof disease.
18. Adequately treated carcinoma in situ without evidence of disease.
19. Women of childbearing potential (WOCP) must have a negative serum pregnancy test atScreening (within 72 hours before first dose of study drug). Non-childbearingpotential is defined as (by other than medical reasons):
20. ≥ 45 years of age and has not menstruated for greater than 1 year.
21. Definitive pelvic radiation for the treatment of cervical cancer.
22. Whose status is post hysterectomy, bilateral oophorectomy, or tubal ligation.
23. WOCP must be willing to use 2 highly effective methods of contraception (definedin the informed consent form) throughout the trial, starting with the ScreeningVisit through 90 days after the last dose of study drug Note: Abstinence isacceptable if this is the established and preferred contraception for thepatient.
24. Is willing and able to comply with the requirements of the protocol.

Exclusion Criteria:

1. Is currently participating and receiving study therapy or has participated in a trialof an investigational agent and received study therapy or used an investigationaldevice within 4 weeks before the first dose of treatment.
2. Has an inadequate period of time prior to first dose of study treatment that isdefined as:
3. Received systemic cytotoxic chemotherapy or biological therapy within 28 daysbefore initiation of study treatment
4. Received radiation therapy within 28 days before initiation of study treatment,except for palliative bone therapy, which can be received 2 weeks prior toinitiation of study treatment
5. Had major surgery within 4 weeks before initiation of study treatment
6. Has received prior therapy with: a. Any antibody/drug targeting T-cell co-regulatory proteins (immune checkpoints) suchas anti-programmed cell death protein 1 and anti-PD-L1 antibodies.
7. Has persisting toxicity related to prior therapy of NCI-CTCAE v5.0 Grade ≥ 1 severity,with the exceptions noted below:
8. Peripheral neuropathy Grade ≤ 2.
9. Alopecia Grade ≤ 2.
10. Is expected to require any other form of systemic or localized antineoplastic therapywhile on trial (including maintenance therapy with another agent, radiation therapy,and/or surgical resection).
11. Has known severe hypersensitivity reactions to fully human monoclonal antibodies (NCICTCAE v5.0 Grade ≥ 3), any history of anaphylaxis, or uncontrolled asthma.
12. Is receiving systemic corticosteroids ≤ 7 days prior to the first dose of trialtreatment or receiving any other form of systemic immunosuppressive medication (corticosteroid use on trial for management of immune-related adverse events and/or asa premedication for intravenous [IV] contrast allergies/reactions is allowed).Patients who are receiving daily corticosteroid replacement therapy are an exceptionto this rule. Examples of permitted therapy are daily prednisone at doses of 5 to 7.5mg or equivalent hydrocortisone dose and steroid therapy administered by topical,intraocular, intranasal, and/or inhalation routes.
13. History of central nervous system tumor, metastasis(es), and/or carcinomatousmeningitis identified either on the baseline brain imaging obtained during theScreening period or identified prior to consent. Note: Patients with a history of brain metastases that have been treated mayparticipate provided they show evidence of stable supra-tentorial lesions at screening (based on 2 sets of brain images, performed ≥ 4 weeks apart, and obtained after thebrain metastases treatment). In addition, any neurologic symptoms that developedeither as a result of the brain metastases or their treatment must have resolved or beminimal and be expected as sequelae from treated lesions. For individuals who receivedsteroids as part of brain metastases treatment, steroids must be discontinued ≥ 7 daysprior to the first dose of study drug.
14. Has active or history of autoimmune disease that requires systemic treatment within 2years of the start of study drug (ie, with use of disease-modifying agents,corticosteroids, or immunosuppressive drugs) Note: Patients with autoimmune conditionsrequiring hormone replacement therapy or topical treatments are eligible.
15. Has had an allogeneic tissue/solid organ transplant requiring ongoingimmunosuppressive treatment.
16. Has or had known drug-induced interstitial lung disease, not fully resolved, or hashad a history of pneumonitis that has required oral or IV corticosteroids.
17. Has an active infection requiring IV systemic treatment.
18. Has known history of HIV (HIV 1/2 antibodies).
19. Has known untreated hepatitis B/hepatitis C virus (HBV/HCV) or tuberculosis. ActiveHBV is defined as a known positive hepatitis B surface antigen result. Active HCV isdefined as a known positive hepatitis C antibody result and known quantitative HCV RNAresults greater than the lower limits of detection of the assay.
20. Has clinically significant (ie, active) cardiovascular disease: cerebral vascularaccident/stroke or myocardial infarction within 6 months before enrollment, unstableangina, congestive heart failure (New York Heart Association Class ≥ II), or seriousuncontrolled cardiac arrhythmia requiring medication.
21. Has other systemic conditions or organ abnormalities that in the opinion of theInvestigator may interfere with the conduct and/or interpretation of the currenttrial.
22. Has known psychiatric or substance use disorders that would interfere with cooperationor compromise participation with the requirements of the trial.
23. Is legally incapacitated or has limited legal capacity.
24. Is pregnant or breastfeeding.
25. Has received a live/attenuated vaccine within 14 days of first dose of study treatmentand other vaccines within 48 hours of first dose of study treatment.