The purpose of this Phase 3 trial is to demonstrate prolongation of OS in patients treated
with BAL as compared to IC chemotherapy.
This Phase 3 trial is an open-label, randomized study with single-agent BAL or IC
chemotherapy (single-agent gemcitabine, irinotecan, pemetrexed, vinorelbine, or topotecan) in
patients with recurrent, persistent, or metastatic cervical cancer who have progressed after
receiving platinum based chemotherapy.
Patients with recurrent, unresectable, or metastatic cervical cancer who have progressed
after receiving at least 1 prior line of platinum-containing chemotherapy with or without
In this study, > 50% of patients will have received prior treatment with bevacizumab, which
will be determined prior to enrollment.
- Histology (squamous cell carcinoma [SCC] vs adenocarcinoma [AC] or adenosquamous
- Region of the world (United States or Europe Union or Australia vs other countries)
- Eastern Cooperative Oncology Group (ECOG) status 0 vs 1
• 2:1, BAL: IC chemotherapy
Approximately 486 patients will be enrolled and randomized with 2:1 allocation between the
BAL and IC chemotherapy arms.
1. Voluntarily agree to participate by giving written informed consent.
2. ≥ 18 years of age.
3. Diagnosis and prior systemic treatment:
1. Has recurrent or metastatic cervical cancer (SCC, AC, or ASC histology) and has
experienced disease progression during or after treatment with a standard
platinum based therapy with or without bevacizumab.
2. 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 in
combination with radiation therapy, should not be counted as a prior systemic therapy
regimen for recurrent, persistent, and/or metastatic cervical cancer.
4. 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, as
defined by RECIST v1.1. Tumors within a previously irradiated field will be designated
as "non target" lesions unless progression is documented, or a biopsy is obtained to
confirm persistence at least 90 days following completion of radiation therapy.
5. Has a life expectancy of at least 3 months and an ECOG performance status of 0 or 1.
6. Patients must have sufficient and adequate formalin-fixed tumor tissue sample
available 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.
7. Has adequate organ function as indicated by the following laboratory values:
1. Adequate hematological function defined by absolute neutrophil count ≥ 1.5 ×
109/L, platelet count ≥ 100 × 109/L, and stable hemoglobin ≥ 8 g/dL (without
transfusions within 1 week before first dose).
2. Adequate hepatic function based by a total bilirubin level ≤ 1.5 × the upper
limit 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 × ULN
for AST/ALT and ALP.
3. Adequate renal function defined as calculated creatinine clearance > 40 mL/min or
a serum creatinine < 1.5 × ULN, per institutional standards (creatinine clearance
should be calculated per institutional standards).
4. Adequate coagulation defined by international normalized ratio or prothrombin
time ≤ 1.5 × institutional upper limit of normal IULN unless the patient is
receiving anticoagulant therapy) and activated partial thromboplastin time ≤ 1.5
× IULN (unless the patient is receiving anticoagulant therapy).
5. Normal thyroid function (thyroid stimulating hormone) whether or not the patient
is on supplemental thyroid hormone.
8. Has no history of another primary malignancy except:
1. Malignancy treated with curative intent and with no known active disease ≥ 5
years before the first dose of study drug and of low potential risk for
2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
3. Adequately treated carcinoma in situ without evidence of disease.
9. Women of childbearing potential (WOCP) must have a negative serum pregnancy test at
Screening (within 72 hours before first dose of study drug). Non-childbearing
potential is defined as (by other than medical reasons):
1. ≥ 45 years of age and has not menstruated for greater than 1 year.
2. Definitive pelvic radiation for the treatment of cervical cancer.
3. Whose status is post hysterectomy, bilateral oophorectomy, or tubal ligation.
4. WOCP must be willing to use 2 highly effective methods of contraception (defined
in the informed consent form) throughout the trial, starting with the Screening
Visit through 90 days after the last dose of study drug Note: Abstinence is
acceptable if this is the established and preferred contraception for the
10. Is willing and able to comply with the requirements of the protocol.
1. Is currently participating and receiving study therapy or has participated in a trial
of an investigational agent and received study therapy or used an investigational
device within 4 weeks before the first dose of treatment.
2. Has an inadequate period of time prior to first dose of study treatment that is
1. Received systemic cytotoxic chemotherapy or biological therapy within 28 days
before initiation of study treatment
2. Received radiation therapy within 28 days before initiation of study treatment,
except for palliative bone therapy, which can be received 2 weeks prior to
initiation of study treatment
3. Had major surgery within 4 weeks before initiation of study treatment
3. Has received prior therapy with:
a. Any antibody/drug targeting T-cell co-regulatory proteins (immune checkpoints) such
as anti-programmed cell death protein 1 and anti-PD-L1 antibodies.
4. Has persisting toxicity related to prior therapy of NCI-CTCAE v5.0 Grade ≥ 1 severity,
with the exceptions noted below:
1. Peripheral neuropathy Grade ≤ 2.
2. Alopecia Grade ≤ 2.
5. Is expected to require any other form of systemic or localized antineoplastic therapy
while on trial (including maintenance therapy with another agent, radiation therapy,
and/or surgical resection).
6. Has known severe hypersensitivity reactions to fully human monoclonal antibodies (NCI
CTCAE v5.0 Grade ≥ 3), any history of anaphylaxis, or uncontrolled asthma.
7. Is receiving systemic corticosteroids ≤ 7 days prior to the first dose of trial
treatment or receiving any other form of systemic immunosuppressive medication
(corticosteroid use on trial for management of immune-related adverse events and/or as
a premedication for intravenous [IV] contrast allergies/reactions is allowed).
Patients who are receiving daily corticosteroid replacement therapy are an exception
to this rule. Examples of permitted therapy are daily prednisone at doses of 5 to 7.5
mg or equivalent hydrocortisone dose and steroid therapy administered by topical,
intraocular, intranasal, and/or inhalation routes.
8. History of central nervous system tumor, metastasis(es), and/or carcinomatous
meningitis identified either on the baseline brain imaging obtained during the
Screening period or identified prior to consent.
Note: Patients with a history of brain metastases that have been treated may
participate 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 the
brain metastases treatment). In addition, any neurologic symptoms that developed
either as a result of the brain metastases or their treatment must have resolved or be
minimal and be expected as sequelae from treated lesions. For individuals who received
steroids as part of brain metastases treatment, steroids must be discontinued ≥ 7 days
prior to the first dose of study drug.
9. Has active or history of autoimmune disease that requires systemic treatment within 2
years of the start of study drug (ie, with use of disease-modifying agents,
corticosteroids, or immunosuppressive drugs) Note: Patients with autoimmune conditions
requiring hormone replacement therapy or topical treatments are eligible.
10. Has had an allogeneic tissue/solid organ transplant requiring ongoing
11. Has or had known drug-induced interstitial lung disease, not fully resolved, or has
had a history of pneumonitis that has required oral or IV corticosteroids.
12. Has an active infection requiring IV systemic treatment.
13. Has known history of HIV (HIV 1/2 antibodies).
14. Has known untreated hepatitis B/hepatitis C virus (HBV/HCV) or tuberculosis. Active
HBV is defined as a known positive hepatitis B surface antigen result. Active HCV is
defined as a known positive hepatitis C antibody result and known quantitative HCV RNA
results greater than the lower limits of detection of the assay.
15. Has clinically significant (ie, active) cardiovascular disease: cerebral vascular
accident/stroke or myocardial infarction within 6 months before enrollment, unstable
angina, congestive heart failure (New York Heart Association Class ≥ II), or serious
uncontrolled cardiac arrhythmia requiring medication.
16. Has other systemic conditions or organ abnormalities that in the opinion of the
Investigator may interfere with the conduct and/or interpretation of the current
17. Has known psychiatric or substance use disorders that would interfere with cooperation
or compromise participation with the requirements of the trial.
18. Is legally incapacitated or has limited legal capacity.
19. Is pregnant or breastfeeding.
20. Has received a live/attenuated vaccine within 14 days of first dose of study treatment
and other vaccines within 48 hours of first dose of study treatment.