The investigators propose to evaluate the efficacy of the combination of standard
chemotherapy with bevacizumab with Pembrolizumab in women with recurrent, persistent, or
metastatic cervical cancer.
This is a single arm, open-label, phase II study to assess progression free survival in
patients treated with pembrolizumab, chemotherapy, and bevacizumab for recurrent, persistent,
or metastatic cervical cancer. Progression free survival will be assessed in patients treated
with this combination.
Eligible patients will require tissue biopsy for diagnostic confirmation of metastatic
disease, disease recurrence or persistence. Patients will be treated with 3 cycles of
combination therapy. A cycle will consist of pembrolizumab at 200mg (IV), paclitaxel 175mg/m2
or 135mg/m2 (IV), cisplatin 50mg/m2 (or carboplatin AUC 5) and bevacizumab 15mg/kg , on day 1
every 21 days. The length of a cycle is 21 days. If disease remains following 3 cycles, a
second biopsy may be obtained. Imaging will be obtained after every 3 cycles to assess for
disease response. Blood collection will be performed before and after pembrolizumab treatment
and at end of study.
Thirty-nine subjects will be accrued and treated at Sylvester Comprehensive Cancer Center
(SCCC)/University of Miami Hospital (UMH) inclusive of its satellite sites, and Jackson
Memorial Hospital for approximately 24 months. Therapy will be administered until study
completion, withdrawal of consent, disease progression and/or unacceptable toxicity,
whichever occurs first.
All subjects will be followed for a Safety Evaluation at approximately 30-days (+7 days)
after the last dose of study treatment or before the initiation of a new anti-cancer
treatment, whichever occurs first. Thereafter subjects will be followed every 3-months for up
to 24 months from the treatment discontinuation for survival data only.
1. Patients must have histologically confirmed recurrent, persistent or metastatic
(primary stage IVB) squamous cell carcinoma, adenosquamous carcinoma or adenocarcinoma
of the cervix that is not amenable to curative treatment with surgery and/or radiation
2. All patients must have measurable disease as defined by Response Evaluation Criteria
In Solid Tumors (RECIST) 1.1.
3. Patients must have recovered from effects of recent surgery or radiotherapy or
4. Patients should be free of active infections requiring antibiotics (with the exception
of uncomplicated urinary tract infection).
5. Tissue from an archival sample or newly obtained core or excisional biopsy of a tumor
lesion within 6 weeks confirming diagnosis.
6. Age ≥ 18 years
7. Life expectancy > 3 months
8. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
9. Patients must have normal organ and marrow function as defined below:
- Absolute neutrophil count (ANC) ≥1,500 /mcL
- Platelets ≥ 100,000 / mcL
- Hemoglobin ≥ 8 g/dL or ≥ 5.6 mmol/L without transfusion or erythropoietin (EPO)
- Serum creatinine ≤ 1.5 X upper limit of normal (ULN) OR Measured or calculated a
creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≥ 60
mL/min for subject with creatinine levels > 1.5 X institutional ULN. Creatinine
clearance should be calculated per institutional standard.
- Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with
total bilirubin levels > 1.5 ULN
- Aspartate transaminase (AST) (SGOT) and alanine transaminase (ALT) (SGPT) ≤ 2.5 X
ULN OR ≤ 5 X ULN for subjects with liver metastases
- Albumin ≥ 2.5 mg/dL
- International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 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.
- 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.
10. Negative urine or serum pregnancy ≤72 hours (i.e. 3 days) prior to receiving the first
dose of study medication if not surgically sterilized. If the urine test is positive
or cannot be confirmed as negative, a serum pregnancy test will be required.
11. Female subjects of childbearing potential (have not been surgically sterilized or have
not been without menses for >1 year) should be willing to use 2 methods of birth
control at the same time or be surgically sterile, or abstain from heterosexual
12. Ability to understand and the willingness to sign a written informed consent document.
1. Patients with a history of other invasive malignancies, with the exception of
nonmelanoma skin cancer, are ineligible if there is any evidence of other malignancy
being present within the last 5 years.
2. Patients who have had prior chemotherapy except when used concurrently with radiation
3. Patients who have received prior radiotherapy to any portion of the abdominal cavity
or pelvis other than for the treatment of cervical cancer within the last 5 years are
excluded. Prior radiation for localized cancer of the breast, head and neck, or skin
is permitted provided that it was completed more than 3 years prior to registration,
and the patient remains free of recurrent or metastatic disease.
4. Patients with an ECOG performance status of 2, 3 or 4.
5. Has received prior therapy with an anti-PD1, anti-PDL1, or anti-PDL2 agent.
6. Patients with known active central nervous system (CNS) metastases and/or
7. Patients with a known sensitivity to humanized antibodies or sensitivity attributed to
compounds of similar chemical or biologic composition to platinum based chemotherapy
or paclitaxel (not responsive to traditional desensitization procedures).
8. Patients with a known history of human immunodeficiency virus (HIV), active bacillus
tuberculosis (TB), or have received a live virus vaccine within 30 days prior to the
first dose of study treatment.
9. Known psychiatric or substance abuse disorders that would interfere with cooperation
with requirements of the study
10. Has active autoimmune disease that has required systemic treatment in the past two
years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (i.e. thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.
11. History of non-infectious pneumonitis that required steroids, evidence of interstitial
lung disease or active, non-infectious pneumonitis, or history of pneumonitis
12. Is pregnant or breastfeeding or expecting to conceive 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.
13. Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).
14. Received live vaccine within 30 days prior to the first dose of study treatment. Note:
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.
15. Patient with known hypersensitivity to pembrolizumab or any of its excipients (active
16. Patient receiving concurrent additional biologic therapy.
17. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to cisplatin and/or paclitaxel not responsive to traditional
18. Any other serious medical or psychiatric illness/condition, in the judgment of the
Investigator(s), is likely to interfere or limit compliance with study
19. Patients who are adults and unable to consent, who are not yet adults, pregnant and
nursing women, and prisoners are ineligible.
20. Any other serious medical or psychiatric illness/condition likely in the judgment of
the Investigator(s) to interfere or limit compliance with study
21. Has an active infection requiring systemic therapy.
22. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to planned first dose of
the study. The use of physiological doses of corticosteroids may be approved after
consultation with the PI.
23. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling, or
child who is an investigational site or sponsor staff directly involved with this
trial, unless prospective institutional review board (IRB) approval (by chair or
designee) is given, allowing exception to this criterion.
24. Thromboembolism (either arterial or venous) within 6 weeks of initiation of treatment.
25. Have significant cardiovascular disease, such as New York Heart Association cardiac
disease (Class II or greater), myocardial infarction, or cerebrovascular accident
within 3 months prior to initiation of study treatment, unstable arrhythmias, or
unstable angina. Patients with known coronary artery disease, congestive heart failure
not meeting the above criteria, or left ventricular ejection fraction <50% must be on
a stable medical regimen that is optimized in the opinion of the treating physician,
in consultation with a cardiologist if appropriate.
26. Undergo major surgical procedure within 28 days prior to first bevacizumab dose or
anticipation of the need for a major surgical procedure during the course of the
27. Have proteinuria, as demonstrated by urine dipstick or >1.0g of protein in a urine
protein-to-creatinine ratio and/or 24hr urine collection. All patients with ≥2+
protein on dipstick urinalysis at baseline must undergo a urine-to-protein ration
and/or 24hr urine collection and demonstrate <1.0g of protein