Platinum Chemotherapy Plus Paclitaxel With Bevacizumab and Atezolizumab in Metastatic Carcinoma of the Cervix

  • End date
    Dec 26, 2023
  • participants needed
  • sponsor
    Grupo Español de Investigación en Cáncer de Ovario
Updated on 26 January 2021


The study will integrate the efficacy of combining the anti programmed death-ligand 1 (anti-PD-L1) agent atezolizumab with the current standard of care in Stage IVB , persistent or recurrent carcinoma of the cervix, namely cisplatin or carboplatin/paclitaxel/bevacizumab. It will be explored the combination of bevacizumab plus atezolizumab, with no patient selection based on PD-L1 expression, allowing an all-comer assessment of atezolizumab activity.

The study is a randomized open label phase III trial to investigate the impact of atezolizumab in combination with bevacizumab and cisplatin or carboplatin /paclitaxel chemotherapy on overall survival and will employ the intent to treat principle, and random assignment to one of the 2 arms will be balanced according to disease histology (squamous cell carcinoma vs adenocarcinoma), prior platinum therapy as a radiation sensitizer (no prior cis-Radiotherapy (RT) versus prior cis-RT) and chemotherapy backbone (cisplatin vs carboplatin).

This trial will be run in an open label design due to the following considerations: the control arm is the standard of care for women diagnosed with metastatic, persistant or recurrent cervical cancer because of its impact on overall survival and the primary endpoint of the study is overall survival (OS), so blinding is not needed to ensure a robust assessment.


Given that both Vascular Endothelial Growth Factor (VEGF) and PD-L1 appear important in cervical cancer pathogenesis, this study is designed to test the hypothesis that breaking of immune tolerance by PD-1/PD-L1 blockade will enhance the efficacy of anti-VEGF therapy in the treatment of patients with metastatic , persistent or recurrent cervical cancer. There are several data suggesting that atezolizumab and bevacizumab may be synergistic. Enhanced tumor angiogenesis is commonly associated with absence of tumor-infiltrating T cells in patients. There is evidence in ovarian cancer that tumor expression of VEGF is negatively correlated to the density of CD8+ TILs and this phenotype is associated with early recurrence, consistent with prior studies showing a correlation of VEGF to early recurrence and short survival. Furthermore, in ascites, high levels of VEGF correlate to low numbers of NK T-like CD3+CD56+ cells.

In addition to promoting tumor angiogenesis, there is increasing evidence that VEGF plays a role in cancer immune evasion through several different mechanisms. Indeed, emerging evidence suggests that the endothelium acts as a selective barrier, allowing certain T cell subsets, notably T regulatory (Treg) cells, to traffic more effectively into the tumor contributing to tumor immune tolerance. In addition, some experiments have shown that tumour hypoxia promotes the recruitment of regulatory T (T reg) cells through induction of expression of the chemokine CC-chemokine ligand 28 (CCL28), which, in turn, promotes tumour tolerance and angiogenesis.

Some immunosuppressive activities of VEGF, however, can be reversed by inhibition of VEGF signaling. Mice exposed to pathophysiologic levels of VEGF exhibited impaired dendritic cell function, which could be restored by blockade of VEGFR2.

In turn, the anti-tumor effect of angiogenesis blockade requires CD8+ T cells supporting the notion that VEGF-A do not simply promote tumor growth through angiogenesis. Thus, peripheral immune tolerance and angiogenesis programs seem closely connected and cooperating to sustain tumour growth.

In addition, there is evidence that anti-VEGF therapy and immunotherapy act synergistically. Motz et al have suggested that the combination of anti-VEGF-A antibody and immunotherapy with adoptive T cell transfer led to a superior infiltration of tumor-reactive T cells than any single approach. Indeed, in a murine melanoma model, VEGF blockade synergized with adoptive immunotherapy, as evidenced by improved anti-tumor activity, prolonged survival, and increased trafficking of T cells into tumors. These data are reminiscent of the additive benefit observed in patients by combining recombinant interferon-alpha therapy and bevacizumab, a recombinant, humanized therapeutic antibody directed against VEGF, for the treatment of metastatic renal cell carcinoma.

More evidence has come from a clinical study of subjects with melanoma combining the checkpoint inhibitor (anti-CTLA-4) ipilimumab and bevacizumab. In 46 patients, the combined therapy yielded a 19.6% objective response rate, stable disease in 13%. All responses were durable >6 months and median survival was 25.1 months, much prolonged compared to ipilimumab's expectation in metastatic melanoma. Activated vessel endothelium with extensive CD8+ T cell and macrophage cell infiltration was observed in post-treatment biopsies, as well as marked increases in CD4/CCR7/CD45ROm central memory cells in peripheral blood in the majority of patients.

Thus, an emerging paradigm supported by the data above is that angiogenesis and immune suppression are two facets of a linked biological program. Tumors seem to co-opt these existing mechanisms that are normally required to limit excessive inflammation and promote tissue recovery during infection or wound healing. The execution of this program sustains tumor growth and promotes immunologic tolerance. Because of the intimate relationship between angiogenesis and immunosuppression, it is thus expected that inhibiting both pathways will result in improved and more durable clinical benefit.

Condition Carcinoma of the Cervix, Stage IVB, Carcinoma of the Cervix, Stage IVB, Carcinoma of the Cervix, Stage IVB, Carcinoma of the Cervix, Stage IVB
Treatment cisplatin, Paclitaxel, bevacizumab, Atezolizumab, Cisplatin/Carboplatin
Clinical Study IdentifierNCT03556839
SponsorGrupo Español de Investigación en Cáncer de Ovario
Last Modified on26 January 2021


Yes No Not Sure

Inclusion Criteria

Is your age greater than or equal to 18 yrs?
Are you female?
Do you have Carcinoma of the Cervix, Stage IVB?
Do you have any of these conditions: Do you have Carcinoma of the Cervix, Stage IVB??
Do you have any of these conditions: Do you have Carcinoma of the Cervix, Stage IVB??
Female patients must be 18 years of age
Signed informed consent before any study-specific procedure
Able (in the investigators judgment) to comply with the study protocol
GOG/Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
Life expectancy 3 months
Histologically- or cytologically-confirmed diagnosis of metastatic (stage IVB), persistent, or recurrent cervical cancer (histologies other than squamous cell, adenocarcinoma, or adenosquamous will be excluded) not amenable for curative treatment with surgery and/or radiation therapy. The inclusion of patients with adenocarcinoma histology will be capped to 20% of the whole study population
No prior systemic anti-cancer therapy for metastatic or recurrent disease
Measureable disease by RECIST v1.1 criteria
A tumor specimen is mandatory at study entry
Adequate organ function
Hemoglobin 9 g/dL ANC 1.5 109/L Lymphocyte count 0.5 109/L Platelet count 100
x 109/L
\. Adequate liver function
Serum albumin 2.5 g/dL Total serum bilirubin 1.5 ULN AST and ALT 2.5 upper
limit normal (ULN) or 5 ULN if tumor involvement (liver) is present
\. Adequate renal function
Patients with serum creatinine <1.5 ULN Urine dipstick for proteinuria <2+
\. Adequate coagulation
Blood coagulation parameters (PTT, PT/INR): PT such that international
normalized ratio (INR) is 1.5 (or an in-range INR, usually between 2 and 3, if
a patient is on a stable dose of therapeutic warfarin for management of venous
thrombosis including pulmonary thromboembolus) and a PTT <1.5 ULN
\. Negative Test Results for Hepatitis
Negative hepatitis B surface antigen (HBsAg) test at screening Negative total
hepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb
test followed by a negative hepatitis B virus (HBV) DNA test at screening.The
HBV DNA test will be performed only for patients who have a positive total
HBcAb test
Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV
antibody test followed by a negative HCV RNA test at screening.The HCV RNA
test will be performed only for patients who have a positive HCV antibody
\. Toxicities related to previous treatments must be recovered to < grade 2
(with the exception of alopecia)
\. Female participants must be postmenopausal ( 12 months of non-therapy-
induced amenorrhoea) or surgically sterile (absence of ovaries and/or uterus
or who received therapeutic radiation to the pelvis) or otherwise have a
negative serum pregnancy test within 7 days of the first study treatment and
agree to abstain from heterosexual intercourse or use single or combined
contraceptive methods that result in a failure rate of <1% per year during the
whole treatment period of the study and for at least 5 months (if the last
study dose contained atezolizumab) or 6 months (if the last study dose
contained bevacizumab) after the last dose of study treatment
Abstinence is acceptable only if it is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal or postovulation methods) and withdrawal are not acceptable methods of contraception

Exclusion Criteria

Disease that is suitable for local therapy administered with curative intent
Prior radiotherapy delivered using cobalt (rather than a linear accelerator)
Patients with Stage IVA not amendable to concurrent chemo-radiation as primary treatment will not be eligible
Ongoing disease involving the bladder or rectum at screening/baseline
Evidence of abdominal free air
Bilateral hydronephrosis, unless it can be alleviated by ureteral stent(s) or percutaneous drainage
Patients previously treated with chemotherapy except when used concurrently with radiation therapy. Patients who have received either concurrent paclitaxel with radiation therapy or carboplatin/paclitaxel as adjuvant therapy are ineligible for the study
Prior treatment with any anti-VEGF drug, including bevacizumab, CD137 agonists or immune checkpoint blockade therapies, anti-PD1, or anti-PDL1 therapeutic antibodies or anti-CTLA 4
Patients with a concomitant malignancy other than non-melanoma skin cancer. Patients with a prior invasive malignancy (except non-melanoma skin cancer ) who have had any evidence of disease within the last 5 years or whose prior malignancy treatment contraindicates the current protocol therapy
Known brain metastases or spinal cord compression. It is mandatory to perform a scan of the brain in cases of suspected brain metastases (CT or MRI) or spinal cord compression (MRI)
History or evidence, following a neurological examination, of central nervous system (CNS) disorders, unless properly treated with standard medical treatment,(e.g. uncontrolled epileptic seizures). History of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) or subarachnoid hemorrhage within six months of the first date of treatment on this study
Patients with serious non-healing wound, ulcer, or bone fracture
Acute intestinal obstruction or sub-occlusion episode in the last 6 months
Active GI bleeding or GI ulcer
History of Crohn's disease or inflammatory bowel disease
Prior bowel resection 6 weeks preceding first study dose
History of diverticulitis requiring medical intervention
NCI CTCAE (version 5.0) grade 2 enteritis
Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to Day 1, Cycle 1
Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1, Cycle 1
Patients with active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major vessels
Current or recent (within 10 days before the first dose of study drug) chronic daily treatment with aspirin (>325 mg/day), clopidogrel (>75 mg/day), or current or recent (within 10 days before first dose of bevacizumab) use of therapeutic oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes
Patients with pre-existing Grade 2 or greater peripheral neuropathy
History of any grade 3 venous thromboembolic event (VTE)
Patients with clinically significant cardiovascular disease
Uncontrolled tumor-related pain
Left ventricular ejection fraction defined by MUGA/ECHO below the institutional lower limit of normal
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently). Patients with indwelling catheters (e.g., PleurX) are allowed
Uncontrolled hypercalcemia (>1.5 mmol/L ionized calcium or calcium >12 mg/dL or corrected serum calcium > ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab
History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjgren's syndrome, Guillain-Barr syndrome, multiple sclerosis, vasculitis, or glomerulonephritis
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g
bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis
or evidence of active pneumonitis on screening chest CT scan
\. History of radiation pneumonitis in the radiation field (fibrosis) is
\. Active tuberculosis
\. Severe infections within 4 weeks prior to Cycle 1, Day 1, including but
not limited to hospitalization for complications of infection, bacteremia, or
severe pneumonia
\. Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1
\. Received therapeutic oral or IV antibiotics within 2 weeks prior to Cycle
Day 1
\. Known human immunodeficiency virus (HIV)
\. Administration of a live, attenuated vaccine within 4 weeks before Cycle
Day 1 or anticipation that such a live attenuated vaccine will be required
during the study Influenza vaccination should be given during influenza season
\. Any other diseases, metabolic dysfunction, physical examination finding
or clinical laboratory finding giving reasonable suspicion of a disease or
condition that contraindicates the use of an investigational drug or that may
affect the interpretation of the results or render the patient at high risk
from treatment complications
\. Treatment with systemic immunostimulatory agents (including but not
limited to IFNs, IL-2) within 6 weeks or 5 half-lives of the drug, whichever
is shorter, prior to Cycle 1, Day 1
\. Treatment with systemic immunosuppressive medications (including but not
limited to prednisone, cyclophosphamide, azathioprine, methotrexate
thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks
prior to Cycle 1, Day 1 The use of corticosteroids is allowed as premedication
for paclitaxel-based regimen. All patients should be premedicated prior to
receiving chemotherapy (including with corticosteroids) according to the
prescription information of paclitaxel and cisplatin/carboplatin and the
\. Currently participating or has participated in a study of an
institutional standard of care guidance
investigational agent and received study therapy or used an investigational
device within 4 weeks prior to the first dose of study treatment
\. Prior anti-cancer monoclonal antibody (mAb), prior chemotherapy, targeted
small molecule therapy as first line treatment for the treatment of metastatic
or recurrent cervical cancer
\. Women that are breastfeeding or pregnant
\. Known hypersensitivity to bevacizumab, atezolizumab or any of theirs
excipients (including Cremophor)
\. Demonstration of any other neurological or metabolic dysfunction, found
upon physical examination or laboratory tests involving a reasonable suspicion
of the existence of a disease or condition that contraindicates the use of an
experimental drug, or that involves an increased risk to the patient of
treatment-related complications
\. No medical or psychiatric illness that may impede the performance of a
systemic or surgical treatment
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