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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03556839
Recruitment Status : Recruiting
First Posted : June 14, 2018
Last Update Posted : December 3, 2019
Sponsor:
Collaborators:
Hoffmann-La Roche
ARCAGY/ GINECO GROUP
Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies
MaNGO
NSGO
Japanese Gynecologic Oncology Group
Gynecologic Oncology Group
AGO Study Group
Information provided by (Responsible Party):
Grupo Español de Investigación en Cáncer de Ovario

Brief Summary:

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/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/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 versus adenocarcinoma), prior platinum therapy as a radiation sensitizer (no prior cis-Radiotherapy (RT) versus prior cis-RT) and chemotherapy backbone (cisplatin versus 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.


Condition or disease Intervention/treatment Phase
Carcinoma of the Cervix, Stage IVB Drug: Atezolizumab Drug: Bevacizumab Drug: Cisplatin Drug: Paclitaxel Phase 3

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Study Type : Interventional
Estimated Enrollment : 404 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Phase III Trial of Platinum Chemotherapy Plus Paclitaxel With Bevacizumab and Atezolizumab Versus Platinum Chemotherapy Plus Paclitaxel and Bevacizumab in Metastatic (Stage IVB), Persistent, or Recurrent Carcinoma of the Cervix
Actual Study Start Date : September 25, 2018
Estimated Primary Completion Date : March 2023
Estimated Study Completion Date : December 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Arm A
Cisplatin 50mg/m2 + paclitaxel 175mg/m2+ bevacizumab 15mg/kg i.v D1 Q3W. Patients who achieve a complete response after ≥6 treatment cycles may be allowed to continue only on biologic therapy, namely bevacizumab, upon investigator discussion.
Drug: Bevacizumab
Intravenous Infusion
Other Name: Avastin

Drug: Cisplatin
Intravenous Infusion

Drug: Paclitaxel
Intravenous Infusion

Experimental: Arm B
cisplatin 50mg/m2 + paclitaxel 175mg/m2 + bevacizumab 15mg/kg + atezolizumab 1200mg i.v, D1 Q3W.Patients who achieve a complete response after ≥6 treatment cycles may be allowed to continue only on biologics therapy, namely bevacizumab plus atezolizumab, upon investigator discussion.
Drug: Atezolizumab
Intravenous Infusion
Other Name: Tecentriq

Drug: Bevacizumab
Intravenous Infusion
Other Name: Avastin

Drug: Cisplatin
Intravenous Infusion

Drug: Paclitaxel
Intravenous Infusion




Primary Outcome Measures :
  1. Overall survival [ Time Frame: 48 months ]
    Time from the date of randomization to the date of death due to any cause


Secondary Outcome Measures :
  1. Progression-free survival [ Time Frame: 48 months ]
    Time from the date of randomization to the date of first documentation of disease progression or death due to any cause, whichever occurs first based on investigator assessment using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v 1.1)

  2. Objective Response Rate [ Time Frame: 48 months ]
    Based on investigator assessment using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v 1.1)

  3. Duration of response [ Time Frame: 48 months ]
    Based on investigator assessment using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v 1.1)

  4. Incidence of Treatment-Emergent Adverse Events of combining atezolizumab to chemotherapy plus bevacizumab compared to cisplatin/paclitaxel (CP) plus bevacizumab. [ Time Frame: 48 months ]
    Incidence, nature and severity of adverse events (AEs) assessed by CTCAE version 4.03

  5. First subsequent therapy [ Time Frame: 48 months ]
    Time from randomization to first subsequent therapy or death due to any cause

  6. Progression-free survival 2 [ Time Frame: 48 months ]
    Time from randomization to the second event of disease progression per radiological criteria, start of a new line of therapy, due to symptomatic deterioration or to death due to any cause

  7. Patient-reported outcomes (PROs) of function and health related quality of life (HR-QOL) associated with atezolizumab + CP + bevacizumab compared to bevacizumab + CP alone, as measured by the functional and GHS/ HRQoL scales of EORTC QLQ-C30 [ Time Frame: 48 months ]
    Mean and mean changes from baseline score in patient function (role, physical) and GHS/HRQoL, by assessment timepoint and between treatment arms, as assessed by the functional and GHS/HRQoL scales of EORTC QLQ-C30.

  8. Pharmacokinetics (PK) of atezolizumab [ Time Frame: 36 months ]
    Serum concentration (Cmin) of atezolizumab

  9. Pharmacokinetics (PK) of atezolizumab [ Time Frame: 36 months ]
    Serum concentration (Cmax) of atezolizumab

  10. Incidence of anti-therapeutic antibodies (ATAs) [ Time Frame: 36 months ]
    Incidence of ATAs during the study relative to the prevalence of ATAs at baseline



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Female patients
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Female patients must be ≥18 years of age.
  2. Signed informed consent before any study-specific procedure
  3. Able (in the investigator´s judgment) to comply with the study protocol
  4. GOG/Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
  5. Life expectancy ≥3 months
  6. 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.
  7. No prior systemic anti-cancer therapy for metastatic or recurrent disease.
  8. Measureable disease by RECIST v1.1 criteria.
  9. A tumor specimen is mandatory at study entry.
  10. Adequate organ function:

    Hemoglobin ≥9 g/dL ANC ≥1.5 × 109/L Lymphocyte count ≥0.5 × 109/L Platelet count ≥100 x 109/L

  11. 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

  12. Adequate renal function:

    Patients with serum creatinine <1.5 × ULN Urine dipstick for proteinuria <2+.

  13. 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.

  14. 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 test.

  15. Toxicities related to previous treatments must be recovered to < grade 2 (with the exception of alopecia).
  16. 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:

  1. Disease that is suitable for local therapy administered with curative intent
  2. Prior radiotherapy delivered using cobalt (rather than a linear accelerator)
  3. Patients with Stage IVA not amendable to concurrent chemo-radiation as primary treatment will not be eligible.
  4. Ongoing disease involving the bladder or rectum at screening/baseline
  5. Evidence of abdominal free air
  6. Bilateral hydronephrosis, unless it can be alleviated by ureteral stent(s) or percutaneous drainage
  7. 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.
  8. 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.
  9. 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.
  10. 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).
  11. 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.
  12. Patients with serious non-healing wound, ulcer, or bone fracture.
  13. Acute intestinal obstruction or sub-occlusion episode in the last 6 months.
  14. Active GI bleeding or GI ulcer
  15. History of Crohn's disease or inflammatory bowel disease
  16. Prior bowel resection ≤6 weeks preceding first study dose
  17. History of diverticulitis requiring medical intervention
  18. NCI CTCAE (version 5.0) grade ≥2 enteritis
  19. Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to Day 1, Cycle 1.
  20. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1, Cycle 1.
  21. Patients with active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major vessels.
  22. 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.
  23. Patients with pre-existing Grade 2 or greater peripheral neuropathy.
  24. History of any grade ≥3 venous thromboembolic event (VTE)
  25. Patients with clinically significant cardiovascular disease.
  26. Uncontrolled tumor-related pain
  27. 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.
  28. 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.
  29. 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, Sjögren's syndrome, Guillain-Barré 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

  30. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
  31. Active tuberculosis
  32. 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
  33. Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1
  34. Received therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1
  35. Known human immunodeficiency virus (HIV)
  36. Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or anticipation that such a live attenuated vaccine will be required during the study Influenza vaccination should be given during influenza season only
  37. 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
  38. 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
  39. 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 and the institutional standard of care guidance.
  40. Currently participating or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks prior to the first dose of study treatment.
  41. 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.
  42. Women that are breastfeeding or pregnant
  43. Known hypersensitivity to bevacizumab, atezolizumab or any of theirs excipients (including Cremophor)
  44. 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
  45. No medical or psychiatric illness that may impede the performance of a systemic or surgical treatment.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03556839


Contacts
Layout table for location contacts
Contact: Javier Sanchez López, MBA MSc +34 669 528 261 jsanchez@grupogeico.net
Contact: Carmen Marqués, MD cmarques@grupogeico.net

Locations
Show Show 72 study locations
Sponsors and Collaborators
Grupo Español de Investigación en Cáncer de Ovario
Hoffmann-La Roche
ARCAGY/ GINECO GROUP
Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies
MaNGO
NSGO
Japanese Gynecologic Oncology Group
Gynecologic Oncology Group
AGO Study Group
Investigators
Layout table for investigator information
Principal Investigator: Ana Oaknin, MD PhD Vall d´Hebron University Hospital

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Grupo Español de Investigación en Cáncer de Ovario
ClinicalTrials.gov Identifier: NCT03556839    
Other Study ID Numbers: ENGOT-Cx10 / BEATcc
2018-000367-83 ( EudraCT Number )
ENGOT-Cx10 ( Other Identifier: ENGOT )
GEICO 68-C ( Other Identifier: GEICO )
JGOG1084 ( Other Identifier: JGOG )
GOG-3030 ( Other Identifier: GOG )
First Posted: June 14, 2018    Key Record Dates
Last Update Posted: December 3, 2019
Last Verified: November 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Grupo Español de Investigación en Cáncer de Ovario:
Cervix
Carcinoma
Atezolizumab
Additional relevant MeSH terms:
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Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Carcinoma
Paclitaxel
Albumin-Bound Paclitaxel
Cisplatin
Bevacizumab
Atezolizumab
Antibodies, Monoclonal
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Immunologic Factors