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Atezolizumab and Bevacizumab in Treating Patients With Recurrent, Persistent, or Metastatic Cervical Cancer

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. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02921269
Recruitment Status : Active, not recruiting
First Posted : October 3, 2016
Last Update Posted : May 2, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase II trial studies how well atezolizumab and bevacizumab work in treating patients with cervical cancer that has come back, remains despite treatment, or has spread to other places in the body. Monoclonal antibodies, such as atezolizumab and bevacizumab, may shrink tumor cell and interfere with the ability of tumor cells to grow and spread.

Condition or disease Intervention/treatment Phase
Cervical Adenocarcinoma Cervical Adenosquamous Carcinoma Cervical Squamous Cell Carcinoma, Not Otherwise Specified Recurrent Cervical Carcinoma Stage IV Cervical Cancer AJCC v6 and v7 Stage IVA Cervical Cancer AJCC v6 and v7 Stage IVB Cervical Cancer AJCC v6 and v7 Drug: Atezolizumab Biological: Bevacizumab Other: Laboratory Biomarker Analysis Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To assess the anti-tumor activity (proportion of patients with objective response by Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST 1.1] criteria) of atezolizumab and bevacizumab in patients with recurrent, persistent or metastatic cervical cancer.

SECONDARY OBJECTIVES:

I. To estimate the duration of progression free survival (PFS) and overall survival (OS).

II. To assess safety by Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v.5.0).

III. To describe the efficacy of the combination of atezolizumab and bevacizumab as measured by objective response, by PD-L1 expression on tumor and immune cells measured by semi-quantitative immunohistochemistry (IHC).

IV. To describe the efficacy of the combination of atezolizumab and bevacizumab as measured by objective response, by intratumoral and peripheral T-cell receptor (TCR) clonality and tumor infiltrating lymphocyte proportion.

OUTLINE:

Patients receive atezolizumab intravenously (IV) over 30-60 minutes and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 22 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2 Study of Atezolizumab (MPDL3280A) in Combination With Bevacizumab in Patients With Recurrent, Persistent or Metastatic Cervical Cancer
Actual Study Start Date : March 10, 2017
Estimated Primary Completion Date : August 1, 2020
Estimated Study Completion Date : August 1, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Cervical Cancer

Arm Intervention/treatment
Experimental: Treatment (atezolizumab, bevacizumab)
Patients receive atezolizumab IV over 30-60 minutes and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Drug: Atezolizumab
Given IV
Other Names:
  • MPDL 3280A
  • MPDL 328OA
  • MPDL-3280A
  • MPDL3280A
  • MPDL328OA
  • RG7446
  • RO5541267
  • Tecentriq

Biological: Bevacizumab
Given IV
Other Names:
  • Anti-VEGF
  • Anti-VEGF Humanized Monoclonal Antibody
  • Anti-VEGF rhuMAb
  • Avastin
  • Bevacizumab Biosimilar BEVZ92
  • Bevacizumab Biosimilar BI 695502
  • Bevacizumab Biosimilar CBT 124
  • Bevacizumab Biosimilar FKB238
  • Bevacizumab Biosimilar MIL60
  • Bevacizumab Biosimilar QL 1101
  • BEVACIZUMAB, LICENSE HOLDER UNSPECIFIED
  • Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer
  • Recombinant Humanized Anti-VEGF Monoclonal Antibody
  • rhuMab-VEGF

Other: Laboratory Biomarker Analysis
Correlative studies




Primary Outcome Measures :
  1. Objective response rate (ORR, either partial or complete response) defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria [ Time Frame: Up to 2 years ]
    A Simon 2-stage Phase II design will be used to address the primary endpoint of ORR. Will be calculated assuming binomial proportions and a 90% confidence interval will be provided.


Secondary Outcome Measures :
  1. Progression free survival [ Time Frame: From start of treatment to investigator determined date of progression, or death due to any cause, whichever occurs first, assessed up to 2 years ]
    Will be determined by RECIST version 1.1 criteria.

  2. Overall survival (OS) [ Time Frame: From start of treatment to death, assessed up to 2 years ]
    The duration of OS will be estimated.

  3. Incidence of adverse events as measured by Common Terminology Criteria for Adverse Events version 5.0 [ Time Frame: Up to 30 days after the last dose of study treatment ]
    The frequency and severity of adverse events will be assessed in those patients who initiate their study treatment.

  4. PD-L1 expression on tumor and immune cells measured by semi-quantitative immunohistochemistry [ Time Frame: Up to 2 years ]
    The efficacy of the combination of atezolizumab and bevacizumab as measured by objective response, will be described in patients according to PD-L1 positive and PD-L1 negative.

  5. Intratumoral and peripheral T-cell receptor (TCR) clonality assessed by TCR sequencing [ Time Frame: Up to 2 years ]
    Will be used to describe the efficacy of the combination of atezolizumab and bevacizumab.


Other Outcome Measures:
  1. Tumor infiltrating lymphocyte proportion [ Time Frame: Up to 2 years ]
    Will be used to describe the efficacy of the combination of atezolizumab and bevacizumab.



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
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have measurable disease per RECIST 1.1; measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded as >= 10 mm (>= 1 cm) with computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam; to be considered pathologically enlarged and measurable, a lymph node must be >= 15 mm (>= 1.5 cm) in short axis
  • Patients must have had one prior systemic chemotherapeutic regimen for management of recurrent, persistent or metastatic carcinoma of the cervix (e.g.; paclitaxel/cisplatin, paclitaxel/cisplatin/bevacizumab), at least one which must have contained bevacizumab

    • NOTE: Patients are allowed to receive 1-2 prior regimens for management of recurrent, persistent or metastatic carcinoma of the cervix; patients who have received more than two prior systemic regimens for management of recurrent, persistent or metastatic carcinoma of the cervix are NOT eligible
    • NOTE: Prior adjuvant therapy is NOT counted as a systemic chemotherapeutic regimen for management of recurrent, persistent or metastatic carcinoma of the cervix; adjuvant therapy includes cisplatin given concurrent with primary radiation therapy (CCRT) and adjuvant chemotherapy given following the completion of concurrent chemotherapy and radiation therapy (e.g., paclitaxel and carboplatin for up to 4 cycles)
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Hemoglobin >= 9 g/dL
  • Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (however, patients with known Gilbert disease who have serum bilirubin level =< 3 x ULN may be enrolled)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x ULN
  • Alkaline phosphatase =< 2.5 x ULN
  • Creatinine =< 1.5 x ULN
  • International normalized ratio (INR) and activated partial thromboplastin time aPTT =< 1.5 x ULN (This applies only to patients who do not receive therapeutic anticoagulation; patients receiving therapeutic anticoagulation, such as low-molecular-weight heparin or warfarin, should be on a stable dose)
  • Urine protein must be screened by urinalysis; if protein is 2+ or higher, 24-hour urine protein should be obtained and the level should be < 1000 mg for patient enrollment
  • Patient must have recurrent, persistent or metastatic cervical cancer including squamous cell, adenocarcinoma and adenosquamous histologies; mesonephric carcinoma, minimal deviation/adenoma malignum, clear cell carcinoma and gastric type are excluded
  • Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 5 months (150 days) after the last dose of atezolizumab; fertile women must agree to use adequate contraceptive measures during study therapy and for at least 6 months after the completion of bevacizumab therapy; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately
  • Ability to understand and the willingness to sign a written informed consent document
  • Tumors within previous radiated field will be designated "non-target" lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy
  • Willingness to undergo a tumor biopsy

Exclusion Criteria:

  • Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation
  • Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events (other than alopecia) due to agents administered more than 4 weeks earlier; however, the following therapies are allowed:

    • Hormone-replacement therapy or oral contraceptives
    • Herbal therapy > 1 week prior to cycle 1, day 1 (herbal therapy intended as anticancer therapy must be discontinued at least 1 week prior to cycle 1, day 1)
  • Prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway-targeting agents
  • Prior treatment with anti-CTLA-4 therapeutic antibody or pathway-targeting agents
  • Treatment with any other investigational agent within 4 weeks prior to cycle 1, day 1
  • Treatment with systemic immunostimulatory agents (including, but not limited to, interferon [IFN]-alpha or interleukin [IL]-2) within 6 weeks 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

    • Patients who have received acute, low dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled
    • The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed
  • Patients taking bisphosphonate therapy for symptomatic hypercalcemia; use of bisphosphonate therapy for other reasons (e.g., bone metastasis or osteoporosis) is allowed
  • Patients with known brain metastases should be excluded from this clinical trial
  • Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
  • History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to bevacizumab or atezolizumab
  • Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease

    • Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible
    • Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA)
  • History or risk of autoimmune disease, including, but not limited to, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis

    • Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone may be eligible
    • Patients with controlled type 1 diabetes mellitus on a stable insulin regimen may be eligible
    • Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions:

      • Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular manifestations
      • Rash must cover less than 10% of body surface area (BSA)
      • Disease is well controlled at baseline and only requiring low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%)
      • No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral steroids)
  • History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) scan; history of radiation pneumonitis in the radiation field (fibrosis) is permitted
  • Patients with active tuberculosis (TB) are excluded
  • 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 oral or intravenous (IV) antibiotics within 2 weeks prior to cycle 1, day 1; patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible
  • Major surgical procedure within 28 days prior to cycle 1, day 1 or anticipation of need for a major surgical procedure during the course of the study
  • 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 and up to 5 months after the last dose of atezolizumab

    • Influenza vaccination should be given during influenza season only (approximately October to March); patients must not receive live, attenuated influenza vaccine within 4 weeks prior to cycle 1, day 1 or at any time during the study
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Patients positive for human immunodeficiency virus (HIV) are NOT excluded from this study, but HIV-positive patients must have:

    • A stable regimen of highly active anti-retroviral therapy (HAART)
    • No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections
    • A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard PCR-based tests
  • Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with atezolizumab and/or bevacizumab
  • Malignancies other than the cervical cancer within 5 years prior to cycle 1, day 1, with the exception of those with a negligible risk of metastasis or death, such as adequately controlled basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the breast
  • Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to day 1
  • Patients with clinically significant cardiovascular disease are excluded

    • Inadequately controlled hypertension (HTN) (systolic blood pressure [SBP] >= 160 mmHg and/or diastolic blood pressure [DBP] >= 90 mmHg despite antihypertensive medication)
    • History of cerebrovascular accident (CVA) within 6 months
    • Myocardial infarction or unstable angina within 6 months
    • New York Heart Association class II or greater congestive heart failure
    • Serious and inadequately controlled cardiac arrhythmia
    • Significant vascular disease (e.g. aortic aneurysm, history of aortic dissection)
    • Clinically significant peripheral vascular disease
  • History of abdominal/pelvic fistula, gastrointestinal perforation and/or intraabdominal abscess within 6 months prior to day 1
  • Evidence of bleeding diathesis or clinically significant coagulopathy
  • Serious or non-healing wound, active ulcer or bone fracture
  • Patients requiring treatment with a RANKL inhibitor (e.g. denosumab) who cannot discontinue it before treatment with atezolizumab

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): NCT02921269


Locations
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United States, California
Los Angeles County-USC Medical Center
Los Angeles, California, United States, 90033
USC / Norris Comprehensive Cancer Center
Los Angeles, California, United States, 90033
Keck Medical Center of USC Pasadena
Pasadena, California, United States, 91105
United States, Colorado
University of Colorado Hospital
Aurora, Colorado, United States, 80045
United States, Florida
Moffitt Cancer Center
Tampa, Florida, United States, 33612
United States, Georgia
Emory University Hospital Midtown
Atlanta, Georgia, United States, 30308
Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia, United States, 30322
United States, Kentucky
University of Kentucky/Markey Cancer Center
Lexington, Kentucky, United States, 40536
United States, Maryland
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, United States, 21287
United States, Massachusetts
Massachusetts General Hospital Cancer Center
Boston, Massachusetts, United States, 02114
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, New Jersey
Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
New Brunswick, New Jersey, United States, 08903
Rutgers Cancer Institute of New Jersey
New Brunswick, New Jersey, United States, 08903
United States, New York
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
United States, Ohio
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States, 43210
United States, Pennsylvania
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, United States, 15232
United States, Texas
M D Anderson Cancer Center
Houston, Texas, United States, 77030
United States, Virginia
University of Virginia Cancer Center
Charlottesville, Virginia, United States, 22908
Virginia Commonwealth University/Massey Cancer Center
Richmond, Virginia, United States, 23298
United States, Wisconsin
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, United States, 53792
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Claire F Friedman JHU Sidney Kimmel Comprehensive Cancer Center LAO

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02921269     History of Changes
Other Study ID Numbers: NCI-2016-01430
NCI-2016-01430 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
17-183
10010 ( Other Identifier: JHU Sidney Kimmel Comprehensive Cancer Center LAO )
10010 ( Other Identifier: CTEP )
UM1CA186691 ( U.S. NIH Grant/Contract )
First Posted: October 3, 2016    Key Record Dates
Last Update Posted: May 2, 2019
Last Verified: January 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Squamous Cell
Adenocarcinoma
Uterine Cervical Neoplasms
Carcinoma, Adenosquamous
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Squamous Cell
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Uterine Cervical Diseases
Uterine Diseases
Genital Diseases, Female
Neoplasms, Complex and Mixed
Bevacizumab
Antineoplastic Agents, Immunological
Atezolizumab
Endothelial Growth Factors
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Immunoglobulin G
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs