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

Phase 2

Completed

Conditions: Cervical Adenocarcinoma
Recurrent Cervical Carcinoma
Stage IV Cervical Cancer AJCC v6 and v7
Cervical Adenosquamous Carcinoma
Stage IVA Cervical Cancer AJCC v6 and v7
Cervical Squamous Cell Carcinoma, Not Otherwise Specified
Stage IVB Cervical Cancer AJCC v6 and v7

Interventions: Drug: Atezolizumab
Biological: Bevacizumab
Other: Laboratory Biomarker Analysis

Registration Number: NCT02921269

Lead Sponsor: 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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 11

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (atezolizumab, bevacizumab)	Laboratory Biomarker Analysis	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.
Treatment (atezolizumab, bevacizumab)	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.
Treatment (atezolizumab, bevacizumab)	Atezolizumab	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Objective Response Rate (ORR, Either Partial or Complete Response) Defined by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Criteria	Up to 2 years	Per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Complete Response (CR) is the disappearance of all lesions and Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Overall Response (OR) is CR+PR.

Secondary Outcome Measures

Name	Time	Method
Progression Free Survival	From start of treatment to investigator determined date of progression, or death due to any cause, whichever occurs first, assessed up to 2 years	Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study and an absolute increase of at least 5 mm (0.5 cm) or the appearance of one or more new lesions.
Overall Survival (OS)	From start of treatment to death, assessed up to 2 years	The duration of OS will be estimated.
Intratumoral and Peripheral T-cell Receptor (TCR) Clonality Assessed by TCR Sequencing	Up to 2 years	Will be used to describe the efficacy of the combination of atezolizumab and bevacizumab.
Percent of Participants With Adverse Events	Up to 30 days after the last dose of study treatment, on average of 4 months	The frequency and severity of adverse events will be assessed in those patients who initiate their study treatment.
PD-L1 Expression on Tumor and Immune Cells Measured by Semi-quantitative Immunohistochemistry	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.

Trial Locations

Locations (22): Emory University Hospital Midtown
🇺🇸
Atlanta, Georgia, United States
University of Colorado Hospital
🇺🇸
Aurora, Colorado, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
🇺🇸
Baltimore, Maryland, United States
Los Angeles County-USC Medical Center
🇺🇸
Los Angeles, California, United States
Rutgers Cancer Institute of New Jersey
🇺🇸
New Brunswick, New Jersey, United States
Massachusetts General Hospital Cancer Center
🇺🇸
Boston, Massachusetts, United States
Beth Israel Deaconess Medical Center
🇺🇸
Boston, Massachusetts, United States
Dana-Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
Ohio State University Comprehensive Cancer Center
🇺🇸
Columbus, Ohio, United States
USC / Norris Comprehensive Cancer Center
🇺🇸
Los Angeles, California, United States
Emory University Hospital/Winship Cancer Institute
🇺🇸
Atlanta, Georgia, United States
Keck Medical Center of USC Pasadena
🇺🇸
Pasadena, California, United States
Moffitt Cancer Center
🇺🇸
Tampa, Florida, United States
Brigham and Women's Hospital
🇺🇸
Boston, Massachusetts, United States
University of Kentucky/Markey Cancer Center
🇺🇸
Lexington, Kentucky, United States
Memorial Sloan Kettering Cancer Center
🇺🇸
New York, New York, United States
Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
🇺🇸
New Brunswick, New Jersey, United States
University of Pittsburgh Cancer Institute (UPCI)
🇺🇸
Pittsburgh, Pennsylvania, United States
M D Anderson Cancer Center
🇺🇸
Houston, Texas, United States
University of Virginia Cancer Center
🇺🇸
Charlottesville, Virginia, United States
Virginia Commonwealth University/Massey Cancer Center
🇺🇸
Richmond, Virginia, United States
University of Wisconsin Hospital and Clinics
🇺🇸
Madison, Wisconsin, United States