Atezolizumab Before and/or With Chemoradiotherapy in Immune System Activation in Patients With Node Positive Stage IB2, II, IIIB, or IVA Cervical Cancer
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| ClinicalTrials.gov Identifier: NCT03738228 |
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Recruitment Status :
Active, not recruiting
First Posted : November 13, 2018
Last Update Posted : November 29, 2022
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Sponsor:
National Cancer Institute (NCI)
Collaborator:
NRG Oncology
Information provided by (Responsible Party):
National Cancer Institute (NCI)
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Brief Summary:
This phase I trial studies how well atezolizumab before and/or with standard of care chemoradiotherapy works in immune system activation in patients with stage IB2, II, IIIB, or IVA cervical cancer that has spread to the lymph nodes. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving atezolizumab before and/or with chemoradiotherapy may lower the chance of tumors growing or spreading.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Cervical Adenocarcinoma Cervical Adenosquamous Carcinoma Cervical Squamous Cell Carcinoma Stage IB2 Cervical Cancer AJCC v8 Stage II Cervical Cancer AJCC v8 Stage IIA Cervical Cancer AJCC v8 Stage IIA1 Cervical Cancer AJCC v8 Stage IIA2 Cervical Cancer AJCC v8 Stage IIB Cervical Cancer AJCC v8 Stage IIIB Cervical Cancer AJCC v8 Stage IVA Cervical Cancer AJCC v8 | Drug: Atezolizumab Radiation: Brachytherapy Drug: Cisplatin Radiation: Radiation Therapy | Phase 1 |
PRIMARY OBJECTIVES:
I. To determine whether differences in sequencing of atezolizumab and chemoradiation result in differential immune activation, as determined by clonal expansion of T cell receptor beta (TCRB) repertoires in peripheral blood on day 21.
SECONDARY OBJECTIVES:
I. To investigate the feasibility of administration of the anti PD-L1 antibody (atezolizumab) as an immune primer and concurrent with chemoradiation (CRT) therapy in patients with locally advanced cervical cancer.
II. To determine the nature and degree of toxicity of the anti PD-L1 antibody (atezolizumab) administered as an immune primer and concurrent with chemoradiation (CRT) therapy in patients with locally advanced cervical cancer.
III. To examine the changes in T cell receptor (TCR) clonality, diversity, and frequency in peripheral blood and tissue and correlate this with clinical outcomes, such as the exploratory response assessment on the post-treatment positron emission tomography (PET)-computed tomography (CT) scan and 2-year disease-free survival (DFS).
IV. To assess the predictive value of baseline and on-treatment PD-L1 expression in the tissue in each treatment arm for clinical outcomes using post-treatment PET-CT scan and 2-year DFS as the outcome measures.
EXPLORATORY OBJECTIVES:
I. To explore baseline and on-treatment blood and tissue biomarkers that could predict response to the combination therapy, as correlated to the exploratory clinical endpoint of the week 12 (day 140) PET-CT scan and 2-year DFS.
II. To explore the response assessment on the exploratory and optional post-treatment week 12 (day 140) PET-CT scan and the clinical 2-year disease free survival (DFS).
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM A: Patients receive atezolizumab intravenously (IV) over 30-60 minutes on days -21, 0, and 21 in the absence of disease progression or unacceptable toxicity. Patients also receive standard of care cisplatin chemotherapy IV over 90 minutes on days 0, 7, 14, 21, 28, and 35. Beginning on day 0, patients also receive standard of care radiation therapy once daily (Monday-Friday) for a total of 25 fractions with image guided brachytherapy beginning in week 4, 5, or at the end of radiation therapy.
ARM B: Patients receive atezolizumab IV over 30-60 minutes on days 0, 21, and 42 in the absence of disease progression or unacceptable toxicity. Patients also receive standard of care cisplatin chemotherapy, radiation therapy, and image guided brachytherapy as in Arm A.
After completion of study treatment, patients are followed up at 1 and 3 months, and then every 3 months for 2 years.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 40 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Anti PD-L1 (Atezolizumab) as an Immune Primer and Concurrently With Extended Field Chemoradiotherapy for Node Positive Locally Advanced Cervical Cancer |
| Actual Study Start Date : | October 26, 2018 |
| Actual Primary Completion Date : | May 1, 2022 |
| Estimated Study Completion Date : | May 23, 2023 |
Resource links provided by the National Library of Medicine
| Arm | Intervention/treatment |
|---|---|
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Experimental: Arm A (atezolizumab, standard cisplatin and radiation therapy)
Patients receive atezolizumab IV over 30-60 minutes on days -21, 0, and 21 in the absence of disease progression or unacceptable toxicity. Patients also receive standard of care cisplatin chemotherapy IV over 90 minutes on days 0, 7, 14, 21, 28, and 35. Beginning on day 0, patients also receive standard of care radiation therapy once daily (Monday-Friday) for a total of 25 fractions with image guided brachytherapy beginning in week 4, 5, or at the end of radiation therapy.
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Drug: Atezolizumab
Given IV
Other Names:
Radiation: Brachytherapy Undergo standard of care image guided brachytherapy
Other Names:
Drug: Cisplatin Given IV
Other Names:
Radiation: Radiation Therapy Undergo standard of care radiation therapy
Other Names:
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Experimental: Arm B (atezolizumab, standard cisplatin and radiation therapy)
Patients receive atezolizumab IV over 30-60 minutes on days 0, 21, and 42 in the absence of disease progression or unacceptable toxicity. Patients also receive standard of care cisplatin chemotherapy, radiation therapy, and image guided brachytherapy as in Arm A.
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Drug: Atezolizumab
Given IV
Other Names:
Radiation: Brachytherapy Undergo standard of care image guided brachytherapy
Other Names:
Drug: Cisplatin Given IV
Other Names:
Radiation: Radiation Therapy Undergo standard of care radiation therapy
Other Names:
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Primary Outcome Measures :
- T cell receptor beta (TCRB) clonal expansion in peripheral blood [ Time Frame: At day 21 ]Arms will be compared by 2-sided t-test at 10% significance level.
Secondary Outcome Measures :
- Incidence of dose-limiting toxicities (DLTs) (Arm A) [ Time Frame: From the start of first dose of atezolizumab until 30 days after the completion of chemoradiation (CRT) ]The number of patients who experience DLTs will be summarized in the DLT-evaluable patients by treatment arm, the corresponding proportion of patients with DLTs and 90% confidence interval will be estimated.
- Incidence of DLTs (Arm B) [ Time Frame: From the start of CRT treatment until 30 days after the completion of CRT ]The number of patients who experience DLTs will be summarized in the DLT-evaluable patients by treatment arm, the corresponding proportion of patients with DLTs and 90% confidence interval will be estimated.
- Frequency and severity of adverse events as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v)5 [ Time Frame: Up to 2 years ]The frequency and maximum severity of acute adverse events will be tabulated by treatment arm graded by CTCAE v5.
- TCR clonality, diversity, and frequency in peripheral blood and tissue [ Time Frame: Up to 2 years ]Summary statistics (and graph where it is appropriate) for the measurements of TCR clonality, diversity and frequency in peripheral blood/tissue at each protocol-specified collecting time point, measures of positron emission tomography (PET)-computed tomography (CT) scan at post-therapy 12 weeks, and the proportion of patients who are alive and disease-free for at least 2 years will be provided by treatment arm. If feasible, repeated measure techniques will be applied to investigate the changes and the trajectories of TCR clonality, diversity, and frequency in peripheral blood by treatment arm, and mixed modeling may be used to explore the corresponding associations with measurement for PET-CT scan at post-therapy 12 weeks and 2-year disease-free survival (DFS).
- PD-L1 expression in tissue [ Time Frame: Up to 2 years ]PD-L1 expression in the tissue by treatment arm will be summarized for each protocol-specified collecting time point. Spearman's correlation coefficient will be used to assess the correlation of PD-L1 expression in the tissue at each protocol-specified collecting time point by arm with DFS at 2 years and measurement for post-treatment PET-CT, respectively.
Other Outcome Measures:
- Biomarker levels in blood and tissue [ Time Frame: Up to 2 years ]Summary statistics (and graphs where it is appropriate) will be done by treatment arm. Spearman's correlation coefficient will be implemented to explore the associations of biomarkers measured at baseline or on-treatment from blood and tissue with 2-year DFS and PET scan at post-therapy 12 weeks (day 140), respectively, by treatment arm.
- Response assessment [ Time Frame: Up to 2 years ]The association of 2-year DFS with the response assessment on the post-treatment week-12 PET-CT scan in each treatment arm will be examined with Chi-squared tests.
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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 with histologically confirmed newly diagnosed advanced cervical cancer (squamous cell carcinoma, adenocarcinoma, and adenosquamous cell carcinoma): Federation of Gynecology and Obstetrics (FIGO) clinical stages IB2/IIA with positive para-aortic nodes, or FIGO clinical stages IIB/IIIB/IVA with positive pelvic or para-aortic lymph nodes (PALN). Pelvic or PALN nodal status confirmed by PET/CT scan or fine needle biopsy or extra peritoneal biopsy or laparoscopic biopsy. The PALN must be inferior to the T12/L1 interspace
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
- Leukocytes >= 2,500/mcL
- Absolute neutrophil count >= 1,500/mcL
- Platelets >= 100,000/mcL (> 50,000 for patients with hematologic malignancies)
- Hemoglobin >= 8 g/dL (can be transfused with red blood cells pre-study)
- 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 (AST and/or ALT =< 5 x ULN for patients with liver involvement)
- Alkaline phosphatase =< 2.5 x ULN (=< 5 x ULN for patients with documented liver involvement or bone metastases)
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Creatinine clearance =< 1.5 mg/dL to receive weekly cisplatin
- Patients whose serum creatinine is between 1.5 and 1.9 mg/dL are eligible for cisplatin if there is no hydronephrosis and the estimated creatinine clearance (CCr) is >= 30 ml/min. For the purpose of estimating the CCr, the formula of Cockcroft and Gault for females should be used
- 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)
- Patient does not have a known allergy to cisplatin or compounds of similar biologic composition
- Patient is not actively breastfeeding (or has agreed to discontinue breastfeeding before the initiation or protocol therapy)
- Thyroid-stimulating hormone (TSH) within normal limits or normal free T4 in those with abnormal TSH
- Ability to understand and the willingness to sign a written informed consent document
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Patients positive for human immunodeficiency virus (HIV) are allowed on 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 polymerase chain reaction (PCR)-based tests
Exclusion Criteria:
- Patients who have received prior radiation therapy to the pelvis or abdominal cavity, PALN radiation, or previous therapy of any kind for this malignancy or pelvic, PALN, or abdominal radiation for any prior malignancy
- Patients with PALN nodal metastasis above the T12/L1 interspace
- Patients who had a radical hysterectomy with positive PALNs are not eligible
- Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation
- Patients previously treated with systemic anticancer therapy (e.g., chemotherapy, targeted therapy, immunotherapy) within 3 years prior to entering the study
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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 or steroids as CT scan contrast premedication) may be enrolled
- The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed
- 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
- Patients requiring treatment with a RANKL inhibitor (e.g., denosumab) who cannot discontinue it before treatment with atezolizumab
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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
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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 are eligible
- Patients with controlled type 1 diabetes mellitus on a stable insulin regimen or type 2 diabetes mellitus are eligible
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Patients with eczema, psoriasis, lichen simplex chronicus or 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 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 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
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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
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Severe, active co-morbidity defined as follows:
- Current (within 28 days of cycle 1, day 1) signs and/or symptoms of bowel obstruction
- Patients who require parental hydration and/or nutrition
- Patients who require drainage gastrostomy tube
- Evidence of bleeding diathesis or clinically significant coagulopathy
- Serious, non-healing or dehiscing wound, active ulcer or untreated bone fracture
- History of hemoptysis (>= 1/2 teaspoon of bright red blood per episode) within 1 month of study enrollment
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Significant cardiovascular or cerebrovascular disease including:
- Uncontrolled hypertension (systolic blood pressure [SBP] >= 150; diastolic blood pressure [DBP] >= 90)
- History of myocardial infarction within 6 months
- Unstable angina
- New York Heart Association functional classification II, III or IV
- Baseline ejection fraction =< 50% as assessed by echocardiogram or multigated acquisition scan (MUGA)
- Cerebral vascular accident (CVA) or transient ischemic attack (TIA) within 6 months
- Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or peripheral arterial thrombosis) within 6 months
- History of abdominal/pelvic or tracheoesophageal fistula or gastrointestinal perforation and/or abscess within 6 months prior to initiation of treatment
- If patients are of child-bearing potential and do not agree to use two forms of birth control then they are ineligible
- Patients who have had a hysterectomy or are planning to have an adjuvant hysterectomy following radiation as part of their cervical cancer treatment are ineligible
- Patients scheduled to be treated with adjuvant consolidation chemotherapy at the conclusion of their standard chemoradiation
- Pregnant women are excluded from this study because radiation therapy has the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with atezolizumab, breastfeeding should be discontinued if the mother is treated with atezolizumab
- Women of child-bearing potential and men 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 the 5 months (150 days) after the last dose of the study agent. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
- Patients taking bisphosphonate therapy for symptomatic hypercalcemia. Use of bisphosphonate therapy for other reasons (e.g. osteoporosis) is allowed
- Patients with known primary central nervous system (CNS) malignancy or CNS metastases are excluded
- Patients with a prior known history of vesicovaginal, enterovaginal or colovaginal fistula
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): NCT03738228
Locations
| United States, Alabama | |
| University of Alabama at Birmingham Cancer Center | |
| Birmingham, Alabama, United States, 35233 | |
| United States, California | |
| UC San Diego Moores Cancer Center | |
| La Jolla, California, United States, 92093 | |
| University of California Davis Comprehensive Cancer Center | |
| Sacramento, California, United States, 95817 | |
| United States, Colorado | |
| University of Colorado Hospital | |
| Aurora, Colorado, United States, 80045 | |
| United States, Georgia | |
| Augusta University Medical Center | |
| Augusta, Georgia, United States, 30912 | |
| United States, Iowa | |
| University of Iowa/Holden Comprehensive Cancer Center | |
| Iowa City, Iowa, United States, 52242 | |
| United States, New York | |
| Roswell Park Cancer Institute | |
| Buffalo, New York, United States, 14263 | |
| Memorial Sloan Kettering Cancer Center | |
| New York, New York, United States, 10065 | |
| United States, Ohio | |
| Cleveland Clinic Foundation | |
| Cleveland, Ohio, United States, 44195 | |
| Ohio State University Comprehensive Cancer Center | |
| Columbus, Ohio, United States, 43210 | |
| United States, Oklahoma | |
| University of Oklahoma Health Sciences Center | |
| Oklahoma City, Oklahoma, United States, 73104 | |
| United States, Pennsylvania | |
| Thomas Jefferson University Hospital | |
| Philadelphia, Pennsylvania, United States, 19107 | |
| University of Pittsburgh Cancer Institute (UPCI) | |
| Pittsburgh, Pennsylvania, United States, 15232 | |
| United States, Rhode Island | |
| Women and Infants Hospital | |
| Providence, Rhode Island, United States, 02905 | |
| United States, Texas | |
| UT Southwestern/Simmons Cancer Center-Dallas | |
| Dallas, Texas, United States, 75390 | |
| United States, Wisconsin | |
| Medical College of Wisconsin | |
| Milwaukee, Wisconsin, United States, 53226 | |
Sponsors and Collaborators
National Cancer Institute (NCI)
NRG Oncology
Investigators
| Principal Investigator: | Jyoti S Mayadev | NRG Oncology |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT03738228 |
| Other Study ID Numbers: |
NCI-2018-02791 NCI-2018-02791 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) NRG-GY017 ( Other Identifier: NRG Oncology ) NRG-GY017 ( Other Identifier: CTEP ) U10CA180868 ( U.S. NIH Grant/Contract ) |
| First Posted: | November 13, 2018 Key Record Dates |
| Last Update Posted: | November 29, 2022 |
| Last Verified: | November 2022 |
| 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 Uterine Cervical Neoplasms Carcinoma, Adenosquamous Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Neoplasms Uterine Neoplasms Genital Neoplasms, Female Urogenital Neoplasms Neoplasms by Site Uterine Cervical Diseases Uterine Diseases Genital Diseases, Female Female Urogenital Diseases |
Female Urogenital Diseases and Pregnancy Complications Urogenital Diseases Genital Diseases Neoplasms, Complex and Mixed Cisplatin Atezolizumab Antibodies, Monoclonal Antineoplastic Agents Immune Checkpoint Inhibitors Molecular Mechanisms of Pharmacological Action Antineoplastic Agents, Immunological Immunologic Factors Physiological Effects of Drugs |