Clinical Trials /

Atezolizumab Before and/or With Chemoradiotherapy in Immune System Activation in Patients With Node Positive Stage IB2, II, IIIB, or IVA Cervical Cancer

NCT03738228

Description:

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.

Related Conditions:
  • Cervical Adenocarcinoma
  • Cervical Adenosquamous Carcinoma
  • Cervical Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Atezolizumab Before and/or With Chemoradiotherapy in Immune System Activation in Patients With Node Positive Stage IB2, II, IIIB, or IVA Cervical Cancer
  • Official Title: Anti PD-L1 (Atezolizumab) as an Immune Primer and Concurrently With Extended Field Chemoradiotherapy for Node Positive Locally Advanced Cervical Cancer

Clinical Trial IDs

  • ORG STUDY ID: NCI-2018-02791
  • SECONDARY ID: NCI-2018-02791
  • SECONDARY ID: NRG-GY017
  • SECONDARY ID: NRG-GY017
  • SECONDARY ID: U10CA180868
  • NCT ID: NCT03738228

Conditions

  • Cervical Adenocarcinoma
  • Cervical Adenosquamous Carcinoma
  • Cervical Squamous Cell Carcinoma, Not Otherwise Specified
  • Positive Lymph Node
  • 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

Interventions

DrugSynonymsArms
AtezolizumabMPDL 3280A, MPDL 328OA, MPDL-3280A, MPDL3280A, MPDL328OA, RG7446, RO5541267, TecentriqArm A (atezolizumab, standard cisplatin and radiation therapy)
CisplatinAbiplatin, Blastolem, Briplatin, CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloridoplatinum, Cis-diamminedichloro Platinum (II), Cis-diamminedichloroplatinum, Cis-dichloroammine Platinum (II), Cis-platinous Diamine Dichloride, Cis-platinum, Cis-platinum II, Cis-platinum II Diamine Dichloride, Cismaplat, Cisplatina, Cisplatinum, Cisplatyl, Citoplatino, Citosin, Cysplatyna, DDP, Lederplatin, Metaplatin, Neoplatin, Peyrone''s Chloride, Peyrone''s Salt, Placis, Plastistil, Platamine, Platiblastin, Platiblastin-S, Platinex, Platinol, Platinol- AQ, Platinol-AQ, Platinol-AQ VHA Plus, Platinoxan, Platinum, Platinum Diamminodichloride, Platiran, Platistin, PlatosinArm A (atezolizumab, standard cisplatin and radiation therapy)

Purpose

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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (atezolizumab, standard cisplatin and radiation therapy)ExperimentalPatients 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.
  • Atezolizumab
  • Cisplatin
Arm B (atezolizumab, standard cisplatin and radiation therapy)ExperimentalPatients 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.
  • Atezolizumab
  • Cisplatin

Eligibility 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)

          -  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

          -  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

          -  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

          -  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

          -  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

               -  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

          -  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

          -  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

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:T cell receptor beta (TCRB) clonal expansion in peripheral blood
Time Frame:At day 21
Safety Issue:
Description:Arms will be compared by 2-sided t-test at 10% significance level.

Secondary Outcome Measures

Measure: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)
Safety Issue:
Description: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.
Measure:Incidence of DLTs (Arm B)
Time Frame:From the start of CRT treatment until 30 days after the completion of CRT
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description:The frequency and maximum severity of acute adverse events will be tabulated by treatment arm graded by CTCAE v5.
Measure:TCR clonality, diversity, and frequency in peripheral blood and tissue
Time Frame:Up to 2 years
Safety Issue:
Description: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).
Measure:PD-L1 expression in tissue
Time Frame:Up to 2 years
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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