Clinical Trials /

Atezolizumab and Bevacizumab in Treating Patients With Rare Solid Tumors

NCT03074513

Description:

This phase II trial studies how well atezolizumab and bevacizumab work in treating patients with rare solid tumors. Immunotherapy with monoclonal antibodies, such as atezolizumab and bevacizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Related Conditions:
  • Anal Canal Squamous Cell Carcinoma
  • Appendix Adenocarcinoma
  • Cervical Squamous Cell Carcinoma
  • Merkel Cell Carcinoma
  • Nasopharyngeal Carcinoma
  • Neuroendocrine Tumor
  • Peritoneal Mesothelioma
  • Pleural Mesothelioma
  • Squamous Cell Carcinoma of the Penis
  • Vaginal Squamous Cell Carcinoma
  • Vulvar Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Atezolizumab and Bevacizumab in Treating Patients With Rare Solid Tumors
  • Official Title: A Phase II, Single-Arm Open-Label Study of the Combination of Atezolizumab and Bevacizumab in Rare Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: 2016-0861
  • SECONDARY ID: NCI-2017-00501
  • SECONDARY ID: 2016-0861
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03074513

Conditions

  • Appendix Adenocarcinoma
  • Human Papillomavirus-Related Anal Squamous Cell Carcinoma
  • Human Papillomavirus-Related Cervical Squamous Cell Carcinoma
  • Human Papillomavirus-Related Squamous Cell Carcinoma of the Penis
  • Human Papillomavirus-Related Vulvar Squamous Cell Carcinoma
  • Neuroendocrine Carcinoma
  • Pancreatic Neuroendocrine Tumor
  • Recurrent Merkel Cell Carcinoma
  • Recurrent Nasopharynx Carcinoma
  • Recurrent Peritoneal Malignant Mesothelioma
  • Recurrent Pleural Malignant Mesothelioma
  • Stage III Merkel Cell Carcinoma AJCC v7
  • Stage III Nasopharyngeal Carcinoma AJCC v7
  • Stage III Pleural Malignant Mesothelioma AJCC v7
  • Stage IV Merkel Cell Carcinoma AJCC v7
  • Stage IV Nasopharyngeal Carcinoma AJCC v7
  • Stage IV Pleural Malignant Mesothelioma AJCC v7
  • Stage IVA Nasopharyngeal Carcinoma AJCC v7
  • Stage IVB Nasopharyngeal Carcinoma AJCC v7
  • Stage IVC Nasopharyngeal Carcinoma AJCC v7
  • Vaginal Squamous Cell Carcinoma, Not Otherwise Specified

Interventions

DrugSynonymsArms
AtezolizumabMPDL 3280A, MPDL 328OA, MPDL-3280A, MPDL3280A, MPDL328OA, RG7446, RO5541267, TecentriqTreatment (atezolizumab, bevacizumab)
BevacizumabAnti-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 HD204, Bevacizumab Biosimilar HLX04, Bevacizumab Biosimilar IBI305, Bevacizumab Biosimilar LY01008, Bevacizumab Biosimilar MIL60, Bevacizumab Biosimilar QL 1101, Bevacizumab Biosimilar SCT501, HD204, 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, SCT501Treatment (atezolizumab, bevacizumab)

Purpose

This phase II trial studies how well atezolizumab and bevacizumab work in treating patients with rare solid tumors. Immunotherapy with monoclonal antibodies, such as atezolizumab and bevacizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the efficacy of atezolizumab when given in combination with bevacizumab (atezo
      bev).

      SECONDARY OBJECTIVES:

      I. To evaluate the efficacy of atezo bev. II. To evaluate the safety of atezo + bev.

      EXPLORATORY BIOMARKER OBJECTIVES:

      I. To identify biomarkers that are predictive of response to atezo bev (i.e., predictive
      biomarkers), are associated with progression to a more severe disease state (i.e., prognostic
      biomarkers), are associated with resistance to atezo bev, are associated with susceptibility
      to developing adverse events, can provide evidence of study treatment activity, or can
      increase the knowledge and understanding of disease biology.

      OUTLINE:

      Patients receive atezolizumab and bevacizumab intravenously (IV) over 60 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (atezolizumab, bevacizumab)ExperimentalPatients receive atezolizumab and bevacizumab IV over 60 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Atezolizumab
  • Bevacizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Signed informed consent form

          -  Ability to comply with the study protocol, in the investigator's judgment

          -  Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST)
             version (v) 1.1; previously irradiated lesions can be considered as measurable disease
             only if progressive disease has been unequivocally documented at that site since
             radiation; the pleural mesothelioma cohort will require measurable disease according
             to modified RECIST

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

          -  Absolute neutrophil count (ANC) >= 1.5 x 10^9/L without granulocyte colony-stimulating
             factor support, obtained within 14 days prior to initiation of study treatment

          -  Lymphocyte count >= 0.5 x 10^9/L, obtained within 14 days prior to initiation of study
             treatment

          -  Platelet count >= 100 x 10^9/L without transfusion, obtained within 14 days prior to
             initiation of study treatment

          -  White blood cell (WBC) count >= 2500/ul, obtained within 14 days prior to initiation
             of study treatment

          -  Hemoglobin >= 90 g/L (patients may be transfused to meet this criterion), obtained
             within 14 days prior to initiation of study treatment

          -  Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline
             phosphatase (ALP) =< 2.5 x upper limit of normal (ULN), obtained within 14 days prior
             to initiation of study treatment, with the following exceptions: patients with
             documented liver metastases: AST and ALT =< 5 x ULN; patients with documented liver or
             bone metastases: alkaline phosphatase (ALP) =< 5 x ULN

          -  Serum bilirubin 1.5 x ULN, obtained within 14 days prior to initiation of study
             treatment

          -  Serum creatinine =< 1.5 x ULN, obtained within 14 days prior to initiation of study
             treatment

          -  Serum albumin >= 2.5 g/dL, obtained within 14 days prior to initiation of study
             treatment

          -  For patients not receiving therapeutic anticoagulation: international normalized ratio
             (INR) or activated partial thromboplastin time (aPTT) =< 1.5 x ULN, obtained within 14
             days prior to initiation of study treatment

          -  For patients receiving therapeutic anticoagulation: stable anticoagulant regimen

          -  For women of childbearing potential: agreement to remain abstinent (refrain from
             heterosexual intercourse) or use a contraceptive method with a failure rate of < 1%
             per year during the treatment period and for 6 months after the last dose of study
             treatment

          -  A woman is considered to be of childbearing potential if she is postmenarchal, has not
             reached a postmenopausal state (>= 12 continuous months of amenorrhea with no
             identified cause other than menopause), and has not undergone surgical sterilization
             (removal of ovaries and/or uterus); examples of contraceptive methods with a failure
             rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal
             contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and
             copper intrauterine devices; the reliability of sexual abstinence should be evaluated
             in relation to the duration of the clinical trial and 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

          -  Appendiceal adenocarcinoma basket

               -  Metastatic appendiceal adenocarcinoma

               -  Not considered candidate for curative surgery

          -  Nasopharyngeal carcinoma basket

               -  Metastatic or locally recurrent disease not amenable to curative intent treatment

               -  Any number of prior therapies, including 0

          -  Human papilloma virus-associated cancers

               -  Histologically proven squamous carcinoma of the anal canal, penile, vaginal,
                  vulva, or refractory cervical cancer with progression or intolerance to at least
                  one treatment regimen including cisplatin, oxaliplatin or carboplatin will be
                  enrolled; human papilloma virus (HPV) confirmation is not required

               -  Patients must have metastatic disease not amenable to surgical resection

               -  If human immunodeficiency virus (HIV)+ positive, all patients infected with human
                  immunodeficiency virus (HIV) and CD4+ T cell count > 400 cells/mm^3 may be
                  eligible for study

               -  Patients co-infected with hepatitis B virus and/or hepatitis C virus may be
                  included in this study provided that their liver function tests remain within the
                  limits listed above; patients must be followed by a hepatologist during the
                  course of this study

          -  Merkel cell carcinoma basket

               -  Metastatic or locally recurrent disease not amenable to curative intent treatment

               -  Prior treatment with CD137 agonists or immune checkpoint blockade therapies,
                  including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies

               -  Any number of prior therapies

          -  Neuroendocrine tumors, pancreatic basket

               -  Grade 1 or grade 2 (or described as low grade, intermediate grade, well
                  differentiated, or moderately differentiated) according to reviewing pathologist

               -  Progressive disease over the preceding 12 months

               -  Any number of prior therapies, including 0

               -  Patients using a somatostatin analogue for symptom control must be on stable
                  doses for 56 days prior to enrollment

          -  Neuroendocrine tumors, extrapancreatic basket

               -  Grade 1 or grade 2 (or described as low grade, intermediate grade, well
                  differentiated, or moderately differentiated; typical or atypical carcinoid if
                  originating in lung) according to reviewing pathologist

               -  Progressive disease over the preceding 12 months

               -  Any number of prior therapies, including 0

               -  Patients using a somatostatin analogue for symptom control must be on stable
                  doses for 56 days prior to enrollment

          -  Peritoneal mesothelioma basket

               -  Refractory or intolerant to platinum and pemetrexed systemic therapy

               -  Any number of prior therapies

          -  Pleural mesothelioma basket

               -  Metastatic or locally recurrent disease not amenable to curative intent treatment

               -  Refractory to platinum and pemetrexed systemic therapy

               -  Any number of prior therapies

        Exclusion Criteria:

          -  Treatment for the studied cancer within 28 days prior to initiation of study treatment

          -  Treatment with investigational therapy within 28 days prior to initiation of study
             treatment

          -  History of severe allergic, anaphylactic, or other hypersensitivity reactions to
             chimeric or humanized antibodies or fusion proteins

          -  Known hypersensitivity to biopharmaceutical agents produced in Chinese hamster ovary
             cells

          -  Known allergy or hypersensitivity to any component of the atezolizumab formulation

          -  Known allergy or hypersensitivity to any component of the bevacizumab formulation

          -  Active or history of autoimmune disease or immune deficiency, including, but not
             limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
             erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid
             antibody syndrome, Wegener granulomatosis, Sjogren's syndrome, Guillain-Barre
             syndrome, or multiple sclerosis, with the following exceptions: patients with a
             history of autoimmune-related hypothyroidism who are on thyroid replacement hormone
             are eligible for the study; patients with controlled type 1 diabetes mellitus who are
             on an insulin regimen are eligible for the study; patients with eczema, psoriasis,
             lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g.,
             patients with psoriatic arthritis are excluded) are eligible for the study provided
             all of following conditions are met:

               -  Rash must cover < 10% of body surface area

               -  Disease is well controlled at baseline and requires only low-potency topical
                  corticosteroids

               -  No occurrence of acute exacerbations of the underlying condition requiring
                  psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents,
                  oral calcineurin inhibitors, or high potency or oral corticosteroids within the
                  previous 12 months

          -  Prior allogeneic stem cell or solid organ transplantation

          -  History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
             obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of
             active pneumonitis on screening chest computed tomography (CT) scan; (history of
             radiation pneumonitis in the radiation field [fibrosis] is permitted)

          -  Positive HIV test at screening (except in cohort 3, HPV-associated cancers)

          -  Except in cohort 3, HPV-associated cancers, active hepatitis B virus (HBV) infection
             (chronic or acute), defined as having a positive hepatitis B surface antigen (HBsAg)
             test at screening; patients with a past or resolved HBV infection, defined as having a
             negative HBsAg test and a positive total hepatitis B core antibody (HBcAb) test and
             negative HBV deoxyribonucleic acid (DNA) test at screening, are eligible for the study

          -  Except in cohort 3, HPV-associated cancers active hepatitis C virus (HCV) infection,
             defined as having a positive HCV antibody test followed by a positive HCV RNA test at
             screening; the HCV RNA test will be performed only for patients who have a positive
             HCV antibody test

          -  Active tuberculosis

          -  Severe infection within 4 weeks prior to initiation of study treatment, including, but
             not limited to, hospitalization for complications of infection, bacteremia, or severe
             pneumonia

          -  Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation
             of study treatment; patients receiving prophylactic antibiotics (e.g., to prevent a
             urinary tract infection or chronic obstructive pulmonary disease exacerbation) are
             eligible for the study

          -  Significant cardiovascular disease, such as New York Heart Association cardiac disease
             (class II or greater), myocardial infarction, or cerebrovascular accident within 3
             months prior to initiation of study treatment, unstable arrhythmia, or unstable angina

          -  Major surgical procedure other than for diagnosis within 4 weeks prior to initiation
             of study treatment, or anticipation of need for a major surgical procedure during the
             course of the study

          -  Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study
             treatment, or anticipation of need for such a vaccine during the course of the study,
             or up to 5 months following the anticipated last dose of atezolizumab

          -  Malignancies other than the disease under study within 5 years prior to cycle 1, day
             1, with the exception of those with a negligible risk of metastasis or death and with
             expected curative outcome (such as adequately treated carcinoma in situ of the cervix,
             basal or squamous cell skin cancer, or ductal carcinoma in situ treated surgically
             with curative intent) or undergoing active surveillance per standard-of-care
             management (e.g., chronic lymphocytic leukemia Rai stage 0)

          -  Any other disease, metabolic dysfunction, physical examination finding, or clinical
             laboratory finding that contraindicates the use of an investigational drug, may affect
             the interpretation of the results, or may render the patient at high risk from
             treatment complications

          -  Except for cohort 4, Merkel cell carcinoma, prior treatment with CD137 agonists or
             immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1
             therapeutic antibodies

          -  Treatment with systemic immunostimulatory agents (including, but not limited to,
             interferon and interleukin 2 [IL-2]) within 4 weeks or five half-lives of the drug
             (whichever is longer) prior to initiation of study treatment

          -  Treatment with systemic immunosuppressive medication (including, but not limited to,
             corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
             anti-TNF-· agents) within 2 weeks prior to initiation of study treatment, or
             anticipation of need for systemic immunosuppressive medication during the course of
             the study, with the following exceptions: patients who received low-dose
             immunosuppressant medication are eligible for the study; patients who received
             mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive
             pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic
             hypotension or adrenal insufficiency are eligible for the study

          -  Pregnant or breastfeeding, or intending to become pregnant during the study; women of
             childbearing potential must have a negative serum pregnancy test result within 14 days
             prior to initiation of study treatment

          -  Inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg
             and/or diastolic blood pressure > 100 mmHg); anti-hypertensive therapy to maintain a
             systolic blood pressure < 150 mmHg and/or diastolic blood pressure < 100 mmHg is
             permitted

          -  Prior history of hypertensive crisis or hypertensive encephalopathy

          -  History of stroke or transient ischemic attack within 6 months prior to cycle 1, day 1

          -  Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or
             recent peripheral arterial thrombosis) within 6 months prior to cycle 1, day 1

          -  Patients with a baseline electrocardiography (ECG) demonstrating a corrected QT (QTc)
             > 460 ms

          -  Evidence of bleeding diathesis or clinically significant coagulopathy (in the absence
             of therapeutic anticoagulation)

          -  Current or recent (within 10 calendar days prior to cycle 1, day 1) use of
             dipyramidole, ticlopidine, clopidogrel, or cilostazol

          -  Core biopsy or other minor surgical procedure, excluding placement of a vascular
             access device, within 7 calendar days prior to the first dose of bevacizumab

          -  History of abdominal or tracheoesophageal fistula or gastrointestinal perforation
             within 6 months prior to cycle 1, day 1

          -  Clinical signs or symptoms of gastrointestinal obstruction or requirement for routine
             parenteral hydration, parenteral nutrition, or tube feeding

          -  Evidence of abdominal free air not explained by paracentesis or recent surgical
             procedure

          -  Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture

          -  Proteinuria, as demonstrated by urine dipstick or > 1.0 g of protein in a 24-hour
             urine collection; all patients with >= 2+ protein on dipstick urinalysis at baseline
             must undergo a 24-hour urine collection for protein

          -  Appendiceal adenocarcinoma basket

               -  Complete or partial bowel obstruction

          -  Epstein-Barr virus-associated nasopharyngeal carcinoma basket:

               -  None

          -  Human papilloma virus-associated cancers basket

               -  None

          -  Merkel cell carcinoma basket:

               -  None

          -  Neuroendocrine tumors, pancreatic basket:

               -  Grade 3, poorly differentiated neuroendocrine carcinoma

               -  Large cell or small cell histology

          -  Neuroendocrine tumors, extrapancreatic basket:

               -  Grade 3, poorly differentiated neuroendocrine carcinoma

               -  Large cell or small cell histology

          -  Peritoneal mesothelioma basket:

               -  None

          -  Pleural mesothelioma basket:

               -  None
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response
Time Frame:Up to 4 years
Safety Issue:
Description:Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (modified RECIST for pleural mesothelioma). Will be defined as a complete response or partial response on two consecutive occasions 4 weeks apart as determined by an independent radiologist. For each tumor group, the best response rate and its 95% exact confidence interval will be estimated using the Clopper and Pearson method. The combination treatment will be assessed by performing the independent binomial test comparing the best response rate versus the historical control for each tumor group. The Bayesian classification and information sharing method proposed by Lee and Chen may be applied.

Secondary Outcome Measures

Measure:Objective response
Time Frame:Up to 4 years
Safety Issue:
Description:Will be assessed by immune-modified RECIST
Measure:Progression free survival
Time Frame:The time from enrollment to the first occurrence of disease progression or death from any cause, whichever occurs first, assessed up to 4 years
Safety Issue:
Description:Will be assessed by RECIST 1.1 (modified RECIST for pleural mesothelioma). Will be estimated using Kaplan-Meier method. The log-rank test will be performed to test the difference in time-to-event distributions between patient groups. Cox proportional hazards model may be utilized to include multiple covariates in the time-to-event analysis.
Measure:Duration of response
Time Frame:The time from the first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first, assessed up to 4 years
Safety Issue:
Description:Will be assessed by RECIST 1.1 (modified RECIST for pleural mesothelioma). For each tumor group the median duration of response and corresponding 2-sided 95% confidence interval will be reported.
Measure:Overall survival
Time Frame:The time from enrollment to death from any cause, assessed up to 4 years
Safety Issue:
Description:Will be estimated using Kaplan-Meier method. The log-rank test will be performed to test the difference in time-to-event distributions between patient groups. Cox proportional hazards model may be utilized to include multiple covariates in the time-to-event analysis.
Measure:Progression free survival
Time Frame:Up to 4 years
Safety Issue:
Description:Will be assessed by immune-modified RECIST
Measure:Duration of response
Time Frame:Up to 4 years
Safety Issue:
Description:Will be assessed by immune-modified RECIST
Measure:Incidence of adverse events
Time Frame:Up to 4 years
Safety Issue:
Description:Will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Verbatim adverse events and severity will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. The safety analyses will include all patients who received at least one dose of study treatment. Toxicity data will be summarized by frequency tables for each tumor type group. The association between the types and severity of toxicity and the tumor group will be evaluated. No formal statistical testing will be performed on these summary.
Measure:Change in targeted vital signs
Time Frame:Baseline up to 4 years
Safety Issue:
Description:
Measure:Change in targeted clinical laboratory test results
Time Frame:Baseline up to 4 years
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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