Translational Study of Nivolumab in Combination With Bevacizumab for Recurrent Glioblastoma

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Brief Title

Translational Study of Nivolumab in Combination With Bevacizumab for Recurrent Glioblastoma

Official Title

A Phase II Open Label, Two-armed Translational Study of Nivolumab in Combination With Bevacizumab for Recurrent Glioblastoma

Brief Summary

      The aim of this study is to make preliminary assessment of PD-L1 and other immune related
      biomarkers that might act as predictors of anti-tumor activity of Nivolumab in patients with
      recurrent glioblastoma
    

Detailed Description

      The effect of Nivolumab in oncologic diseases is to modulate the immune system in order to
      generate and/or restore a durable anti-tumor response leading to clearance of tumor. Clinical
      data generated with Nivolumab monotherapy in a variety of settings support the hypothesis
      that blockade of the PD-1 pathway results in rejection of tumor by the host immune system.
      The precise mechanisms by which Nivolumab exerts its anti-tumor activity are still under
      investigation. To contribute to this knowledge, tumor tissue from primary operation for all
      patients and tumor tissue from patients in the surgical Arm A will be used for further
      analysis.

      Targeted sequencing with next generation sequencing (NGS) and Genome-wide Associations
      Studies (GWAS) with the use of single nucleotide polymorphism (SNP)-arrays and micro-array
      for expression profiling will be performed in order to describe the profile of the tumor. At
      Rigshospitalet has initiated a program of NGS of patients with GBM after informed content, by
      obtaining fresh tissue from primary or relapse surgery. In the surgical group (Arm A) of this
      study NGS will be repeated after one dose of Nivolumab. This information will be used in
      combination with the clinical observations for each patient receiving the combination of
      Nivolumab and Bevacizumab and the aim is that these results could be useful towards finding
      prognostic and/or predictive biomarkers in GBM.

      In order to study the interaction between tumor cells and the immune system investigation of
      intratumoral and peripheral changes in tumor-infiltration lymphocytes (TILs) will be
      performed. By looking at TILs and peripheral blood lymphocytes (PBLs) Surgical samples will
      be compared to sequencing of baseline surgical samples (before Nivolumab). The interaction of
      TILs and tumor cells will be assessed with in vitro functional assays of autologous tumor
      cell recognition. Functional patterns of antitumor CD8+ and CD4+ TILs and PBLs will be
      investigated, with assays combining characterization of major T cell functions and
      simultaneous surface staining of PD-1 after co-culture with autologous tumor cells. This may
      detect treatment-induced changes in the functional repertoires of CD4+ and CD8+ TILs both in
      the tumor microenvironment (TILs) and in the periphery (PBLs). It is expected that these
      analyses will reveal whether significant functional changes (defined as increased frequency
      of tumor-reactive T cells or as functional shifting from a monofunctional to a
      multifunctional profile) are induced in the whole repertoire of T cells, or whether these
      changes are restricted to PD-1 positive T cells.

      Regarding the immune-reactivity, CD8 T cell recognition of tumor-specific-antigens (TSA),
      i.e. and mutation derived neoepitopes will be analyzed in enrolled patients. To analyze for
      immune reactivity on a personalized basis by comprising epitope-maps based on both
      mutation-derived neoepitopes and shared tumor antigens selected based on the individual tumor
      mRNA expression level.

      For the prediction of mutation- and splice-variation derived epitopes, whole exome sequencing
      (WES) and mRNA sequencing will be conducted on tumor versus germline-control samples.
      Cancer-specific mutations, indels, frameshifts and splice variations will be mapped to
      predict T cell epitopes overlapping these regions based on the patient HLA type, using
      available prediction tools, netMHC. A pipeline for processing next-generation sequencing data
      into tumor-specific neo-epitope maps has been generated to include analyses of tumor
      heterogeneity and generate personalized peptide libraries for each patient and analyze for T
      cell recognition of personalized neoepitopes in each patient included in the study. A novel
      technology will tag and track multiple (>1000) antigen specific T cell specificities based on
      their peptide-MHC (pMHC) recognition motif through a pMHC multimer with a co-attached 'DNA
      barcode'. Through use of this technology T cell recognition will be assessed against large
      libraries of peptides in limited biological samples, such as tissue biopsies, TILs and
      peripheral blood mononuclear cells (PBMCs). Data will reveal to what extend mutation and
      splice-variant derived neoepitopes are contributing to immune recognition as a consequence of
      checkpoint inhibition. If these are significantly recognized, then they are likely to play a
      crucial role for the clinical response to checkpoint inhibition.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Number of indels as determined using mRNA sequencing

Secondary Outcome

 Progression-Free Survival (PFS)

Condition

Recurrent Adult Brain Tumor

Intervention

Nivolumab

Study Arms / Comparison Groups

 Arm B Nivolumab and bevacizumab
Description:  Nivolumab and bevacizumab in patients not undergoing salvage surgery

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

40

Start Date

October 1, 2018

Completion Date

August 1, 2022

Primary Completion Date

February 1, 2022

Eligibility Criteria

        Inclusion Criteria:

          1. Pathologically confirmed GBM (including all histologic variants);

          2. Age ≥ 18 years;

          3. Evidence of radiological (MRI-scan) measurable recurrent progressive GBM evaluated by
             the Response Assessment in Neuro-Oncology (RANO) criteria;

          4. In arm B measurable disease according to the RANO guidelines, within 14 days of
             starting treatment. Measurable disease after surgery on arm A is not required with
             radiographic evidence of recurrent disease after treatment with temozolomide and
             radiotherapy;

          5. An interval of at least 4 weeks between prior radiotherapy or chemotherapy and
             enrolment on this protocol;

          6. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-2;

          7. Life expectancy, in the opinion of the investigator > 3 month;

          8. Written informed consent obtained prior to any screening procedures. Patients must be
             willing and able to comply with the protocol and aware of the investigational nature
             of this study;

          9. Patients must have adequate bone marrow function and organ function within 2 weeks of
             study treatment as defined by the following laboratory criteria;

               1. Hematopoietic function: total white blood cell count (WBC) ≥ 3000/mm³, absolute
                  neutrophil count (ANC) ≥ 1500/mm³, platelet count ≥ 125,000/mm³; hemoglobin ≥
                  9g/dL

               2. Hepatic function: bilirubin < 1.5 times the upper limit of normal (ULN)
                  (excluding Gilberts Syndrome, for which bilirubin must be < 4 times ULN), ALAT <
                  2.5 times ULN;

               3. Renal function: serum creatinine < 1.5 ULN or estimated creatinine clearance of ≥
                  50 mL/min, calculated using the formula of Cockcroft and Gault;

               4. APTT and INR < normal limit

         10. All female patients and partners of childbearing potential must agree to use adequate
             birth control during study treatment and for 5 months after the last dose of study
             drug and have a negative serum pregnancy test at screening. Acceptable methods of
             contraception are oral, implantable or injectable contraceptives, contraceptive patch,
             intrauterine device, or a sexual partner who is surgically sterilized or
             post-menopausal.

         11. Fertile males must be willing to employ adequate means of contraception during study
             treatment and for 7 months after the last dose of study drug;

         12. Archived paraffin-embedded tissue (approximately 10 unstained slides or a tumor block)
             must be available for confirmation of tumor diagnosis and correlative studies;

         13. Patients in the surgical arm (Arm A) must be predicted pre-operatively to have
             sufficiently sized recurrent tumor to allow for 500 mg of enhancing tumor and 300 mg
             of non-enhancing tumor to be resected;

         14. Patients must be on a stable or decreasing dose of corticosteroids (or none) for at
             least 5 days prior to MRI and maximum of a dose of 20 mg prednisolone per day at
             enrollment of the study.

        Exclusion Criteria:

          1. Patients must not have significant medical illness that in the investigator's opinion
             cannot be adequately controlled with appropriate therapy or would compromise the
             patient's ability to tolerate this therapy;

          2. Co-medication that may interfere with study results; e.g. immuno-suppressive agents
             other than corticosteroids (equivalent to max dose of 20 mg prednisolone per day) and
             stable for at least 5 days prior to day 1;

          3. Any condition (medical, social, psychological), which would prevent adequate
             information and follow-up;

          4. Any other active malignancy or previous malignancies within the last 5 years, except,
             adequately treated basal or squamous cell carcinoma of the skin, or carcinoma in situ;

          5. Uncontrolled hypertension (systolic blood pressure (BP) > 150 mmHg and/or diastolic BP
             > 100 mmHg), unstable angina, congestive heart failure (CHF) of any New York Heart
             Association (NYHA) classification, serious cardiac arrhythmia requiring treatment
             (exceptions: atrial fibrillation, paroxysmal supraventricular tachycardia), history of
             myocardial infarction within 6 months of enrollment;

          6. Clinically significant peripheral vascular disease

          7. Evidence of bleeding diathesis, coagulopathy or taking ASA, NSAIDs or clopidogrel;

          8. Patients with coagulation problems and medically significant bleeding in the month
             prior to start of treatment (e.g., peptic ulcer, epistaxis, spontaneous bleeding);

          9. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
             prior to day 0, anticipation of need for major surgical procedure during the curse of
             the study;

         10. Minor surgical procedures, fine needle aspirations or core biopsies within 7 days
             prior to day 0;

         11. History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess
             within 6 months prior to day 0;

         12. Known active hepatitis A, B or C infection; or known to be positive for HCV RNA or
             HBsAg (HBV surface antigen); hepatitis testing is not required;

         13. Known HIV infection; HIV testing is not required;

         14. Active infection requiring parenteral systemic antibiotics;

         15. Administration of a live, attenuated vaccine within 4 weeks before first dose of
             Nivolumab prior to surgery in Arm A or Cycle 1 Day 1 (Arm A and B) or anticipation
             that such a live attenuated vaccine will be required during the study. Influenza
             vaccination should be given during influenza season only (approximately October to
             March). Patients must not receive live, attenuated influenza vaccine (e.g., FluMist)
             within 4 weeks before first dose of Nivolumab prior to surgery in Arm A or Cycle 1 Day
             1 (Arm A and B) or at any time during the study;

         16. 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;

         17. 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;

         18. Any other diseases, metabolic dysfunction, physical examination finding, or clinical
             laboratory finding giving reasonable suspicion of a disease or condition that would
             contraindicate the use of an investigational drug;

         19. Dementia or altered mental status that would prohibit informed consent;

         20. History of organ allograft;

         21. 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, Wegner´s granulomatosis, Sjogren´s
             syndrome, Bell´s palsy, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or
             glomerulonephritis;

         22. 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 CT scan.
             History of radiation pneumonitis in the radiation field (fibrosis) is permitted;

         23. Pregnant or breast-feeding women

         24. Prior treatment with PD-1/PD-L1 inhibitors

         25. Known hypersensitivity to any of the components of Nivolumab or Bevacizumab;

         26. Investigational therapy (defined as treatment for which there is no regulatory
             authority; within 28 days prior to Cycle 1 Day 1;

         27. Any approved anti-cancer therapy, including chemotherapy or hormonal therapy, within 3
             weeks prior to Cycle 1 Day 1, with the following exceptions:

             a. Hormone-replacement therapy or oral contraceptives

         28. Treatment with systemic immunosuppressive medications including, but not limited to:
             cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF agents within
             2 weeks prior to Cycle 1, Day 1. The use of inhaled corticosteroids and
             mineralocorticoids (e.g. fludrocortisone) for patients with orthostatic hypotension or
             adrenocortical insufficiency is allowed

         29. Concurrent therapy with approved or investigational anticancer therapeutics;

         30. Body weight significantly below ideal body weight in the opinion of the investigator.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Ulrik Lassen, MD, PHD, +4535453545, [email protected]

Location Countries

Denmark

Location Countries

Denmark

Administrative Informations


NCT ID

NCT03890952

Organization ID

CA209-9UP

Secondary IDs

2017-003925-13

Responsible Party

Sponsor-Investigator

Study Sponsor

Ulrik Lassen

Collaborators

 Herlev Hospital

Study Sponsor

Ulrik Lassen, MD, PHD, Principal Investigator, Rigshospitalet, Denmark


Verification Date

October 2020