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Translational Study of Nivolumab in Combination With Bevacizumab for Recurrent Glioblastoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03890952
Recruitment Status : Recruiting
First Posted : March 26, 2019
Last Update Posted : October 6, 2020
Sponsor:
Collaborators:
Herlev Hospital
University of Copenhagen
Information provided by (Responsible Party):
Ulrik Lassen, Rigshospitalet, Denmark

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

Condition or disease Intervention/treatment Phase
Recurrent Adult Brain Tumor Drug: Nivolumab Drug: Bevacizumab Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Two parallel arms, non-randomized, not for comparison
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: A Phase II Open Label, Two-armed Translational Study of Nivolumab in Combination With Bevacizumab for Recurrent Glioblastoma
Actual Study Start Date : October 1, 2018
Estimated Primary Completion Date : February 1, 2022
Estimated Study Completion Date : August 1, 2022


Arm Intervention/treatment
Experimental: Arm B Nivolumab and bevacizumab
Nivolumab and bevacizumab in patients not undergoing salvage surgery
Drug: Nivolumab
Treatment with the combination of Nivolumab and bevacizumab every 2 weeks
Other Name: Checkpoint inhibitor

Drug: Bevacizumab
Treatment with the combination of Nivolumab and bevacizumab every 2 weeks
Other Name: Angiogenesis inhibitor

Experimental: Arm A Nivolumab and bevacizumab
Nivolumab and bevacizumab in patients undergoing salvage surgery
Drug: Nivolumab
Treatment with the combination of Nivolumab and bevacizumab every 2 weeks
Other Name: Checkpoint inhibitor

Drug: Bevacizumab
Treatment with the combination of Nivolumab and bevacizumab every 2 weeks
Other Name: Angiogenesis inhibitor




Primary Outcome Measures :
  1. Number of indels as determined using mRNA sequencing [ Time Frame: 8 weeks ]
    whole exome sequencing (WES) and mRNA sequencing on tumor versus germline-control samples. We will map cancer-specific mutations, indels, frameshifts and splice variations, and predict T cell epitopes overlapping these regions based on the patient HLA type, using available prediction tools, netMHC


Secondary Outcome Measures :
  1. Progression-Free Survival (PFS) [ Time Frame: 6 months ]
    Progression-Free Survival (PFS) in both treatment Arms



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

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): NCT03890952


Contacts
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Contact: Benedikte Hasselbalch, MD, PHD +4535453545 benedikte.hasselbalch@regionh.dk
Contact: Simone B Ejbye, MD

Locations
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Denmark
Rigshospitalet Recruiting
Copenhagen, Denmark
Contact: Ulrik Lassen, MD         
Principal Investigator: Ulrik Lassen, MD, PH.D         
Sponsors and Collaborators
Ulrik Lassen
Herlev Hospital
University of Copenhagen
Investigators
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Principal Investigator: Ulrik Lassen, MD, PHD Rigshospitalet, Denmark
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Responsible Party: Ulrik Lassen, Head of Departmen, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier: NCT03890952    
Other Study ID Numbers: CA209-9UP
2017-003925-13 ( EudraCT Number )
First Posted: March 26, 2019    Key Record Dates
Last Update Posted: October 6, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Bevacizumab
Nivolumab
Angiogenesis Inhibitors
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors