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Hypofractionated Stereotactic Irradiation With Nivolumab, Ipilimumab and Bevacizumab in Patients With Recurrent High Grade Gliomas

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ClinicalTrials.gov Identifier: NCT02829931
Recruitment Status : Recruiting
First Posted : July 12, 2016
Last Update Posted : August 8, 2019
Sponsor:
Information provided by (Responsible Party):
H. Lee Moffitt Cancer Center and Research Institute

Brief Summary:
The main purpose of this study is to evaluate the safety, and tolerability of nivolumab, ipilimumab, and bevacizumab given in combination with hypofractionated stereotactic re-irradiation of recurrent high grade gliomas.

Condition or disease Intervention/treatment Phase
Malignant Glioma Radiation: Hypofractionated Stereotactic Irradiation Drug: Nivolumab Drug: Bevacizumab Drug: Ipilimumab Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 26 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Trial of Hypofractionated Stereotactic Irradiation (HFSRT) Combined With Nivolumab, Ipilimumab and Bevacizumab in Patients With Recurrent High Grade Gliomas
Actual Study Start Date : August 9, 2016
Estimated Primary Completion Date : April 2020
Estimated Study Completion Date : April 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Combination Therapy

Safety Cohort: The first 6 participants will receive Hypofractionated Stereotactic Irradiation (HFSRT) followed by Ipilimumab + Nivolumab + Bevacizumab.

Dose Expansion Cohort: All 26 participants will be treated with Hypofractionated Stereotactic Irradiation (HFSRT), followed by Ipilimumab + Nivolumab +Bevacizumab

Radiation: Hypofractionated Stereotactic Irradiation
Hypofractionated Stereotactic Irradiation (HFSRT) prior to nivolumab.
Other Names:
  • HFSRT
  • radiation therapy

Drug: Nivolumab
Nivolumab intravenously (IV): 240 mg every (q) 3 weeks x 4 months followed by 480 mg X 4 months.
Other Name: OPDIVO

Drug: Bevacizumab
Bevacizumab intervenously (IV): 15 mg/kg every (q) 3 weeks when given with Ipilumumab and Nivolumab combination. Dose changed to 10mg/kg every 2 weeks when given with Nivolumab only.
Other Name: Avastin

Drug: Ipilimumab
Ipilimumab 1mg/kg intervenously (IV) 200 mg (5 mg/mL) every (q) 3 weeks for 4 months.
Other Name: Yervoy




Primary Outcome Measures :
  1. Number of Participants with Treatment Related Adverse Events [ Time Frame: Up to 24 months ]
    Safety and tolerability of nivolumab, given in combination with hypofractionated stereotactic re-irradiation of recurrent high grade gliomas.


Secondary Outcome Measures :
  1. Response Rate [ Time Frame: Up to 36 months ]
    All participants will receive efficacy assessments with brain MRI at time points specified in Trial Flow Chart. Cases of suspected radiologic disease progression will be confirmed by an MRI performed approximately 8 weeks after the initial radiological assessment of progression. Immunotherapy Response Assessment in Neuro-Oncology (iRANO) and Response Assessment Criteria for High-Grade Gliomas (RANO Criteria) will be used for assessing the response to study treatment.

  2. Overall Survival (OS) Rate at 6 Months [ Time Frame: 6 months ]
    OS, utilizing 95% confidence interval (95%CI).

  3. Overall Survival (OS) Rate at 9 Months [ Time Frame: 9 months ]
    OS, utilizing 95% confidence interval (95%CI).



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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:

  • Histologically confirmed diagnosis of World Health Organization (WHO) Grade III or IV malignant glioma.
  • Documented recurrence by diagnostic biopsy or contrast enhanced magnetic resonance imaging (MRI) performed within 28 days of entry in to the trial as per Response Assessment in Neuro-Oncology (RANO) criteria.
  • Maximum diameter of enhancing tumor (target lesion) should be ≤ 4 cm.
  • An interval of at least 6 months after the end of prior radiation therapy is required unless there is a new recurrence outside of the previous radiotherapy treatment field.
  • Previous first line treatment with at least standard dose of radiotherapy (total dose ≥ 54 Gy) and temozolomide
  • An interval of ≥ 4 weeks since surgical resection prior to study treatment.
  • An interval of ≥ 4 weeks after the last administration of any investigational agent, bevacizumab, or prior cytotoxic therapy.
  • ≥18 years of age on day of signing informed consent.
  • Karnofsky performance status of 70 or higher.
  • Demonstrate adequate organ function. All screening labs should be performed within 14 days of treatment initiation.
  • Resting baseline O2 saturation by pulse oximetry of ≥ 92% at rest.
  • Must have recovered from the toxic effects of prior therapies (≤ Grade 1).
  • Willing and able to provide written informed consent for the trial.
  • Life expectancy ≥ 12 weeks
  • Women of childbearing potential (WOCBP) should have a negative urine or serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. WOCBP should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 5 months after the last dose of study medication.
  • Males should agree to use an adequate method of contraception starting with the first dose of study therapy through 7 months after the last dose of study therapy.

Exclusion Criteria:

  • Has more than three recurrences of high grade glioma. Previous recurrences of low grade glioma is not considered.
  • Has received re-radiation to recurrent disease (other than standard frontline adjuvant radiation therapy).
  • Recurrent tumors near the brainstem and optic chiasm must not have received prior radiation therapy.
  • Has infratentorial, or leptomeningeal evidence of recurrent disease.
  • Has recurrent or persistent tumor (enhancing area) greater than 4 cm in maximum diameter.
  • Has prior treatment with Gliadel unless it was administered as first line treatment and at least 3 months prior to study treatment.
  • Is unable (due to existent medical condition) or unwilling to have a contrast enhanced MRI of brain.
  • Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment.
  • Has a diagnosis of immunodeficiency or is receiving systemic immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Physiologic doses of steroid therapy (≤ 10 mg/day prednisone equivalents) is allowed.
  • Has had a prior chemotherapy, targeted small molecule therapy, or monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
  • Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
  • Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Potential participants with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Potential participants that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Potential participants with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study.
  • Has evidence of interstitial lung disease or active, non-infectious pneumonitis.
  • Has an active infection requiring systemic therapy.
  • Had major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to day 1 of treatment on study.
  • Requires escalating or chronic supraphysiologic doses of corticosteroids (> 10 mg/day prednisone equivalents).
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with participation for the full duration of the trial, or is not in the best interest of the participant, in the opinion of the treating investigator.
  • Has prior history of uncontrolled hypertension, hypertensive crisis or hypertensive encephalopathy.
  • Has history of non-healing wound, ulcer, or bone fracture within 90 days (3 months) prior to entry into the trial.
  • Has history of gastrointestinal bleeding or any other hemorrhage/bleeding event ≥ grade 3 (CTCAE, v. 4) within 30 days prior to entry in to the trial.
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  • Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
  • Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
  • Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
  • Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C Virus (HCV) (e.g., HCV RNA [qualitative] is detected).
  • Has received a live vaccine within 30 days prior to the first dose of trial treatment.

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): NCT02829931


Locations
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United States, Florida
H. Lee Moffitt Cancer Center and Research Institute Recruiting
Tampa, Florida, United States, 33612
Contact: Melissa Wicklund    813-745-3620    melissa.wicklund@moffitt.org   
Contact: Solmaz Sahebjam    813-745-6101    solmaz.sahebjam@moffitt.org   
Principal Investigator: Solmaz Sahebjam, M.D.         
Sub-Investigator: John A. Arrington, M.D.         
Sub-Investigator: Peter Forsyth, M.D.         
Sub-Investigator: Peter A. Johnstone, M.D.         
Sub-Investigator: Nam D. Tran, M.D., Ph.D.         
Sub-Investigator: H. Michael Yu, M.D.         
Sub-Investigator: Sepideh Mokhtari, M.D.         
United States, Ohio
Ohio State University Comprehensive Cancer Center Not yet recruiting
Columbus, Ohio, United States, 43210
Contact: Raju Raval    614-685-2435      
Principal Investigator: Raju Raval, M.D.         
Sponsors and Collaborators
H. Lee Moffitt Cancer Center and Research Institute
Investigators
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Principal Investigator: Solmaz Sahebjam, M.D. H. Lee Moffitt Cancer Center and Research Institute

Additional Information:
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Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
ClinicalTrials.gov Identifier: NCT02829931     History of Changes
Other Study ID Numbers: MCC-18661
First Posted: July 12, 2016    Key Record Dates
Last Update Posted: August 8, 2019
Last Verified: August 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by H. Lee Moffitt Cancer Center and Research Institute:
recurrent glioma
high grade glioma
head and neck disease
grade III glioma
grade IV glioma
radiation therapy
Additional relevant MeSH terms:
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Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Bevacizumab
Nivolumab
Ipilimumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors