Clinical Trials /

Anti-GITR/Anti-PD1/Stereotactic Radiosurgery, in Recurrent Glioblastoma

NCT04225039

Description:

This is a phase II study of the combination of the GITR agonist monoclonal antibody INCAGN01876, the anti-PD1 monoclonal antibody INCMGA00012, and stereotactic radiosurgery (SRS) for recurrent Glioblastoma (GBM). The investigators hypothesize that the proposed regimen will be safe and stimulate a robust anti-tumor immune response and result in improved tumor responses.

Related Conditions:
  • Diffuse Astrocytoma
  • Glioblastoma
  • Glioblastoma, IDH-Wildtype
  • Gliosarcoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Anti-GITR/Anti-PD1/Stereotactic Radiosurgery, in Recurrent Glioblastoma
  • Official Title: A Phase II Study of the Anti-GITR Agonist INCAGN1876 and the PD-1 Inhibitor INCMGA00012 in Combination With Stereotactic Radiosurgery in Recurrent Glioblastoma

Clinical Trial IDs

  • ORG STUDY ID: 834197
  • NCT ID: NCT04225039

Conditions

  • Glioblastoma

Interventions

DrugSynonymsArms
INCMGA00012Cohort A
INCAGN01876Cohort A
SRSstereotactic radiosurgeryCohort A

Purpose

This is a phase II study of the combination of the GITR agonist monoclonal antibody INCAGN01876, the anti-PD1 monoclonal antibody INCMGA00012, and stereotactic radiosurgery (SRS) for recurrent Glioblastoma (GBM). The investigators hypothesize that the proposed regimen will be safe and stimulate a robust anti-tumor immune response and result in improved tumor responses.

Detailed Description

      The study has 2 arms:

      Arm A (Cohort A) is a nonsurgical arm (N=16) that will serve as the primary study cohort and
      evaluated for the primary study endpoint. Subjects in this arm receive a single priming dose
      of both INCMGA00012 and INCAGN01876 prior to stereotactic radiosurgery (SRS), then undergo
      SRS (8 Gy x 3 fractions). Following SRS, INCMGA00012 (IV every 4 weeks) and INCAGN01876 (IV
      every 2 weeks) are resumed and continued until disease progression, unacceptable toxicity, or
      for 2 years, whichever occurs first.

      Arm B (Cohort B) is a surgical arm (N=16) that will allow for evaluation of the effects on
      the tumor immune microenvironment of INCMGA00012, INCAGN01876, and SRS. In order to be
      enrolled on this arm, subjects must have a clinical indication for surgical resection of the
      recurrent GBM tumor. Prior to planned surgical resection, subjects receive neoadjuvant
      immunotherapy (one of two possible combinations, as outlined below). Subjects then undergo
      surgery. Postoperatively, the immunotherapy combination of INCMGA00012 (IV every 4 weeks) and
      INCAGN01876 (IV every 2 weeks) is resumed and continued until disease progression,
      unacceptable toxicity, or for 2 years, whichever occurs first. Subjects in the surgical arm
      with a focus of contrast-enhancing tumor that is amenable to SRS will be assigned to surgical
      sub-arm #1 of Cohort B (N=8). These subjects will receive neoadjuvant INCMGA00012 +
      INCAGN01876 + SRS. All other subjects enrolled on Cohort B (N=8) are treated with neoadjvuant
      INCMGA00012 + INCAGN01876 (without SRS).
    

Trial Arms

NameTypeDescriptionInterventions
Cohort AExperimentalSubjects in this arm (N=16) receive a single priming dose of both INCMGA00012 (500mg) and INCAGN01876 (300mg) prior to stereotactic radiosurgery (SRS), then undergo SRS (8 Gy x 3 fractions). Following SRS, INCMGA00012 (500mg IV every 4 weeks) and INCAGN01876 (300mg IV every 2 weeks) are resumed and continued until disease progression, unacceptable toxicity, or for 2 years, whichever occurs first.
  • INCMGA00012
  • INCAGN01876
  • SRS
Cohort B sub-arm #1ExperimentalSubjects in this arm (N=8) receive neoadjuvant immunotherapy INCMGA00012 (500mg) + INCAGN01876 (300mg) + SRS. Subjects then undergo surgery. Postoperatively, the immunotherapy combination of INCMGA00012 (500 mg IV every 4 weeks) and INCAGN01876 (300mg IV every 2 weeks) is resumed and continued until disease progression, unacceptable toxicity, or for 2 years, whichever occurs first.
  • INCMGA00012
  • INCAGN01876
  • SRS
Cohort B sub-arm #2ExperimentalSubjects in this arm (N=8) receive neoadjuvant immunotherapy INCMGA00012 + INCAGN01876 (without SRS). Subjects then undergo surgery. Postoperatively, the immunotherapy combination of INCMGA00012 (IV every 4 weeks) and INCAGN01876 (IV every 2 weeks) is resumed and continued until disease progression, unacceptable toxicity, or for 2 years, whichever occurs first.
  • INCMGA00012
  • INCAGN01876

Eligibility Criteria

        Inclusion Criteria:

          1. Prior histopathologically proven diagnosis of World Health Organization (WHO) grade IV
             glioblastoma, OR histopathologically proven diagnosis of gliosarcoma, OR molecular
             diagnosis of glioblastoma per c-IMPACT-NOW criteria ("diffuse astrocytic glioma,
             IDH-wildtype, with molecular features of glioblastoma, WHO grade IV"; this requires
             presence of either amplification of EGFR, whole chromosome 7 gain AND whole chromosome
             10 loss, or TERT promoter mutation).

          2. Glial tumor must be recurrent and progressive following prior first-line radiation
             therapy (prior dose must have been 40-75 Gy and may have been either photon or proton
             radiation), defined as meeting any one of the following criteria:

               -  New contrast-enhancing lesion outside the 80% isodose line of the original
                  radiation field as determined by the treating investigator

               -  Surgically proven recurrence of tumor

               -  Per RANO criteria, an increase by >=25% of the sum of the products of
                  perpendicular diameters between the smallest tumor measurements previously
                  obtained by the subject following radiation and a scan at least 12 weeks from
                  completion of radiation therapy (on stable or increasing doses of
                  corticosteroids) AND MRI performed at the University of Pennsylvania with
                  advanced imaging (dynamic contrast-enhanced [DCE] and dynamic susceptibility
                  contrast [DSC] perfusion imaging for perfusion and permeability data) that is
                  favored by the University of Pennsylvania Brain Tumor Board, based on these
                  advanced imaging metrics, to represent true tumor progression rather than
                  pseudoprogression

          3. Cohort A and Sub-Arm 1 of Cohort B only: Patient must have at least one measurable
             (>=1cm x 1cm) contrast-enhancing tumor focus for which stereotactic radiosurgery (SRS)
             is clinically indicated, as determined by the Investigator, and must be able to
             achieve radiation target coverage without exceeding dose constraints. The target must
             not be larger than 4 cm in maximal diameter. Multifocal disease is allowed as long as
             this criterion is met

               -  Sub-Arms 2 of Cohort B can have any size tumor, and the tumor does not need to be
                  amenable to SRS

          4. Cohort B (surgical) patients only: patients must be undergoing surgery that is
             clinically indicated as determined by their care providers

          5. Tumor O-6-methylguanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT)
             methylation status must be available from any prior GBM tumor specimen; results of
             routinely used methods for MGMT methylation testing (e.g. mutagenically separated
             polymerase chain reaction [MSPCR] or quantitative polymerase chain reaction [PCR]) are
             acceptable)

          6. Patients may have had treatment for an unlimited number of prior relapses but must not
             have had prior bevacizumab or other vascular endothelial growth factor (VEGF/VEGFR)
             inhibitors (exception: prior bevacizumab is allowed if it was administered for the
             treatment of radiation necrosis rather than progressive tumor and was stopped at least
             4 weeks prior to MRI showing demonstrating tumor progression). Prior gliadel wafers
             are only allowed if placed during the first surgery for GBM at initial diagnosis.

          7. Patients must have recovered from severe toxicity of prior therapy; the following
             intervals from previous treatments are required to be eligible:

               -  6 weeks from a nitrosourea cytotoxic chemotherapy

               -  3 weeks from a non-nitrosourea cytotoxic chemotherapy

               -  4 weeks from any investigational (not Food and Drug Administration [FDA]-approved
                  for glioblastoma) agents, or within a time interval less than at least 5
                  half-lives of the investigational agent whichever is shorter

               -  3 weeks from any major surgery, including brain surgery for recurrent tumor
                  resection

          8. Patients must be maintained on a systemic corticosteroid dose of 2mg dexamethasone (or
             equivalent) daily or less for a minimum of 5 days prior to first dose of study drug

          9. Patients must be able to swallow oral medications

         10. Age 18 or older

         11. Karnofsky performance status >= 60

         12. Life expectancy >3 months

         13. Adequate hematologic parameters, including:

               -  Absolute neutrophil count >= 1,500/ul

               -  Absolute lymphocyte count >= 600/uL

               -  Platelets >= 100,000/ul and without a platelet transfusion within 4 weeks prior
                  to initiating protocol therapy

               -  Hemoglobin >= 9 g/dl and without a packed red blood cell transfusion within 4
                  weeks prior to initiating protocol therapy

         14. Adequate hepatic function within 7 days prior to start of study treatment, defined as
             follows

               -  Total bilirubin (except patients with Gilbert's Syndrome, who are eligible for
                  the study but exempt from the total bilirubin eligibility criterion) ≤ 2.0 mg/dl

               -  ALT and AST ≤ 2.5x upper limit of normal (ULN)

         15. Adequate renal function within 7 days prior to start of study treatment, defined as
             follows:

               -  Serum creatinine <=1.5 x institutional ULN OR calculated creatinine clearance
                  (glomerular filtration rate can also be used in place of creatinine or CrCl) >=50
                  mL/min for subjects with creatinine levels >1.5x institutional ULN

         16. Reproductive Status

               1. Women of childbearing potential (WOCBP) must have a negative serum or urine
                  pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 7
                  days prior to the start of study drug.

               2. Women must agree to not breastfeed during the study or for 180 days after the
                  last dose of study treatment

               3. WOCBP must agree to use an adequate method to avoid pregnancy (as defined below)
                  from the time of study screening through 180 days from last dose of study drug

               4. Males who are sexually active with WOCBP must agree to follow instructions for
                  method(s) of contraception (as defined below) starting with the first dose of
                  study drug through 180 days after the last dose of study

               5. Azoospermic males and WOCBP who are continuously not heterosexually active are
                  exempt from contraceptive requirements. However, these WOCBP must still undergo
                  pregnancy testing.

         17. Participant must, in the opinion of the Investigator, be able to comply with study
             procedures

         18. Patients must be able to understand the study procedures and agree to participate in
             the study by providing written informed consent (or have legally authorized
             representative sign on patient's behalf if patient physically unable to sign consent
             due to neurologic deficit)

        Exclusion Criteria:

          -  Any of the following would exclude the subject from participation in the study:

               1. Contrast-enhancing tumor in brainstem or spinal cord (subjects do not need spinal
                  MRI for screening, but known spinal cord tumor is exclusionary)

               2. Diffuse leptomeningeal disease

               3. Prior bevacizumab or other vascular endothelial growth factor (VEGF/VEGFR)
                  inhibitors (exception: prior bevacizumab is allowed if it was administered for
                  the treatment of radiation necrosis rather than progressive tumor and was stopped
                  at least 4 weeks prior to MRI showing demonstrating tumor progression).

               4. Patients with clinically significant mass effect or midline shift (e.g., 1-2 cm
                  of midline shift)

               5. Use of any immunosuppressive medication other than steroids, including but not
                  limited to antimetabolites, calcineurin inhibitors, and/or anti-TNF agents within
                  six months of start of study drug

               6. Prior diagnosis of immunodeficiency

               7. Prior solid organ or bone marrow transplantation

               8. Autoimmune or connective tissue disease that is EITHER (a) actively flaring OR
                  (b) has required systemic treatment in the past 2 years (i.e., with use of
                  disease modifying agents, corticosteroids, or immunosuppressive drugs).

                  EXCEPTIONS: Subjects with type I diabetes mellitus, hypothyroidism only requiring
                  hormone replacement, adrenal insufficiency requiring only replacement dose
                  corticosteroids, skin disorders (such as vitiligo, psoriasis, pemphigus, or
                  alopecia) controlled with topical medications, or conditions not expected to
                  recur in the absence of an external trigger are permitted to enroll. Patients
                  with asthma that is not actively flaring are allowed. Patients with history of
                  Grave's disease that is previously treated with thyroidectomy or radioiodine are
                  allowed. Patients with celiac disease whose symptoms are controlled with a
                  gluten-free diet are allowed. Patients with rheumatoid arthritis and other
                  arthropathies such as ankylosing spondylitis, Sjogren's syndrome, Raynaud
                  syndrome, and patients with positive serologies, such as antinuclear antibodies
                  (ANA) or anti-thyroid antibodies, should be evaluated for the presence of target
                  organ involvement and potential need for systemic treatment but should otherwise
                  be eligible.

               9. History of non-infectious pneumonitis that required steroid treatment

              10. Prior immune checkpoint inhibitor therapy (targeted against PD-1, PD-L1, PD-L2,
                  CTLA-4, e.g.) or prior immune costimulatory agonist therapy (targeted against
                  GITR, OX40, CD137, e.g.)

              11. Known active hepatitis B virus (HBsAg reactive) or active hepatitis C virus (HCV
                  RNA detectable by PCR)

              12. Human immunodeficiency virus (HIV)-positive patients on antiretroviral therapy

              13. Patients with a prior or concurrent malignancy whose natural history or treatment
                  has the potential to interfere with the safety or efficacy assessment of the
                  investigational regimen are excluded from this trial. Otherwise, patients with
                  prior or concurrent malignancy are eligible.

              14. Any serious, uncontrolled medical disorder, nonmalignant systemic disease, or
                  active, uncontrolled infection that, in the opinion of the investigator, would
                  put the subject at undue risk from the study treatment.

              15. Patients with uncontrolled or significant cardiovascular disease including, but
                  not limited to, any of the following are ineligible:

                    -  Myocardial infarction or uncontrolled angina within 90 days prior to consent

                    -  History of clinically significant arrhythmia (such as ventricular
                       tachycardia, ventricular fibrillation, or torsades pointes)

                    -  History of cardiomyopathy, pericarditis, significant pericardial effusion,
                       myocarditis, or New York Heart Association (NYHA) functional class III-IV
                       congestive heart failure

              16. Known hypersensitivity to another monoclonal antibody that cannot be controlled
                  with standard measures (e.g., antihistamines and corticosteroids)

              17. Prisoners or subjects who are involuntarily incarcerated

              18. Subjects who are compulsorily detained for treatment of either a psychiatric or
                  physical (eg, infectious disease) illness

              19. Pregnant women are excluded

              20. Received a live vaccine within 30 days prior to first dose of study drug.
                  Examples include but are not limited to measles, mumps, rubella,
                  varicella/zoster, yellow fever, rabies, Bacillus Celmette-Guerin (BCG), and
                  typhoid. Intranasal influenza vaccines are not allowed.

              21. Participant must not be simultaneously enrolled in any interventional clinical
                  trial
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective radiographic response (ORR)
Time Frame:26 months
Safety Issue:
Description:Objective radiographic response (ORR), as measured by modified Response Assessment in Neuro-Oncology (RANO) criteria. ). The response is classified as Complete Response (CR), Partial Response (PR), Stable Disease (SD), and Progressive Disease (PD).

Secondary Outcome Measures

Measure:Incidence of Treatment-Emergent Adverse Events as assessed by NCI CTCAE v 5.0
Time Frame:25 months
Safety Issue:
Description:Adverse events will be evaluated by monitoring frequency, duration, and severity of adverse events (AEs) per NCI CTCAE v 5.0
Measure:Overall survival
Time Frame:84 months
Safety Issue:
Description:OS, defined as the time from date of enrollment until death from any cause
Measure:Progression Free Survival
Time Frame:84 months
Safety Issue:
Description:PFS, defined as the time from date of enrollment until the earliest date of disease progression (as determined by modified RANO criteria) or death due to any cause

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of Pennsylvania

Last Updated

January 15, 2020