Clinical Trials /

AB154 Combined With AB122 for Recurrent Glioblastoma

NCT04656535

Description:

This is a phase 0/I exploratory study. Patients at first or second recurrence of glioblastoma will be enrolled. The study will be divided into two cohorts: Cohort A (safety cohort) and Cohort B (surgical patient cohort). Cohort A: Eligible patients will be sequentially enrolled to receive intravenous AB154 combined with AB122 (N=6). AB154 will be given at a dose of 10 mg/kg and AB122 will be given at a dose of 240 mg (flat). Cohort B: Expansion surgical cohort. The purpose of cohort B is to provide an additional safety evaluation of AB154 + AB122 as well as tissue and blood for exploratory ancillary studies investigating the effects of AB154 + AB122 in the tumor and tumor microenvironment. A total of 40 patients will be enrolled in this cohort.

Related Conditions:
  • Glioblastoma
Recruiting Status:

Not yet recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: AB154 Combined With AB122 for Recurrent Glioblastoma
  • Official Title: A Multi-Center Phase 0/I Trial of Anti-TIGIT Antibody AB154 in Combination With Anti-PD-1 Antibody AB122 for Recurrent Glioblastoma.

Clinical Trial IDs

  • ORG STUDY ID: 2000028799
  • NCT ID: NCT04656535

Conditions

  • Glioblastoma

Interventions

DrugSynonymsArms
AB122AB122 + AB154 Safety Cohort (Cohort A)
AB154AB122 + AB154 Safety Cohort (Cohort A)
PlaceboAB122 Surgical Cohort (Cohort B2)

Purpose

This is a phase 0/I exploratory study. Patients at first or second recurrence of glioblastoma will be enrolled. The study will be divided into two cohorts: Cohort A (safety cohort) and Cohort B (surgical patient cohort). Cohort A: Eligible patients will be sequentially enrolled to receive intravenous AB154 combined with AB122 (N=6). AB154 will be given at a dose of 10 mg/kg and AB122 will be given at a dose of 240 mg (flat). Cohort B: Expansion surgical cohort. The purpose of cohort B is to provide an additional safety evaluation of AB154 + AB122 as well as tissue and blood for exploratory ancillary studies investigating the effects of AB154 + AB122 in the tumor and tumor microenvironment. A total of 40 patients will be enrolled in this cohort.

Detailed Description

      This is a phase 0/I exploratory study. Patients at first or second recurrence of glioblastoma
      will be enrolled. The study will be divided into two cohorts: Cohort A (safety cohort) and
      Cohort B (surgical patient cohort).

      Cohort A: Eligible patients will be sequentially enrolled to receive intravenous AB154
      combined with AB122 (N=6). AB154 will be given at a dose of 10 mg/kg and AB122 will be given
      at a dose of 240 mg (flat).

      Cohort B: Expansion surgical cohort. The purpose of cohort B is to provide an additional
      safety evaluation of AB154 + AB122 as well as tissue and blood for exploratory ancillary
      studies investigating the effects of AB154 + AB122 in the tumor and tumor microenvironment. A
      total of 40 patients will be enrolled in this cohort.

      Following completion of cohort A, patients who are candidates for surgical resection for
      management of tumor progression (i.e. need for diagnostic confirmation or tumor debulking)
      will be enrolled prior to surgical resection, and initiate study treatment approximately two
      weeks prior to the resection.

      Patients will be randomized to one of the four treatment arms and initiate treatment prior to
      surgery, according to treatment assignment.

      The pre-surgical dose (neoadjuvant treatment) will be double-blinded. A total of 10 patients
      will be allocated to each one of the following groups in a blinded fashion, approximately two
      weeks before surgery:

        -  B1 (N=10): AB154 single agent (10 mg/kg) + placebo

        -  B2 (N=10): AB122 single agent (240 mg) + placebo

        -  B3 (N=10): AB154 (10 mg/kg) +AB122 (240 mg)

        -  B4 (N=10): Two placebo infusions

      Following surgery, all patients (N=40) will initiate treatment with the combination of AB154
      and AB122.
    

Trial Arms

NameTypeDescriptionInterventions
AB122 + AB154 Safety Cohort (Cohort A)ExperimentalEligible patients will be sequentially enrolled to receive intravenous AB154 combined with AB122 (N=6). AB154 will be given at a dose of 10 mg/kg and AB122 will be given at a dose of 240 mg (flat).
  • AB122
  • AB154
AB154 Surgical Cohort (Cohort B1)ExperimentalCandidates for surgical resection will be enrolled and initiate study treatment approximately two weeks prior to the resection. The pre-surgical dose (neoadjuvant treatment) will be double-blinded. B1 (N=10): AB154 single agent (10 mg/kg) + placebo Following surgery, all patients will initiate treatment with the combination of AB154 and AB122. AB154 will be given at a dose of 10 mg/kg and AB122 will be given at a dose of 240 mg (flat).
  • AB154
  • Placebo
AB122 Surgical Cohort (Cohort B2)ExperimentalCandidates for surgical resection will be enrolled and initiate study treatment approximately two weeks prior to the resection. The pre-surgical dose (neoadjuvant treatment) will be double-blinded. B2 (N=10): AB122 single agent (240 mg) + placebo Following surgery, all patients will initiate treatment with the combination of AB154 and AB122. AB154 will be given at a dose of 10 mg/kg and AB122 will be given at a dose of 240 mg (flat).
  • AB122
  • Placebo
AB154 + AB122 Surgical Cohort (Cohort B3)ExperimentalCandidates for surgical resection will be enrolled and initiate study treatment approximately two weeks prior to the resection. The pre-surgical dose (neoadjuvant treatment) will be double-blinded. B3 (N=10): AB154 (10 mg/kg) +AB122 (240 mg) Following surgery, all patients will initiate treatment with the combination of AB154 and AB122. AB154 will be given at a dose of 10 mg/kg and AB122 will be given at a dose of 240 mg (flat).
  • AB122
  • AB154
Placebo Surgical Cohort (Cohort B4)ExperimentalCandidates for surgical resection will be enrolled and initiate study treatment approximately two weeks prior to the resection. The pre-surgical dose (neoadjuvant treatment) will be double-blinded. B4 (N=10): Two placebo infusions Following surgery, all patients will initiate treatment with the combination of AB154 and AB122. AB154 will be given at a dose of 10 mg/kg and AB122 will be given at a dose of 240 mg (flat).
  • Placebo

Eligibility Criteria

        Inclusion Criteria:

          1. Grade IV glioma (glioblastoma and its variants according to the World Health
             Organization 2016), confirmed in tissue at time of initial diagnosis.

          2. First or second recurrence after treatment. Prior treatment must include at least
             radiation therapy.

          3. Measurable contrast enhancing tumor by Response Assessment in Neuro-Oncology (RANO)
             criteria.

          4. Age ≥18 years.

          5. Karnofsky performance status ≥80

          6. Patients must have adequate organ and marrow function as defined below within 14 days
             of treatment

               -  Absolute neutrophil count (ANC) ≥1,500 /mcL

               -  Platelets ≥100,000 / mcL

               -  Hemoglobin ≥9 g/dL or ≥ 5.6 mmol/L without transfusion or Erythropoietin (EPO)
                  dependency (within 7 days of assessment)

               -  Serum creatinine ≤1.5 X upper limit of normal (ULN) OR measured or calculated
                  creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≥ 60
                  mL/min for subject with creatinine levels > 1.5 X institutional ULN

               -  Serum total bilirubin ≤ 1.5 X ULN OR direct bilirubin ≤ ULN for subjects with
                  total bilirubin levels > 1.5 ULN

               -  aspartate aminotransferase and alanine transaminase (SGPT) ≤ 2.5 X ULN

               -  Albumin >2.5 mg/dL

               -  International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless
                  subject is receiving anticoagulant therapy as long as PT or PTT is within
                  therapeutic range of intended use of anticoagulants

               -  Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is
                  receiving anticoagulant therapy as long as PT or PTT is within therapeutic range
                  of intended use of anticoagulants

          7. An interval of >=12 weeks from the end of prior radiation therapy is required unless
             there is either: i) histopathologic confirmation of recurrent tumor, or ii) new
             enhancement on MRI outside of the radiation treatment field.

          8. An interval of >=3 weeks or 5 half-lives (whichever is longer) after the last
             administration of any investigational agent or any other treatment prior to first
             study dose.

          9. Female subjects of childbearing potential should have a negative urine or serum
             pregnancy test. If the urine test is positive or cannot be confirmed as negative, a
             serum pregnancy test will be required. Female subjects of childbearing potential must
             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 120 days after the last dose
             of study medication. Subjects of childbearing potential are those who have not been
             surgically sterilized or have not been free from menses for > 1 year. Male subjects
             should agree to use an adequate method of contraception starting with the first dose
             of study therapy through 120 days after the last dose of study therapy.

         10. Ability to understand and the willingness to sign a written informed consent document.

             ADDITIONAL CRITERIA FOR COHORT B

         11. Deemed a candidate for tumor debulking, as determined by the neurosurgeon.

        Exclusion Criteria:

          1. Patients who have been treated with bevacizumab.

          2. Patients who have not recovered from adverse events due to prior therapy (i.e. >Grade
             1) with the exception of alopecia and fatigue.

          3. Patients with multifocal disease.

          4. Subjects requiring escalating or chronic supraphysiologic doses of corticosteroids (>
             10 mg/d of prednisone equivalent or > 2 mg dexamethasone) for control of disease at
             the time of registration.

          5. Patients receiving previous or current treatment with an immune checkpoint inhibitor.

          6. Patients with a known diagnosis of immunodeficiency, including Human Immunodeficiency
             Virus (HIV) or acquired immunodeficiency syndrome (AIDS).

          7. Has known active Hepatitis B (e.g., Hepatitis B surface antigen reactive) or Hepatitis
             C (e.g., Hepatitis C Virus RNA [qualitative] is detected)

          8. Has a known history of active tuberculosis (Bacillus Tuberculosis).

          9. Has a known additional malignancy that is progressing or requires active treatment.
             Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
             skin that has undergone potentially curative therapy or in situ cervical cancer.

         10. Has active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment.

         11. Has known history of, or any evidence of active, non-infectious pneumonitis.

         12. Has an active infection requiring systemic therapy.

         13. Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the trial, interfere with the subject's
             participation for the full duration of the trial, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator.

         14. Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

         15. 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.

         16. Unable to undergo MRI of the brain with and without contrast enhancement (i.e.
             pacemaker, allergy to MRI contrast agent or any other contraindication for MRIs).

         17. Has received a live vaccine within 30 days of planned start of study therapy. Note:
             Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
             are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live
             attenuated vaccines, and are not allowed.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] associated with the combination AB122 and AB154 in patients with recurrent glioblastoma
Time Frame:through study completion, an average of 2 years
Safety Issue:
Description:Adverse events will be listed individually by patient and treatment group. The number of patients experiencing each adverse event will be summarized by organ and grade. The number and percentage of patients with adverse events in the different categories will be summarized by treatment group.

Secondary Outcome Measures

Measure:Single cell RNA sequencing of tumor and blood after exposure to AB154 with and without AB122
Time Frame:through study completion, an average of 2 years
Safety Issue:
Description:Pharmacodynamic effects of each pre-surgery treatment will be evaluated with single-cell RNA sequencing of tumor and blood to determine effects of each intervention on the immune response.
Measure:Tregs and CD8 T cells ratio by immunofluorescence
Time Frame:through study completion, an average of 2 years
Safety Issue:
Description:Resected tumors in cohorts B1 to 4 will be analyzed utilizing immunofluorescence for the ratio between Tregs and CD8 T cells, calculated by counting cells that are positive for a FoxP3 or a CD8 staining.

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Yale University

Trial Keywords

  • Glioblastoma
  • Recurrent
  • PD1
  • TIGIT
  • Immunotherapy

Last Updated

December 7, 2020