AB154 Combined With AB122 for Recurrent Glioblastoma

Study 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.

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

No
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

Interventional
Eligible Ages 18 Years and Over
Gender All
More Inclusion & Exclusion 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. Note: Previous use of intra-arterial bevacizumab may be allowed, contingent upon review and approval by study principal investigator and sponsor. 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. (Cohort B only) 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.

Trial Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

NCT04656535
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Early Phase 1
Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

Yale University
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

Antonio Omuro, MD
Principal Investigator Affiliation Professor of Neurology
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

Other, Industry, NIH
Overall Status Recruiting
Countries United States
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

Glioblastoma
Additional Details

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.

Arms & Interventions

Arms

Experimental: AB122 + AB154 Safety 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).

Experimental: AB154 Surgical Cohort (Cohort B1)

Candidates 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).

Experimental: AB122 Surgical Cohort (Cohort B2)

Candidates 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).

Experimental: AB154 + AB122 Surgical Cohort (Cohort B3)

Candidates 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).

Experimental: Placebo Surgical Cohort (Cohort B4)

Candidates 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).

Interventions

Drug: - AB122

AB122 is a fully human immunoglobulin G4 (hIgG4) monoclonal antibody (mAb) that targets PD-1 immune checkpoint.

Drug: - AB154

AB154 is a humanized immunoglobulin G1 (IgG1) monoclonal antibody that targets TIGIT immune checkpoint.

Drug: - Placebo

Saline placebo comparator for pre-surgery treatment in cohort B4

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

University of California San Francisco, San Francisco, California

Status

Recruiting

Address

University of California San Francisco

San Francisco, California, 94143

Site Contact

Stephanie Lewis

NeuroOncNewPatientCoord@ucsf.edu

415-353-2193

Yale University, New Haven, Connecticut

Status

Recruiting

Address

Yale University

New Haven, Connecticut, 06519

Site Contact

Adam Blanchard

adam.blanchard@yale.edu

203-737-7173

Dana Farber Cancer Institute, Boston, Massachusetts

Status

Recruiting

Address

Dana Farber Cancer Institute

Boston, Massachusetts, 02215

Site Contact

Alyssa Russ

Alyssa_Russ@DFCI.HARVARD.EDU

203-737-7173

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