A Toll-like Receptor Agonist as an Adjuvant to Tumor Associated Antigens (TAA) Mixed With Montanide ISA-51 VG With Bevacizumab for Patients With Recurrent Glioblastoma

• ClinicalTrials.gov Identifier: NCT02754362
• Recruitment Status: Withdrawn
• First Posted: April 28, 2016
• Last Update Posted: January 13, 2020
• Sponsor: NYU Langone Health
• Collaborator: MOUNT SINAI HOSPITAL
• Information provided by (Responsible Party): NYU Langone Health

Study Description

Brief Summary:

This is a phase II study to determine the immunogenicity and efficacy of a vaccine composed of tumor associated long synthetic peptides mixed with Montanide ISA-51 VG administered with polyinosinic-polycytidylic acid - poly-L-lysine carboxymethylcellulose (Poly-ICLC) and bevacizumab in adults with recurrent glioblastoma.

Condition or disease	Intervention/treatment	Phase
Glioblastoma; Glioma	Drug: Bevacizumab; Biological: Peptide Vaccine; Drug: Poly-ICLC as immune adjuvant; Drug: Keyhole limpet hemocyanin (KLH)	Phase 2

Detailed Description:

All patients will receive the same dose of vaccine, Poly-ICLC and bevacizumab. The therapy consists of 3 blocks. During the first block, patients will receive bevacizumab every 2 weeks for 2 doses. During block 2, patients will receive vaccine + Poly-ICLC + bevacizumab on weeks 1, 3, 5 and 7. An MRI will be performed after week 7 therapy. If there is no significant progression, then the patients will continue with block 3. During block 3, therapy consists of vaccine + Poly-ICLC monthly and bevacizumab every 2 weeks for 10 months. Keyhole limpet hemocyanin (KLH) will be given as a positive control with the first vaccine. Immune studies will be performed in all patients enrolled in this study.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 0 participants
• Allocation: Non-Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Toll-like Receptor Agonist as an Adjuvant to Tumor Associated Antigens (TAA) Mixed With Montanide ISA-51 VG With Bevacizumab for Patients With Recurrent Glioblastoma
• Actual Study Start Date: November 2016
• Estimated Primary Completion Date: June 2019
• Estimated Study Completion Date: June 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Block 1	Drug: Bevacizumab; Bevacizumab is a humanized monoclonal antibody that targets vascular endothelial growth factor (VEGF), a proangiogenic factor which aids in tumor vessel formation.; Other Name: Hiltonol®
Experimental: Block 2	Drug: Bevacizumab; Bevacizumab is a humanized monoclonal antibody that targets vascular endothelial growth factor (VEGF), a proangiogenic factor which aids in tumor vessel formation.; Other Name: Hiltonol®; Biological: Peptide Vaccine; Vaccine of long synthetic peptides encoding T cell epitopes in tumor associated antigens. Vaccine Consists of: EGFRvIII peptide 100 mcg IL13Ralpha peptide 100 mcg EphA2 peptide 100 mcg Her2/neu peptide 100 mcg YKL-40 peptide 100 mcg; Drug: Poly-ICLC as immune adjuvant; Poly-ICLC is a toll like receptor 3 agonist which directly activates dendritic cells and triggers natural killer cells to kill tumor cells.; Drug: Keyhole limpet hemocyanin (KLH); Potent Immunogen used in vaccine approaches for a number of diseases including cancer, AIDS, and infectious diseases
Experimental: Block 3	Drug: Bevacizumab; Bevacizumab is a humanized monoclonal antibody that targets vascular endothelial growth factor (VEGF), a proangiogenic factor which aids in tumor vessel formation.; Other Name: Hiltonol®; Biological: Peptide Vaccine; Vaccine of long synthetic peptides encoding T cell epitopes in tumor associated antigens. Vaccine Consists of: EGFRvIII peptide 100 mcg IL13Ralpha peptide 100 mcg EphA2 peptide 100 mcg Her2/neu peptide 100 mcg YKL-40 peptide 100 mcg; Drug: Poly-ICLC as immune adjuvant; Poly-ICLC is a toll like receptor 3 agonist which directly activates dendritic cells and triggers natural killer cells to kill tumor cells.

Outcome Measures

Primary Outcome Measures :

1. Assays to determine immunity to the vaccine's antigen [ Time Frame: 9 Weeks ]
2. Measure of Humoral Immune Responses measured by ELISA [ Time Frame: 9 Weeks ]
3. Antigen specific CD4+ and CD8+ T-cell reactivity to the peptide antigens measured by intracellular cytokine staining [ Time Frame: 9 Weeks ]
   Measured either ex-vivo (assayed directly from thawed PBMCs) or following in-vitro pre-sensitization.
4. CD4+ and CD8+ T cell reactivity to KLH measured by T cell proliferation quantified by tritiated thymidine incorporation [ Time Frame: 9 Weeks ]
5. Measure of Tumor Responses measured by the Response Evaluation Criteria in Solid Tumors (RECIST). [ Time Frame: 1 Day ]

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Disease Status. Patients with first recurrence of glioblastoma (WHO IV). Patients must have histological confirmation of glioblastoma (WHO grade IV) either at diagnosis or at first recurrence. Patients with diffuse intrinsic pontine glioma (DIPG) are not eligible.
• Karnofsky performance status > 50. Patients who are unable to walk because of paralysis but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• Adequate organ function:

Hematologic: absolute lymphocyte count > 200/mm3 Platelets > 100,000 Hepatic:AST/ALT < 5 x the upper limit of institutional normal Total bilirubin < 1.5 x the upper limit of institutional normal Renal: serum creatinine < 1.5 mg/ml; Urine protein/creatinine ratio < 2.0 at screening Cardiac: Hypertension must be well controlled on stable doses of medication. BP must be < 140/90.

• Life expectancy >3 months
• Patients must have fully recovered from previous surgery, chemotherapy, radiotherapy and biologic therapy. No surgery, chemotherapy, radiation therapy or immunotherapy within 4 weeks prior to the first dose of study agent or bevacizumab (6 weeks for nitrosureas).
• Patients must have no measurable disease or minimal residual disease defined as <1.5cm2 enhancement. Patients may have surgery to achieve < 1.5cm2 residual.
• Tumor tissue must be available either from initial diagnosis or relapse for testing of antigen expression.
• Informed consent must be signed by the patient. Individuals who lack capacity to sign consent will be excluded. Patients must be able to read and/or understand the details of the study and provide written evidence of informed consent as approved by the IRB.

Exclusion Criteria:

• Serious illness, such as uncontrolled infections requiring antibiotics
• History of immunodeficiency disease (such as HIV) or autoimmune disease except vitiligo
• Concomitant treatment with systemic dexamethasone (or it's equivalent) greater than 2mg/day. Topical (but not at the proposed vaccination site) or inhalational steroids are permitted
• Participation in any other clinical trial involving another investigational agent within 4 weeks prior the first dose of study agent.
• Pregnant or lactating women are not permitted.
• Women of child-bearing potential not using medically acceptable means of contraception.
• Prior vaccine therapy for high grade glioma is not allowed.
• Other malignancy within 3 years prior to entry into the study, except for treated early-stage melanoma or non-melanoma skin cancer, or cervical carcinoma in situ
• Significant bleeding history
• Patients with serious or non-healing wound, ulcer, or bone fractures are not eligible.
• Patients must not have a history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months prior to study entry.
• Patients must not have a known bleeding diathesis or coagulopathy.
• Patients must not have had significant vascular disease (eg, aortic aneurysm requiring surgical repair, deep venous or arterial thrombosis) within the last 6 months prior to study entry.
• Patients must not have evidence of new CNS hemorrhage on baseline MRI obtained within 14 days prior to study enrollment.
• Patients must not have a known thrombophilic condition (i.e. protein S, protein C or antithrombin III deficiency, Factor V Leiden, Factor II G20210A mutation, homocysteinemia or antiphospholipid antibody syndrome). Testing is not required in patients without thrombophilic history.
• Patients must not have a history of stroke, myocardial infarction, transient ischemic attack (TIA), severe or unstable angina, peripheral vascular disease, or grade II or greater congestive heart failure within the past 6 months prior to study entry.
• Patients must not have serious and inadequately controlled cardiac arrhythmias.
• Patients must not have a major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to the first dose of bevacizumab or anticipation of need for major surgical procedure during the course of the study.
• Patients must not have minor surgical procedures, fine needle aspirations, or core biopsies within 7 days prior to study enrollment.
• Patients with organ allografts.

Contacts and Locations

Locations

United States, New York

NYU Perlmutter Cancer Center

New York, New York, United States, 10016

Sponsors and Collaborators

NYU Langone Health

MOUNT SINAI HOSPITAL

Investigators

• Principal Investigator: Sharon Gardner, MD; New York University Medical School

More Information

• Responsible Party: NYU Langone Health
• ClinicalTrials.gov Identifier: NCT02754362
• Other Study ID Numbers: 15-00044
• First Posted: April 28, 2016
• Last Update Posted: January 13, 2020
• Last Verified: January 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by NYU Langone Health:

Poly-ICLC and bevacizumab; humanized monoclonal antibody

Additional relevant MeSH terms:

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; Poly ICLC; Keyhole-limpet hemocyanin; Adjuvants, Immunologic; Antineoplastic Agents, Immunological; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Physiological Effects of Drugs; Growth Inhibitors; Interferon Inducers; Immunologic Factors