ERC1671 to Treat Malignant Gliomas When Given in Combination With GM-CSF, Cyclophosphamide, Bevacizumab and Pembrolizumab

Sponsor

Epitopoietic Research Corporation (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT05366062

Collaborator

(none)

Enrollment

Location

Arm

Anticipated Duration (Months)

0.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a treatment clinical trial to assess the efficacy of ERC1671 in combination with bevacizumab and pembrolizumab in patients with GBM that has progressed following treatment with radiation and temozolomide.

Patients will have surgery to collect the maximum amount of GBM tissue that can be reasonably collected. This tissue will be used to manufacturer ERC1671 for the patient.

The patients will receive ERC1671 in combination with GM-CSF and cyclophosphamide, in combination with bevacizumab and pembrolizumab.

Condition or Disease	Intervention/Treatment	Phase
Glioma, Malignant	Drug: ERC1671 Drug: GM-CSF Drug: Cyclophosphamide Drug: Pembrolizumab	Phase 2

Detailed Description

The treatment cycles will be 28 days long and follow the schedule below. There are 28 days (± 7 days) from surgery date to start of Cycle 1 day 1 to permit production of ERC-D vaccine:

The treatment will be repeated every 28-days until progression of disease, intolerance, or a decision by the physician and/or patient to withdraw from the treatment plan.

Efficacy will be evaluated as a foundation of Overall Survival reported at twelve months (OS12)

Safety will be evaluated, as a secondary objective, throughout the trial by the incidence of serious adverse events (AEs), physical examination findings, vital signs and clinical laboratory test results. SAEs will be graded for severity using NCI Common Terminology Criteria for Adverse Events (CTCAE) v. 5.0.

Patients will undergo brain MRI as part of standard care before starting cycle 1 and every 8 weeks thereafter (+/- 7 days) until disease progression, and whenever progression is suspected based on clinical symptoms. Tumor response will be assessed using both the Macdonald and the iRANO response criteria for high-grade gliomas, which considers radiologic imaging, neurological status, and steroid dosing.

Whenever clinically appropriate, stereotactic biopsy or resection will be performed in accordance with standard of care for patients with progressive disease. To differentiate true progression from potentially toxic or therapeutic inflammatory responses presenting as radiographic or clinical changes, histologic verification of progression will be performed whenever feasible and appropriate.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

28 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase II Clinical Trial to Assess the Efficacy of ERC1671 to Treat Malignant Gliomas When Given in Combination With GM-CSF, Cyclophosphamide, Bevacizumab and Pembrolizumab in Patients Who Have Failed Prior Treatment With Radiation and Temozolomide

Anticipated Study Start Date :

Jul 1, 2022

Anticipated Primary Completion Date :

Jul 31, 2025

Anticipated Study Completion Date :

Jul 31, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment Arm This is a Treatment Protocol for patients with severe and immediately life-threatening GBM that had surgical resection and first line treatment with radiation therapy and temozolamide per current standard of care. Patients will be treated with recurring 28-day cycles of ERC1671, GM-CSF, Cyclophosphomide, Bevacizumab, and Pembrolizumab until progression of disease and at the discretion of the treating physician.	Drug: ERC1671 ERC1671 is an autologous and allogeneic cells and lysates suspension generated from human glioblastoma (GBM) tumors harvested from patients undergoing surgery for glioblastoma. For each patient the treatment is composed of three allogeneic cells vaccine and lysates vaccine (ERC1671 A, B, C) plus from one autologous cells and lysate (ERC1671D). Drug: GM-CSF Sargramostim (Leukomax®, Leukine®); yeast-derived, recombinant human granulocyte-macrophage colony stimulating factor (rhu GM-CSF) Drug: Cyclophosphamide Cyclophosphamide is an alkylating agent, used for immunopotentiation. This drug is FDA approved and is being used off-label for the condition of hematopoietic stem cell transplant conditioning as an antineoplastic and immunosuppressant agent to modulate immunity. Drug: Pembrolizumab A therapeutic antibody that binds to and blocks PD-1 located on lymphocytes. The receptor is generally responsible for preventing the immune system from attacking the body's own tissues - it is an immune checkpoint inhibitor. Other Names: Keytruda

Arm

Intervention/Treatment

Experimental: Treatment Arm

This is a Treatment Protocol for patients with severe and immediately life-threatening GBM that had surgical resection and first line treatment with radiation therapy and temozolamide per current standard of care. Patients will be treated with recurring 28-day cycles of ERC1671, GM-CSF, Cyclophosphomide, Bevacizumab, and Pembrolizumab until progression of disease and at the discretion of the treating physician.

Drug: ERC1671

ERC1671 is an autologous and allogeneic cells and lysates suspension generated from human glioblastoma (GBM) tumors harvested from patients undergoing surgery for glioblastoma. For each patient the treatment is composed of three allogeneic cells vaccine and lysates vaccine (ERC1671 A, B, C) plus from one autologous cells and lysate (ERC1671D).

Drug: GM-CSF

Sargramostim (Leukomax®, Leukine®); yeast-derived, recombinant human granulocyte-macrophage colony stimulating factor (rhu GM-CSF)

Drug: Cyclophosphamide

Cyclophosphamide is an alkylating agent, used for immunopotentiation. This drug is FDA approved and is being used off-label for the condition of hematopoietic stem cell transplant conditioning as an antineoplastic and immunosuppressant agent to modulate immunity.

Drug: Pembrolizumab

A therapeutic antibody that binds to and blocks PD-1 located on lymphocytes. The receptor is generally responsible for preventing the immune system from attacking the body's own tissues - it is an immune checkpoint inhibitor.

Other Names:

Keytruda

Outcome Measures

Primary Outcome Measures

Overall Survival at 12 months [12 months]
Overall Survival at 12 months as assessed per iRANO Criteria.

Secondary Outcome Measures

Progression-free survival [12 Months]
Dates from date of first injection of vaccine.
Radiographic Response [12 Months]
Radiographic Response, categorized per iRANO Criteria.
Number of participants with Adverse Events [Safety and Tolerability] [12 months]
As indicated by the number and rate of adverse events, categorized by the CTCAE v. 5.0

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients must have histologically confirmed diagnosis of a recurrent/progressive WHO grade IV malignant gliomas (glioblastoma) and meet the following inclusion criteria:
Age ≥18 years of age.
KPS of ≥ 60%.
Life expectancy > 12 weeks.
First, second, third or fourth relapse of glioblastoma.
Previous treatment for glioblastoma must include surgery (biopsy, partial resection, or full surgical resection), conventional radiation therapy and temozolomide (TMZ).
MRI record must be obtained showing the MRI was done at least 4 weeks after any salvage surgery, and at least 12 weeks after radiation therapy, or at least 4 weeks after radiation for a new lesion outside the prior primary radiation field unless relapse is confirmed by tumor biopsy or new lesion outside of radiation field, or if there are two MRIs confirming progressive disease that are 8 weeks apart.
If prior therapy with gamma knife or other focal high-dose radiation, must have subsequent histologic documentation of local relapse, or relapse with new lesion outside the irradiated field.
Resolution of all chemotherapy or radiation-related toxicities ≤ CTCAE Grade severity, except for alopecia and hematologic toxicity. Patients taking temozolomide can start study treatment 23 days from the last temozolomide dose. For all other chemotherapy drugs, study treatment can start as long as all adverse events related to their prior treatment are no higher than Grade 1.
Systemic corticosteroid therapy must be at a dose of ≤ 4 mg of dexamethasone or equivalent per day during the week prior to Day 1.
Bi-dimensionally measurable disease (as per iRANO criteria).
Patients must have normal organ and marrow function as defined below:
Hemoglobin (Hbg) > 9g/dL,
Leukocytes >1,500/mcL
Absolute neutrophil count>1,000/mcL
CD4 count > 300/mcl
Platelets >125,000/mcL
Serum bilirubin = 1.5 × upper limit of normal (ULN) or = 3 x ULN if Gilbert's disease is documented AST(SGOT) and ALT(SGPT)<2.5 x institutional upper limit of normal
Serum creatinine < 1.5 mg/dl
Signed informed consent approved by the Institutional Review Board;
If sexually active, patients must agree to take contraceptive measures for the duration of the treatments.

Exclusion Criteria:

Subjects unable to undergo an MRI with contrast
Subjects able and willing to participate in an open and accruing ERC clinical trial
Presence of diffuse leptomeningeal disease
History, presence, or suspicion of metastatic disease
Administration of immunosuppressive drugs less than 2 weeks prior to first dose of ERC1671 except dexamethasone for cerebral edema as detailed above;
Known contraindication or hypersensitivity to any component of bevacizumab.
Evidence of recent hemorrhage on screening MRI of the brain with the following exceptions: presence of hemosiderin; resolving hemorrhagic changes related to surgery; presence of punctate hemorrhage in the tumor.
Significant vascular disease (e.g., aortic aneurysm, aortic dissection) or recent peripheral arterial thrombosis within 6 months prior to Day 1.
Evidence of bleeding diathesis or coagulopathy as documented by an elevated PT, PTT or bleeding time and clinically significant;
History of abdominal fistula, gastrointestinal perforation, or intraabdominal abscess within 6 months prior to Day 1.
Urine protein: creatinine ratio 1.0 at screening;
Anticipation of need for major surgical procedure during the course of the study.
Serious non-healing wound, ulcer, or bone fracture.
Active infection requiring treatment, known immunosuppressive disease, active systemic autoimmune diseases such as lupus, receipt of systemic immunosuppressive therapy, human immunodeficiency virus (HIV) infection, Hepatitis B or Hepatitis C.
Uncontrolled hypertension, blood pressure of > 150 mmHg systolic and > 100 mmHg diastolic, or history of hypertensive encephalopathy. Subjects with any known uncontrolled inter-current illness including ongoing or active infection, symptomatic congestive heart failure (NYHA Gr.2 or >), myocardial infarction, unstable angina pectoris within the past 12 months
Stroke, transient ischemic attack, unstable angina, myocardial infarction or congestive heart failure (New York Heart Association Grade II or greater) within the past 12 months. Unstable or severe intercurrent medical conditions, chronic renal disease, or uncontrolled diabetes mellitus.
Women who are pregnant or lactating. All female patients with reproductive potential must have a negative pregnancy test prior to Day 1 and agree to use reliable contraception whilst study participant.
Men refusing to exercise a reliable form of contraception.
History of any malignancy (other than glioblastoma) during the last three years except non-melanoma skin cancer, in situ cervical cancer, treated superficial bladder cancer or cured, early-stage prostate cancer in a patient with Prostate Surface Antigen (PSA) level <ULN.