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

Glioma, Malignant Clinical Trial

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05366062
• Other study ID #: ERC1671PEM
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: July 1, 2022
• Est. completion date: July 31, 2026

Study information

• Verified date: May 2022
• Source: Epitopoietic Research Corporation
• Contact: Joseph Elliott, PhD
• Phone: +1-416-721-5116
• Email: jelliot[@]erc-usa.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 28
• Est. completion date: July 31, 2026
• Est. primary completion date: July 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Glioma
• Glioma, Malignant

Intervention

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

Locations

Country	Name	City	State
Thailand	Bumrungrad International Hospital	Bangkok	Vadhana

Sponsors (1)

Lead Sponsor	Collaborator
Epitopoietic Research Corporation

Country where clinical trial is conducted

Thailand, 

References & Publications (14)

Ammirati M, Galicich JH, Arbit E, Liao Y. Reoperation in the treatment of recurrent intracranial malignant gliomas. Neurosurgery. 1987 Nov;21(5):607-14. — View Citation

Barker FG 2nd, Chang SM, Gutin PH, Malec MK, McDermott MW, Prados MD, Wilson CB. Survival and functional status after resection of recurrent glioblastoma multiforme. Neurosurgery. 1998 Apr;42(4):709-20; discussion 720-3. — View Citation

Ben-Efraim S. Immunomodulating anticancer alkylating drugs: targets and mechanisms of activity. Curr Drug Targets. 2001 Jun;2(2):197-212. Review. — View Citation

BLOOM WH, CARSTAIRS KC, CROMPTON MR, McKISSOCK W. Autologous glioma transplantation. Lancet. 1960 Jul 9;2(7141):77-8. — View Citation

Bowles AP Jr, Perkins E. Long-term remission of malignant brain tumors after intracranial infection: a report of four cases. Neurosurgery. 1999 Mar;44(3):636-42; discussion 642-3. Review. — View Citation

Brem S, Cotran R, Folkman J. Tumor angiogenesis: a quantitative method for histologic grading. J Natl Cancer Inst. 1972 Feb;48(2):347-56. — View Citation

Bystryn JC, Rigel D, Friedman RJ, Kopf A. Prognostic significance of hypopigmentation in malignant melanoma. Arch Dermatol. 1987 Aug;123(8):1053-5. — View Citation

Clarke JL, Ennis MM, Yung WK, Chang SM, Wen PY, Cloughesy TF, Deangelis LM, Robins HI, Lieberman FS, Fine HA, Abrey L, Gilbert MR, Mehta M, Kuhn JG, Aldape KD, Lamborn KR, Prados MD; North American Brain Tumor Consortium. Is surgery at progression a prognostic marker for improved 6-month progression-free survival or overall survival for patients with recurrent glioblastoma? Neuro Oncol. 2011 Oct;13(10):1118-24. doi: 10.1093/neuonc/nor110. Epub 2011 Aug 2. — View Citation

Coley WB. The treatment of malignant tumors by repeated inoculations of erysipelas. With a report of ten original cases. 1893. Clin Orthop Relat Res. 1991 Jan;(262):3-11. — View Citation

Crane CH, Ellis LM, Abbruzzese JL, Amos C, Xiong HQ, Ho L, Evans DB, Tamm EP, Ng C, Pisters PW, Charnsangavej C, Delclos ME, O'Reilly M, Lee JE, Wolff RA. Phase I trial evaluating the safety of bevacizumab with concurrent radiotherapy and capecitabine in locally advanced pancreatic cancer. J Clin Oncol. 2006 Mar 1;24(7):1145-51. — View Citation

D'Adamo DR, Anderson SE, Albritton K, Yamada J, Riedel E, Scheu K, Schwartz GK, Chen H, Maki RG. Phase II study of doxorubicin and bevacizumab for patients with metastatic soft-tissue sarcomas. J Clin Oncol. 2005 Oct 1;23(28):7135-42. — View Citation

Dang Y, Wagner WM, Gad E, Rastetter L, Berger CM, Holt GE, Disis ML. Dendritic cell-activating vaccine adjuvants differ in the ability to elicit antitumor immunity due to an adjuvant-specific induction of immunosuppressive cells. Clin Cancer Res. 2012 Jun 1;18(11):3122-31. doi: 10.1158/1078-0432.CCR-12-0113. Epub 2012 Apr 17. — View Citation

Deorah S, Lynch CF, Sibenaller ZA, Ryken TC. Trends in brain cancer incidence and survival in the United States: Surveillance, Epidemiology, and End Results Program, 1973 to 2001. Neurosurg Focus. 2006 Apr 15;20(4):E1. — View Citation

Emens LA. GM-CSF-secreting vaccines for solid tumors. Curr Opin Investig Drugs. 2009 Dec;10(12):1315-24. Review. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival at 12 months	Overall Survival at 12 months as assessed per iRANO Criteria.	12 months
Secondary	Progression-free survival	Dates from date of first injection of vaccine.	12 Months
Secondary	Radiographic Response	Radiographic Response, categorized per iRANO Criteria.	12 Months
Secondary	Number of participants with Adverse Events [Safety and Tolerability]	As indicated by the number and rate of adverse events, categorized by the CTCAE v. 5.0	12 months