INO-5401 and INO-9012 Delivered by Electroporation (EP) in Combination With Cemiplimab (REGN2810) in Newly-Diagnosed Glioblastoma (GBM)

Sponsor

Inovio Pharmaceuticals (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03491683

Collaborator

(none)

Enrollment

Locations

Arms

Anticipated Duration (Months)

2.5

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Phase 1/2 trial to evaluate safety, immunogenicity and preliminary efficacy of INO-5401 and INO-9012 in combination with cemiplimab (REGN2810), with radiation and chemotherapy, in subjects with newly-diagnosed glioblastoma (GBM).

Condition or Disease	Intervention/Treatment	Phase
Glioblastoma	Biological: INO-5401 Biological: INO-9012 Biological: Cemiplimab Radiation: Radiation Therapy Drug: Temozolomide	Phase 1/Phase 2

Detailed Description

This is a phase 1/2, open-label, multi-center trial to evaluate safety, immunogenicity and preliminary efficacy of INO-5401 and INO-9012 in combination with cemiplimab in subjects with newly-diagnosed glioblastoma (GBM). INO-5401 and INO-9012 will be delivered by intramuscular (IM) injection followed by electroporation (EP) in combination with cemiplimab and chemoradiation and radiation. There will be 2 cohorts in this trial. Cohort A will be participants with a tumor with an unmethylated O6-methylguanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT) promoter. Cohort B will be participants with a tumor with a MGMT methylated promoter or who have indeterminate MGMT status. Both cohorts will receive INO-5401 and INO-9012 and cemiplimab at the same doses and on the same dosing schedule, and both cohorts will receive radiation and temozolomide (TMZ), if clinically indicated.

Study Design

Study Type:

Interventional

Actual Enrollment :

52 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

An Open-Label, Multi-Center Trial of INO-5401 and INO-9012 Delivered by Electroporation (EP) in Combination With REGN2810 in Subjects With Newly-Diagnosed Glioblastoma (GBM)

Actual Study Start Date :

May 31, 2018

Anticipated Primary Completion Date :

Dec 31, 2022

Anticipated Study Completion Date :

Dec 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort A: Unmethylated MGMT Promoter Cohort A will include participants with a glioblastoma tumor with an unmethylated MGMT promoter. Participants will receive INO-5401 and INO-9012 and cemiplimab as well as radiation and temozolomide (TMZ; only during radiation therapy), if clinically indicated.	Biological: INO-5401 INO-5401 is a combination of 3 separate DNA plasmids targeting Wilms tumor gene-1 (WT1) antigen, prostate-specific membrane antigen (PSMA) and human telomerase reverse transcriptase (hTERT) genes. Starting on Day 0 three milligrams (mg) of each plasmid will be delivered IM followed by EP using the CELLECTRA® 2000 EP device every three weeks for four doses, and then every 9 weeks until disease progression as defined by immunotherapy Response Assessment in Neuro-Oncology (iRANO), unacceptable toxicity, withdrawal of consent, or death. Biological: INO-9012 INO-9012 is a DNA plasmid for expression of human interleukin-12 (IL-12). Starting on Day 0 one mg plasmid will be delivered IM followed by EP using the CELLECTRA® 2000 EP device every three weeks for four doses, and then every 9 weeks until disease progression as defined by iRANO, unacceptable toxicity, withdrawal of consent, or death. Biological: Cemiplimab Cemiplimab is an antibody to programmed death-1 (PD-1) protein. Starting on Day 0 cemiplimab will be administered intravenously (IV) every three weeks at a dose of 350 mg per dose in the absence of dose holding, until disease progression as defined by iRANO, unacceptable toxicity, withdrawal of consent, or death. Other Names: REGN2810 Radiation: Radiation Therapy Radiation therapy (RT) will begin no later than 42 days after surgical intervention, and should start approximately 2 weeks after Day 0. RT will be given for three weeks. Drug: Temozolomide Temozolomide (TMZ) will be given daily during radiation therapy (RT) at a dose of 75 milligrams per square meter (mg/m^2).
Experimental: Cohort B: Methylated MGMT Promoter Cohort B will include participants with a glioblastoma tumor with a methylated MGMT promoter or with indeterminate MGMT status. Participants will receive INO-5401 and INO-9012 and cemiplimab as well as radiation and temozolomide (TMZ), if clinically indicated. Participants will continue to receive TMZ following radiation therapy, for up to six additional cycles, if clinically indicated.	Biological: INO-5401 INO-5401 is a combination of 3 separate DNA plasmids targeting Wilms tumor gene-1 (WT1) antigen, prostate-specific membrane antigen (PSMA) and human telomerase reverse transcriptase (hTERT) genes. Starting on Day 0 three milligrams (mg) of each plasmid will be delivered IM followed by EP using the CELLECTRA® 2000 EP device every three weeks for four doses, and then every 9 weeks until disease progression as defined by immunotherapy Response Assessment in Neuro-Oncology (iRANO), unacceptable toxicity, withdrawal of consent, or death. Biological: INO-9012 INO-9012 is a DNA plasmid for expression of human interleukin-12 (IL-12). Starting on Day 0 one mg plasmid will be delivered IM followed by EP using the CELLECTRA® 2000 EP device every three weeks for four doses, and then every 9 weeks until disease progression as defined by iRANO, unacceptable toxicity, withdrawal of consent, or death. Biological: Cemiplimab Cemiplimab is an antibody to programmed death-1 (PD-1) protein. Starting on Day 0 cemiplimab will be administered intravenously (IV) every three weeks at a dose of 350 mg per dose in the absence of dose holding, until disease progression as defined by iRANO, unacceptable toxicity, withdrawal of consent, or death. Other Names: REGN2810 Radiation: Radiation Therapy Radiation therapy (RT) will begin no later than 42 days after surgical intervention, and should start approximately 2 weeks after Day 0. RT will be given for three weeks. Drug: Temozolomide Temozolomide (TMZ) will be given daily during radiation therapy (RT) at a dose of 75 milligrams per square meter (mg/m^2).

Arm

Intervention/Treatment

Experimental: Cohort A: Unmethylated MGMT Promoter

Cohort A will include participants with a glioblastoma tumor with an unmethylated MGMT promoter. Participants will receive INO-5401 and INO-9012 and cemiplimab as well as radiation and temozolomide (TMZ; only during radiation therapy), if clinically indicated.

Biological: INO-5401

INO-5401 is a combination of 3 separate DNA plasmids targeting Wilms tumor gene-1 (WT1) antigen, prostate-specific membrane antigen (PSMA) and human telomerase reverse transcriptase (hTERT) genes. Starting on Day 0 three milligrams (mg) of each plasmid will be delivered IM followed by EP using the CELLECTRA® 2000 EP device every three weeks for four doses, and then every 9 weeks until disease progression as defined by immunotherapy Response Assessment in Neuro-Oncology (iRANO), unacceptable toxicity, withdrawal of consent, or death.

Biological: INO-9012

INO-9012 is a DNA plasmid for expression of human interleukin-12 (IL-12). Starting on Day 0 one mg plasmid will be delivered IM followed by EP using the CELLECTRA® 2000 EP device every three weeks for four doses, and then every 9 weeks until disease progression as defined by iRANO, unacceptable toxicity, withdrawal of consent, or death.

Biological: Cemiplimab

Cemiplimab is an antibody to programmed death-1 (PD-1) protein. Starting on Day 0 cemiplimab will be administered intravenously (IV) every three weeks at a dose of 350 mg per dose in the absence of dose holding, until disease progression as defined by iRANO, unacceptable toxicity, withdrawal of consent, or death.

Other Names:

REGN2810

Radiation: Radiation Therapy

Radiation therapy (RT) will begin no later than 42 days after surgical intervention, and should start approximately 2 weeks after Day 0. RT will be given for three weeks.

Drug: Temozolomide

Temozolomide (TMZ) will be given daily during radiation therapy (RT) at a dose of 75 milligrams per square meter (mg/m^2).

Experimental: Cohort B: Methylated MGMT Promoter

Cohort B will include participants with a glioblastoma tumor with a methylated MGMT promoter or with indeterminate MGMT status. Participants will receive INO-5401 and INO-9012 and cemiplimab as well as radiation and temozolomide (TMZ), if clinically indicated. Participants will continue to receive TMZ following radiation therapy, for up to six additional cycles, if clinically indicated.

Biological: INO-5401

Biological: INO-9012

Biological: Cemiplimab

Other Names:

REGN2810

Radiation: Radiation Therapy

Radiation therapy (RT) will begin no later than 42 days after surgical intervention, and should start approximately 2 weeks after Day 0. RT will be given for three weeks.

Drug: Temozolomide

Temozolomide (TMZ) will be given daily during radiation therapy (RT) at a dose of 75 milligrams per square meter (mg/m^2).

Outcome Measures

Primary Outcome Measures

Percentage of Participants with Adverse Events (AEs) [From Day 0 to 30 days after the last dose of study treatment (non-serious AEs) and to 6 months after the last dose of study treatment (immune-related AEs, AEs of special interest and serious AEs) up to approximately 24 months]

Secondary Outcome Measures

Overall survival at 18 months (OS18) [At Month 18]
Change from Baseline in Interferon-gamma Secreting T Lymphocytes in Peripheral Blood Mononuclear Cells (PBMCs) [From Day 0 to last dose of study treatment up to approximately 18 months]
Change from Baseline in T-Cell Phenotypes in PBMCs [From Day 0 to last dose of study treatment up to approximately 18 months]
Change from Baseline in T Cell Receptor (TCR) Subtypes in PBMCs [From Day 0 to last dose of study treatment up to approximately 18 months]
Change from Baseline in Antigen-Specific Humoral Response [From Day 0 to last dose of study treatment up to approximately 18 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Newly-diagnosed brain cancer with histopathological diagnosis of GBM;
Karnofsky Performance Status (KPS) rating of >/=70 at baseline;
Receive dexamethasone equivalent dose </=2 mg per day, stable or decreased for >/= three days prior to Day 0;
Recovery from the effects of prior GBM surgery as defined by the Investigator;
Electrocardiogram (ECG) with no clinically significant findings as assessed by the Investigator;
Adequate organ function as demonstrated by hematological, renal, hepatic laboratory assessments;
Agree that during the trial, men will not father a child, and women cannot be or become pregnant. Participants must be of non-child bearing potential or agree to use one highly effective or combined contraceptive methods that result in a failure rate of <1% per year during the treatment period and at least through week 12 after last dose;
Ability to tolerate magnetic resonance imaging (MRI).

Exclusion Criteria:

Presence of greater than 1 cm x 1 cm residual tumor enhancement on postoperative MRI;
Multifocal disease or leptomeningeal disease (LM) disease on post-operative MRI;
Not scheduled to start radiation within 42 days of surgical resection of tumor;
Dexamethasone equivalent dose >2 mg per day;
Prior treatment with an agent that blocks the PD-1/PD-Ligand 1 pathway;
Receipt of previous approved or investigative immune modulatory agent within 28 days of receiving the first dose of treatment;
Prior treatment with idelalisib;
Past, current or planned treatment with tumor treatment fields; oncolytic viral treatment; or prior exposure to an investigational agent or device within 28 days of receiving the first dose of treatment;
Allergy or hypersensitivity to cemiplimab or to any of its excipients;
History of documented allergic reactions or acute hypersensitivity reaction attributed to antibody treatments;
Ongoing or recent (within 5 years) evidence of autoimmune disease that required treatment with systemic immunosuppressive treatments;
Diagnosis of immunodeficiency or treatment with systemic immunosuppressive therapy within 28 days prior to the first dose of trial treatment, other than dexamethasone for the underlying disease under investigation, as noted in the inclusion criteria;
History of clinically significant, medically unstable disease which, in the judgment of the investigator, would jeopardize the safety of the subject, interfere with trial assessments or endpoint evaluation, or otherwise impact the validity of the trial results.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope	Duarte	California	United States	91010
2	Stanford University, School of Medicine	Palo Alto	California	United States	94304
3	University of California, San Francisco	San Francisco	California	United States	94143
4	University of Miami - Sylvester Comprehensive Cancer Center	Miami	Florida	United States	33136
5	Moffitt Cancer Center	Tampa	Florida	United States	33612
6	Emory University School of Medicine	Atlanta	Georgia	United States	30322
7	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
8	Henry Ford Health System	Detroit	Michigan	United States	48202
9	Rutgers University - Cancer Institute of New Jersey	New Brunswick	New Jersey	United States	08901
10	New York University Langone Medical Center; Perlmutter Cancer Center	New York	New York	United States	10016
11	Icahn School of Medicine at Mount Sinai	New York	New York	United States	10029
12	Columbia University Medical Center The Neurological Institute of New York	New York	New York	United States	10032
13	New York-Presbyterian Hospital/Weill Cornell Medical Center	New York	New York	United States	10065
14	University of North Carolina School of Medicine	Chapel Hill	North Carolina	United States	27599
15	Stephenson Cancer Center	Oklahoma City	Oklahoma	United States	73104
16	Oregon Health & Science University	Portland	Oregon	United States	97239
17	University of Pennsylvania Health System: Penn Medicine	Philadelphia	Pennsylvania	United States	19104
18	UPMC Cancer Center Neuro-Oncology; UPMC Cancer Pavilion	Pittsburgh	Pennsylvania	United States	15232
19	Texas Oncology	Austin	Texas	United States	78705
20	Baylor College of Medicine	Houston	Texas	United States	77030
21	Huntsman Cancer Institute	Salt Lake City	Utah	United States	84112