Safety and Efficacy Study of GL-0817 (With Cyclophosphamide) for the Prevention of Recurrence of Squamous Cell Carcinoma of the Oral Cavity

Sponsor

Gliknik Inc. (Industry)

Overall Status

Completed

CT.gov ID

NCT02873819

Collaborator

(none)

Enrollment

Locations

Arms

49.8

Actual Duration (Months)

2.4

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a multi-center, randomized, double-blind clinical trial to assess the safety and efficacy of GL-0817 as a means to prevent disease recurrence in patients considered at high-risk following surgery and adjuvant chemoradiotherapy.

Condition or Disease	Intervention/Treatment	Phase
Squamous Cell Carcinoma of the Oral Cavity	Drug: GL-0817 Drug: Hiltonol Drug: Sargramostim Drug: cyclophosphamide Drug: Placebo	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

80 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

A Phase 2 Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Determine the Safety and Efficacy of GL-0817 (With Cyclophosphamide) for the Prevention of Recurrence in HLA-A2+ Patients With High-Risk Squamous Cell Carcinoma of the Oral Cavity

Actual Study Start Date :

Mar 30, 2017

Actual Primary Completion Date :

May 17, 2021

Actual Study Completion Date :

May 25, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: GL-0817 Subjects in active treatment will be vaccinated with GL-0817 with the adjuvants Poly-ICLC (Hiltonol®) and GM-CSF (Sargramostim, Leukine®) 3 times at 3-week intervals followed by 7 doses at 3-month intervals beginning at Week 18. Patients will receive IV Cyclophosphamide 1 day prior to the first 3 vaccinations.	Drug: GL-0817 GL-0817, IV at the dose 1.5 mg will be administered 3 times at 3-week intervals followed by 7 doses at 3-month intervals beginning at the Week 18 visit Other Names: Biropepimut-S Drug: Hiltonol Hiltonol will be administered intramuscularly at the dose of 1.4 mg as adjuvant to GL0817, 3 times at 3-week intervals followed by 7 doses at 3-month intervals beginning at the Week 18 visit Other Names: Poly-ICLC Drug: Sargramostim Sargramostim will be administered intramuscularly at the dose of 100 μg/m2, as adjuvant to GL0817, 3 times at 3-week intervals followed by 7 doses at 3-month intervals beginning at the Week 18 visit Other Names: GM-CSF Leukine Drug: cyclophosphamide cyclophosphamide will be administered IV at a dose of 200 mg/m2 (maximum dose 400 mg) one day prior to first three vaccinations of GL0817 with adjuvants
Placebo Comparator: Placebo Subjects in placebo arm will receive placebo to cyclophosphamide (normal saline solution) followed by Poly-ICLC/GM-CSF/placebo vaccine injections on the same schedule as the GL-0817 cohort.	Drug: Placebo Placebo (normal saline) will be administered as per the schedule of cyclophosphamide and GL0817/adjuvants administration

Arm

Intervention/Treatment

Experimental: GL-0817

Subjects in active treatment will be vaccinated with GL-0817 with the adjuvants Poly-ICLC (Hiltonol®) and GM-CSF (Sargramostim, Leukine®) 3 times at 3-week intervals followed by 7 doses at 3-month intervals beginning at Week 18. Patients will receive IV Cyclophosphamide 1 day prior to the first 3 vaccinations.

Drug: GL-0817

GL-0817, IV at the dose 1.5 mg will be administered 3 times at 3-week intervals followed by 7 doses at 3-month intervals beginning at the Week 18 visit

Other Names:

Biropepimut-S

Drug: Hiltonol

Hiltonol will be administered intramuscularly at the dose of 1.4 mg as adjuvant to GL0817, 3 times at 3-week intervals followed by 7 doses at 3-month intervals beginning at the Week 18 visit

Other Names:

Poly-ICLC

Drug: Sargramostim

Sargramostim will be administered intramuscularly at the dose of 100 μg/m2, as adjuvant to GL0817, 3 times at 3-week intervals followed by 7 doses at 3-month intervals beginning at the Week 18 visit

Other Names:

GM-CSF

Leukine

Drug: cyclophosphamide

cyclophosphamide will be administered IV at a dose of 200 mg/m2 (maximum dose 400 mg) one day prior to first three vaccinations of GL0817 with adjuvants

Placebo Comparator: Placebo

Subjects in placebo arm will receive placebo to cyclophosphamide (normal saline solution) followed by Poly-ICLC/GM-CSF/placebo vaccine injections on the same schedule as the GL-0817 cohort.

Drug: Placebo

Placebo (normal saline) will be administered as per the schedule of cyclophosphamide and GL0817/adjuvants administration

Outcome Measures

Primary Outcome Measures

Disease-free interval [Up to 2 years]

Secondary Outcome Measures

Disease-free survival (DFS) [up to 2 years]
Overall survival (OS) [up to 5 years]
Disease-free interval in a per protocol analysis [up to 2 years]
Adverse event profile [up to week 94]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age > 18 years
Histologic diagnosis of squamous cell carcinoma of the oral cavity including the lip, floor of mouth, anterior 2/3 of tongue, alveolus and gingiva, buccal mucosa, hard palate and retromolar trigone
Subjects must have undergone primary gross total resection (no re-resected patients are allowed) with fulfillment of at least 1 of the following histologic criteria for high-risk disease:

Histologic involvement of 2 or more regional lymph nodes
Any lymph node with histologic extracapsular extension (ECS)
Close (<3mm) or positive surgical margins on microscopic evaluation with no gross residual tumor

No evidence of locoregional disease or distant metastases at screening. Subjects must have negative scans (CT, CT-PET or MRI) for locoregional recurrence, brain or lung metastases. A negative biopsy will be mandated in patients with a positive scan. Other evaluations should be performed as clinically indicated.
No history of distant metastases.
Tumor tissue from surgery or biopsy must be available to determine MAGE-A3 expression for correlative studies.
Following surgery, the patient must have received external beam radiotherapy (58-66 Gy in 2 Gy fractions, 5 days per week) with concomitant cisplatin starting within 8 weeks of surgery. A brief delay in the initiation of radiotherapy following 8 weeks post-surgery due to administrative reasons (e.g., start of RT on Mondays) may be permitted by the Medical Monitor. The cumulative dose of cisplatin the subject received must be > 150 mg/m2. Protocol therapy must be initiated within a period of 4-8 weeks (28-56 days) following the end of RT.
The patient is, in the investigator's opinion, adequately recovered from the effects of surgery and chemoradiotherapy to participate in this study.
Blood HLA-A2 phenotype
ECOG Performance Status < 1
Laboratory values obtained ≤ 14 days prior to randomization:

Absolute neutrophil count (ANC) ≥ 1500/μL (without intervention, e.g., G-CSF)
Platelets ≥ 75,000/μL (without intervention, e.g., transfusion)
Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥8.0 g/dl is acceptable).
Alkaline phosphatase ≤ 2.5 x upper limit of normal (ULN)
AST and ALT ≤ 2 x ULN
Creatinine < 2 x ULN
Bilirubin < 1.5x ULN (except for patients with Gilbert's disease, for whom the upper acceptable limit of serum bilirubin is 3mg/dL)

A female subject is eligible to enter the study if she is:

not pregnant or nursing; Female participants must not breastfeed during the study and for a period of 30 days following the last dose.
of non-childbearing potential (i.e., women who had a hysterectomy, are postmenopausal which is defined as 1 year without menses, have both ovaries surgically removed or have current documented tubal ligation); or
of childbearing potential (i.e., women with functional ovaries and no documented impairment of oviductal or uterine function that would cause sterility). This category includes women with oligomenorrhea [even severe], women who are perimenopausal or have just begun to menstruate. These women must have a negative serum pregnancy test at screening, and agree to one of the following:
complete abstinence from intercourse from 2 weeks prior to administration of the 1st dose of study agent and 6 months after the last dose of study agent; or
consistent and correct use of 1 of the following highly effective methods of birth control for one month prior to the start of the study agent and 6 months after the last dose:
combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal)
progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)
intrauterine device (IUD)
intrauterine hormone-releasing system ( IUS)
bilateral tubal occlusion
vasectomized partner (if vasectomized is the sole sexual partner and has received medical confirmation of surgical success)

A male subject who is sexually active with a woman of childbearing potential is eligible to enter the study if he agrees to use effective contraception throughout the study and for 6 months after the last dose of study agent.
The subject must be capable of understanding the investigational nature, potential risks and benefits of the study and capable of providing valid informed consent. The subject must provide study specific informed consent prior to any protocol procedures that are not a part of standard care, including consent for assessment of HLA-A2 status, mandatory tissue submission for MAGE-A3 analysis and correlative studies.
The subject must be willing to return to the study center for vaccinations and study-related follow up procedures including blood and tumor collections and completion of imaging studies as required by the protocol.

Exclusion Criteria:

Known HIV or hepatitis B/C infection (testing not required). Subjects who are hepatitis C antibody positive may be enrolled if they are confirmed to have a negative viral load at screening.
Subjects with active autoimmune disease or a history of autoimmune disease requiring systemic steroids or other immunosuppressive treatment.
Subjects who have used systemic corticosteroids or other immunosuppressants for any condition within 14 days of randomization. Inhaled or topical steroids are permitted.
Any medical condition which would, in the investigator's opinion, compromise the patient's ability to mount an immune response, renders the patient a poor candidate for this trial or could confound the results of the study
Major surgery or traumatic injury within 28 days of randomization
Prior splenectomy or organ allograft
Any other prior, concurrent or planned chemotherapy, immunotherapy, radiotherapy, device, or investigational therapy for this cancer other than those specified in this study.
History of other malignancy (i.e., excluding disease under study) within 3 years of randomization. Exceptions include: adequately-treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix or breast, or adequately treated non-metastatic prostate cancer.
Known hypersensitivity to GM-CSF, yeast-derived products or any component of the GM-CSF drug product (e.g., mannitol) or poly-ICLC (e.g., carboxymethylcellulose).
Known hypersensitivity to cyclophosphamide, its metabolites or any other components, or known urinary outflow obstruction.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Maryland Greenebaum Cancer Center	Baltimore	Maryland	United States	21201
2	National Institute of Oncology	Budapest		Hungary
3	Semmelweis University	Budapest		Hungary
4	University of Debrecen Clinical Center	Debrecen		Hungary
5	Bacs-Kiskun County Teaching Hospital	Kecskemét		Hungary
6	Medical Center of the University of Pecs	Pecs		Hungary
7	Oncology Center of Prof. Franciszek Lukaszczyk in Bydgoszcz	Bydgoszcz		Poland
8	Swietokrzyskie Oncology Center in Kielce	Kielce		Poland
9	Clinical Oncology Center	Omsk		Russian Federation
10	Rostov Oncology Research Institute	Rostov-on-Don		Russian Federation
11	Leningrad Regional Oncology Center	Saint Petersburg		Russian Federation
12	Oncology Center of Moskovskiy District	Saint Petersburg		Russian Federation
13	Ogarev Mordovia State University	Saransk		Russian Federation
14	Clinical Hospital #1	Sterlitamak		Russian Federation
15	Republican Clinical Oncology Center	Ufa		Russian Federation
16	Regional Clinical Oncology Hospital	Yaroslavl		Russian Federation
17	Institute of Oncology and Radiology of Serbia	Belgrade		Serbia
18	Military Medical Academy, Clinic of Maxillofacial Surgery	Belgrade		Serbia
19	Oncology Institute of Vojvodina (IOV), Clinic of Medical Oncology	Sremska Kamenica		Serbia
20	University Hospital Vall d'Hebron (HUVH)	Barcelona		Spain
21	University Hospital La Paz	Madrid		Spain
22	Parc Tauli Health Corporation	Sabadell		Spain
23	Cherkasy Regional Oncology Center	Cherkasy		Ukraine
24	Chernihiv Regional Oncology Center	Chernihiv		Ukraine
25	Dnipropetrovsk I.I. Mechnykov Regional Clinical Hospital	Dnipro		Ukraine
26	Ivano-Frankivsk Regional Oncology Center	Ivano-Frankivsk		Ukraine
27	Communal Non-profit enterprise "Regional Center of Oncology"	Kharkiv		Ukraine
28	Kyiv Regional Oncology Center	Kyiv		Ukraine
29	Lviv Regional Clinical Hospital	Lviv		Ukraine
30	Odesa Regional Oncology Center	Odesa		Ukraine
31	Poltava Regional Clinical Oncology Center	Poltava		Ukraine
32	Sumy Regional Clinical Oncology Center	Sumy		Ukraine
33	Podillia Regional Oncology Center	Vinnytsia		Ukraine