Glioma, Malignant
Conditions
Keywords
D2C7, D2C7-IT, Glioblastoma, Glioma, 2141-V11, Pro00104852, Duke, Rockefeller, CD40, epidermal growth factor receptor (EGFR), EGFR, Landi
Brief summary
This is a phase 1 study of an anti-CD40 monoclonal antibody (2141-V11) in combination with D2C7-IT for patients with recurrent World Health Organization (WHO) grade III or IV malignant glioma at the Preston Robert Tisch Brain Tumor Center (PRTBTC) at Duke.
Detailed description
Within this study, a maximum of 30 patients with recurrent WHO grade III and IV malignant glioma will receive D2C7-IT and 2141-V11 to determine the impact of the combination of D2C7-IT and 2141-V11 on safety. D2C7-IT and 2141-V11 will be delivered sequentially directly into the tumor by Convection Enhanced Delivery (CED) using an intracerebral catheter placed within the enhancing portion of the tumor. Based on phase 1 studies of D2C7-IT alone and D2C7-IT in combination with atezolizumab in adult patients with recurrent glioblastoma (GBM), the amount of D2C7-IT to be delivered will be 4613.2 ng/mL (36 mL). 2141-V11 will be dose escalated during the study to determine the maximum tolerated dose (MTD) when used in combination with D2C7-IT. Upon approval of v.9.0 of the protocol, patients will be eligible to receive D2C7-IT + 2141-V11 (via CED and CPL) with or without prior implantation of Tumor Monorail Device (TMD). Patients will be stratified into the following subgroups: * Subgroup #1: Patients accrued before Protocol Version v.5.0 * Subgroup #2: Patients accrued after Protocol Version v.5.0 who did not have a TMD implanted. * Subgroup #3: Patients accrued after Protocol Version v.9.0 for whom a TMD implantation was initiated. Patients who enroll in subgroup #3, once identified as safe to proceed with the TMD (e.g. smaller tumor) and after obtaining their agreement, will receive the TMD approximately 14 days before intracranial D2C7-IT + 2141-V11 infusion in a modified 3+3 design (a minimum of 3 patients and a maximum of 9). All patients who do not meet inclusion criteria for the TMD and/or refuse to receive the TMD, will be treated under subgroup #2 and will proceed directly to CED catheter implantation followed by D2C7-IT + 2141-V11. For patients enrolled subgroup #3, an initial 3 patients will be observed for safety before enrolling the next cohort of 3 patients. Intraoperative CT will be performed post implant to ensure device location accuracy and to check for hemorrhage. Prior to CED catheter insertion for D2C7-IT + 2141-V11 infusion, the first tumor/fluid sampling through the TMD will occur. Repeated tumor/fluid sampling via the TMD will occur before every perilymphatic injection of 2141-V11, i.e., approximately 2 weeks (+ 1 week) after D2C7-IT, which will be repeated again 2 weeks later and then every 3 weeks for 1 year. If fewer than 2 of the first 3 patients who receive the TMD experience an unacceptable adverse event within 14 days of TMD implantation, 3 more patients will receive the TMD. The TMD sampling time can be adjusted from every 3 weeks to every 6 weeks (i.e., every other 2141-V11 infusion) if not enough cellular and genomic material is sampled in the first cohort. With protocol version 10.0, patients who have completed 1 year of CPL subcutaneous injections of 2141-V11 at 2.0 mg every 3 weeks, who benefit from the therapy, and desire to continue on therapy will receive CPL subcutaneous injections of 2141-V11 at 2.0 mg every 4-6 weeks.
Sponsors
Darell Bigner
Rockefeller University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Study population: 1. Subgroup #2: Histopathologically confirmed recurrent supratentorial WHO grade 3 or 4 malignant glioma (high grade glioma with molecular features of glioblastoma will be eligible under WHO grade 4 malignant glioma) 2. Subgroup #3: Histopathologically confirmed recurrent supratentorial WHO grade 4 malignant glioma (high grade glioma with molecular features of glioblastoma will be eligible under WHO grade 4 malignant glioma) and found amenable for Tumor Monorail Device (TMD) implantation as per the treating neurosurgeon 2. Patient or partner(s) meets one of the following criteria: 1. Non-childbearing potential (i.e.) not sexually active, physiologically incapable of becoming pregnant, including people who are post-menopausal or surgically sterile. Surgically sterile people are defined as those with a documented hysterectomy and/or bilateral oophorectomy or tubal ligation or have had a vasectomy. Postmenopausal for purposes of this study is defined as 1 year without menses.; or 2. Childbearing potential and agrees to use one of the following methods of birth control: approved hormonal contraceptives (e.g. birth control pills, patches, implants, or infusions), an intrauterine device, or a barrier method of contraception (e.g. a condom or diaphragm) used with spermicide. 3. Age ≥ 18 years of age at the time of entry into the study 4. Karnofsky Performance Score (KPS) ≥ 70% 5. Hemoglobin ≥ 9 g/dl prior to biopsy 6. Platelet count ≥ 100,000/µl unsupported is necessary for eligibility on the study; however, because of risks of intracranial hemorrhage with catheter placement, platelet count ≥ 125,000/µl is required for the patient to undergo biopsy and catheter insertion, which can be attained with the help of platelet transfusion 7. Neutrophil count ≥ 1000 prior to biopsy 8. Creatinine ≤ 1.5 x normal range prior to biopsy 9. Total bilirubin ≤ 1.5 x ULN prior to biopsy (Exception: Participant has known or suspected Gilbert's Syndrome for which additional lab testing of direct and/or indirect bilirubin supports this diagnosis. In these instances, a total bilirubin of ≤ 3.0 x ULN is acceptable.) 10. AST/ALT ≤ 2.5 x ULN 11. Prothrombin and Partial Thromboplastin Times ≤ 1.2 x normal prior to biopsy. Patients with prior history of thrombosis/embolism are allowed to be on anticoagulation, understanding that anticoagulation will be held in the perioperative period per the neurosurgical team's recommendations. Low molecular weight heparin (LMWH) is preferred. If a patient is on warfarin, the international normalized ratio (INR) is to be obtained and value should be below 2.0 prior to biopsy. 12. At the time of biopsy, prior to administration of D2C7-IT, the presence of recurrent tumor must be confirmed by histopathological analysis 13. A signed informed consent form approved by the Institutional Review Board (IRB) will be required for patient enrollment into the study. Patients must be able to read and understand the informed consent document and must sign the informed consent indicating that they are aware of the investigational nature of this study 14. Able to undergo brain MRI with and without contrast
Exclusion criteria
1. Patients who are pregnant or breastfeeding/chestfeeding 2. Patients with an impending, life-threatening cerebral herniation syndrome, based on the assessment of the study neurosurgeons or their designate 3. Patients with severe, active co-morbidity, defined as follow: 1. Patients with an active infection requiring intravenous treatment or having an unexplained febrile illness (Tmax \> 99.5°F/37.5°C) 2. Patients with known immunosuppressive disease or known human immunodeficiency virus infection 3. Patients with unstable or severe intercurrent medical conditions such as severe heart disease (New York Heart Association Class 3 or 4) 4. Patients with known lung (forced expiratory volume in the first second of expiration (FEV1) \< 50%) disease or uncontrolled diabetes mellitus 5. Patients with albumin allergy 4. Patients may not have received chemotherapy or bevacizumab ≤ 4 weeks \[except for nitrosourea (6 weeks), or metronomic dosed chemotherapy such as daily etoposide or cyclophosphamide (1 week)\] prior to starting the study drug unless patients have recovered from side effects of such therapy 5. Patients may not have received immunotherapy ≤ 4 weeks prior to starting the study drug unless patients have recovered from side effects of such therapy 6. Patients may not have received treatment with tumor treating fields (e.g., Optune) ≤ 1 week prior to starting the study drug 7. Patients may not be less than 12 weeks from radiation therapy, unless progressive disease outside of the radiation field or 2 progressive scans at least 4 weeks apart or histopathologic confirmation 8. Patients who have not completed all standard of care treatments, including surgical procedure and radiation therapy (Please note: For patients under 65 years old, standard radiation therapy is typically at least 59 Gy in 30 fractions over 6 weeks. For patients 65 years or older, standard RT is often reduced to a minimum 40 Gy in 15 fractions over 3 weeks.) 1. If the MGMT promoter in their tumor is known to be unmethylated, patients are not mandated to have received chemotherapy prior to participating in this trial 2. If the MGMT promoter in their tumor is known to be methylated or the MGMT promoter methylation status is unknown at time of screening, patients must have received at least one chemotherapy regimen prior to participating in this trial 9. Patients with neoplastic lesions in the brainstem, cerebellum, or spinal cord; radiological evidence of active (growing) disease (active multifocal disease); extensive subependymal disease (tumor touching subependymal space is allowed); tumor crossing the midline or leptomeningeal disease 10. Patients on greater than 4 mg per day of dexamethasone within the 2 weeks prior to the D2C7-IT infusion 11. Patients with worsening steroid myopathy (history of gradual progression of bilateral proximal muscle weakness, and atrophy of proximal muscle groups) 12. Patients with prior, unrelated malignancy requiring current active treatment with the exception of cervical carcinoma in situ and adequately treated basal cell or squamous cell carcinoma of the skin 13. Patients with active autoimmune disease requiring systemic immunomodulatory treatment within the past 3 months 14. Only for patients in Subgroup #3 (TMD subgroup): Patients with known allergies to silicone, polyurethane and titanium, which are materials contained in the TMD Subject Eligibility Salvage Treatment (Effective with Protocol Version v.5.0) Before being allowed to proceed with salvage treatment, the subject must satisfy the following inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of patients with dose-limiting toxicity (DLT) within each dose level | 28 days after catheter removal | DLTs are defined as any of the following events that are at least possibly, probably, or definitely attributable to study treatment (2141-V11 or the combination of D2C7-IT and 2141-V11) during dose escalation. As the optimal dose of D2C7-IT in monotherapy has been well established, only toxicity starting or increasing in grade at any time after the start of 2141-V11 will be considered for DLT definition. |
| Proportion of patients with unacceptable toxicity resulting from injections of 2141-V11 in the CPL area ipsilateral to the tumor | 28 days after catheter removal | For the purpose of monitoring adverse events occurring with perilymphatic injections of 2141-V11, we will define an unacceptable toxicity as any adverse event that satisfies the definition of DLT. |
| The proportion of patients with Tumor Monorail Device (TMD)-related unacceptable adverse event | 14 days following TMD placement | Unacceptable adverse events following TMD placement are defined as follows * Cerebral edema (grade 3 or higher) due to device implantation * New neurological symptoms (grade 3 or higher) that do not resolve within 2 weeks and not due to tumor progression * Device-related infection (grade 3 or higher) * Intracranial hemorrhage (grade 3 or higher) * Tumor mis-migration (extracranial extension) |
Countries
United States
Contacts
CONTACTAnnick Desjardins, MD. FRCPC
CONTACTStevie Threatt
PRINCIPAL_INVESTIGATORAnnick Desjardins, MD,FRCPC
Duke University
Outcome results
None listed