Phase 1 Trial of D2C7-IT in Combination With 2141-V11 for Recurrent Malignant Glioma

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 1 Trial of D2C7-IT in Combination With an Fc-engineered Anti-CD40 Monoclonal Antibody (2141-V11) Administered Intratumorally Via Convection-Enhanced Delivery for Adult Patients With Recurrent Malignant Glioma

Conditions
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Glioma, Malignant

Intervention / Treatment
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* Drug: D2C7-IT
* Drug: 2141-V11


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histopathologically confirmed recurrent supratentorial WHO grade III or IV malignant glioma (high grade glioma with molecular features of glioblastoma will be eligible under WHO grade IV malignant glioma) Patient or partner(s) meets one of the following criteria: Non-childbearing potential (i.e. not sexually active, physiologically incapable of becoming pregnant, including any female who is post-menopausal or surgically sterile, or any male who has had a vasectomy). Surgically sterile females are defined as those with a documented hysterectomy and/or bilateral oophorectomy or tubal ligation. Postmenopausal for purposes of this study is defined as 1 year without menses.; or 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. Age ≥ 18 years of age at the time of entry into the study Karnofsky Performance Score (KPS) ≥ 70% Hemoglobin ≥ 9 g/dl prior to biopsy 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 Neutrophil count ≥ 1000 prior to biopsy Creatinine ≤ 1.5 x normal range prior to biopsy Total bilirubin ≤ 1.5 x upper limit of normal (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) Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 x ULN 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. At the time of biopsy, prior to administration of D2C7-IT, the presence of recurrent tumor must be confirmed by histopathological analysis 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 Able to undergo brain MRI with and without contrast Exclusion Criteria: Females who are pregnant or breast-feeding Patients with an impending, life-threatening cerebral herniation syndrome, based on the assessment of the study neurosurgeons or their designate Patients with severe, active co-morbidity, defined as follows: Patients with an active infection requiring intravenous treatment or having an unexplained febrile illness (Tmax > 99.5°F/37.5°C) Patients with known immunosuppressive disease or known human immunodeficiency virus infection Patients with unstable or severe intercurrent medical conditions such as severe heart disease (New York Heart Association Class 3 or 4) Patients with known lung (forced expiratory volume in the first second of expiration (FEV1) < 50%) disease or uncontrolled diabetes mellitus Patients with albumin allergy 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 Patients may not have received immunotherapy ≤ 4 weeks prior to starting the study drug unless patients have recovered from side effects of such therapy Patients may not have received treatment with tumor treating fields (e.g., Optune) ≤ 1 week prior to starting the study drug 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 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 15v fractions over 3 weeks.) If the O^6-methylguanine-DNA methyltransferase (MGMT) promoter in their tumor is known to be unmethylated, patients are not mandated to have received chemotherapy prior to participating in this trial 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 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 Patients on greater than 4 mg per day of dexamethasone within the 2 weeks prior to the D2C7-IT infusion Patients with worsening steroid myopathy (history of gradual progression of bilateral proximal muscle weakness, and atrophy of proximal muscle groups) 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 Patients with active autoimmune disease requiring systemic immunomodulatory treatment within the past 3 months

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: D2C7-IT + 2141-V11<br>Single D2C7-IT intratumoral infusion (4613.2 ng/mL in 36 mL) over 72 hours followed by single 2141-V11 infusion (5 dose levels) over 7 hours | Drug: D2C7-IT<br>* D2C7-IT intratumoral infusion<br>Drug: 2141-V11<br>* 2141-11 intratumoral infusion<br>* Other names: anti-CD40;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with dose-limiting toxicity (DLT) within each dose level | 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. | 28 days after catheter removal | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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D2C7, D2C7-IT, Glioblastoma, Glioma, 2141-V11, Pro00104852, Duke, Rockefeller, CD40, epidermal growth factor receptor (EGFR), EGFR, Landi