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

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 exclusion criteria. This option is available only for patients treated prior to Protocol Version v.5.0 - Subgroup #1:

Inclusion Criteria Salvage Treatment

1. Patients must have a recurrence of their supratentorial WHO grade IV4 malignant glioma based on imaging studies with measurable disease requiring therapy other than per protocol allowed reduced dose bevacizumab
2. Patients must be ≥ 4 months since their intratumoral administration of D2C7-IT + 2141-V11
3. A new signed informed consent form for the treatment with 2141-V11 in the CPL area ipsilateral to the tumor approved by the Institutional Review Board (IRB) of record will be required. 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 the injection of 2141-V11 in the CPL subcutaneous area.
4. If the subject is able to produce sperm and is sexually active, they are eligible to enter and receive treatment with 2141-V11 injected in the CPL subcutaneous area if their partner(s) meets the criteria outlined in sub-bullet a. below or if they or their partner(s) are using one of the methods of birth control outlined in sub-bullet b. below. If the subject is potentially able to become pregnant, they are eligible to enter and participate in this study if they meet the following criteria:

   1. Non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including people who are postmenopausal or surgically sterile). Surgically sterile people 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
   2. Childbearing potential, has a negative serum pregnancy test at screening, 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. Please note: If the patient has had a vasectomy or is using a condom with spermicide, their partner does not need to use additional birth control noted in 4a and 4b.
5. Total bilirubin ≤ 1.5 x ULN prior to CPL injection (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.)
6. AST/ALT ≤ 2.5 x ULN prior to CPL injection.
7. Neutrophil count ≥ 1000 prior to CPL injection.
8. Platelet count ≥ 50,000/µL unsupported is necessary prior to CPL injection.
9. Creatinine ≤ 1.2 x normal range prior to CPL injection.

Exclusion Criteria Salvage Treatment

1. Patients who are pregnant or breastfeeding/chestfeeding
2. 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
3. Karnofsky Performance Score \< 60%
4. Patients on greater than 4 mg per day of dexamethasone within the 2 weeks prior to the 2141-V11 injection in the CPL area
5. Patients with active autoimmune disease requiring systemic immunomodulatory treatment within the past 3 months