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

Inclusion Criteria:

1. Study population:

2. Subgroup #2: Histopathologically confirmed recurrent supratentorial WHO grade 3or 4 malignant glioma (high grade glioma with molecular features ofglioblastoma will be eligible under WHO grade 4 malignant glioma)

3. Subgroup #3: Histopathologically confirmed recurrent supratentorial WHO grade 4malignant glioma (high grade glioma with molecular features of glioblastomawill be eligible under WHO grade 4 malignant glioma) and found amenable forTumor Monorail Device (TMD) implantation as per the treating neurosurgeon

4. Patient or partner(s) meets one of the following criteria:

5. Non-childbearing potential (i.e.) not sexually active, physiologicallyincapable of becoming pregnant, including people who are post-menopausal orsurgically sterile. Surgically sterile people are defined as those with adocumented hysterectomy and/or bilateral oophorectomy or tubal ligation or havehad a vasectomy. Postmenopausal for purposes of this study is defined as 1 yearwithout menses.; or

6. Childbearing potential and agrees to use one of the following methods of birthcontrol: approved hormonal contraceptives (e.g. birth control pills, patches,implants, or infusions), an intrauterine device, or a barrier method ofcontraception (e.g. a condom or diaphragm) used with spermicide.

7. Age ≥ 18 years of age at the time of entry into the study

8. Karnofsky Performance Score (KPS) ≥ 70%

9. Hemoglobin ≥ 9 g/dl prior to biopsy

10. 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 andcatheter insertion, which can be attained with the help of platelet transfusion

11. Neutrophil count ≥ 1000 prior to biopsy

12. Creatinine ≤ 1.5 x normal range prior to biopsy

13. Total bilirubin ≤ 1.5 x ULN prior to biopsy (Exception: Participant has known orsuspected Gilbert's Syndrome for which additional lab testing of direct and/orindirect bilirubin supports this diagnosis. In these instances, a total bilirubin of ≤ 3.0 x ULN is acceptable.)

14. AST/ALT ≤ 2.5 x ULN

15. Prothrombin and Partial Thromboplastin Times ≤ 1.2 x normal prior to biopsy.Patients with prior history of thrombosis/embolism are allowed to be onanticoagulation, understanding that anticoagulation will be held in theperioperative period per the neurosurgical team's recommendations. Low molecularweight heparin (LMWH) is preferred. If a patient is on warfarin, the internationalnormalized ratio (INR) is to be obtained and value should be below 2.0 prior tobiopsy.

16. At the time of biopsy, prior to administration of D2C7-IT, the presence of recurrenttumor must be confirmed by histopathological analysis

17. A signed informed consent form approved by the Institutional Review Board (IRB) willbe required for patient enrollment into the study. Patients must be able to read andunderstand the informed consent document and must sign the informed consentindicating that they are aware of the investigational nature of this study

18. 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 onthe assessment of the study neurosurgeons or their designate

3. Patients with severe, active co-morbidity, defined as follow:

4. Patients with an active infection requiring intravenous treatment or having anunexplained febrile illness (Tmax > 99.5°F/37.5°C)

5. Patients with known immunosuppressive disease or known human immunodeficiencyvirus infection

6. Patients with unstable or severe intercurrent medical conditions such as severeheart disease (New York Heart Association Class 3 or 4)

7. Patients with known lung (forced expiratory volume in the first second ofexpiration (FEV1) < 50%) disease or uncontrolled diabetes mellitus

8. Patients with albumin allergy

9. Patients may not have received chemotherapy or bevacizumab ≤ 4 weeks [except fornitrosourea (6 weeks), or metronomic dosed chemotherapy such as daily etoposide orcyclophosphamide (1 week)] prior to starting the study drug unless patients haverecovered from side effects of such therapy

10. Patients may not have received immunotherapy ≤ 4 weeks prior to starting the studydrug unless patients have recovered from side effects of such therapy

11. Patients may not have received treatment with tumor treating fields (e.g., Optune) ≤ 1 week prior to starting the study drug

12. Patients may not be less than 12 weeks from radiation therapy, unless progressivedisease outside of the radiation field or 2 progressive scans at least 4 weeks apartor histopathologic confirmation

13. Patients who have not completed all standard of care treatments, including surgicalprocedure 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.)

14. If the MGMT promoter in their tumor is known to be unmethylated, patients arenot mandated to have received chemotherapy prior to participating in this trial

15. If the MGMT promoter in their tumor is known to be methylated or the MGMTpromoter methylation status is unknown at time of screening, patients must havereceived at least one chemotherapy regimen prior to participating in this trial

16. 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); tumorcrossing the midline or leptomeningeal disease

17. Patients on greater than 4 mg per day of dexamethasone within the 2 weeks prior tothe D2C7-IT infusion

18. Patients with worsening steroid myopathy (history of gradual progression ofbilateral proximal muscle weakness, and atrophy of proximal muscle groups)

19. Patients with prior, unrelated malignancy requiring current active treatment withthe exception of cervical carcinoma in situ and adequately treated basal cell orsquamous cell carcinoma of the skin

20. Patients with active autoimmune disease requiring systemic immunomodulatorytreatment within the past 3 months

21. Only for patients in Subgroup #3 (TMD subgroup): Patients with known allergies tosilicone, 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 malignantglioma based on imaging studies with measurable disease requiring therapy other thanper 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 areaipsilateral to the tumor approved by the Institutional Review Board (IRB) of recordwill be required. Patients must be able to read and understand the informed consentdocument and must sign the informed consent indicating that they are aware of theinvestigational 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 toenter and receive treatment with 2141-V11 injected in the CPL subcutaneous area iftheir partner(s) meets the criteria outlined in sub-bullet a. below or if they ortheir partner(s) are using one of the methods of birth control outlined insub-bullet b. below. If the subject is potentially able to become pregnant, they areeligible to enter and participate in this study if they meet the following criteria:

5. Non-childbearing potential (i.e., physiologically incapable of becomingpregnant, including people who are postmenopausal or surgically sterile).Surgically sterile people are defined as those with a documented hysterectomyand/or bilateral oophorectomy or tubal ligation. Postmenopausal for purposes ofthis study, is defined as 1 year without menses); or

6. Childbearing potential, has a negative serum pregnancy test at screening, andagrees to use one of the following methods of birth control: approved hormonalcontraceptives (e.g., birth control pills, patches, implants, or infusions), anintrauterine device, or a barrier method of contraception (e.g., a condom ordiaphragm) used with spermicide.

7. Please note: If the patient has had a vasectomy or is using a condom withspermicide, their partner does not need to use additional birth control notedin 4a and 4b.

8. Total bilirubin ≤ 1.5 x ULN prior to CPL injection (Exception: Participant has knownor suspected Gilbert's Syndrome for which additional lab testing of direct and/orindirect bilirubin supports this diagnosis. In these instances, a total bilirubin of ≤ 3.0 x ULN is acceptable.)

9. AST/ALT ≤ 2.5 x ULN prior to CPL injection.

10. Neutrophil count ≥ 1000 prior to CPL injection.

11. Platelet count ≥ 50,000/µL unsupported is necessary prior to CPL injection.

12. 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:

3. Patients with an active infection requiring intravenous treatment or having anunexplained febrile illness (Tmax > 99.5°F/37.5°C)

4. Patients with known immunosuppressive disease or known human immunodeficiencyvirus infection

5. Patients with unstable or severe intercurrent medical conditions such as severeheart disease (New York Heart Association Class 3 or 4)

6. Patients with known lung (forced expiratory volume in the first second ofexpiration [FEV1] < 50%) disease or uncontrolled diabetes mellitus

7. Karnofsky Performance Score < 60%

8. Patients on greater than 4 mg per day of dexamethasone within the 2 weeks prior tothe 2141-V11 injection in the CPL area

9. Patients with active autoimmune disease requiring systemic immunomodulatorytreatment within the past 3 months