Brain Metastases, Adult, Malignant Primary Brain Tumors
Conditions
Brief summary
Pritumumab is a human IgG1 kappa antibody that binds to a malignant tumor associated antigen, ecto domain-vimentin (EDV) which is expressed in a variety of tumor cells. Pritumumab was shown to have relatively high reactivity with brain cancer cell lines, while no reactivity was demonstrated with normal neurons, astrocytes or fetal cerebral cells. Pritumumab has notable antibody-dependent cellular cytotoxicity (ADCC), brain tumor penetration and antitumor activity in nude mouse human xenograft models. Primary Objectives \- To determine the safety and/or tolerability and the recommended Phase 2 dose (RP2D) of escalating, intravenously (IV) administered Pritumumab doses in patients with recurrent gliomas or with brain metastases. Secondary Objectives * To determine pharmacokinetics and pharmacodynamics of Pritumumab * To identify preliminary signals of anti-tumor response to Pritumumab * To explore disease-related, patient-reported outcomes
Detailed description
This is an open-label, Phase 1, outpatient, dose escalation study of Pritumumab in patients with brain cancer who have failed prior therapy and have no other available options. In the first part of the study, escalating doses of Pritumumab of 1.6, 4.8, 8.0, 12.0, and 16.2 mg/kg will be administered in a sequential, safety-driven manner to eligible patients according to standard 3+3 scheme, as an 1-hour IV infusion on Days 1, 8, 15, and 22 of each 28-day treatment cycle. The dose levels may be modified upon obtained results. Once the maximum tolerated dose (MTD) is determined, an expansion cohort including 6-12 patients in selected tumor type at a dose equal or below to MTD is planned to determine the recommended Phase 2 dose (RP2D). A total of 42 patients may be administered with Pritumumab in this study. Patients will be treated with Pritumumab for a maximum of 6 cycles or until cancer progression or unacceptable toxicity. Patients will be followed after treatment completion every four months or until death or lost to follow-up. Standard clinical, laboratory and functional assessments will be employed to monitor for safety, tolerability and tumor response, including blood sampling for clinical biochemistries, pharmacokinetics, CSF and tissue samples, at frequency specified by the protocol. Patient-reported outcomes will also be assessed.
Interventions
BIOLOGICALPritumumab
Pritumumab IgG1 human monoclonal antibody
Sponsors
Hoag Memorial Hospital Presbyterian
Nascent Biotech
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open label, non-randomized, 3+3 dose escalation to determine MTD, followed by exoansion to 6-12 patients to determine RP2D. Subjects will continue study treatment until progressive disease or unacceptable toxicity. Follow-up will occur until death or lost to follow-up.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Subjects must meet all of the inclusion criteria to participate in this study. 1. Ability to understand and the willingness to provide informed consent. 2. Diagnosis Histologically confirmed diagnosis of brain cancer: * glioblastoma (GBM), * anaplastic astrocytoma (AA), * anaplastic oligodendroglioma (AO), * anaplastic mixed oligoastrocytoma (AMO), * low grade gliomas, * brain metastases, * meningiomas, chordomas, medulloblastoma, craniopharyngiomas, pituitary tumors or * leptomeningeal metastases 3. Prior Therapy Has failed prior standard therapy including maximal safe surgical resection, radiation therapy (when appropriate for the specific cancer type), or systemic therapy or is intolerant of, or has refused other available therapies, but is still in need of therapy. No patients may receive Pritumumab prior to any surgery for their cerebral tumor 4. Progression/Recurrence Has progression of brain cancer and measurable disease by magnetic resonance imaging (MRI) or computed tomography (CT) scan. For leptomeningeal metastases, positive cytology is acceptable if imaging is not measurable. 5. Age Age ≥ 18 years. 6. Performance Status Karnofsky Performance Status ≥ 60% (see Appendix A). Subjects must have a life expectancy of equal to or greater than 8 weeks. 7. Organ and Marrow Function Requirements Hematology: * Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L * Platelet count ≥ 100 x 109/L * Hemoglobin ≥ 9.0 g/dL * White blood cell (WBC) count ≥ 3.0 x 109/L Biochemistry: * AST/SGOT and ALT/SGPT ≤ 5 x institution's ULN * Total bilirubin ≤ 3 x institution's ULN * Serum creatinine ≤ 2 x institution's ULN or 24-hour creatinine clearance ≥ 50 mL/min * Alkaline phosphatase (ALP) ≤ 3 x ULN unless considered tumor related * Estimated GFR \> 50 mL/min Coagulation: * INR ≤ 1.4 * PT/aPTT ≤ 1.2 x institution's ULN 8. Contraception All fertile females and any man with a partner of child-bearing potential agrees to use adequate contraception which will include two of the following: hormonal or barrier method of birth control, or abstinence prior to study entry, for the duration of study participation, and for 30 days following completion of therapy. 9. Although Pritumumab shows notable immunohistologic reactivity against active endometrial tissues, fertile female patients will be included in this study.
Exclusion criteria
Subjects meeting any of the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | Up to 24 weeks | Number of participants with treatment-related adverse events as assessed by NCI-CTCAE v.5.0 during first 24 weeks of treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Intra-cranial Objective Response Rate | 2 months | Intra-cranial objective response rate at 2 months as assessed by the Response Assessment in Neuro-oncology (RANO) criteria |
Countries
United States
Outcome results
None listed