BrUOG 263: Prostate Specific Membrane Antigen (PSMA) Glioblastoma Multiforme (GBM)

PSMA expression has been demonstrated in the tumor neovasculature of Glioblastoma Multiforme
(GBM) by immunohistochemical staining. Strong reactivity to the antibody component of PSMA
ADC was observed in the endothelial cells of new tumor blood vessels in GBM. Since the
endothelial cells are located on the luminal surface of blood vessels, PSMA ADC does not need
to cross the blood brain barrier to reach its target. Following binding and internalization
of PSMA ADC, the cytotoxic component of PSMA ADC will be released and destroy the
neovasculature that supports tumor growth. Therefore, PSMA ADC may be an active treatment for
GBM.

Bevacizumab, an inhibitor of angiogenesis, has been shown to be effective in improving
progression-free survival as a single agent. Thus PSMA ADC, which targets tumor angiogenesis
by a mechanism different from that of bevacizumab, may be a novel therapeutic modality for
GBM.

A phase 2 study of PSMA ADC is proposed for patients with GBM that have progressed after
standard treatment that includes radiation, temozolomide and bevacizumab. A phase 1 study of
PSMA ADC in prostate cancer is ongoing and a phase 2 dose level of 2.5 mg/kg IV every 3 weeks
has been defined. Treatment after bevacizumab failure for patients with GBM is a major unmet
medical need. If activity were demonstrated in this trial, a definitive randomized study
would be proposed.

Inclusion Criteria:

- Males and females Histologically confirmed GBM (Patients with gliosarcoma are also
eligible)

- Assessable or measurable disease by MRI

- Progression after prior treatment that includes radiation, temozolomide and
bevacizumab.

-> 4 weeks since prior chemotherapy, bevacizumab and other systemic treatment and > 3
weeks from prior radiation.

- age >18 years

- Weight < 150 kg.

- Karnofsky performance score > 60

- Life expectancy >12 weeks

- Brain MRI within 21 days prior to registration

- Laboratory results requirements

- Absolute neutrophil count (ANC) ≥ 1000/mm3.

- Platelets (Plt) ≥ 100,000/mm3

- Hemoglobin (Hgb) ≥ 8.0 g/dL

- Total bilirubin ≤ 2.0 mg/dL

- Serum alanine transferase/ Serum aspartate transaminase (ALT/AST) ≤ 2.5x the
upper limit of normal (ULN)

- Serum creatinine ≤ 2.0 mg/dL

- Pancreatic Amylase (p-amylase) ≤ the ULN

- Negative serum pregnancy test for women of child-bearing potential

- Stable corticosteroid dose at least 14 days prior to registration

- Women of childbearing potential must have a negative pregnancy test.

- Men and women of childbearing potential must be willing to consent to using effective
contraception while on treatment and for at least 3 months thereafter.

- Patients must not be on enzyme-inducing anti-epileptic drugs (EIAED). Patients may be
on non-enzyme inducing anti-epileptic drugs (NEIAED) or may not be taking any
anti-epileptic drugs. A list of AED that cause modest or no induction of hepatic
metabolic enzymes will be discussed

Exclusion Criteria:

- Non-GBM primary invasive malignant neoplasm within the five years prior to screening
except for:

- keratinocyte (non-melanoma) (i.e., basal cell, squamous cell) carcinoma of the
skin; or low-grade papillary superficial transitional cell carcinoma of the
bladder.However, patients with stage 1 cancers not requiring cancer therapy
including chemotherapy or hormone therapy, for which a lifespan of greater than 3
years without treatment is expected (such as early stage prostate cancer) may be
enrolled.

- Clinically significant cardiac disease (New York Heart Association Class III/ IV or
severe debilitating pulmonary disease

- Subjects with QTc>500 msec (either Bazzett's or Fridericia's method)

- Radiation therapy, cytotoxic chemotherapy, bevacizumab or other treatment for GBM
within previous three weeks

- Evidence of an active infection requiring ongoing intravenous antibiotic therapy

- Any toxicity ≥ grade 2 (non-laboratory) (NCI CTCAE, Version 4.03) prior to first dose
of study drug

- Prior treatment with PSMA ADC or other therapies targeting PSMA, or other anti-body
drug conjugate (ADC) products that contain monomethyl auristatin E (MMAE) (e.g.,
brentuximab vedotin, glembatumumab vedotin, ASG-5ME)

- Known hypersensitivity reactions to PSMA ADC or any of its components.

- Any medical condition that in the opinion of the Investigator may interfere with a
subject's participation in or compliance with the study

- Patients with a prior history of pancreatitis