GBM, Glioblastoma Multiforme, Gliosarcoma
Conditions
Keywords
GBM, Glioblastoma Multiforme, Gliosarcoma
Brief summary
The purpose of this study is to evaluate the effectiveness of Prostate Specific Membrane Antigen (PSMA ADC), as well as its safety and side effects for patients with advanced brain tumors. This study will also study how your body metabolizes (breaks down) PSMA ADC.
Detailed description
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.
Interventions
DRUGPSMA ADC
2.5 mg/kg, IV, over 60 minutes every 3 weeks
Sponsors
Progenics Pharmaceuticals, Inc.
Rhode Island Hospital
University of Texas
Heinrich Elinzano, MD
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate (Progression) for Patients With Glioblastoma That Have Progressed After Prior Treatment That Has Included Radiation, Temozolomide and Bevacizumab. | 3 months until progression, potentially up to 1 year | The response assessment in neuro-oncology (RANO) will be used to define radiographic response. (PD): A \>25% increase in tumor area (product of two diameters) OR appearance of a new lesion/site, OR clear clinical worsening or failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Who Experienced Toxicities (Adverse Events) Who Received PSMA ADC for Recurrent Glioblastoma. | at least every 3 weeks for a maximum of 30 post coming off drug, approximately 6 months | Please note that toxicities outlined may not all be related to the treatment regimen. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PSMA ADC 2.5 mg/kg, IV, over 60 minutes every 3 weeks
PSMA ADC: 2.5 mg/kg, IV, over 60 minutes every 3 weeks | 6 |
| Total | 6 |
Baseline characteristics
| Characteristic | PSMA ADC |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants |
| Age, Continuous | 60.3 years |
| Region of Enrollment United States | 6 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 6 / 6 |
| serious Total, serious adverse events | 4 / 6 |
Outcome results
Primary
Response Rate (Progression) for Patients With Glioblastoma That Have Progressed After Prior Treatment That Has Included Radiation, Temozolomide and Bevacizumab.
The response assessment in neuro-oncology (RANO) will be used to define radiographic response. (PD): A \>25% increase in tumor area (product of two diameters) OR appearance of a new lesion/site, OR clear clinical worsening or failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).
Time frame: 3 months until progression, potentially up to 1 year
Population: Progression
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PSMA ADC | Response Rate (Progression) for Patients With Glioblastoma That Have Progressed After Prior Treatment That Has Included Radiation, Temozolomide and Bevacizumab. | 6 participants |
Secondary
Number of Patients Who Experienced Toxicities (Adverse Events) Who Received PSMA ADC for Recurrent Glioblastoma.
Please note that toxicities outlined may not all be related to the treatment regimen.
Time frame: at least every 3 weeks for a maximum of 30 post coming off drug, approximately 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PSMA ADC | Number of Patients Who Experienced Toxicities (Adverse Events) Who Received PSMA ADC for Recurrent Glioblastoma. | 6 Participants |