WP1066 for the Treatment of Recurrent or Refractory and Progressive Malignant Brain Tumors
Brain & Spinal Cord Tumor
3 - 25 Years, Male and Female
AFLACST1901 (primary)
NCI-2020-07428
IRB00113194
Summary
This phase I trial identifies the side effects and best dose of WP1066 in treating patients with cancerous (malignant) brain tumors that have come back (recurrent) or have not responded to treatment (refractory), and are growing, spreading, or getting worse (progressive). WP1066 is designed to target the STAT3 pathway in tumor cells, which makes these cells divide, increases new blood vessels to the tumor, causes the tumor cells to move throughout the body and brain, and avoids them being detected by the immune system. Targeting this pathway may cause the immune system to kill the tumor cells. Giving WP1066 may help to control the disease.
Objectives
PRIMARY OBJECTIVES:
I. Identify the maximum tolerated dose (MTD) of STAT3 inhibitor WP1066 (WP1066) in pediatric patients with recurrent or refractory and progressive malignant brain tumors for which there is no known treatment with clinical benefit.
II. Assess the safety and tolerability of WP1066 in this pediatric study population using the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) with special attention directed at determining whether any induced autoimmune reactions occur.
SECONDARY OBJECTIVES:
I. Pharmacokinetic analysis of the in vivo bioavailability of WP1066 in children.
II. Assess overall response rate (ORR) of WP1066 treatment for this pediatric study population in those with radiographically measurable disease.
III. Assess immunological response in this pediatric study population treated with WP1066.
IV. Assess time to radiographically assessed progression and/or response in this pediatric study population treated with WP1066.
V. Assess progression-free survival (PFS) and overall survival (OS) in this pediatric study population treated with WP1066.
EXPLORATORY OBJECTIVES:
I. Correlate levels of expression of phosphorylated (p)-STAT3 in peripheral blood mononuclear cells (PBMCs) and circulating immunosuppressive regulatory T cells (Tregs) in response to WP1066 treatment.
II. Evaluate circulating biomarker effects following drug exposure to determine if treatment with WP1066 will result in an increase in the functional effector T cells:Treg ratio and improve the anti-tumor immune response.
III. Evaluate tumor tissue levels of p-STAT3, tumor infiltrating macrophages, and Tregs pre-treatment, and post-treatment if surgical biopsy/debulking is clinically indicated at any time during treatment or at relapse/progression and correlate these levels with response to WP1066.
OUTLINE: This is a dose-escalation study.
Patients receive WP1066 orally (PO) (or via nasogastric tube or G-tube if not tolerated by mouth) twice daily (BID) on Monday, Wednesday, and Friday of weeks 1 and 2 of each 28-day cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 2 months.
Eligibility
- Patients must have histologically confirmed progressive medulloblastoma, malignant glioma or any other recurrent/progressive malignant brain tumor, for which curative measures do not exist. Primary spinal tumors are eligible. Diffuse intrinsic pontine glioma (DIPG) and diffuse midline glioma (DMG) H3K27M do not require histological confirmation
- Patients must have previously undergone standard-of-care treatment including surgery, radiation, and/or first line adjuvant chemotherapy prior to the experimental treatment (WP1066)
- Patients must have recovered from the acute treatment related toxicities (defined as < grade 1 if not defined in eligibility criteria) of all prior chemotherapy, immunotherapy or radiotherapy prior to entering this study. There is no upper limit to the number of prior therapies that is allowed
- Karnofsky or Lansky performance scale score >= 60%
- Absolute neutrophil count >= 1,000/mcL
- Platelets >= 100,000/mcL
- Total bilirubin within normal institutional limits
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 x (< 10 x if taking steroids) institutional upper limit of normal
- Creatinine within normal institutional limits for age OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
- Prothrombin time (PT)/partial thromboplastin time (PTT) < 1.5 x normal institutional standard
- Patients with stable seizures (e.g., no seizures for >= 14 days and not requiring escalation or addition of anti-epileptic drugs) will be eligible
- Signed informed written consent obtained from patient if 18 years of age or older, or from guardian/legal representative if patient is less than 18 years of age
Treatment Sites in Georgia
1405 Clifton Road NE
3rd Floor
Atlanta, GA 30322
404-785-0853
www.choa.org
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