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Pediatric Brain Cancer

OVERVIEW

Pediatric Brain Cancer (PBC)

Cancer is the leading cause of death by disease among children in the United States. Brain and spinal cord tumors are the 2nd most common cancers in children, accounting for approximately 26% of childhood cancers.

Plus Therapeutics is developing 186RNL (Rhenium-186 NanoLiposome) for the treatment of rare, frequently fast-growing pediatric brain and spinal cord tumors with a poor prognosis — diffuse intrinsic pontine glioma (DIPG), ependymoma, and high-grade glioma (HGG).

Diffuse Intrinsic Pontine Glioma

Overview

Rare, fast-growing CNS tumor that forms in glial cells in the pons region of the brain stem; spreads to nearby tissue and other parts of the brain stem, are hard to treat, and have a poor prognosis

Incidence

Brain tumors are the most common cancer and cause of cancer-related death in children less than 15 years of age; DIPG accounts for 10-15% of all brain tumors in children; 300 children diagnosed with DIPG each year in the U.S. with a median age of onset of 5-9 years; DIPG is the most common brainstem tumor in children, representing 75-80% of all pediatric brainstem tumors

Quality of Life

Causes double vision and difficulty in controlling eye/eyelid movement and facial expression, chewing and swallowing, speaking, headaches

Survival
  • 10% at 2 years and 2% at 5 years
  • Median:  8-11 months
Current Treatments
  • Once diagnosed, the standard course of treatment is steroids followed by external beam radiation therapy (EBRT); EBRT is an effective palliative treatment that improves symptoms in ~80% of patients and extends survival 2 to 3 months; however, the dose of EBRT is limited by the tolerance of the surrounding normal brain tissue and may result in a common complication – radiation necrosis (brain tissue cell death).
  • No chemotherapies have demonstrated a survival benefit; challenges for chemotherapies are crossing the blood-brain barrier and overcoming the resistance posed by brainstem glioma tumor cells
  • Surgery for DIPGs is challenging because they are diffuse, intrinsic, and located in the brainstem; because DIPGs grow into surrounding tissue, it’s not possible for a surgeon to separate normal from abnormal tissue
  • Following initial treatment, in almost all cases, the DIPG tumor starts to grow again within 6 to 12 months; no further treatment has demonstrated improved survival

Ependymoma

Overview

Rare, slow- or fast-growing (depends on Grade) primary CNS tumor that forms in ependymal cells that line the ventricles of the brain and the center of the spinal cord; may spread throughout the CNS but spread outside of the CNS is rare; all can recur but often patients are tumor-free for years before testing shows new tumor growth, either at the same location as the first tumor or somewhere else within the CNS

Incidence

3rd most common pediatric brain tumor; most common type of primary spinal cord tumor; most often occurs in brain; 250 children diagnosed each year in U.S.

Quality of Life

Symptoms depend on tumor location and size; causes irritability, sleeplessness, vomiting, nausea, back pain, arm/leg weakness, and headaches

Survival

5-year rate depends on tumor grade and on how much of the tumor can be removed

  • Grade II, 71% vs. Grade III (anaplastic), 57%
  • Total resection, 75% vs. subtotal resection, 54%
Current Treatments

Treatment is a combination of surgery, radiation therapy, and/or chemotherapy

  • First step is to surgically remove the tumor
  • Second step is to administer radiation therapy, particularly in older children, even if the tumor was completely removed; patients receiving radiation therapy may not be able to receive additional radiation
  • The role of chemotherapy is unclear, but may be used for recurrent tumors following radiation therapy or to delay radiation in infants and very young children

High-Grade Glioma

Overview

Rare, fast-growing CNS tumor that forms in glial cells of the brain and spinal cord; can be found almost anywhere within the CNS, but are most commonly within the supratentorium in children ages 15-19; HGG found in children are different from those in adults

Incidence

360-400 new cases per year in North America

Quality of Life

Symptoms depend on tumor location; causes headaches, seizures, and difficulty achieving developmental milestones

Survival

Prognosis is generally poor, <20% at 5 years, but some children can be cured

Current Treatments
  • Spreads quickly through brain tissue, making them difficult to treat; classified by location and microscopic evaluation (grade III anaplastic astrocytoma and grade IV glioblastoma), which helps determine disease progression & best potential treatments
  • The standard of care accepted by most experts is to attempt a complete surgical resection followed by a combination of focal radiotherapy and chemotherapy in children >3 years of age. If tumor recurrence follows chemotherapy and radiation, special experimental treatments may be considered

DEVELOPMENT RATIONALE

“The ReSPECT trial (for recurrent glioblastoma) demonstrates how 186RNL can deliver a very high dose of radiation directly to adult brain tumors safely, effectively and conveniently.  Children with brain tumors have limited options and 186RNL delivered with a minimally invasive procedure could be an important new potential option for these patients.”

 

Michael G. DeCuypere, MD, PhD, FAANS

Northwestern University Feinberg School of Medicine

Presenter at the 2021 AANS Annual Scientific Meeting

“We are eager to explore the use of 186RNL in children with pediatric brain tumors of various types.  Dr. DeCuypere and the team at Lurie Children’s Hospital in Chicago have been great academic partners and are uniquely positioned to bring 186RNL forward rapidly to treat these tough problems in children.”

Marc H. Hedrick, MD

President and Chief Executive Officer of Plus Therapeutics

ReSPECT™-PBC CLINICAL TRIAL

NOT YET RECRUITING

In August 2021, PLUS THERAPEUTICS presented plans for a proposed two-part, Phase 1 dose-finding study to be followed by an expansion cohort to explore the efficacy of 186RNL in pediatric patients with brain tumors.

Part one of the trial will enroll up to 18 subjects to determine the maximum feasible dose of 186RNL administered by CED with the tumor diameter limited to four centimeters and a volume of 34 milliliters. While Part two of the study will independently evaluate 186RNL in up to 39 patients across 3 different cohorts based on their specific disease diagnosis.

The primary endpoint of the study will be the overall response rate, and the secondary endpoints will include progression free survival-24 and overall survival-24 or progression free survival-12 and overall survival-12 in cohort A and cohorts B and C, respectively. Patient enrollment for this study is expected to begin by mid 2022.

Visit ReSPECT-Trials.com to learn more.

The U.S. Food and Drug Administration (FDA) has not approved 186RNL for this specific disease.  This clinical trial plan is subject to change pending FDA IND approval.

REGULATORY STATUS

In the second quarter of 2021, the Company received a positive response to the 186RNL pre-IND (Investigational New Drug) meeting briefing package that it submitted in the first quarter of 2021 to the U.S. FDA for the treatment of pediatric brain cancer (PBC).  Briefly, the FDA provided constructive feedback on the study synopsis that should be helpful as a full protocol is developed and confirmed that no additional GLP toxicology studies are required to support initiation of a pediatric clinical trial.

The Company intends to submit an IND application to the U.S. FDA and, upon approval, begin a ReSPECT™-PBC Phase 1 clinical trial of 186RNL for the treatment of PBC in 2022.