A Phase I Trial of DM-CHOC-PEN in Adolescent and Young Adult (AYA) Subjects With Advanced Cancers

The primary goal of this Phase I pediatric oncology clinical trial will be to evaluate the safety and use of 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN), as anticancer therapy for AYA with advanced cancer +/- central nervous system (CNS) involvement.

DM-CHOC-PEN is a polychlorinated pyridine cholesteryloxycarbonate that crosses the blood brain barrier (BBB), accumulates in CNS tumor tissue in humans and has produced objective responses, with acceptable/reversible hepatic toxicities (in patients with prior liver disease) and no evidence of hematological, renal, neuro-toxicities with improved quality of life and overall survival in adult Phase I/II clinical trials - IND - 68,876 (1-6).

The FDA supports the proposed Phase I clinical trial designed to identify safety, toxicities and an acceptable MTD in AYA cancers subjects now that the adult Phase I trial has been completed with acceptable toxicity and MTDs identified (2, 3, 5, 6).

Almost 700,000 people in the US are living with tumors involving the CNS or spinal nervous system (SNS) tumors (6). Nearly 15% of these tumors involve the adolescent/young adult (AYA) population, aged 15-39 years of age (6). It is predicted that 10,617 AYA individuals will be diagnosed with brain or CNS tumors resulting in 434 deaths this year in the US (6). Trends in CNS tumors have sharply increased since 1989 for AYA individuals with a history of cancer, who appeared to have 'beaten the odds', only to have a reoccurrence from cancer involving the CNS after years of remission; the most common types of cancer in AYA individuals are - melanoma, leukemia and sarcomas (7). This group of individuals deserve special care.

For males and female individuals <20 years of age, primary brain and secondary cancers of the CNS and spinal nervous system (SNS) are the most common causes of death from cancer and in the 20-39 year age group the first cause of cancer-related deaths in males and the fifth cause of cancer-related deaths in females. The incidence and histology of cancer types does vary according to subject age ( ).

A critical component in designing an agent that will cross the protective blood brain barrier (BBB) is that the agent must be readily transported intracerebrally, does not produce local irritation/neurotoxicity and is not recycled back into the general circulation. After IV administration DM-CHOC-PEN readily penetrates the BBB, is not a substrate for the transporter protein P-glycoprotein (P-gp) and has shown anticancer activity in CNS tumors (4). The effective transport of DM-CHOC-PEN into CNS tumors in adults without neurotoxic behavioral alterations and associated events supports the drug's use in children with CNS tumors at an age in which brain development and maturation is still very active with cognitive lability. The observed responses noted in adults with metastatic cancers involving the CNS and cerebellum treated with DM-CHOC-PEN (Table 1) may also occur in medulloblastoma in AYA (7, 9). Thus, the drug's unique properties and lack of toxicities noted in the adult studies merits the Phase I trial proposed here in children.

The specific objectives of this Phase I study will be to:

1. Conduct a Phase I clinical trial with DM-CHOC-PEN in AYA that have advanced cancers with +/- the central nervous system to document toxicities, define an acceptable maximum tolerated dose (MTD), and identify anticancer activity for the drug. All data will be communicated through an e-RAP program. This will be accomplished through IND - 68.876.
2. Studying the pharmacokinetic/dynamic profiles of DM-CHOC-PEN and metabolites in AYAs with advanced cancers involving the central nervous system.
3. Analyze data and prepare a Phase II clinical trial in AYA subjects for FDA review.