A Phase II: Safety and Tolerance of 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) in Adolescent and Young Adults (AYA) With Malignancies Involving the CNS

The primary goal of this Phase II AYA oncology clinical trial was to evaluate the safety and efficacy of 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN), as anticancer therapy in AYA individuals with advanced cancer involving the central or spinal nervous system (CNS & SNS). 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 adolescent, young adult and adult Phase I/II clinical trials - IND - 68,876. The FDA has supported the Phase II clinical trial designed to identify safety and efficacy in AYA cancers subjects and the trial has been completed with acceptable toxicity and MTDs identified. Almost 700,000 people in the US are living with tumors involving the CNS or spinal nervous system (SNS) tumors. Nearly 15% of these tumors involve the adolescent/young adult (AYA) population, aged 15-39 years of age. 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. 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 re-occurrence from cancer involving the CNS after years of remission; the most common types of cancer in AYA individuals are - melanoma, leukemia and sarcomas. This group of individuals deserves special attention. 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. The effective transport of DM-CHOC-PEN into CNS tumors in adults without neurotic 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 may also occur in medulloblastoma in AYA. 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 were to: Conduct a Phase II clinical trial with DM-CHOC-PEN in AYA individuals that have advanced cancers with central or spinal nervous systems involvements and monitor safety and document anticancer activity for the drug. All data was between investigators communicated through an e-RAP program. This was accomplished through IND - 68.876. AYA patients will be administered DM-CH-CHOC-PEN per dose as above every 21 days until toxicity or failure. Verify the pharmacokinetic/dynamic profiles of DM-CHOC-PEN and metabolites in AYA subjects with advanced cancers involving the central nervous system. Analyze data and prepare an Orphan Drug Designated package for FDA submission for AYA subjects with CNS involvement from cancer for review. Research Accomplishments for 5 R44 CA203351-05 The present R44 SBIR grant was awarded 09/24/2019 to support a Phase II clinical trial evaluation of 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) as anticancer therapy for adolescents and young adults (AYA) (15-39 y/o) with malignancies involving the central nervous system (CNS) (brain and spine) through FDA IND 68,876. An Extension was initiated 09-01-20, however, the COV-19 crisis was in progress at that time and patient enrollment was limited. Trial is now completed. The trial has enrolled/treated 19-AYA individuals with cancers involving the CNS to date. Three (3) AYA patients are still alive at the present time with diagnoses of breast cancer, astrocytoma, or lung cancer involving the CNS and are experiencing good qualities of life at 12, 59 and 96+ mos., resp. after initiating DM-CHOC-PEN. All patients have been followed with lab tests, scans and virtual exams. Now that the centers are no longer virtually managing patients, we may restart the hands-on trial. The FDA is pleased with the results and we have been encouraged to develop a Phase III or Orphan Drug study. To date the results are as follows: The FDA reviewed (Dec. 2020) the Phase II clinical trial with DM-CHOC-PEN as treatment for AYA subjects with malignancies involving the CNS [IND 68,876]. Arivis Inc. Phoenix, AZ, monitors the e-CTD data conversion and monitors/reviews all communications with the FDA. 1) The Western Investigational Research Board (WIRB) monitored the protocol and served as the central IRB. Most trial centers also use their own FDA approved IRBs. Clinical Centers Involved are: Tulane University Medical Center, NOLA; Ochsner Med Center, NOLA; Detroit Clin Res & Mich Res Center - Lansing, Grosse Pointe, Owosso & Detroit, MI; SUNY, NY & Roswell Park, NY and, MCMRC, Dallas, TX. Dr. R.S. Weiner (Ret) - Clinical Onc, Tulane University Medical Center, will be a consultant. Presbyterian Medical Center, NY, NY is reviewing the protocol and consent. Service Initiation Visits (SIVs) have been conducted at all of the above. ClinicalTrials.gov - NCT03668847. 2) The dosing for DM-CHOC-PEN (established from Phase I studies) was 75 mg/m2 for subjects with liver disease and 98.7 mg/m2 for subjects with no liver disease. Tumor responses were monitored with imaging and examinations per RECIST guidelines. Toxicity and PK profiling were conducted as part of laboratory monitoring; no toxicity issues to date. 3) An e-RAP electronic recording network system to enroll and monitor subjects was established between DEKK-TEC and the trial sites. 4) A support team is now available at DEKK-TEC - Lee Roy Morgan, MD, PhD, Andrew Rodgers, PhD, chemist; Jeanne Robinson, PhD, psychologist; Rob Courtney, MD, minister; Meredith Morgan, MS, Clin Dietician. 5) A blog has been established and provides AYA individuals and families with cancer the opportunity to review literature and discuss issues with DEKK-TEC's healthcare support team - https://dti-aya.com. [Directed by Eric K. Morgan, MBA through BigTuna Web Sites, Inc.]. The blog is being up-graded to reflect the survival to date. 6) The WHO approved the non-proprietary name for DM-CHOC-PEN - Mipicoledine (#11,547), 2020. 7) Tumor tissue banking collaboration has been established and remains active between all centers and DEKK-TEC. OVERALL PROGRESS - the goal of the healthcare platform team at DEKK-TEC will continue to be making DM-CHOC-PEN available as cancer therapy for other groups interested in developing trials and assist with the 'desire/determination to survive attitude' toward overcoming negative responses, unfavorable reactions and poor progress from malignancies involving the CNS - via the blog https://dti-aya.com or through personnel contact with team members. The data is being up-graded to reflect the survival of AYA subjects with brain tumors. The response and toxicity data for DM-CHOC-PEN has been published and presented - Morgan, Weiner, Ware, Bhandari Mahmood & Friedlander, AACR, 2020; recently in Global Health Care, 2021 and submitted to NCI. EORTC, 21. DEKK-TEC is discussing developing new trials with the FDA. To date the following individuals have been treated: breast - 4; glioma - 1; melanoma - 2; gastric - 1; ALL - 2; astrocytoma - 1; lung cancer - 1; & H&N - 1. Th lung cancer, astrocytoma, and breast cancer patient did the best with long term survival.