Aclarubicin for the Treatment of Retinal Vasculopathy With Cerebral Leukodystrophy

NCT02723448 | Completed Phase 1

• 1 other identifier: ATK2016001
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of the investigator is to utilize Aclarubicin to treat patients with Retinal Vasculopathy with Cerebral Leukodystrophy (RVCL), a rare and devastating genetic disease with no available specific treatment. RVCL results from a mutation in the tail end of the TREX1 (Three Prime Repair Exonuclease 1) gene, a major deoxyribonucleic acid (DNA) repair enzyme. The RVCL-specific mutations cause expression of a truncated and mislocalized protein. RVCL is an inherited disorder whose symptoms begin at middle age and initially predominantly affects the eye and brain. Because it is an 'autosomal dominant' disease, it strikes both males and females equally. A person with RVCL has a 50-50 chance of transmitting the gene to each child. The investigator's published studies demonstrated in a mouse model for RVCL and in vitro studies with patients' cells that defects were corrected by use of Aclarubicin, an anthracycline antibiotic often used to treat cancer. Thus, there is a strong rationale for conducting a clinical trial of aclarubicin in patients with RVCL. The dosage to be initially administered to RVCL patients initially will be \< 10% of that typically used in cancer therapeutics and will be given monthly on four consecutive days for six months. Patients will undergo assessments every six months to determine disease response. Patients that do not have clear objective response may be dose escalated by 1 dose level with permission of the principal investigator permitting the patient has not previously experienced any toxicities requiring dose modifications. We will evaluate the safety and clinical efficacy of Aclarubicin for the treatment of RVCL and evaluate its effects on cellular function. This work will generate the first clinical research data on the investigational product's utility in treating RVCL. Patients are followed for at least 2 years upon completion of Aclarubicin administration completion. We are not longer administering the drug, but are in the post-drug follow up arm of the study.

Conditions

Vasculopathy, Retinal, With Cerebral Leukodystrophy; Cerebroretinal Vasculopathy, Hereditary

Outcome Measures

Primary Outcomes (1)

• Change in Lesion Pattern on Fluid-Attenuated Inversion Recovery (FLAIR) Magnetic Resonance Imaging (MRI) in Retinal Vasculopathy Cerebral Leukodystrophy (RVCL) patients

  Volume increase in lesions on FLAIR MRI between baseline and six months is assessed

  Change from baseline at six months

Study Arms (1)

Single Arm Study

OTHER

Aclarubicin (6 mg/m²) will be administered intravenously through a central venous access device over 1 hour for four consecutive days (Days 2-5) of each 28 day cycle to each participant \[Retinal Vasculopathy with Cerebral Leukodystrophy (RVCL) patients\]. There is no maximum number of cycles.

Drug: aclarubicin

Interventions

aclarubicin DRUG

Aclarubicin (3 mg/m²) will be administered intravenously through a central venous access device over 1 hour for four consecutive days per 28 day cycle. There is no maximum number of cycles.

Also known as: aclacinomycin-A (HCl)

Single Arm Study

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• A diagnosis of Retinal Vasculopathy with Cerebral Leukodystrophy (RVCL)
• At least 18 years of age at the time of study registration
• Normal hematologic function defined as: WBC (white blood cell count) \> 4 x10⁹/L, ANC (absolute neutrophil count) ( \>1.5 x 10⁹/L and Platelets \> 100 x10⁹/L
• Females of childbearing potential (FCBP) must agree to refrain from becoming pregnant while on study drug and for 3 months after discontinuation from study drug, and must agree to use adequate contraception including hormonal contraception, (i.e. birth control pills, etc), barrier method contraception (i.e. condoms), or abstinence during that time frame.
• Able to understand and willing to sign an IRB (Institutional Review Board) approved written informed consent document (or that of legally authorized representative, if applicable)

You may not qualify if:

• Acute bacterial, fungal, or viral infection
• Known human immunodeficiency virus (HIV) or active hepatitis B or C virus infection
• Pregnant and/or breastfeeding
• Cardiovascular disease including: congestive heart failure \[left ventricular ejection fraction (LVEF) \< 55%\] at screening; electrocardiogram (EKG) evidence of acute ischemia or medically significant conduction system abnormalities; or unstable arrhythmia or angina
• Cumulative prior anthracycline dose of 300 mg/m²
• Known hypersensitivity to one or more of the study agents
• Currently receiving or has received any investigational drugs within the 14 days prior to the first dose of study drug
• Currently receiving or has received any immunosuppressants within the 14 days prior to the first dose of study drug

Sponsors & Collaborators

• Washington University School of Medicine: lead

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Publications (6)

• Hasan M, Fermaintt CS, Gao N, Sakai T, Miyazaki T, Jiang S, Li QZ, Atkinson JP, Morse HC 3rd, Lehrman MA, Yan N. Cytosolic Nuclease TREX1 Regulates Oligosaccharyltransferase Activity Independent of Nuclease Activity to Suppress Immune Activation. Immunity. 2015 Sep 15;43(3):463-74. doi: 10.1016/j.immuni.2015.07.022. Epub 2015 Aug 25.

  PMID: 26320659 BACKGROUND

• Kavanagh D, Spitzer D, Kothari PH, Shaikh A, Liszewski MK, Richards A, Atkinson JP. New roles for the major human 3'-5' exonuclease TREX1 in human disease. Cell Cycle. 2008 Jun 15;7(12):1718-25. doi: 10.4161/cc.7.12.6162. Epub 2008 Jun 16.

  PMID: 18583934 BACKGROUND

• Karanes C, Young JD, Samson MK, Smith LB, Franco LA, Baker LH. Phase I trial of aclacinomycin-A. A clinical and pharmacokinetic study. Invest New Drugs. 1983;1(2):173-9. doi: 10.1007/BF00172077.

  PMID: 6590531 BACKGROUND

• Kerpel-Fronius S, Gyergyay F, Hindy I, Decker A, Sawinsky I, Faller K, Mechl Z, Nekulova M, Kolaric K, Tomek R, et al. Phase I-II trial of aclacinomycin A given in a four-consecutive-day schedule to patients with solid tumours. A South-East European Oncology Group (SEEOG) Study. Oncology. 1987;44(3):159-63. doi: 10.1159/000226469.

  PMID: 3474571 BACKGROUND

• Case DC Jr, Ervin TJ, Boyd MA, Bove LG, Sonneborn HL, Paul SD. Phase II study of aclarubicin in acute myeloblastic leukemia. Am J Clin Oncol. 1987 Dec;10(6):523-6. doi: 10.1097/00000421-198712000-00014.

  PMID: 3479891 BACKGROUND

• Stam AH, Kothari PH, Shaikh A, Gschwendter A, Jen JC, Hodgkinson S, Hardy TA, Hayes M, Kempster PA, Kotschet KE, Bajema IM, van Duinen SG, Maat-Schieman MLC, de Jong PTVM, de Smet MD, de Wolff-Rouendaal D, Dijkman G, Pelzer N, Kolar GR, Schmidt RE, Lacey J, Joseph D, Fintak DR, Grand MG, Brunt EM, Liapis H, Hajj-Ali RA, Kruit MC, van Buchem MA, Dichgans M, Frants RR, van den Maagdenberg AMJM, Haan J, Baloh RW, Atkinson JP, Terwindt GM, Ferrari MD. Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations. Brain. 2016 Nov 1;139(11):2909-2922. doi: 10.1093/brain/aww217.

  PMID: 27604306 BACKGROUND

MeSH Terms

Conditions

Vasculopathy, Retinal, With Cerebral Leukodystrophy

Interventions

Aclarubicin

Intervention Hierarchy (Ancestors)

Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates

Study Officials

• John P Atkinson, MD

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Study Record Dates

• First Submitted: March 2, 2016
• First Posted: March 30, 2016
• Study Start: December 5, 2016
• Primary Completion: July 23, 2020
• Study Completion: July 23, 2020
• Last Updated: November 19, 2020

Record last verified: 2020-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: The data is currently being shared among the principal investigator and the subinvestigators
• Access Criteria: IPD is available on REDCap or as provided by principal investigator

Locations

US (1)