A Study of APO866 for the Treatment of Cutaneous T-cell Lymphoma - Full Text View

Sponsor:	TopoTarget A/S
Information provided by:	TopoTarget A/S
ClinicalTrials.gov Identifier:	NCT00431912

Purpose

This phase II study is designed to determine the efficacy and safety of APO866 for the treatment of patients with advanced forms of cutaneous T-cell lymphoma (CTCL). APO866 has shown to induce growth inhibition in cultures of human CTCL cells as well as in animal models with subcutaneously implanted human CTCL tumors. APO866 was considered to be safe and well-tolerated in a phase I study that treated 24 patients with advanced cancer. APO866 is administered by intravenous infusion continuously for 96 hours and that is repeated every 4 weeks. Patients will receive 3 cycles of treatment and the primary efficacy endpoint will be assessed at Week 16. patients will be followed up for 12 months

Condition	Intervention	Phase
Cutaneous T-cell Lymphoma	Drug: APO866	Phase 2

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Multicenter Open Label Phase II Study of to Assess the Efficacy and Safety of APO866 in the Treatment of Patients With Refractory or Relapsed Cutaneous T-cell Lymphoma

Resource links provided by NLM:

MedlinePlus related topics: Cancer Lymphoma

U.S. FDA Resources

Further study details as provided by TopoTarget A/S:

Primary Outcome Measures:

The proportion of eligible patients with refractory or relapsed CTCL whom have a complete response or partial response on cutaneous lesions (Tumor Burden Index) and extra-cutaneous disease. [ Time Frame: Week 16 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Safety and tolerability, time to response, duration of overall response, duration of stable disease and time to treatment failure. [ Time Frame: Week 16 ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	25
Study Start Date:	December 2006
Estimated Study Completion Date:	November 2011
Estimated Primary Completion Date:	September 2011 (Final data collection date for primary outcome measure)

Intervention Details:

APO866 is administered as 0.126 mg/m²/hr for 4 consecutive days (96 hours), every 3 weeks for a total of 3 cycles

Detailed Description:

CTCL is the most frequent occurring cutaneous non-Hodgkin lymphoma characterized by an indolent and protracted course of patches, plaques and tumors. It is highly symptomatic, debilitating, disfiguring and impacting on the patient's quality of life. The treatment strategy for CTCL is based on the exact diagnosis including the stage of disease and aims to preserve cellular immune function, while achieving an anti-tumor effect. Given the nature of the disease and the cumulative and additive toxicities of treatments used, the intensity and duration of long-term therapy is limited.

APO866 is novel drug that induces cell death by specifically inhibiting the biosynthesis of NAD+ from niacinamide, which is essential for the cellular metabolism, protein modification (e.g. PARP mediated DNA repair, sirtuins (histone deacetylation)) and Calcium dependent messenger synthesis. APO866 is not subject to the commonly known mechanisms of MDR. Its activity is cell cycle independent. APO866 exerted high anti-tumor activity on a broad range of different tumor cells derived from both human solid cancers and leukemias in vitro and on large number of human xenografts in nude mice and rats in vivo. Hematologic cancer cells were highly sensitive to APO866. Lymphocytes are the most sensitive normal cells to APO866 resulting to lymphocytopenia and reticulocytopenia in rats, monkeys and cancer patients. Furthermore, APO866 may have anti-angiogenic properties as shown in vivo and in patients.

APO866 has shown to induce, at low nM level, growth inhibition of human Myla CTCL cells as well as in human subcutaneous xenografts of Myla CTCL in Balb-C nude mice.

APO866 was investigated in 24 patients with advanced cancers in a phase I study aiming to determine the DLT and MTD. Treatment was well tolerated and safe. The unique DLT was thrombocytopenia. At dose levels higher than 0.036 mg/m2/hr CTC grade III lymphocytopenia, thought not be clinically relevant, preceded all other toxicities. The recommended dose for phase II studies of APO866 is 0.126 mg/m2/hr administered by civ infusion for 4 consecutive days (MTD). This dose was selected because of its safety profile, and the translational observation that Css of APO866 at MTD was similar or higher as compared to the concentrations at which efficacy was established in vitro and in vivo.

No objective tumor response was observed. However, 4 patients had stable disease for at least 3 months: prostate cancer (4 months), melanoma (5 months), sarcomatoid mesothelioma (3 months) and oropharyngeal cancer (5 months). In addition, lesion size reductions were observed in the melanoma patient (80% size reduction and stable size of other lesions) at an APO866 dose level of 0.072 mg/m2/hr, and in the mesothelioma patient (moderate size reductions of pleural lesions) at 0.108 mg/m2/hr.

Treatment with APO866 was safe and well tolerated. The anti-tumor effect of APO866, in particular on hematological cancer cells in vitro and ex vivo, and its lymphocytopenic effect in patients support the rationale to conduct an open phase II study of APO866 in patients with refractory or relapsed CTCL qualifying for systemic chemotherapy

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Histologically confirmed diagnosis of CTCL including mycosis fungoides and Sézary syndrome
Stage Ib to IVb disease (AJCC TNM staging, see Appendix B)
Relapsed or refractory disease or intolerant to ≥ 2 prior systemic therapy. PUVA, topical nitrogen mustard, spot or total skin electron beam therapy or other radiotherapy, oral retinoids, immunotherapy (e.g. interferon-α, denileukin difitox, alemtuzumab) or mono- or poly-chemotherapy regimen will be considered systemic therapy.
ECOG Performance Status < 2 (see Appendix C)
Age > 18 years, of either sex
Female patients with childbearing potential must be using a hormonal contraceptive, intra uterine device, diaphragm with spermicide or condom with spermicide for the duration of the study. Women of childbearing potential must have a negative serum or urinary hCG pregnancy test
Male patients, who are not surgically sterile, must use a condom with spermicide for the duration of the study
Have given written informed consent, prior to any study related procedure not part of the patient's normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.

Exclusion Criteria:

Have participated in any other investigational study or received an experimental therapeutic procedure considered to interfere with the study in the 2 months preceding SD1
Have had PUVA, topical nitrogen mustard, spot or total skin electron beam therapy, oral retinoids, or any, immunotherapy (e.g. interferon-α, denileukin difitox, alemtuzumab) or chemotherapy regimen within 2 weeks of SD1. Patients must have recovered from all acute toxicities.
Evidence of CNS lymphoma
Use of prohibited medication due to CYP3A4 metabolism of APO866, as specified in Section 6.6.2. concomitant use of these drugs will not be allowed during the study.
Uncontrolled medical conditions, requiring surgical or pharmacological treatment (exceptions must be approved by the Study Director).
Serious concomitant disease (e.g. significant cardiac disease) are not eligible
Primary or acquired thrombocytopenia
Inadequate bone marrow reserve: WBC < 3.5x10^9/L, neutrophils < 1.0x10^9/L, thrombocytes < 100x10^9/L, Hb < 8.5 g/dL or coagulation abnormalities
Inadequate liver function: total bilirubin > 1.5 x upper limit of normal values (ULN), AST, ALT, or alkaline phosphatase > 2.5 x ULN
Have inadequate renal function, defined by serum creatinine > 250 μmol/L
Retinopathy, history of retinal laser surgery, or an ERG < 50% of normal

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00431912

Contacts

Contact: Nis Nissen, MD

+45 39178392

clinicaltrial@topotarget.com

Locations

Austria
Department of Dermatology, Medical University Graz	Recruiting
Graz, Austria, 8036
Contact: Regina Fink-Puches, MD +43 316 385 80428 regina.fink@meduni-graz.at
Principal Investigator: Regina Fink-Puches, MD
Sub-Investigator: Ingrid Wolf, Associate Prof, MD
France
Deapartment of Dermatology	Recruiting
Créteil, France, 94010
Contact: Olivier Chosidow, MD +33 1 49812504 olivier.chosidow@hmn.aphp.fr
Principal Investigator: Olivier Chosidow, MD
department of Dermatologie, Hotel Dieu	Recruiting
Nantes, France, 44093
Contact: Brigitte Dreno, Prof, MD +33 40 7485515 brigitte.dreno@wanadoo.fr
Principal Investigator: Brigitte Dreno, Prof, MD
Germany
Department of Dermatology, Charité University Hospital Berlin	Not yet recruiting
Berlin, Germany, 10117
Contact: Wolfram Sterry, Prof, MD +49 30 450518061 wolfram.sterry@charite.de
Contact: Chalid Assaf, MD 49 30 450 518063 chalid.assaf@charite.de
Principal Investigator: Chalid Assaf, MD
University Clinic for Dermatology, Medical Faculty of Mannheim of the Heidelberg University	Recruiting
Mannheim, Germany, 68167
Contact: Dirk Schadendorf, Prof, MD +49 621 3833918 dirk.schadendorf@haut.ma.uni-heidelberg.de
Contact: Claus-Detlev Klemke, MD +49 621 3833918 claus-detlev.klemke@haut.ma.uni-heidelberg.de
Principal Investigator: Dirk Schadendorf, Prof, MD
Principal Investigator: Claus-Detlev Klemke, MD
Switzerland
Department of Dermatology, University Hospital of Zürich	Recruiting
Zürich, Switzerland, 8091
Contact: Reinhard Dummer, Prof, MD PhD +41 44 2552507 reinhard.dummer@usz.ch
Sub-Investigator: Sharon Gobbi, MD
Principal Investigator: Reinhard Dummer, Prof, MD PhD

Sponsors and Collaborators

TopoTarget A/S

Investigators

Principal Investigator:	Reinhard Dummer, MD PhD	Department of Dermatology, University Hospital of Zürich, Gloriastrasse 31, 8091 Zürich, Switzerland
Study Director:	René Goedkoop, MD	Apoxis SA, 18-20 Avenue de Sévelin, 1004 Lausanne, Switzerland

More Information

No publications provided

Responsible Party:	Lars Damstrup, MD, PhD/Medical Director, TopoTarget A/S
ClinicalTrials.gov Identifier:	NCT00431912 History of Changes
Other Study ID Numbers:	AP3001
Study First Received:	February 5, 2007
Last Updated:	June 15, 2011
Health Authority:	Germany: Federal Institute for Drugs and Medical Devices France: Afssaps - French Health Products Safety Agency Switzerland: Swissmedic Austria: Agency for Health and Food Safety

Keywords provided by TopoTarget A/S:

cutaneous T-cell lymphoma
mycosis fungoides
Sézary syndrome
APO866
phase II study

Additional relevant MeSH terms:

Lymphoma
Lymphoma, T-Cell
Lymphoma, T-Cell, Cutaneous
Neoplasms by Histologic Type
Neoplasms

Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin

ClinicalTrials.gov processed this record on May 22, 2012