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Goldinger SM, Gobbi Bischof S, Fink-Puches R, et al. Efficacy and Safety of APO866 in Patients With Refractory or Relapsed Cutaneous T-Cell Lymphoma: A Phase 2 Clinical Trial. JAMA Dermatol. 2016;152(7):837–839. doi:10.1001/jamadermatol.2016.0401
For cutaneous T-cell lymphoma (CTCL),1 there is need for new treatment options. APO866 is an injectable molecule that induces cell death by inhibiting the biosynthesis of NAD+ (oxidized nicotinamide adenine dinucleotide), which is essential for cell survival.2-4 Previous studies have shown in vitro and in vivo that lymphocytes and hematologic cancer cells are very sensitive to APO866, which induced cell death at low concentration in various human tumor cells, including lymphomas.5
This open-label, single-arm, multicenter, phase 2 clinical trial took place from February 2007 to January 2011. We analyzed the efficacy (measured by objective response rates using the Tumor Burden Index [TBI]6 for cutaneous disease and imaging for extracutaneous disease), safety, and tolerability (using descriptive statistics) of APO866 in relapsed or refractory CTCL. APO866 (provided by Apoxis SA and later by Topotarget A/S) was administered every 28 days for a total of 3 cycles by continuous intravenous infusion via pump at 0.126 mg/m2/h over the course of 96 hours. The study was approved by the respective national and regional ethics committees and conducted according Good Clinical Practice guidelines (NCT00431912), and all participants provided their written informed consent.
All the patients had a histologically confirmed diagnosis of CTCL, including mycosis fungoides and Sézary syndrome,1 ranging from stage IB to stage IVB disease according to TNM staging and had relapsed or refractory disease or were intolerant to 2 or more prior systemic therapies.
The primary efficacy end point was defined as the proportion of patients who achieved complete response (CR) or partial response (PR, defined as ≥50% TBI reduction from baseline) assessed at week 16.6 The statistical design of the trial was an extension of the Simon optimal design and based on a trinomial model. The study was conducted according to the optimal 2-stage design with trilevel end points (CR + PR, stable disease [SD], and progressive disease [PD]). A prespecified efficacy evaluation was planned after recruitment of the first 11 patients. In case of the presence of 2 or more responders (PR or CR), the study would continue up to the recruitment of a total of 25 patients. These calculations assumed type I and type II error rates of 10%. We report the results of the prespecified efficacy analysis after the recruitment of the first 14 patients.
Fourteen patients, 7 women and 7 men (age range, 19-83 years), were enrolled in the study and were part of the intention-to-treat analysis. One patient was classified as having stage IB CTCL; 2 and 3 patients were classified as having stage IIA and IIB disease, respectively; and 8 patients had stage IVA CTCL (Table 1). Five patients were considered treated per protocol (PP) (n = 5). The PP population included all patients who completed all 3 treatment cycles and had no major protocol violations. Nine of the 14 patients terminated the trial before completion of the 3 treatment cycles and were excluded from the PP analysis owing to consent withdrawal (n = 2), early disease progression (n = 5), or development of adverse events (AEs) (n = 2). There was no major protocol violation.
The overall response to therapy including cutaneous and extracutaneous disease is summarized in Table 2. At week 16, 1 patient (1 of 12) had achieved PR; 6 of 12 had SD; and 5 of 12 had PD. No participant achieved CR. In the PP-treated group, 1 of 5 had PR, and 4 of 5 had SD. A total of 141 AEs were reported, of which 77 were judged to be drug related. Most patients (86%; n = 12) experienced mild to moderate AEs. In general, AEs affected rapidly regenerative tissues such as blood cells and gastrointestinal tissue. Hematologic changes included anemia, thrombocytopenia, and lymphopenia. A total of 18 serious AEs occurred, 7 of which were judged to be drug related. These included pyrexia, lymphopenia (n = 2), spondylitis, staphylococcal sepsis, rhabdomyolysis, and thrombocytopenia. Four deaths were reported but not considered study-drug related.
In previous studies, APO866 induced cell death at low concentration in human hematologic malignancy cells, including lymphomas.5 No resistance mechanisms are known. In the present study, APO866 showed a reasonable toxic effect in CTCL. Severe lymphocytopenia and thrombocytopenia were observed, and the other AEs were mild to moderate. However, the drug was not powerful enough, and the study was stopped early after the prespecified interim analysis owing to lack of drug efficacy. For these reasons, we do not see a justification for further development of APO866 in CTCL. However, owing to its mode of action with immunosuppression and insulin-mimicking effects, APO866 might play a role the treatment of other conditions.
Accepted for Publication: February 5, 2016.
Corresponding Author: Reinhard Dummer, MD, Department of Dermatology, University Hospital of Zurich, Gloriastrasse 31, 8091 Zurich, Switzerland (firstname.lastname@example.org).
Published Online: March 23, 2016. doi:10.1001/jamadermatol.2016.0401.
Author Contributions: Dr Dummer had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Goldinger and Gobbi Bischof contributed equally to this work.
Study concept and design: GobbiBischof, Dréno, Dummer.
Acquisition, analysis, or interpretation of data: Goldinger, GobbiBischof, Fink-Puches, Klemke, Bagot, Dummer.
Drafting of the manuscript: Goldinger, GobbiBischof, Dummer.
Critical revision of the manuscript for important intellectual content: Goldinger, Gobbi Bischof, Fink-Puches, Klemke, Dréno, Bagot, Dummer.
Statistical analysis: Dummer.
Administrative, technical, or material support: Gobbi Bischof, Fink-Puches, Dummer.
Study supervision: Goldinger, Dréno, Dummer.
Conflict of Interest Disclosures: Dr Goldinger has received research funding from the University Hospital of Zurich and consultancy and travel support from Merck Sharp & Dohme (MSD), Bristol-Myers Squibb, Novartis, and Roche. Dr Klemke has received travel support for scientific conferences and lecture fees for scientific presentations from TEVA/Cephalon Pharma GmbH and Therakos, Johnson & Johnson Medical GmbH. He is a member of the TEVA Cutaneous Lymphoma Advisory Board. Dr Dréno has no personal conflicts to declare, but her institution receives financial support through Association pour le Developpement et la Recherche en Biotechnologie Cutanee (ADRBC). Dr Dummer receives research funding from Novartis, MSD, Bristol-Myers Squibb, Roche, and GlaxoSmithKline and has a consultant or advisory board relationship with Novartis, MSD, Roche, Bristol-Myers Squibb, GlaxoSmithKline, and Amgen. No other disclosures are reported.
Funding/Support: This study was sponsored by Apoxis SA and later by Topotarget A/S. In July 2014, Topotarget A/S merged with BioAlliance Pharma SA to form Onxeo, the named sponsor of this study at clinicaltrials.gov. The merger occurred after this trial was completed. For more information, see http://www.onxeo.com/en/les-actionnaires-de-bioalliance-pharma-topotarget-approuvent-la-fusion-transfrontaliere-pour-creer-onxeo/.
Role of the Funder/Sponsor: Apoxis played a role in the design and conduct of the study; Topotarget played a role in the collection, management, analysis, and interpretation of the data; no funder had any role in , review, or approval of the manuscript and decision to submit the manuscript for publication.
Additional Contributions: We would like to thank Lars E. French, MD (Zurich, Switzerland), Antonio Cozzio, MD (Zurich, Switzerland), Huilin Ding, MD (Zurich, Switzerland), and Chalid Assaf, MD (Krefeld, Germany), for critical revision of the manuscript. In addition, Topotarget A/S performed statistical analysis for this study. No contributor received compensation for their contributions.