A Multi-centre, Two-stage, Open Label Phase II Study to Assess the Efficacy and Safety of APO866 in the Treatment of Patients With Advanced Melanoma.
Advanced melanoma is one of the most chemo-resistant types of human cancers. The incidence
increases by about 2.5% on an annual basis, with may partially be related to aging and
growth of the population, as well as other environmental risk factors. Virtually no recent
progress has been made in the treatment of patients with this disease. In the past 30 years,
the FDA has approved only 2 agents, dacarbazine and interleukin-2, on the basis of overall
response and response duration, respectively. However, these outcomes were not accompanied
by a survival benefit. The most recent randomized study of DTIC yielded an overall response
rate of 7%, and to date, no other treatments, including combination therapies, have shown to
improve survival when compared to DTIC alone. Hence, the mainstay of treatment for patients
with advanced melanoma is DTIC-based therapy.
APO866 is a novel drug that induces cell death by specifically inhibiting the biosynthesis
of NAD+ from niacinamide, which is essential for the cellular metabolism, protein
modification and 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 a large number of human xenografts in nude mice, including melanoma, and rats
in vivo. Hematologic cancer cells were highly sensitive to APO866. Lymphocytes are the most
sensitive normal cells to APO866 resulting in lymphocytopenia and reticulocytopenia in rats,
monkeys. Furthermore, APO866 may have anti-angiogenic properties as shown in vivo.
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,
not thought to 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 evry 4 weeks. 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. In addition, a
transient decrease of serum VEGF levels, a surrogate marker of angiogenesis, was observed
within 96 hrs after the start of treatment in 9 out of 11 patients treated at MTD and the
0.144 mg/m2/hr dose level of APO866.
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 melanoma cells in vitro and in vivo, and its anti-angiogenic propriety support
the rationale to conduct a open phase II study of APO866 in patients with advanced melanoma.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To determine the tumor response rate (according RECIST criteria) as the proportion of eligible patients with stage IV cutaneous melanoma or stage III not amenable to surgery.
Uwe Trefzer, MD PhD
Department of Dermatology, Charité University Hospital, Schumannstrasse 20-21, 10117 Berlin, Germany
Germany: Federal Institute for Drugs and Medical Devices