A Study to Assess APO866 for the Treatment of Advanced Melanoma
This phase II study is designed to determine the efficacy and safety of APO866 for the treatment of patients with advanced cutaneous melanoma. APO866 has shown to induce growth inhibition in cultures of human melanoma cells as well as in animal models with subcutaneously implanted melanoma tumors. APO866 was considered to be safe and well tolerated in a phase I study that treated 24 patients with advanced cancer. In that study one of the two patients with advanced melanoma had a stable disease for 5 months with size reduction of some lesions. APO866 is administered by intravenous infusion continuously for 96 hours 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 follow-up for 12 months.
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||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.|
- 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. [ Time Frame: Week 16 ] [ Designated as safety issue: Yes ]
- Safety and tolerability [ Time Frame: Week 16 and 12 months follow-up ] [ Designated as safety issue: Yes ]
- Time to response [ Time Frame: Week 16 ] [ Designated as safety issue: Yes ]
- Duration of response [ Time Frame: Week 16 ] [ Designated as safety issue: Yes ]
- Progression free survival [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
- Overall survival [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
- Evolution of serum VEGF and IL-8 during treatment [ Time Frame: Week 16 ] [ Designated as safety issue: Yes ]
|Study Start Date:||July 2006|
|Study Completion Date:||March 2009|
|Primary Completion Date:||February 2008 (Final data collection date for primary outcome measure)|
|Experimental: 2-stage mono therapy||
APO866 is administered as 0.126 mg/m²/hr IV every 4 weeks for 4 consecutive days (96 hours) for a total of 3 cycles
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.
|Department of Dermatology, Medical University Graz|
|Graz, Austria, 8036|
|Department of Dermatology, Hopital Henri Modor|
|Créteil, France, 94010|
|Department of Dermatologie, Hotel Dieu|
|Nantes, France, 44093|
|Department of Dermatology, Charité University Hospital Berlin|
|Berlin, Germany, 10117|
|University Clinic for Dermatology, Medical Faculty of Mannheim of the Heidelberg University|
|Mannheim, Germany, 68167|
|Department of Dermatology, University Hospital of Zürich|
|Zürich, Switzerland, 8091|
|Principal Investigator:||Uwe Trefzer, MD PhD||Department of Dermatology, Charité University Hospital, Schumannstrasse 20-21, 10117 Berlin, Germany|