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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.

Phase 2
18 Years
Not Enrolling

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Trial Information

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.

Inclusion Criteria:

- Histologically confirmed diagnosis of melanoma

- Stage IV disease or stage III not amenable to surgery (AJCC, see Appendix A)

- Measurable disease, defined as at least 1 malignant lesion that could be accurately
and serially measured in at least 1 dimension and for which the greatest diameter is
> or = 10 mm as measured by spiral computed tomography (CT) scan or magnetic
resonance imaging (MRI), or > or = 20 mm with conventional techniques. A caliper can
be used for the measurement of superficial cutaneous metastases which are > or = 10

- Patients must be able to undergo either contrast-enhanced CT-scan or
contrast-enhanced MRI scan for tumor assessment

- Only one previous systemic treatment (excluding prior systemic treatment as
postoperative adjuvant therapy) is allowed and should have been terminated > 4 weeks
before Study Day 1 (SD1).

- Lack of response or progression of disease after the most recent systemic therapy for
advanced melanoma

- Patients must have recovered from the toxicity of any previously used treatment. All
Adverse events of previous systemic treatment must have resolved to < grade I Common
Terminology Criteria for Adverse Events (CTC v3.0, see Appendix)

- ECOG Performance Status < 1 (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 within 7 days prior to Study Day 1 (SD1)

- Male patients, who are not surgically sterile, must use a condom with spermicide for
the duration of the study and 3 months thereafter

- 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 4 weeks preceding

- History of brain metastases or leptomeningeal disease

- Bone-only metastatic disease

- 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.

- Use of biphosphonate drug during the 30 days preceding the APO866 infusion and during
the treatment period will not be allowed

- Uncontrolled medical conditions, requiring surgical or pharmacological treatment
(exceptions must be approved by the Medical Responsible of the study).

- Serious concomitant disease (e.g. significant cardiac disease)

- History of second cancer that was treated with curative intent and in complete
remission for < 5 years, with the exception of basal cell carcinoma or cervical
cancer in situ

- Primary or acquired thrombocytopenia

- Inadequate bone marrow reserve: WBC < 3.5x10^9/L, neutrophils < 1.0x10^9/L,
thrombocytes < 100x10^9/L, Hb < 10.0 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 > 1.5x ULN

- Retinopathy, history of retinal laser surgery, or an ERG < 50% of normal

- Pregnant of lactating female

- Abuse of alcohol or other recreational drugs

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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.

Outcome Time Frame:

Week 16

Safety Issue:


Principal Investigator

Uwe Trefzer, MD PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Department of Dermatology, Charité University Hospital, Schumannstrasse 20-21, 10117 Berlin, Germany


Germany: Federal Institute for Drugs and Medical Devices

Study ID:




Start Date:

July 2006

Completion Date:

March 2009

Related Keywords:

  • Melanoma
  • Advanced cutaneous melanoma
  • Phase II study
  • Melanoma