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
18 Years
N/A
Both
Cutaneous T-cell Lymphoma
Trial Information
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
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
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
Type of Study:
Interventional
Study Design:
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
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.
Outcome Time Frame:
Week 16
Safety Issue:
Yes
Principal Investigator
Reinhard Dummer, MD PhD
Investigator Role:
Principal Investigator
Investigator Affiliation:
Department of Dermatology, University Hospital of Zürich, Gloriastrasse 31, 8091 Zürich, Switzerland
Authority:
Germany: Federal Institute for Drugs and Medical Devices
Study ID:
AP3001
NCT ID:
NCT00431912
Start Date:
February 2007
Completion Date:
September 2011
Related Keywords:
- Cutaneous T-cell Lymphoma
- cutaneous T-cell lymphoma
- mycosis fungoides
- Sézary syndrome
- APO866
- phase II study
- Lymphoma
- Lymphoma, T-Cell
- Lymphoma, T-Cell, Cutaneous
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