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Sponsored by: |
Apoxis SA |
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Information provided by: | Apoxis SA |
ClinicalTrials.gov Identifier: | NCT00435084 |
This phase I/II study is designed to determine the safety and tolerability of APO866 for the treatment of refractory B-CLL not amenable to aHSCT. APO866 has shown to induce growth inhibition in cultures of a wide variety of human hematological malignant cells as well as in models with subcutaneously implanted human tumors. APO866 was considered to be safe and well-tolerated in a phase I study that treated 24 patients with advanced cancer. APO866 is administered by intravenous infusion continuously for 96 hours and is repeated every 4 weeks. In this study patients will receive only one cycle of treatment and the study endpoints will be evaluated 4 weeks after the start of infusion. Patients will be followed up for 12 weeks for safety.
Condition | Intervention | Phase |
---|---|---|
B-Cell Chronic Lymphocytic Leukemia |
Drug: APO866 |
Phase I Phase II |
Study Type: | Interventional |
Study Design: | Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Safety/Efficacy Study |
Official Title: | An Open Phase I/II Clinical Study Assessing the Safety and Tolerability of APO866 in Patients With Refractory B-Cell Chronic Lymphocytic Leukemia (B-CLL) Not Amenable to Allogeneic Hematopoietic Stem Cell Transplantation (aHSCT) |
Estimated Enrollment: | 10 |
Study Start Date: | December 2006 |
Estimated Study Completion Date: | September 2007 |
B-CLL is one of the most common types of leukemia, remains incurable, and has only limited therapeutic options available including alkylating agents and fludarabine. The identification of new, selective, and non-toxic forms of therapy for patients with B-CLL is therefore a high priority.
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, including CD38- and CD38+ cell lines, and on a large number of human xenografts in nude mice and rats in vivo. Hematologic cancer cells were highly sensitive to APO866 (lower than 6 nM). Lymphocytes are the most sensitive normal cells to APO866 resulting in lymphocytopenia and reticulocytopenia in rats and monkeys. Furthermore, APO866 may have anti-angiogenic properties as shown in vivo and dose-dependent decrease of VEGF levels in patients treated in the phase I study.
It is unclear why CD38 positivity is associated with a short patient survival and poor responsiveness to chemotherapy. It is possible that CD38 expression confers to B-CLL of a more malignant cellular phenotype. This seems plausible given that the antigen has an important role as a modulator of intracellular signaling and that cross-linking of CD38 up-regulates BCL-2 and inhibits apoptosis in normal mature B cells. Indeed, CD38/CD3l interactions lead to increased B-CLL proliferation and survival. This study has been designed to recruit patients with progressive or refractory B-CLL of whom, in line with the literature, about 50% will be CD38+.
We hypothesize that CD38+ lymphocytes will be more sensitive to the APO866 therapy due to increased intracellular NAD+ consumption as substrate for the PARP dependent DNA repair (instable genome, proliferation). However, CD38+ and CD38- B-CLL cells seem to be equally sensitive to APO866 in vitro. In addition, decreased intracellular NAD+ levels will reduce the anabolism of cADPR. CD38+ can catalyze the synthesis of cADPR from NAD+ and can further hydrolyze cADPR to ADP-ribose.85,86,87 The cADPR is a potent Ca++-mobilizing activator and a potential endogenous regulator.88 The ability of cADPR to release Ca++ from intracellular pools is thought to be part of CD38-mediated signalling pathways that result in cell growth, apoptosis, and differentiation.
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 every 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
This forms the rationale to conduct a “Proof of concept” study of APO866, administered at the recommended dose in patients with progressive refractory B-CLL non-eligible for aHSCT, either CD38- or CD38+.
Ages Eligible for Study: | 18 Years and older |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Exclusion Criteria:
Contact: Peter Hillmen, MD | +44 113 3923974 | peter.hillmen@nhs.net |
Contact: René Goedkoop, MD | +41 21 6206080 | goedkoop@apoxis.com |
United Kingdom | |
Department of Heamtology, Leeds General Infirmary | Recruiting |
Leeds, United Kingdom, LS1 3EX | |
Contact: Peter Hillmen, MD PhD +44 113 3923974 peter.hillmen@nhs.net | |
Contact: Catherine Norton +44 113 3923766 catherine.norton@leedslh.nhs.uk | |
Principal Investigator: Peter Hillmen, MD | |
Department of Heamtology, University Hospital of NHS Trust | Recruiting |
Nottingham, United Kingdom, NG5 1PB | |
Contact: Andy Haynes, MD +44 115 9691169 ext 45597 andy.haynes@nottingham.ac.uk | |
Contact: Richard Stanley, Study RN +44 1159691169 ext 45702 richard.stanley@nuh.nhs.uk | |
Principal Investigator: Andy Haynes, MD | |
Department of Heamtology, Cardiff and Vale NHS Trust | Recruiting |
cardiff, United Kingdom, CF14 4 WX | |
Contact: Chris Poynton, Prof, MD +44 2920 742654 poynton@cardiff.ac.uk | |
Contact: Carrie Thompson, Study RN +44 2920 748344 | |
Principal Investigator: Chris Poynton, Prof, MD | |
Department of Heamtology, Bart's and the London NHS Trust | Recruiting |
London, United Kingdom, EC1A 7BE | |
Contact: John Gribben, Prof, MD +44 207 8826126 john.gribben@cancer.org.uk | |
Principal Investigator: John Gribben, Prof, MD |
Principal Investigator: | Peter Hillmen, MD PhD | Department of Heamatology, D Floor, Brotherton Wing, Leeds General Infirmary, Great George street, Leeds LS1 3EX |
Study Director: | René Goedkoop, MD | Apoxis SA, 18-20 Avenue de Sévelin, 1004 Lausanne, Switzerland |
Study ID Numbers: | AP3005, EudraCT number 2006-002850-31 |
Study First Received: | February 13, 2007 |
Last Updated: | June 4, 2007 |
ClinicalTrials.gov Identifier: | NCT00435084 |
Health Authority: | United Kingdom: Medicines and Healthcare Products Regulatory Agency |
Refractory B-CLL phase I/II CD38 |
Chronic lymphocytic leukemia Lymphatic Diseases Leukemia Leukemia, Lymphoid Immunoproliferative Disorders |
Leukemia, Lymphocytic, Chronic, B-Cell Leukemia, B-cell, chronic Lymphoproliferative Disorders Leukemia, B-Cell |
Neoplasms Neoplasms by Histologic Type Immune System Diseases |