Tolerability of PTK787/ZK 222584 in a Phase II Study of Post-Transplant Maintenance Therapy in Patients with Multiple Myeloma Following High-Dose Chemotherapy and Autologous Stem Cell Transplant.

Background: Currently, High-Dose Chemotherapy (HDCT) followed by autologous stem-cell transplantation (ASCT) is the standard of care in Multiple Myeloma (MM). This therapy improves overall and event-free survival, but is not curative, necessitating further therapies that will enhance and prolong remission duration. PTK787/ZK 222584 is a potent, orally available, angiogenesis inhibitor that blocks all known VEGF receptors in a dose-dependent fashion. Preclinical studies have demonstrated that PTK/ZK is able to inhibit tyrosine phosphorylation of VEGFR-1 in MM cells, as well as inhibit MM cell migration and proliferation. Based on this, a phase II study was designed to assess efficacy and tolerability of PTK/ZK as maintenance therapy for individuals treated HDCT and ASCT for MM.

Study Design: Patients with MM treated with HDCT and ASCT with persistent measurable paraproteinemia or persistent abnormal serum κ/λ ratio were selected for treatment with PTK/ZK. Primary endpoint is overall response rate and secondary endpoints are time to progression, disease free survival, and safety. Patients were initiated on 750mg daily of PTK/ZK, with doses escalated to 1250 mg daily.

Results: Nine patients have received PTK/ZK and their baseline characteristics are as follows: median number of days on PTK/ZK is 129 (range 3–252); median number of cycles administered is 5 (range 1–14); median age is 57 (range 38–71); stage IIIA (7), stage IIA (1), stage IA (1); IgG isotype (7), IgA isotype (2); median β2-microglobulin level was 1.7 (range 1.2–4.2). Of the nine patients who initially received PTK/ZK, four remain on the medication, three patients have stopped due to progressive disease, and two have stopped due to toxicities. One patient has demonstrated a PR (11%), three patients have SD, and three patients had PD. There have been no deaths. Toxicities are as follows: one patient developed grade 3 elevated ALT as well as motor and sensory neuropathy, one patient developed grade 3 neutropenia, and one patient developed grade 3 prolongation of the QTc interval. Two patients were withdrawn from the study due to toxicities, one with grade 3 prolongation of the QTc interval as well as grade 4 Hypertension, and one patient with grade 4 Hypertension alone. The remaining five patients have had no significant adverse drug events.

Conclusion: Continued patient accrual is underway for analysis of time to progression and disease free survival as well as overall response rate. Bone marrow samples are also being evaluated for change in microvessel density by immunohistochemistry with treatment.