Phase II Study of VEGF Inhibitor, PTK787/ZK222584, in Patients with Refractory or Relapsed Diffuse Large B-Cell Lymphoma

Diffuse Large B-cell Lymphoma (DLBCL) patients with primary refractory or multiply relapsed disease have limited treatment options. Therefore it is imperative that novel drugs be tested to find new, effective approaches for these patients. With evidence demonstrating that increased vascularity and pro-angiogenic factors correlate with adverse prognosis in the hematologic malignancies, angiogenesis has emerged as a novel therapeutic target. PTK787/ZK222584 is an orally active amino-phthalazin that inhibits all known tyrosine kinase receptors of vascular endothelial growth factor (VEGF). The efficacy, safety and tolerability of PTK787/ZK222584 in patients with rel/ref DLBCL was evaluated in this non-randomized phase II study.

Patients with relapsed or refractory DLBCL were eligible. Additional key inclusion criteria were negative proteinuria, and normal renal and liver function. Central nervous system disease, prior allogeneic transplant, recent chemotherapy, or previous anti-VEGF therapy excluded subjects from enrollment. All patients inititated PTK787/ZK222584 at a dose of 750mg by mouth (PO) daily on day 1 of a 28 day cycle. Drug dose was increased weekly, initially to a dose of 1000mg PO daily and then to a target dose of 1250mg daily unless a grade ≥2 toxicity (using NCI CTC V3.0) developed. Primary endpoint was response (complete response (CR) + partial response (PR)); secondary endpoints included safety and tolerability.

Twenty patients (11 female) with a median age of 60 years were enrolled. Sixty three percent of patients had received >3 prior therapies and 26% had prior autologous stem cell transplantation. Patients received a median of 3 cycles of PTK787/ZK222584 (range 0–6). Ten patients were on study drug for at least 3 cycles and are evaluable for response: one patient had a CR, four patients had stable disease (SD), and the remaining 5 patients had progressive disease. The patient with a CR subsequently underwent autologous stem cell transplantation and was alive without evidence of disease 64 months after study completion. One patient with SD withdrew to pursue other treatment options and the other 3 continued study drug, but all developed progressive disease within the next 3 months.

Of the 10 patients who withdrew prior to completing 3 cycles, six withdrew after a median of 1 cycle because of rapidly progressive disease. Three withdrew because of adverse events of sepsis resulting in death in one patient, altered mental status despite dose reductions in one, and recurrent grade 3 transaminitis in the third. One patient withdrew to pursue other treatment options.

Eighteen of the 20 patients enrolled escalated to the full target dose of 1250mg, but 6 required at least 1 dose reduction due to adverse events (sepsis, vertigo, transaminitis, rash or fatigue). There were no episodes of grade 3 / 4 proteinuria but grade 3 / 4 hypertension occurred in 10% and grade 3 / 4 thrombocytopenia in 20%, with the remainder of grade 3 / 4 toxicities occurring in <10%. The most common toxicities occurring in greater than 15% of patients across all grades included nausea (75%), fatigue (65%), anorexia (45%), anemia (35%), vomiting (35%), thrombocytopenia (25%), HTN (25%), diarrhea (25%), proteinuria (25%), fever (20%), constipation (20%), and dizziness (20%).

PTK787/ZK222584 is an orally active VEGF inhibitor which was generally well tolerated in a heavily pretreated population of patients with DLBCL. Although 1 patient achieved a CR and remains disease free after autologous stem cell transplant, the remaining patients developed progressive disease or had adverse events suggesting that this agent is unlikely to be useful as a single agent in aggressive lymphoma. The excellent response in one patient, however, raises the possibility that drug response may occur in a subset of patients so the identification of tumor specific biomarkers to predict responding patients is needed.

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