Dose-limiting toxicity and treatment modifications
pulmonary embolism, neutropenia, toxicity, toxicities, thrombocytopenia, hepatotoxicity
PULMONARY EMBOLISM, RECURRENCE, NEUTROPENIA, ADVERSE EVENTS, THROMBOCYTOPENIA, EVENTS
To determine the maximum tolerated dose of oral pazopanib as a combination partner of topotecan, 38 documented chemotherapy cycles were evaluated in phase I (Table Characteristics of the treatment cohortsThe summarized analysis of the dose escalation phase I included 10 evaluable patients, considering 3 of them who received all planned 6 cycles of pazopanib with topotecan without premature treatment discontinuation (2 at dose level 1 and one at dose level 2) and seven patients who have stopped the combination either due to recurrence (3 after the third and one after the fourth cycle), due to DLT (one with pulmonary embolism and the second one due to prolonged severe neutropenia and thrombocytopenia after third cycle), or due to own request resulting of prolonged haematological adverse events (AE’s) and hepatotoxicity. Two patients of the phase I entered the maintenance part receiving 52 treatment cycles with pazopanib (Table Treatment delay with interruptions of the chemotherapy courses during the dose escalation study were most common under topotecan (68%) and rarely caused by pazopanib (24%). Altogether 35 dose modifications of topotecan have been reported, 58% of them caused by haematological toxicity like thrombocytopenia, while further nine modifications were caused by pazopanib. Interestingly the only one patient who received all planned six cycles of topotecan and pazopanib at dose level 2 and developed consequently haematological and non-haematological toxicities, switched after first cycle to reduced dose of 400 mg pazopanib and continued it for 192 weeks (49 cycles). For this patient five treatment delays, mostly caused by an isolated gamma-glutamyl transferase (GGT) increase were documented. No dose reductions in the phase I maintenance were observed.The recommended dose for the phase II of the TOPAZ trial was pazopanib 400 mg daily and topotecan 4 mg/mThe most common reason for treatment delay during the phase II chemotherapy resulted due to haematologic AE’s under topotecan (115 of 174 cycles, 66%), while pazopanib caused 57 (33%) of all treatment interruptions. During the six courses of chemotherapy 164 dose modifications for topotecan were documented, mostly due to haematological events (65%), followed by non-hematologic events (8%) or patient’s preference (6%). Pazopanib caused 87 dose modifications during this study phase, mostly due to haematological events (72%). During the maintenance only for two patients’ treatment interruption of pazopanib was documented, not due to toxicity reasons, but several times on patient’s request. For two other participants dose reduction was necessary due to non-haematological events (lever enzymes increase or general condition), after that one of both patients continued with pazopanib maintenance for overall 60 weeks without course delay.