Low-Dose Metronomic Topotecan and Pazopanib (TOPAZ) in Children with Relapsed or Refractory Solid Tumors: A C17 Canadian Phase I Clinical Trial

Abstract

Oral metronomic topotecan represents a novel approach to chemotherapy delivery which, in preclinical models, may work synergistically with pazopanib in targeting angiogenesis. A phase I and pharmacokinetic (PK) study of this combination was performed in children with relapsed/refractory solid tumors. Oral topotecan and pazopanib were each administered daily without interruption in 28-day cycles at five dose levels (0.12 to 0.3 mg/m2 topotecan and 125 to 160 mg/m2 pazopanib powder for oral suspension (PfOS)), with dose escalation in accordance with the rolling-six design. PK studies were performed on day 1 and at steady state. Thirty patients were enrolled, with 26 evaluable for dose-limiting toxicity (DLT), with median age 12 years (3–20). Toxicities were generally mild; the most common grade 3/4 adverse events related to protocol therapy were neutropenia (18%), thrombocytopenia (11%), lymphopenia (11%), AST elevation (11%), and lipase elevation (11%). Only two cycle 1 DLTs were observed on study, both at the 0.3/160 mg/m2 dose level comprising persistent grade 3 thrombocytopenia and grade 3 ALT elevation. No AEs experienced beyond cycle 1 required treatment discontinuation. The best response was stable disease in 10/25 patients (40%) for a median duration of 6.4 (1.7–45.1) months. The combination of oral metronomic topotecan and pazopanib is safe and tolerable in pediatric patients with solid tumors, with a recommended phase 2 dose of 0.22 mg/m2 topotecan and 160 mg/m2 pazopanib. No objective responses were observed in this heavily pre-treated patient population, although 40% did achieve stable disease for a median of 6 months. While this combination is likely of limited benefit for relapsed disease, it may play a role in the maintenance setting.

Relationship between Osteosarcoma Therapy and Tumorigenesis, Metastasis, Immune Evasion, and Chemoresistance

“…For all these trials, there are only two main types of OS: soft and solid, as observed in the table. The following active pharmaceutical ingredients (API) are appropriate for OS: topotecan (Tpt) [45], pazopanib (Pzp) [46], placebo (Plb) [47], gemcitabine (Gct) [48], M6620 [49][50], regorafenib (Rgf) [51][52], glembatumumab vedotin (GV) [53][54], lenvatinib [55], etoposide and ifosfamide (EnI) [56], nab-rapamycin (Rpm) [57][58], cyclophosphamide (Cfa) [59], simvastatin (Sim) [60], myeloid growth factor (MGF) [61], nab-paclitaxel [62][63], methotrexate (Mtx) [64], and doxorubicin (Dox) [65]. Besides, the primary tests, such as laboratory biomarker analyses [66] and dose escalation studies [67], were conducted for these successful triumphs.…”

Metronomic Chemotherapy in Pediatric Oncology: From Preclinical Evidence to Clinical Studies

“…Manji and colleagues [ 84 ] conducted a phase I clinical trial with the aim of establishing the maximum tolerated doses of metronomic topotecan and pazopanib, detecting the toxicities of the combined schedule, and describing the pharmacokinetics of oral metronomic topotecan and pazopanib prepared as a powder for oral suspension (PfOS) in 30 patients (age 2–21 years) with relapsed or refractory solid tumors. The initial doses of topotecan and pazopanib PfOS were 0.12 mg/m 2 e 125 mg/m 2 , respectively.…”

“…Ten patients (4 neuroblastoma, 3 osteosarcoma, 2 Ewing sarcoma/PNET, and 1 medulloblastoma) had stable disease with a median duration of 6.4 months (1.7–45.1). The longest stable disease was 45 months, and the therapy was continued as compassionate use even after the study ended [ 84 ].…”