Phase I study of vinblastine and temsirolimus in pediatric patients with recurrent or refractory solid tumors: Canadian Cancer Trials Group Study IND.218

Abstract

Combining mammalian target of rapamycin (mTOR) inhibitors and vinca alkaloids has shown therapeutic synergy in xenograft models of pediatric cancers. This phase I study assessed safety and toxicity of temsirolimus in combination with vinblastine in children. Procedure Patients ≥ 1 and ≤ 18 years with recurrent/refractory solid or CNS tumors were eligible. Vinblastine (4 mg/m2) and temsirolimus (15 mg/m2) were administered i.v. weekly, with planned dose escalation of vinblastine using a rolling six phase I design. Pharmacokinetic and pharmacodynamic data were collected. Results Seven patients with median age 12 years (range, 8–18 years) were enrolled; all were evaluable for toxicity and six for response. At dose level 1, four of six patients developed grade 3 mucositis, of which one met duration criteria for dose‐limiting toxicity (DLT). Four patients required dose omissions for grade 3 or 4 hematologic toxicity, including one prolonged neutropenia DLT. A subsequent patient was enrolled on dose level −2 (temsirolimus 10 mg/m2, vinblastine 4 mg/m2) with no protocol‐related toxicity > grade 1, except grade 2 neutropenia. Two serious adverse events (SAE) occurred—an allergic reaction to temsirolimus (grade 2) and an intracranial hemorrhage in a CNS tumor patient (grade 3)—unlikely related to study therapy. Soluble VEGFR2 was reduced at cycle 1, day 36 in keeping with inhibition of angiogenesis. Four patients achieved prolonged stable disease for a median of 5.0 months (range, 3.1–8.3 months). Conclusion The combination of weekly temsirolimus (15 mg/m2) and vinblastine (4 mg/m2) exceeds the maximum tolerated dose in children, with frequent oral mucositis and hematologic toxicity.

A phase I study of sirolimus in combination with metronomic therapy (CHOAnome) in children with recurrent or refractory solid and brain tumors

“…28 Hypercholesterolemia and hypertriglyceridemia are common in both adult and pediatric mTOR inhibitor studies, although in pediatric studies, this tends to be low grade and/or infrequent, and easily managed. [28][29][30][31] The results of this study are consistent with these data as only one patient had > grade 2 hypertriglyceridemia and no patient had > grade one hypercholesterolemia.…”

“…In contrast, the maximum grade of mucositis for all patients in subsequent cycles was grade 2 ( n = 2), suggesting this toxicity improves in subsequent cycles as reported in other studies . Hypercholesterolemia and hypertriglyceridemia are common in both adult and pediatric mTOR inhibitor studies, although in pediatric studies, this tends to be low grade and/or infrequent, and easily managed . The results of this study are consistent with these data as only one patient had > grade 2 hypertriglyceridemia and no patient had > grade one hypercholesterolemia.…”

SFCE-RAPIRI Phase I Study of Rapamycin Plus Irinotecan: A New Way to Target Intra-Tumor Hypoxia in Pediatric Refractory Cancers

“…Our results showed that this combination was well tolerated without severe toxicities, despite a heavily pretreated population. All toxicities were manageable and were already described when using each compound alone [14][15][16][17][18][19][20][21][40][41][42][43]. As in multiple phase I exploring targeted therapies, the MTD was not determined in absence of significant DLT events up to the tenth level (rapamycin at 2.5 mg/m 2 /day and D1/D15 irinotecan at 240 mg/m 2 ).…”

“…Several studies have showed that tumors, like neuroblastoma, rhabdomyosarcoma, high-grade glioma, or osteosarcoma, are overexpressing these targets and are sensitive to mTor inhibition [4,5,[12][13][14][15][16][17][18][19]. Therefore, rapamycin has been used in multiple phase I trials in these malignancies as single agent or in combination with chemotherapy [12][13][14][15][16][17][18][19][20][21]. The results of these protocols were promising, but they also showed limitations due to a positive feedback loop, reactivating constantly mTor through upstream RAS/mitogen-activated protein kinase (MAPK) pathway [22][23][24][25].…”

Mitotic Poisons in Research and Medicine

“…Nowadays, compound 14a is still being used in the clinical practice and still undergoes various research trials. Most considered is its co-administration with other commonly used drugs, as seen, for example, in [ 147 ]. In 1963, another preparation containing vinca alkaloid 14b has entered the drug market, namely, Oncovin ® .…”