Phase 2 trial of pemetrexed in children and adolescents with refractory solid tumors: A Children's Oncology Group study

Abstract

Background Pemetrexed is a multi-targeted antifolate that inhibits key enzymes involved in nucleotide biosynthesis. We performed a phase 2 trial of pemetrexed in children with refractory or recurrent solid tumors, including CNS tumors, to estimate the response rate and further define its toxicity profile. Procedure Pemetrexed, at a dose of 1910 mg/m2, was administered as a 10-minute intravenous infusion every 21 days. Patients also received vitamin B12, daily multivitamin supplementation, and dexamethasone. A two-stage design (10 + 10) was employed in each of the following disease strata: osteosarcoma, Ewing sarcoma/peripheral primitive neuroectodermal tumor (PNET), rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/supratentorial PNET, and non-brainstem high-grade glioma. Results Seventy-two eligible subjects (39 males) were enrolled. Median age was 11 years (range 3–23). Sixty-eight were evaluable for response. The median number of cycles administered was 2 (range 1–13). No complete or partial responses were observed. Stable disease, for a median of 5 (range 4–13) cycles, was observed in 5 patients (ependymoma, Ewing sarcoma, medulloblastoma, neuroblastoma, osteosarcoma; n=1 each). Neutropenia (44%), anemia (35%), and elevated alanine transaminase (35%) attributable to pemetrexed were the most commonly recurring toxicities observed in patients receiving multiple cycles. Other toxicities attributed to pemetrexed occurring in ≥10% of cycles included thrombocytopenia (30%), fatigue (18%), nausea (14), hyperglycemia (13%), rash (11%), vomiting (13%), and hypophosphatemia (11%). Conclusions Pemetrexed, administered as an intravenous infusion every 21 days, was tolerable in children and adolescents with refractory solid tumors, including CNS tumors, but did not show evidence of objective anti-tumor activity in the childhood tumors studied.

Pemetrexed and Gemcitabine as Combination Therapy for the Treatment of Group3 Medulloblastoma

“…Although the anti-folate agents methotrexate and 5-fluorouracil have been widely used for decades in the treatment of malignant tumors, pemetrexed is a relatively new therapeutic agent currently approved as a first line treatment for mesothelioma (Dowell et al, 2012), NSCLC in association with platinum-based chemotherapy (Mubarak et al, 2012), and in newly diagnosed brain metastasis (Bailon et al, 2012). It also showed clinical activity in other adult tumors such as breast, colorectal, bladder, cervical, gastric and pancreatic cancers (Adjei, 2004; Chattopadhyay et al, 2007; Warwick et al, 2013). Genes regulating pyrimidine metabolism were also enriched in mouse G3 MBs compared with mouse GNPs and SHH MBs, in agreement with the anti-proliferation effects of gemcitabine, a pyrimidine cytidine analogue.…”

Expression of Methylthioadenosine Phosphorylase (MTAP) in Pilocytic Astrocytomas

“…This is particularly relevant for lymphomas, leukemias [27,29] and nonsmall-cell lung carcinoma [34,45] . Nevertheless, chemotherapy regimens with pemetrexed were not effective for pediatric patients with medulloblastomas, ependymomas and high-grade gliomas [49] , and the addition of methotrexate in the chemotherapeutic treatment of infratentorial ependymomas did not improve the response to these drugs [50] . However, none of these studies assessed MTAP expression in the tumors.…”

Current Therapeutic Strategies and Novel Approaches in Osteosarcoma

“…However, even though PMX was less toxic, it did not induce apoptosis more effectively than MTX in OS cell lines in vitro [80]. In the same vein, a phase II study of PMX conducted in patients with high-grade, advanced, or refractory osteosarcoma to assess response rate and toxicity (NCT00523419) showed that PMX was well-tolerated but did not enhance anti-tumor activity [81,82]. …”