Phase 1 and pharmacokinetic study of concurrent carboplatin and irinotecan in subjects aged 1 to 21 years with refractory solid tumors

Abstract

Objective Spleen tyrosine kinase (Syk) has been identified as an important modulator of immune signaling in B cells and cells bearing Fcγ‐activating receptors. R788, a prodrug of active metabolite R406, has been shown to be an inhibitor of Syk kinase, active in a variety of in vitro and in vivo models, suggesting potential activity in the treatment of rheumatoid arthritis (RA). Methods We enrolled 189 patients with active RA despite methotrexate therapy in a 3‐month, multicenter, ascending‐dose, double‐blind, placebo‐controlled trial. The primary end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12. Results Twice‐daily oral doses of 100 mg and 150 mg of R788 were significantly superior to placebo or twice‐daily oral doses of 50 mg at week 12 (ACR20 achieved in 65% and 72% versus 38% and 32% of patients, respectively [P < 0.01]). ACR50 (achieved in 49% and 57% versus 19% and 17% of patients, respectively) and ACR70 (achieved in 33% and 40% versus 4% and 2% of patients, respectively) scores showed a similar pattern. Clinical effect was noted as early as 1 week after initiation of therapy. Reductions in serum interleukin‐6 and matrix metalloproteinase 3 levels also occurred as early as week 1 in the groups receiving 100 mg and 150 mg R788. The major adverse effects were gastrointestinal side effects (predominantly diarrhea) and neutropenia (<1,500/mm3), both of which were dose related. Conclusion These results indicate that an inhibitor of Syk kinase produces significant clinical benefits at 12 weeks in a population of patients with active RA receiving methotrexate therapy. Syk kinase may be an important new therapeutic target in RA and related autoimmune conditions.

Tumor Regression and Curability of Preclinical Neuroblastoma Models by PEGylated SN38 (EZN-2208), a Novel Topoisomerase I Inhibitor

“…D and F, columns, mean value of VEGF and CD31 and MMP-2 and MMP-9 expressions; errors bars, 95% CI; n.s., not significant; *, P < 0.05; **, P < 0.01;***, P < 0.001. disease stabilization (29), or no objective response (6), as in treatment with the camptothecin analogue topotecan (5). When given in combination with other agents, camptothecin analogs have shown efficacy in preclinical neuroblastoma models (30,31) and in phase I clinical trials (32,33). More interestingly, an orally available formulation of irinotecan, in combination with temozolomide, led to partial response in a small number of relapsed high-risk neuroblastoma patients and was well tolerated (34).…”

Irinotecan for relapsed Wilms tumor in pediatric patients: SIOP experience and review of the literature—A report from the SIOP Renal Tumor Study Group

“…Irinotecan‐related toxicity appeared to be acceptable in our study and previous phase I and II trials, where toxicity was generally well documented, and neutropenia and diarrhea were consistently reported as the most common toxicities, with only occasional cases of grade 3–4 toxicity …”

“…observed more responses to topotecan in patients with intermediate‐risk (IR) histology compared to those with high‐risk (HR) histology . So far, limited information on irinotecan for relapsed WT is available from preclinical and phase I/II studies, showing some antitumor activity, but no randomized studies have been performed . Researchers from the Children's Oncology Group are evaluating irinotecan combined with other chemotherapeutic agents in upfront treatment for metastatic diffuse anaplastic WT, a diagnosis with a poor prognosis .…”

Irinotecan for Treatment of Childhood Cancers: A Promising Therapeutic Partner

“…Toxicity was manageable, particularly when amifostine was used to reduce myelosuppression. Levy et al have recently reported a pediatric Phase I study of single-dose carboplatin and dx5x2 intravenous irinotecan [70]. Prominent toxicities were diarrhea/abdominal pain and myelosuppression, despite the planned use of filgrastim.…”