Refractory Pediatric Solid Tumors Research Articles

Irinotecán y temozolomida en tumores sólidos pediátricos en recaída o refractarios

IntroductionThe prognosis of refractory or relapsed pediatric solid tumors is very poor, and there is no standard treatment for this condition. The combination of irinotecan and temozolomide has proved useful in adults as a second-line treatment of different solid tumors. In pediatric patients, this combination has been effective in Ewing's sarcoma, neuroblastoma, and relapsed or refractory rhabdomyosarcoma. Patients and methodsA retrospective study was conducted on 32 pediatric patients with refractory or relapsed solid tumors, who were treated with irinotecan and temozolomide in the Oncology Department at Children's Hospital Niño Jesus from September 2005 to June 2012. The clinical characteristics, treatment performed, toxicity and outcome, were analyzed. ResultsThirty-two patients received a total of 180 cycles. Of the 30 evaluable patients, 10 (33%) had a positive response (2 complete remission and 8 partial remission), and in 8 (27%) the disease remained stable. Almost all (94%) of the patients achieved a response in the first four cycles. Of the 180 cycles analyzed, only 50 (28%) had toxicity, and of these only 15 (8%) were grade iii-iv. The most common toxicity was diarrhea appearing in 18 patients. All patients received ambulatory treatment, except three of them who required hospitalization due to symptoms of their underlying disease. ConclusionThe combination of irinotecan and temozolomide is well tolerated and active against pediatric refractory or relapsed solid tumors.

A phase II trial and pharmacokinetic study of oxaliplatin in children with refractory solid tumors: A Children's Oncology Group study

Platinating agents are used in the treatment of a spectrum of childhood cancers. Oxaliplatin, a third generation platinum compound, may provide less toxicity and be more effective. A phase 2 study was performed to estimate the response rate to single agent oxaliplatin in patients with refractory pediatric solid tumors, and to further describe the toxicities and pharmacokinetics of the drug in this population. Subjects, < or =21 years of age at original diagnosis, received oxaliplatin (130 mg/m(2)) intravenously every 21 days. Prior platinum exposure was acceptable. Histologies included: Ewing sarcoma/peripheral PNET, osteosarcoma, rhabdomyosarcoma, neuroblastoma, high and low grade astrocytoma, brain stem glioma, ependymoma, hepatoblastoma and selected rare tumors. A two-stage design, enrolling 10 + 10 subjects, was used for each disease stratum. Limited sampling pharmacokinetic studies were performed. Of 124 eligible subjects (75 males), 113 were evaluable for response and 69 (62%) had received platinum previously. Only one objective response was observed, a partial response in a 6-year-old child with ependymoma. An additional 13 subjects with various other solid tumors had stable disease, receiving a median (range) of 13.5 (2-17) cycles. Five subjects completed 17 treatment cycles. Thrombocytopenia was the most common toxicity observed. The median (range) terminal half-life and clearance for ultrafiltrable platinum were 293 (187-662 hr) and 14.0 (1.9-24.9 L/hr/m(2)), respectively (n = 49). Although reasonably well tolerated, oxaliplatin administered as a single agent has limited activity in pediatric patients with relapsed or refractory solid tumors.

An investigator-initiated registration-directed phase I/II clinical trial of irinotecan hydrochroride for refractory pediatric solid tumors.

9547 Background: Although irinotecan hydrochloride (CPT-11) is a promising chemotherapeutic agent to treat refractory pediatric solid tumors, this indication and effect is not labeled in US, EU, and Japan. Therefore, we conducted the phase I/II trial of CPT-11 monotherapy in a registration-directed setting. Methods: Patients (Pt) aged 2 to 18 years with pediatric solid tumors refractory to, or relapsed after treatment with standard chemotherapies are eligible. This multi-center phase I/II trial consists of phase I part (PI), in which dose-escalation from level 1 (40 mg/m2/day) to estimate the maximum tolerating dose (MTD) was planned, followed by phase II part (PII), in which the recommended dose (RD) at one level lower than the MTD was adopted. CPT-11 was administered intravenously on days 1, 2, 3 and 8, 9, 10, repeated every 21-day cycle up to 8 cycles. Primary endpoints are the dose limiting toxicity (DLT) in PI, and response rate per RECIST criteria including patients entered in PI and PII. Pharmacokinetic study was planned in selected Pt. Results: Seventeen Pt (11 in PI and 6 in PII) received CPT-11. Because DLTs were observed in 1 Pt (diarrhea) in level 1 and 3 Pt (diarrhea, febrile neutropenia, and elevated serum amylase) in level 2 (45 mg/m2/day), the level 2 was regarded as the MTD and the RD was determined to be 40 mg/m2/day. Tumor responses included one confirmed PR in poorly-differentiated sarcoma, one unconfirmed PR in neuroblastoma, two SD continued more than 24 weeks in rhabdomyosarcoma and Ewing/PNET, respectively. The response rate was 5.9%, which was lower than expected. Pharmacokinetic parameters in 11 Pt showed a similar pattern to results of the past pediatric reports. Conclusions: The RD of CPT-11 in this treatment schedule is 40 mg/m2/day. CPT-11 monotherapy is not active enough to expect tumor shrinkage but possibly active to stabilize disease even in refractory pediatric solid tumors. Nontheless, the clinical data from this registration-directed clinical trial is not enough to obtain approval for pediatric solid tumors. Further investigations including possible combination chemotherapy are warranted. No significant financial relationships to disclose.

Phase II trial of pemetrexed in children with refractory solid tumors: A Children's Oncology Group study.

9535 Background: Pemetrexed is a multi-targeted antifol that inhibits key enzymes involved in nucleotide biosynthesis. We performed a phase 2 trial of pemetrexed in children with refractory or recurrent solid tumors to estimate the response rate and further define its toxicity profile. Methods: Pemetrexed, at a dose of 1,910 mg/m2, was administered as a 10-minute intravenous infusion every 21 days. Patients also received vitamin B12 (500–1,000 mcg IM, q 3 courses), daily multivitamin supplementation and dexamethasone (0.1 mg/kg/dose bid × 3 days q course). A two-stage design (10 + 10) was employed for each of the following disease strata: osteosarcoma, Ewing sarcoma/ peripheral PNET, rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/ supratentorial PNET and non-brainstem high-grade glioma. Results: Of 72 eligible subjects (39 males), 68 were evaluable for response. No complete or partial responses were observed. Stable disease, for a median (range) of 5 (4- 8+) cycles, was observed in 5 patients: ependymoma, Ewing sarcoma, medulloblastoma, neuroblastoma, osteosarcoma (n=1 each); one patient with Ewing sarcoma is still on study after 8 cycles. Seventy patients fully evaluable for toxicity received 112 treatment cycles. Rash, a DLT in the phase I study, was generally < grade 2 and occurred in 23% of patients. Other toxicities occurring in >10% of patients overall included: elevated ALT (40%) and AST (36%), fatigue (33%), itching (15%), nausea (24%), vomiting (20%), hypophosphatemia (20%), and hyperglycemia (24%), anemia (40%), and neutropenia (47%), and thrombocytopenia (40%). Neutropenia and elevated ALT were the most commonly recurring toxicities observed in patients receiving multiple cycles. One patient discontinued protocol therapy because of persistently elevated ALT. Two allergic reactions occurred, each with the first dose. Conclusions: Although reasonably well tolerated, pemetrexed as administered in this study has no significant activity in a broad spectrum of refractory pediatric solid tumors. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly Lilly Lilly

Pharmacokinetic and pharmacodynamic investigation of irinotecan hydrochloride in pediatric patients with recurrent or progressive solid tumors

A multicenter Phase I/II study of Irinotecan hydrochloride (CPT-11; 40-45 mg/m(2)/dose) was conducted for the treatment of refractory pediatric solid tumors. The pharmacokinetics of CPT-11 and its metabolites were characterized using both traditional noncompartmental analysis and population pharmacokinetics using NONMEM VI; pharmacokinetic pharmacodynamic relationships of SN-38 with indices of toxicity were also evaluated. 11 patients between 3 and 18 years were enrolled. Pharmacokinetic parameters and consideration of relevant covariates (performance status (PS), BSA, corrected body weight (CBW), exponent of 3/4 on weight, etc.) were evaluated. Relationships between pharmacokinetic parameters of SN-38 and percentage change from baseline in patient biochemical response data were investigated via regression analysis. CPT-11 exhibited a mean clearance (CL) of 15.31 +/- 5.95 (l/h) (13.06 +/- 3.58 (l/hr/m(2))) and AUC(0-inf) of 3547.0 +/- 1406.5 (ng x h/ml); the AUC ratio of parent CPT-11 to SN-38 was 5.0%. Based on the population pharmacokinetic analysis, decreasing PS was significantly dependent on reduction in CL of CPT-11 (p < 0.001). The final model for CPT-11 are as follows: CL (l/h) = 1.31 x CBW(0.75) (omegaCL = 21.7%), Vss (l) = 2.66 x CBW (omegaVss = 21.2%), Vc (l) = 1.13 x CBW, inter-compartment CL (l/h) = 0.257 x CBW(0.75). Percentage changes of leucocyte and neutrophil count within a first month treatment were significantly correlated with Cmax of SN-38 (r = 0.78 and r = 0.74) and AUC0-2 of SN-38 (r = 0.73 and r = 0.73). Pharmacokinetic parameters were similar to results published in several past reports. An allometric scaling of CBW(0.75) would seem to provide a good index of dosage requirement of CPT-11 in pediatric patients.

Phase 2 trial of imatinib mesylate (IM) for treatment of recurrent or refractory pediatric solid tumors: A Children’s Oncology Group study

8520 Background: In in vitro studies, IM inhibits KIT and PDGF receptor tyrosine kinases. Clinical activity has been demonstrated against gastrointestinal stromal tumors (KIT mutations) and dermato...

High dose ifosfamide (IFOS) and mesna (M) in refractory pediatric solid tumors after previous exposure to “conventional” IFOS

High dose ifosfamide (IFOS) and mesna (M) in refractory pediatric solid tumors after previous exposure to “conventional” IFOS

Treatment of recurrent and refractory pediatric solid tumors with high-dose busulfan and cyclophosphamide followed by autologous bone marrow rescue.

The purpose of this study was to determine the toxicities of and responses to high-dose busulfan and cyclophosphamide with autologous bone marrow transplant (ABMT) in patients with recurrent or refractory pediatric solid tumors. We treated 18 patients (ages, 2 to 38 years; median, 14) who had tumors that were resistant to conventional chemotherapy and radiotherapy with busulfan 16 mg/kg and cyclophosphamide 200 mg/kg. Seventeen patients received bone marrow purged with 4-hydroperoxycyclophosphamide; one received unpurged marrow. Despite extensive prior treatment, including radiotherapy in 16 patients, toxicity generally was acceptable. For seven patients with measurable disease, there were three partial responses of 2, 10, and 20 months' duration, three patients with stable disease (SD), and one early, toxic death. Of the 11 patients with no measurable disease at the time of transplantation, one patient with osteosarcoma continues in remission at 57+ months and one third of the patients survived for at least 16 months. Mucositis was the predominant nonhematopoietic toxicity. Although the high-dose busulfan and cyclophosphamide combination showed modest activity, changes in the preparative regimen should be considered to improve the response rate in refractory tumors.

Phase I clinical and pharmacokinetic study of bisantrene in refractory pediatric solid tumors.

Fourteen patients with pediatric malignant solid tumors, median age 15 years, received 22 courses of bisantrene in a Phase I study. Dosage escalations ranged from 10 to 120 mg/m2 daily for 5 consecutive days. Toxicity included myelosuppression and phlebitis. A sensitive (detection limit of 2 ng/ml) and specific HPLC method was developed to quantitate bisantrene in patient's plasma and urine. Peak plasma concentrations at the end of 60 minute infusions ranged from 568 ng/ml at 10 mg/m2 to 6800 ng/ml at the 100 mg/m2 dosage. The elimination half life (T 1/2 beta) averaged about 10 hours but increased to 20 hours in a patient with liver disease. Only 2.4 - 10% of the bisantrene dose was eliminated in the urine suggesting that the liver may be the major route of elimination for this antineoplastic anthracene derivative.