071: Evaluation of Palbociclib & Combinatorial Chemotherapy Pharmacokinetics in Pediatric Patients With Recurrent or Refractory Solid Tumors

Statement of Purpose, Innovation or Hypothesis: Irinotecan (IRN)/Temozolomide (TMZ) and Cyclophosphamide (CTX)/Topotecan (TOPO) are used in pediatric patients with solid tumors, but outcomes remain poor. Non-clinical and clinical data suggest aberrations in CDK4/6 pathway can drive the growth of pediatric tumors. Palbociclib is a highly selective, reversible, CDK4/6 inhibitor. Hence, the objective of this study was to evaluate the PK of palbociclib, TMZ, IRN, CTX, and TOPO in pediatric patients when given in combination.

Description of Methods & Materials: This was an open-label, multicenter, non-randomized Phase 1 portion of the study (ClinicalTrials.gov ID: NCT03709680) of palbociclib in combination with either IRN and TMZ or TOPO and CTX in children, adolescent, and young adult patients with recurrent/refractory solid tumors. Palbociclib was administered orally QD on Days 1 to 14 followed by 7 days off in both combinations (doses of 55, 75, and 95 mg/m² with IRN/TMZ and 75 mg/m² with CTX/TOPO). TMZ was administered QD at 100 mg/m², IRN was administered IV at 50 mg/m² over 90 minutes, CTX was administered IV at 250 mg/m² over 30-60 minutes, and TOPO was administered IV at 0.75 mg/m² over 30 minutes, all on days 1 to 5. PK samples were collected as detailed in Table 1. PK parameters were calculated for each analyte, each participant and treatment, using noncompartmental analysis.

Data & Results: 33 and 26 participants were treated in Palbociclib/IRN/TMZ and Palbociclib/CTX/TOPO combination, respectively. Palbociclib exposure increased proportionally with dose (mean C1D5 C_max of 80.44, 113.2, 127.9 ng/mL and AUC_τ of 1161, 1538, 2082 h∙ng/mL at doses of 55, 75, and 95 mg/m²_, respectively with IRN/TMZ). Palbociclib exposure on C1D5 (75 mg/m² dose) when dosed with IRN/TMZ was similar to that observed when dosed with CTX/TOPO (mean (CV%) AUC_τ and C_max of 1290 h∙ng/mL (59%) and 91.45 ng/mL (58%)).Palbociclib exposure was similar to exposure in adult participants following 125 mg QD dosed as monotherapy (Day 1 to Day 21 followed by 7 days off) on C1D21 (mean AUC_τ = 1733 h∙ng/mL and C_max = 97.4 ng/mL)¹. Exposure of IRN/SN-38 (mean IRN C_max = 629.3, 595.5, 1033 ng/mL, mean SN-38: C_max = 7.386, 8.746, 11.32 ng/mL for 55, 75, and 95 mg/m² palbociclib dose combination, respectively), TMZ (mean C_max = 3930, 3960, 4404 ng/mL for 55, 75, and 95 mg/m² palbociclib dose combination, respectively), CTX (mean CL=3.772 L/h/m²), and TOPO (mean AUC_τ = 49.27 h∙ng/mL) were also generally consistent with exposure/parameters observed in published studies ^2,3,4,5 (mean IRN C_max = 726 ng/mL, SN-38 C_max = 13 ng/mL; mean TMZ C_max= 3510 ng/mL; mean CTX CL = 2.14 L/h/m²; mean TOPO AUC_τ = 42.8 h∙ng/mL).

Interpretation, Conclusion or Significance: Palbociclib exhibited dose-proportional PK over the range of 55-95 mg/m² QD and comparable exposure across the chemotherapy combinations. Palbociclib and combinatorial chemotherapy had similar exposure as reported in previous studies indicating a lack of drug-drug interaction between them. Palbociclib exposure at the 75 mg/m² QD was similar to that observed in adult participants at the approved 125 mg QD dose suggesting appropriate body surface area-based dosing and attainment of expected target exposure in pediatric population.

Disclosures: The study was sponsored by Pfizer.

Citations/References: 1. Flaherty KT, et al, Clin Cancer Res 2012;18(2):568-76. 2. Bomgaars LR, et al. J Clin Oncol 2007;25(29):4622-7. 3. Baruchel S, et al. Eur J Cancer 2006 4. Tasso MJ., et al. Cancer Chemotherapy and Pharmacology 1992;30 3:207-211. 5. Saylors RL, et al. J Clin Oncol. 1998;16(3):945-52.

Additional Information/Authors: The authors would like to thank Dr. Mohamed Elmeliegy and Dr. Diane Wang for their initial contribution to the study and scientific discussions on the PK data, and Dr Ariadna Holynskyj, Dr Jodi Muscal, and Dr Ayşe Neslihan Aslan for their continuous scientific and clinical support for study execution.