Denic, Kristina Z.

ABSTRACT Background Nab ‐sirolimus (ABI‐009, nab ‐rapamycin; Aadi Bioscience Inc. [Aadi]) is a human albumin‐bound form of sirolimus nanoparticles, a potent mTOR inhibitor. This phase I trial was conducted to define dose‐limiting toxicities (DLT), maximum tolerated or recommended phase II dose (MTD/RP2D), and pharmacokinetics of Nab ‐sirolimus in combination with temozolomide and irinotecan. Methods Using a rolling 6 design, Nab ‐sirolimus was administered intravenously (IV) on days (D) 1 and 8 of cycle (C) 1. In subsequent cycles, Nab ‐sirolimus was administered D1 and D8 in combination with temozolomide (125 mg/m 2 /dose, maximum 250 mg/dose) and irinotecan (90 mg/m 2 /dose) orally, daily on D1–5. Cycle duration was 21 days. Three dose levels (DL) of Nab ‐sirolimus were investigated (DL1: 35 mg/m 2 /dose, DL‐1: 20 mg/m 2 /dose, and DL‐2: 15 mg/m 2 /dose). The observation period for estimating the MTD/RP2D was defined by cycles 1 and 2. Results Thirty‐three patients were enrolled, 32 were eligible. Dose determination included 17 evaluable patients, median (range) age 12 (2–20) years and six additional patients were enrolled (four evaluable for toxicity) on a pharmacokinetic cohort. C1 or C2 DLTs were primarily thrombocytopenia including 2/5 patients at DL1, 2/6 patients at DL‐1, and 1/6 patients at DL‐2. One patient (DL1) with Ewing Sarcoma had a partial response and remained on study for 35 cycles. Rapamycin clearance was dose dependent. Irinotecan clearance and its active metabolite SN‐38 exposure were not affected by coadministration with Nab ‐sirolimus. Conclusion The MTD for Nab ‐sirolimus was 15 mg/m 2 /dose IV on D1 and D8 in combination with temozolomide 125 mg/m 2 /dose and oral irinotecan 90 mg/m 2 /dose daily for 5 days during 21D cycles. Trial Registration ClinicalTrials.gov identifier NCT02975882

Abstract Introduction: Irinotecan is an inhibitor of the topoisomerase I enzyme that is essential in DNA transcription, replication, and repair. It is considered a “backbone” regime in colorectal cancer in adults and in pediatric gliomas to which other antineoplastic agents are added to improve the outcome. It is used as well in the treatment of many other types of adult and pediatric cancers. Irinotecan acts as a prodrug of SN-38 which has approximately 100-1000-fold greater cytotoxic activity. The metabolic and pharmacokinetic behavior of irinotecan is very complex and currently not completely elucidated. Clinical data have shown high variability in treated patients in the efficacy, toxicity, and pharmacokinetic profile of the drug. To increase safety and efficacy, a physiologically based pharmacokinetic modeling (PBPK) approach was used to predict the optimal dose for treatment initiation. Methods: Clinical data were used in combination with measured physicochemical and blood-binding data to inform the model. Hence a middle-out approach was used to build the parent model for a population of adult cancer patients. While the default Sim-Cancer population available within the Simcyp Simulator (v21) was used, the unbound fraction in plasma for the healthy population was incorporated into the PBPK model. By using the reverse translational tool and a retrograde approach, the irinotecan metabolism was described by incorporating CYP3A (Km 14.4±1.6 μM, Vmax 14.7± 0.6 pmol/min/mg protein) and an additional clearance. This additional clearance was then explained by scaled esterases (CES1 and CES2) enzyme kinetic from in vitro data. Besides the clinical study that was used to build the model, other independent intravenously administered irinotecan studies were used for verification. Results: The model predicted the plasma concentration of the parent drug and its metabolite (SN-38) in good agreement with observed data from the clinical study that was used to build the model, as well as from several clinical studies that were not used to build the initial model, covering a dose range of 50-750 mg/m2. Conclusion: We developed a PBPK model that accurately predicts the pharmacokinetic behavior of irinotecan and its metabolite (SN-38) in an adult cancer population. Future directions involve the adaption of the model to the pediatric cancer population to predict the optimal dose for initiation of first-in-human Phase I studies and to identify potential drug interactions and unanticipated toxicities when this “backbone” regimen is combined with other investigated anticancer agents. This will then lead to an increase in individualized treatment. Citation Format: Kristina Zoran Denic, Sibylle Neuhoff, Joel Reid, Rachel Kudget. A physiologically based pharmacokinetic modeling approach for predicting the exposure of irinotecan and its active metabolite (SN-38) in cancer patients [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A140.

Abstract Background Cyclin D has been shown to play an essential role in acute lymphoblastic leukemia (ALL) initiation and progression, providing rationale for targeting the CDK4/6‐cyclin D complex that regulates cell cycle progression. Procedure The Children's Oncology Group AINV18P1 phase 1 trial evaluated the CDK4/6 inhibitor, palbociclib, in combination with standard four‐drug re‐induction chemotherapy in children and young adults with relapsed/refractory B‐ and T‐cell lymphoblastic leukemia (ALL) and lymphoma. Palbociclib (50 mg/m 2 /dose) was administered orally once daily for 21 consecutive days, first as a single agent (Days 1–3) and subsequently combined with re‐induction chemotherapy. This two‐part study was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D), followed by an expansion pharmacokinetic cohort. Results Twelve heavily pretreated patients enrolled, all of whom were evaluable for toxicity. One dose‐limiting hematologic toxicity (DLT) occurred at the starting dose of 50 mg/m 2 /dose orally for 21 days. No additional DLTs were observed in the dose determination or pharmacokinetic expansion cohorts, and overall rates of grade 3/4 nonhematologic toxicities were comparable to those observed with the chemotherapy platform alone. Five complete responses were observed, two among four patients with T‐ALL and three among seven patients with B‐ALL. Pharmacokinetic studies showed similar profiles with both liquid and capsule formulations of palbociclib. Conclusions Palbociclib in combination with re‐induction chemotherapy was well tolerated with a RP2D of 50 mg/m 2 /day for 21 days. Complete responses were observed among heavily pretreated patients.

e15131 Background: Elimusertib is a highly selective oral inhibitor of the Ataxia telangiectasia and Rad3 related (ATR) kinase, which is required for efficient end-joining repair of double-stranded breaks, particularly during DNA replication. Many pediatric cancers involve potential ATR susceptibilities such as increased replication stress due to oncogenic fusions, specific DNA damage repair (DDR) deficiencies, oncogenic activation of DNA damage and nucleases such as PGBD5, as well as alternative lengthening of telomeres. We report the initial phase 1 results of PEPN2112 (NCT05071209), an ongoing pediatric phase 1/2 clinical trial of elimusertib monotherapy. Methods: Eligible patients (pts) included children, adolescents, and young adults with relapsed or refractory tumors with: (1) Ewing sarcoma or related EWSR1 fusion positive tumors (EWS), (2) alveolar rhabdomyosarcoma, PAX3-FOXO1 fusion positive (aRMS), or (3) non-CNS primary tumors exhibiting specific DDR pathway defects anticipated to sensitize to ATR inhibition. For pts < 18 years (yrs), a rolling-six design was used to evaluate elimusertib administered BID x3 days/week of a 28-day cycle starting at the adult equivalent recommended phase 2 dose (RP2D) of 24 mg/m2/dose (max 40 mg) with a potential de-escalation to 18 mg/m2/dose (max 30 mg). The pediatric RP2D determination was based upon dose limiting toxicity (DLT) criteria (CTCAEv5) during cycle 1. Pharmacokinetic (PK) studies were performed. Pts > 18 yrs could enroll onto the phase 2 cohorts at the adult RP2D simultaneously with the pediatric phase 1. Once the pediatric RP2D was defined, pts < 18 yrs accrued to the phase 2 cohorts and a PK expansion for pts < 12 yrs was opened. Results: 8 eligible pts were enrolled (4 males) on the phase 1 part of the study. 2 pts were inevaluable for DLT as they received < 75% of protocol therapy. Median (range) age was 13 (10-17) yrs. Diagnoses included: EWS (n = 4) and 1 pt each with aRMS, adrenocortical carcinoma, clear cell sarcoma, and osteosarcoma. At 24 mg/m2/dose, no DLTs were observed. Toxicities were hematologic, with grade 3 toxicities including anemia (n = 3), neutropenia (n = 4), and decreased white blood cells (n = 1). One pt experienced grade 4 lymphopenia. There were no grade 3/4 non-hematologic toxicities. Day 1 mean ± SD values of Tmax, Cmax, AUC0-8h and t1/2 were 1.6 ± 0.5 h, 1532 ± 385 ng/mL, 5863 ± 1841 h*ng/mL and 3.6 ± 0.9 h, respectively. Conclusions: Elimusertib-related toxicities were primarily hematologic. The RP2D for elimusertib monotherapy in pediatric pts is 24 mg/m2/dose (max 40 mg) orally BID x3 days/week continuously, analogous to dosing in adults with similar PK. Phase 2 and PK expansion cohorts as well as pharmacodynamic studies are ongoing. Clinical trial information: NCT05071209 .

Abstract Introduction: Tegavivint is a first in class small molecule inhibitor of Wnt-ß-catenin signaling that functions by disrupting the interaction of ß-catenin and TBL1/TBLR1 resulting in degradation of nuclear ß-catenin. Aberrant Wnt signaling has been identified as a key mechanism of cancer biology, resulting in uncontrolled transcription of pro-oncogenic Wnt target genes. Pre-clinical in vivo studies of tegavivint demonstrated anti-tumor activity in a variety of pediatric solid tumors, including osteosarcoma, Ewing sarcoma, and lymphoma. Methods: We conducted a phase 1 dose-escalation study of single agent tegavivint in children aged ≥12 months to ≤21 years with relapsed or refractory solid tumors including lymphoma and desmoid tumors. The dose escalation was conducted using a rolling six design starting with the recommended phase 2 dose (RP2D) in adults, 5 mg/kg, administered intravenously over four hours on days 1, 8 and 15 of a 28 day cycle. A single de-escalation to 4 mg/kg and escalations to 6.5 mg/kg and 8 mg/kg if pharmacokinetic (PK) parameters indicated were planned. Once the RP2D is defined a PK cohort and phase 2 cohorts including Ewing sarcoma, desmoid tumor, osteosarcoma, liver tumors, Wilms tumor and a disease agnostic cohort including cancers with Wnt alterations will be evaluated. Results: A total of 15 patients were enrolled on the phase 1 part of the study. Two patients were not treated due to pre-therapy DEXA scan demonstrating grade 1 osteoporosis; therefore, 13 patients received treatment with tegavivint on 2 dose levels (5 mg/kg and 6.5 mg/kg). The median age of treated patients was 16 years (range 3-21). Patient diagnoses included desmoid tumor (5), Wilms tumor (3), and one each of Ewing sarcoma, osteosarcoma, CIC::DUX4 sarcoma, neuroblastoma, and hepatocellular carcinoma. There were no dose limiting toxicities among 4 DLT-evaluable patients at DL1 and 6 at DL2. The maximum tolerated dose was not determined. Grade three or higher adverse events at least possibly related to treatment included anemia (2) and lymphopenia (2). A single patient had a grade 3 QT prolongation requiring cessation of tegavivint after cycle 3. At 5 mg/kg, the mean AUC was 94,900 hr*ng/mL (range 52,000-136,000), and at 6.5 mg/kg was 91,200 hr*ng/mL (range 28,400-144,000). The pediatric RP2D dose was determined to be 6.5 mg/kg based on the pre-specified objective of achieving pharmacologically relevant plasma concentrations and less than 20% difference in mean AUC between the two tested dose levels. Conclusions: Tegavivint is well tolerated in children with refractory solid tumors, the pediatric RP2D is 6.5 mg/kg demonstrating pharmacologically relevant plasma concentrations. The study is currently enrolling patients to a pharmacokinetic expansion cohort and will then proceed to phase 2. Citation Format: Sarah B. Whittle, Joseph G. Pressey, Xiaowei Liu, Charles G. Minard, Kristina Z. Denic, Joel M. Reid, Stacey L. Berg, Elizabeth Fox, Brenda J. Weigel. PEPN2011: a phase 1/2 study of tegavivint in children, adolescents, and young adults with recurrent or refractory solid tumors, including lymphomas and desmoid tumors: a report from the pediatric early phase clinical trials network [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT090.

Background Cyclin D has been shown to play an essential role in acute lymphoblastic leukemia (ALL) initiation and progression, providing rationale for targeting the CDK4/6-cyclin D complex that regulates cell cycle progression. Procedure The Children’s Oncology Group AINV18P1 phase 1 trial evaluated the CDK4/6 inhibitor, palbociclib, in combination with standard four-drug reinduction chemotherapy in children and young adults with relapsed/refractory B- and T-cell lymphoblastic leukemia (ALL) and lymphoma. Palbociclib (50 mg/m 2 /dose) was administered orally once daily for 21 consecutive days, first as a single agent (days 1-3) and subsequently combined with reinduction chemotherapy. This two-part study was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) followed by an expansion pharmacokinetic (PK) cohort. Results Twelve heavily pretreated patients enrolled, all of whom were evaluable for toxicity. One dose-limiting hematologic toxicity (DLT) occurred at the starting dose of 50 mg/m 2 /dose orally for 21 days. No additional DLTs were observed in the dose determination or PK expansion cohorts and overall rates of grade 3/4 non-hematologic toxicities were comparable to those observed with the chemotherapy platform alone. Five complete responses were observed, two among four patients with T-ALL and three among seven patients with B-ALL. Pharmacokinetic studies showed similar profiles with both liquid and capsule formulations of palbociclib. Conclusions Palbociclib in combination with reinduction chemotherapy was well tolerated with a RP2D of 50 mg/m 2 /day for 21 days. Complete responses were observed among heavily pretreated patients.