The PARP inhibitor olaparib combined with ceralasertib-an investigational ATR inhibitor-showed clinical benefit among pediatric patients with solid tumors exhibiting DNA replication stress and/or DNA repair deficiencies. These findings from a Phase I portion of the Phase I/II AcSe-ESMART trial, which were presented during the AACR Annual Meeting 2023, also demonstrated that this combination approach was well-tolerated with a manageable safety profile (Abstract CT019).
"To our knowledge, the combination of PARP inhibitors and ATR inhibitors has not been widely investigated in adult tumor types," said Susanne Gatz, MD, PhD, Associate Clinical Professor in Pediatric Oncology at the Institute of Cancer and Genomic Sciences of the University of Birmingham in the U.K. "This is the first proof of principle that the combination is well-tolerated and can lead to clinically relevant responses in pediatric cancers."
Study Details
AcSe-ESMART is a proof-of-concept, platform therapeutic, stratification trial of molecular anomalies in relapsed or refractory tumors, according to Gatz. Eligible patients include children and adolescents with relapsed or refractory cancer who had undergone advanced molecular profiling at relapse. So far, Gatz and colleagues have evaluated 15 different treatments-the majority combination approaches-in more than 220 children.
Each arm of the study is conducted independently. Arm N of the trial is tailored toward patients with malignancies that exhibit defects in DNA replication and damage repair. In this arm, the primary objective of Phase I is to define the recommended Phase II dose of olaparib plus ceralasertib in children and adolescents, Gatz said. In Phase II, the primary objective is to define and determine the preliminary activity in the molecularly enriched patient cohorts.
"Secondary objectives include characterization of the toxicity profile, characterization of the PK of both drugs in combination, and to explore relationships between tumor response and molecular alterations," she explained during a press conference.
All patients had to have molecular alterations consistent with homologous recombination deficiency (HRD) or replication/transcription stress (RS) in their tumor, according to the study authors. Researchers enrolled 18 pediatric and young adult patients in the Phase I portion of AcSe-ESMART Arm N. Of these patients, eight had sarcoma, five had central nervous system tumors, four had neuroblastoma, and one had carcinoma. Sixteen patients, or 89 percent, had metastatic disease.
The study authors evaluated three dose levels of twice-daily oral olaparib given continuously and ceralasertib given on Days 1-14 of each 28-day cycle. Patients received a median of 3.5 cycles of treatment. The recommended Phase II dose was determined to be 150 mg of olaparib and 80 mg of ceralasertib in patients ages 12-18. The recommended dose regimen for children younger than 12 has yet to be determined.
Gatz and colleagues reported that the combination treatment was well-tolerated overall and toxicity was mainly hematologic-thrombocytopenia, neutropenia, anemia-and gastrointestinal that included nausea/vomiting. Five patients experienced dose-limiting toxicities (thrombocytopenia and neutropenia). Two of these events occurred at the recommended Phase II dose.
While discussing efficacy, Gatz noted that preliminary activity was observed among patients treated with a combination of olaparib and ceralasertib. The researchers reported one confirmed partial response in a patient with pineoblastoma who received treatment for 11 cycles.
A patient with neuroblastoma had stable disease that converted to a partial response following Cycle 9 of treatment. This response was confirmed after Cycle 11, according to Gatz, who noted that the patient is still undergoing treatment in Cycle 12. Another three patients-two in Cycle 8 and one in Cycle 15-remain on treatment.
Gatz reported that nine patients had stable disease as their best response to the treatment regimen. This included two patients with neuroblastoma and one with a papillary spinal cord tumor who had prolonged stable disease (>4 cycles).
"Olaparib and ceralasertib in combination are well-tolerated," Gatz summarized. "We have a recommended Phase II dose, which equals the adult optimized Phase II dose in children 12 and older."
The pharmacokinetics is still in progress, according to Gatz, who noted that recruitment in two expansion cohorts (HRD and RS) is ongoing at the recommended Phase II dose. Confirmation of the recommended Phase II dose in younger children is also ongoing.
While presenting her team's research, Gatz concluded, "Retrospective molecular in-depth correlative analysis will be key to better understand which patients benefit, and close interaction and exchange with the involved pharma partner is crucial to allow development of these drugs in children."
Catlin Nalley is a contributing writer.