Pediatric phase 2 trial of a WEE1 inhibitor, adavosertib (AZD1775), and irinotecan for relapsed neuroblastoma, medulloblastoma, and rhabdomyosarcoma

Abstract

Background: Inhibition of the WEE1 kinase by adavosertib (AZD1775) potentiates replicative stress from genomic instability or chemotherapy. This study reports the pediatric solid tumor phase 2 results of the ADVL1312 trial combining irinotecan and adavosertib.

Methods: Pediatric patients with recurrent neuroblastoma (part B), medulloblastoma/central nervous system embryonal tumors (part C), or rhabdomyosarcoma (part D) were treated with irinotecan and adavosertib orally for 5 days every 21 days. The combination was considered effective if there were at least three of 20 responses in parts B and D or six of 19 responses in part C. Tumor tissue was analyzed for alternative lengthening of telomeres and ATRX. Patient's prior tumor genomic analyses were provided.

Results: The 20 patients with neuroblastoma (part B) had a median of three prior regimens and 95% had a history of prior irinotecan. There were three objective responses (9, 11, and 18 cycles) meeting the protocol defined efficacy end point. Two of the three patients with objective responses had tumors with alternative lengthening of telomeres. One patient with pineoblastoma had a partial response (11 cycles), but parts C and D did not meet the protocol defined efficacy end point. The combination was well tolerated and there were no dose limiting toxicities at cycle 1 or beyond in any parts of ADVL1312 at the recommended phase 2 dose.

Conclusion: This is first phase 2 clinical trial of adavosertib in pediatrics and the first with irinotecan. The combination may be of sufficient activity to consider further study of adavosertib in neuroblastoma.

Keywords: AZD1775; WEE1; adavosertib; alternative lengthening of telomeres (ALT); irinotecan; pediatric cancer.

FIGURE 1

Swimmer plot to summarize the patient level methods of evaluation, response, and ALT and ATRX status for neuroblastoma (Part B). The colored bars indicate response or prolonged SD; the gray bars are neither response nor SD. Where there is no bar (subjects 18–20), subjects did not have end of cycle 1 disease evaluations. In the case of responders, the first marker on the bar is placed at the time of the confirmed response. For nonresponders, the first marker will be cycle 1. The final marker is the status at the final study evaluation. Although not marked, routine evaluations occurred after cycle 1 and cycle 2; every other cycle × 2 and then every three cycles until progression or a maximum of 18 cycles. If there is no red or black outline around the bar, this indicates that tissue was not available for correlative biology studies. All patients had MYCN‐nonamplified disease except for subjects 13 and 18 (MYCN amplified) and 3 and 4 (unknown MYCN status). All patients had been treated at some point with a prior irinotecan‐containing regimen, except subject 4. Subject 3 (PR) enrolled on ADVL1312 after progressing on an irinotecan‐containing regimen. PR indicates partial response; SD, stable disease.

FIGURE 2

Representative images from subject 3 who had both measurable and MIBG‐evaluable neuroblastoma and an overall central radiology reviewed PR from cycles 3 through 8, and PD at cycle 11. This patient enrolled with a history of progressive disease on a prior irinotecan‐containing regimen. The left top panel shows the baseline 3.5‐cm paraspinal mass (denoted by the red arrow), which is absent in cycle 5 in the top right panel. The bottom panels demonstrate the corresponding MIBG imaging. The bottom left panel shows the baseline pretherapy MIBG imaging of the paraspinal mass. Although the cycle 5 MIBG paraspinal mass demonstrated a CR (lower half, bottom right panel), there remained a small focus of residual MIBG‐avid disease at the L5 vertebrae at cycle 5 (denoted by the * on the upper half bottom right panel), so the overall response was a PR (Figure S1). CR, complete response; MIBG, metaiodobenzylguanidine; PD, progressive disease; PR, partial response.

FIGURE 3

Swimmer plot to summarize the patient level diagnosis and response for the medulloblastoma/embryonal tumor (part C) and rhabdomyosarcoma (part D) cohorts. The patterned bars indicate response or prolonged stable disease (≥6 cycles); the gray solid bars are neither response nor SD. In the case of the responder, the first marker on the bar is placed at the time of the confirmed response. For nonresponders, the first marker will be cycle 1. The final marker is the status at the final study evaluation. Although not marked, routine evaluations occurred after cycle 1 and cycle 2; every other cycle × 2 and then every 3 cycles until progression or a maximum of 18 cycles. SD indicates stable disease.

FIGURE 4

Ultrabright telomeric foci by multiplex Tel‐FISH and immunofluorescence. (A) Archival tissue obtained at diagnosis from subject 7 demonstrates colocalization in the middle right panel of nuclear Phox2B (green) and ultrabright telomeric foci (red) in the neuroblastoma tumor, which is absent in nonneuroblastoma cells that stain only for DAPI nuclear stain (blue). ATRX IHC in the lower right panel demonstrates loss of nuclear ATRX protein staining (brown) in the neuroblastoma nuclei consistent with an ATRX‐mutant tumor. (B) Archival tissue from subject 3 similarly demonstrates colocalization of nuclear Phox2B and ultrabright telomeric foci in a scattered clusters of residual neuroblastoma after induction chemotherapy. The lower right panel is a magnified image of the left middle panel to highlight the telomeric foci. The DAPI, Phox2B, and ultrabright telomeric foci for subject 3 are imaged from the same histopathology slide. Although the H&E and ATRX immunohistochemistry images (Figure S2) are from the same tissue block and are from adjacent sections, they are different slides and hence show different cellular clusters of the tumor. H&E, hematoxylin and eosin; IHC, immunohistochemistry.