Details

Autor(en) / Beteiligte

• Cole, Kristina A.
• Ijaz, Heba
• Surrey, Lea F.
• Santi, Mariarita
• Liu, Xiaowei
• Minard, Charles G.
• Maris, John M.
• Voss, Stephan
• Reid, Joel M.
• Fox, Elizabeth
• Weigel, Brenda J.

Titel

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

Ist Teil von

• Cancer, 2023-07, Vol.129 (14), p.2245-2255

Ort / Verlag

United States: Wiley Subscription Services, Inc

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. This is the first phase 2 clinical trial of the WEE1 inhibitor adavosertib in pediatrics and the first in combination with irinotecan in cancer. The combination met the phase 2 clinical trial efficacy end point in neuroblastoma.