TY - JOUR
T1 - Pilot Study of High-Dose Pemetrexed in Patients with Progressive Chordoma
AU - Kesari, Santosh
AU - Wagle, Naveed
AU - Carrillo, Jose A.
AU - Sharma, Akanksha
AU - Nguyen, Minhdan
AU - Truong, Judy
AU - Gill, Jaya M.
AU - Nersesian, Raffi
AU - Nomura, Natsuko
AU - Rahbarlayegh, Elnaz
AU - Barkhoudarian, Garni
AU - Sivakumar, Walavan
AU - Kelly, Daniel F.
AU - Krauss, Howard
AU - Bustos, Matias A.
AU - Hoon, Dave S.B.
AU - Anker, Lars
AU - Singh, Arun S.
AU - Sankhala, Kamalesh K.
AU - Juarez, Tiffany M.
N1 - Publisher Copyright:
©2023 American Association for Cancer Research.
PY - 2024/1/15
Y1 - 2024/1/15
N2 - Purpose: Chordomas are ultrarare tumors of the axial spine and skull-base without approved systemic therapy. Most chordomas have negative expression of thymidylate synthase (TS), suggesting a potential for responding to the antifolate agent pemetrexed, which inhibits TS and other enzymes involved in nucleotide biosynthesis. We evaluated the therapeutic activity and safety of high-dose pemetrexed in progressive chordoma. Patients and Methods: Adult patients with previously treated, progressive chordoma participated in an open-label, single-institution, single-arm, pilot clinical trial of intravenous pemetrexed 900 mg/m2 every 3 weeks and supportive medications of folic acid, vitamin B12, and dexamethasone. The primary endpoint was objective response rate according to RECIST v1.1. Secondary endpoints included adverse events, progression-free survival (PFS), tumor molecular profiles, and alterations in tissue and blood-based biomarkers. Results: Fifteen patients were enrolled and the median number of doses administered was 15 (range, 4–31). One patient discontinued treatment due to psychosocial issues after four cycles and one contracted COVID-19 after 13 cycles. Of the 14 response-evaluable patients, 2 (14%) achieved a partial response and 10 (71%) demonstrated stable disease. Median PFS was 10.5 months (95% confidence interval: 9 months–undetermined) and 6-month PFS was 67%. Adverse events were expected and relatively mild, with one grade 3 creatinine increased, and one each of grade 3 and 4 lymphopenia. No grade 5 adverse events, unexpected toxicities, or dose-limiting toxicities were observed. Several patients reported clinical improvement in disease-related symptoms. Conclusions: High-dose pemetrexed appears tolerable and shows objective antitumor activity in patients with chordoma. Phase II studies of high-dose pemetrexed are warranted.
AB - Purpose: Chordomas are ultrarare tumors of the axial spine and skull-base without approved systemic therapy. Most chordomas have negative expression of thymidylate synthase (TS), suggesting a potential for responding to the antifolate agent pemetrexed, which inhibits TS and other enzymes involved in nucleotide biosynthesis. We evaluated the therapeutic activity and safety of high-dose pemetrexed in progressive chordoma. Patients and Methods: Adult patients with previously treated, progressive chordoma participated in an open-label, single-institution, single-arm, pilot clinical trial of intravenous pemetrexed 900 mg/m2 every 3 weeks and supportive medications of folic acid, vitamin B12, and dexamethasone. The primary endpoint was objective response rate according to RECIST v1.1. Secondary endpoints included adverse events, progression-free survival (PFS), tumor molecular profiles, and alterations in tissue and blood-based biomarkers. Results: Fifteen patients were enrolled and the median number of doses administered was 15 (range, 4–31). One patient discontinued treatment due to psychosocial issues after four cycles and one contracted COVID-19 after 13 cycles. Of the 14 response-evaluable patients, 2 (14%) achieved a partial response and 10 (71%) demonstrated stable disease. Median PFS was 10.5 months (95% confidence interval: 9 months–undetermined) and 6-month PFS was 67%. Adverse events were expected and relatively mild, with one grade 3 creatinine increased, and one each of grade 3 and 4 lymphopenia. No grade 5 adverse events, unexpected toxicities, or dose-limiting toxicities were observed. Several patients reported clinical improvement in disease-related symptoms. Conclusions: High-dose pemetrexed appears tolerable and shows objective antitumor activity in patients with chordoma. Phase II studies of high-dose pemetrexed are warranted.
UR - http://www.scopus.com/inward/record.url?scp=85182741997&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-23-2317
DO - 10.1158/1078-0432.CCR-23-2317
M3 - Article
C2 - 38047868
AN - SCOPUS:85182741997
SN - 1078-0432
VL - 30
SP - 323
EP - 333
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 2
ER -