TY - JOUR
T1 - Phase 1 trial of nelfinavir added to standard cisplatin chemotherapy with concurrent pelvic radiation for locally advanced cervical cancer
AU - Garcia-Soto, Arlene E.
AU - McKenzie, Nathalie D.
AU - Whicker, Margaret E.
AU - Pearson, Joseph M.
AU - Jimenez, Edward A.
AU - Portelance, Lorraine
AU - Hu, Jennifer J.
AU - Lucci, Joseph A.
AU - Qureshi, Rehman
AU - Kossenkov, Andrew
AU - Schwartz, Lauren
AU - Mills, Gordon B.
AU - Maity, Amit
AU - Lin, Lilie L.
AU - Simpkins, Fiona
N1 - Funding Information:
Gordon B. Mills reports grants, personal fees, nonfinancial support, and other support from Amphista, AstraZeneca, Chrysallis Biotechnology, Myriad Genetics, ImmunoMET, Ionis, Lilly, PDX Pharmaceuticals, Signalchem Lifesciences, Symphogen, Tarveda, Turbine, Zentalis Pharmaceuticals, Genentech, Glaxo‐Smith‐Kline, and Catena Pharmaceuticals, outside the submitted work. Lilie L. Lin reports grants and travel support from AstraZeneca and grants from Pfizer, outside the submitted work. The remaining authors made no disclosures.
Funding Information:
This study was supported in part by an American Society for Clinical Oncology (ASCO) Young Investigator Award (Nathalie D. McKenzie, principal investigator; Fiona Simpkins, mentor), an Abramson Cancer Center Radiation Oncology pilot grant (Fiona Simpkins, Lilie L. Lin, and Amit Maity), the National Institutes of Health (grant R01 CA174976; Amit Maity), and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (Gordon B. Mills).
Publisher Copyright:
© 2021 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.
PY - 2021/7/1
Y1 - 2021/7/1
N2 - Background: Nelfinavir (NFV), an HIV-1 protease inhibitor, has been shown to sensitize cancer cells to chemoradiation (CRT). The objectives of this phase 1 trial were to evaluate safety and identify the recommended phase 2 dose of NFV added to concurrent CRT for locally advanced cervical cancer. Methods: Two dose levels of NFV were evaluated: 875 mg orally twice daily (dose level 1 [DL1]) and 1250 mg twice daily (DL2). NFV was initiated 7 days before CRT and continued through CRT completion. Toxicity, radiographic responses, and pathologic responses were evaluated. Serial tumor biopsies (baseline, after NFV monotherapy, on NFV + CRT, and posttreatment) were evaluated by immunohistochemistry, NanoString, and reverse-phase-protein-array analyses. Results: NFV sensitized cervical cancer cells to radiation, increasing apoptosis and tumor suppression in vivo. Patients (n = 13) with International Federation of Gynecology and Obstetrics stage IIA through IVA squamous cell cervical carcinoma were enrolled, including 7 patients at DL1 and 6 patients at DL2. At DL1, expansion to 6 patients was required after a patient developed a dose-limiting toxicity, whereas no dose-limiting toxicities occurred at DL2. Therefore, DL2 was established as the recommended phase 2 dose. All patients at DL2 completed CRT, and 1 of 6 experienced grade 3 or 4 anemia, nausea, and diarrhea. One recurrence was noted at DL2, with disease outside the radiation field. Ten of 11 evaluable patients remained without evidence of disease at a median follow-up of 50 months. NFV significantly decreased phosphorylated Akt levels in tumors. Cell cycle and cancer pathways also were reduced by NFV and CRT. Conclusions: NFV with CRT is well tolerated. The response rate is promising compared with historic controls in this patient population and warrants further investigation.
AB - Background: Nelfinavir (NFV), an HIV-1 protease inhibitor, has been shown to sensitize cancer cells to chemoradiation (CRT). The objectives of this phase 1 trial were to evaluate safety and identify the recommended phase 2 dose of NFV added to concurrent CRT for locally advanced cervical cancer. Methods: Two dose levels of NFV were evaluated: 875 mg orally twice daily (dose level 1 [DL1]) and 1250 mg twice daily (DL2). NFV was initiated 7 days before CRT and continued through CRT completion. Toxicity, radiographic responses, and pathologic responses were evaluated. Serial tumor biopsies (baseline, after NFV monotherapy, on NFV + CRT, and posttreatment) were evaluated by immunohistochemistry, NanoString, and reverse-phase-protein-array analyses. Results: NFV sensitized cervical cancer cells to radiation, increasing apoptosis and tumor suppression in vivo. Patients (n = 13) with International Federation of Gynecology and Obstetrics stage IIA through IVA squamous cell cervical carcinoma were enrolled, including 7 patients at DL1 and 6 patients at DL2. At DL1, expansion to 6 patients was required after a patient developed a dose-limiting toxicity, whereas no dose-limiting toxicities occurred at DL2. Therefore, DL2 was established as the recommended phase 2 dose. All patients at DL2 completed CRT, and 1 of 6 experienced grade 3 or 4 anemia, nausea, and diarrhea. One recurrence was noted at DL2, with disease outside the radiation field. Ten of 11 evaluable patients remained without evidence of disease at a median follow-up of 50 months. NFV significantly decreased phosphorylated Akt levels in tumors. Cell cycle and cancer pathways also were reduced by NFV and CRT. Conclusions: NFV with CRT is well tolerated. The response rate is promising compared with historic controls in this patient population and warrants further investigation.
KW - carcinoma
KW - chemoradiotherapy
KW - nelfinavir
KW - squamous cell
KW - uterine cervical neoplasms
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U2 - 10.1002/cncr.33449
DO - 10.1002/cncr.33449
M3 - Article
C2 - 33932031
AN - SCOPUS:85105171446
SN - 0008-543X
VL - 127
SP - 2279
EP - 2293
JO - Cancer
JF - Cancer
IS - 13
ER -