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- Title
Phase 1 trial of nelfinavir added to standard cisplatin chemotherapy with concurrent pelvic radiation for locally advanced cervical cancer.
- Authors
Garcia‐Soto, Arlene E.; McKenzie, Nathalie D.; Whicker, Margaret E.; Pearson, Joseph M.; Jimenez, Edward A.; Portelance, Lorraine; Hu, Jennifer J.; Lucci, Joseph A.; Qureshi, Rehman; Kossenkov, Andrew; Schwartz, Lauren; Mills, Gordon B.; Maity, Amit; Lin, Lilie L.; Simpkins, Fiona; Garcia-Soto, Arlene E; Lucci, Joseph A 3rd
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>NFV with CRT is well tolerated. The response rate is promising compared with historic controls in this patient population and warrants further investigation.
- Subjects
CERVICAL cancer; HIV protease inhibitors; RADIATION injuries; CISPLATIN; SQUAMOUS cell carcinoma
- Publication
Cancer (0008543X), 2021, Vol 127, Issue 13, p2279
- ISSN
0008-543X
- Publication type
journal article
- DOI
10.1002/cncr.33449