Radiosensitizing Effect of Nelfinavir in Locally Advanced Carcinoma of Cervix

The primary aim of the trial is to study the impact of nelfinavir on 3 year disease free survival in patients with advanced carcinoma of cervix receiving standard chemoradiation (Cisplatin and Radiotherapy). There will be two study groups. One group will receive standard treatment (concurrent chemoradiation and brachytherapy) \& other group will receive nelfinavir 5-7 days prior to standard treatment (chemoradiation \& brachytherapy).

Sex

Female

Minimum age

18 Years

Maximum age

65 Years

Inclusion Criteria

* ECOG 0 to 2
* FIGO 2018 Stage IIIA (TNM stage T3a N0 M0) FIGO 2018 Stage IIIB (TNM stage T3b N0 M0) FIGO 2018 Stage IIIC (TNM stage Any T N1 M0)
* No previous irradiation to the pelvis or chemotherapy
* Age 18 years and above
* Ability to tolerate full course of pelvic radiotherapy and brachytherapy
* Adequate bone marrow, liver, and kidney function defined as neutrophil count ≥ 1500 platelet count ≥ 100,000, total bilirubin less than 1.5 x upper limit of normal (ULN), AST and ALT ≤ 2.5 x ULN, and creatinine less than 1.5 upper limit of normal or Creatinine clearance greater than 60 mL/min/1.73 m2
* No recent (less than 3 months) severe cardiac disease (arrhythmia, congestive heart failure, infarction)
* Ability to understand and the willingness to sign an informed consent document
* Should be willing to undergo extra biopsy and blood collection for pharmacokinetic studies

Exclusion criteria

* Patients with newly diagnosed diabetes , uncontrolled DM (patient with HbA1c of \> 6.5% or FBS value or BSF\>=126 mg/dL respectively on primary evaluation)
* Pts on any drugs which has pharmacological interaction with nelfinavir:

  * Terfenadine, cisapride, sildenafil, lovastatin or simvastatin and medication that are metabolized by the CYP3A4 isoenzyme.
  * Antiarrhythmics (amiodarone, quinidine).
  * Neuroleptics (pimozide).
  * Sedative/Hypnotic agents (midazolam, triazolam).
  * Ergot derivatives.
  * HMG-CoA reductase inhibitors (atorvastatin).
  * Rifampicin, Rifabutin.
  * Felodipine, Nifedipine.
* Pregnant or lactating
* Active co existing malignancy.
* HIV positive patients will be excluded.
* Patients with hemophilia.
* Patients with reduced creatinine clearance ( less than 50 ml/ min) or unilateral or bilateral hydronephrosis will be excluded.
* History of psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

• BACKGROUNDDiehl JA, Cheng M, Roussel MF, Sherr CJ. Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev. 1998 Nov 15;12(22):3499-511. doi: 10.1101/gad.12.22.3499. PMID 9832503
• BACKGROUNDKoumenis C. ER stress, hypoxia tolerance and tumor progression. Curr Mol Med. 2006 Feb;6(1):55-69. doi: 10.2174/156652406775574604. PMID 16472113
• BACKGROUNDToulany M, Kasten-Pisula U, Brammer I, Wang S, Chen J, Dittmann K, Baumann M, Dikomey E, Rodemann HP. Blockage of epidermal growth factor receptor-phosphatidylinositol 3-kinase-AKT signaling increases radiosensitivity of K-RAS mutated human tumor cells in vitro by affecting DNA repair. Clin Cancer Res. 2006 Jul 1;12(13):4119-26. doi: 10.1158/1078-0432.CCR-05-2454. PMID 16818713
• BACKGROUNDGupta AK, McKenna WG, Weber CN, Feldman MD, Goldsmith JD, Mick R, Machtay M, Rosenthal DI, Bakanauskas VJ, Cerniglia GJ, Bernhard EJ, Weber RS, Muschel RJ. Local recurrence in head and neck cancer: relationship to radiation resistance and signal transduction. Clin Cancer Res. 2002 Mar;8(3):885-92. PMID 11895923
• BACKGROUNDKeys HM, Bundy BN, Stehman FB, Muderspach LI, Chafe WE, Suggs CL 3rd, Walker JL, Gersell D. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med. 1999 Apr 15;340(15):1154-61. doi: 10.1056/NEJM199904153401503. PMID 10202166
• BACKGROUNDRose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, Clarke-Pearson DL, Insalaco S. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med. 1999 Apr 15;340(15):1144-53. doi: 10.1056/NEJM199904153401502. PMID 10202165
• BACKGROUNDMorris M, Eifel PJ, Lu J, Grigsby PW, Levenback C, Stevens RE, Rotman M, Gershenson DM, Mutch DG. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med. 1999 Apr 15;340(15):1137-43. doi: 10.1056/NEJM199904153401501.