Nelfinavir in combination with Cisplatin and Pelvic Radiation Therapy

Cervical Cancer

Nelfinavir (NFV) will be prescribed orally twice daily for 7 days prior to initiation of cisplatin and pelvic radiation at the starting dose level, 875 mg BID

Nelfinavir

Cisplatin at 40 mg/m2 (maximum total dose of 70 mg per week), will be infused intravenously once per week on either Day 1, 2, 3, 4, or 5 of weeks 2 to 6, preferably approximately four hours prior to radiation therapy. One additional cycle of cisplatin will be given either week 7 or 8 for a total of 6 cycles of cisplatin. Patients are not to be dosed more than 70 mg/week.

Cisplatin

Pelvic external beam radiation therapy (PEBRT) will be delivered in combination with weekly IV cisplatin (40mg/mg2) and twice daily oral NFV.PEBRT should be delivered once each day during the business week (Monday to Friday) according to the acceptable standards of care as prescribed by the treating radiation oncologist(s). The radiation therapy should consist of whole pelvic external beam radiation therapy (WPEBRT) with or without a parametrial boost (PB). PEBRT will be interdigitated with one administration of intrauterine brachytherapy (BT) given on any business day of week 7 or 8.

Pelvic External Beam Radiation Therapy

PEBRT will be interdigitated with one administration of intrauterine brachytherapy (BT) given on any business day of week 7 or 8.

Brachytherapy

Serum levels of Nelfinavir will be assayed at the following 3 time points: 5-8 days after initiation of NFV single agent (on Day 5, 6, or 7 of week 1 or day 1 of week 2), 1 week after combined NFV and cisplatin pelvic radiation (on day 15, 16, or 17 if start on Monday) for measurement of steady state, and at the completion of treatment (within the last 3 days of radiation in week 6). Blood samples will be taken before drug administration on the day of the sample to make sure the concentrations are actually at a minimum and before tumor biopsies.

Pharmacokinetic Sampling

Three punch biopsies of cervical tumor will be obtained during office visit at each time point (for PCR, IHC, and banked for future research). NFV serum levels will be obtained once NFV has been started (day 5-8 pre chemoradiation and at completion of chemoradiation) before each cervical biopsy

Cervical Biopsy

Pre-Treatment, at the end of treatment +/- 1 week, every 3 months +/- 2 weeks after therapy (x 1 year)

Pelvic Examination

Recommended. Every 3 months +/- 2 weeks after therapy (x 1 year)

Pap Smear

Required in patients with history of hearing loss; 28 days within starting treatment and every other cycle.

Audiogram

Proctoscopy

Cytoscopy

Renal Ultrasound

CT Scan of Chest/Abdomen/Pelvis, pre-treatment,Immediately at end of trial +/- 1 week, Every 3 months +/- 2 weeks after therapy (x 1 year)

CT Scan

In lieu of CT Scan, pre-treatment,Immediately at end of trial +/- 1 week, Every 3 months +/- 2 weeks after therapy (x 1 year)

Whole Body PET/CT Scan

University of Miami

Safety Study of Nelfinavir + Cisplatin + Pelvic Radiation Therapy to Treat Cervical Cancer

Phase 1 Study of Nelfinavir Added to Cisplatin Chemotherapy Concurrent With Pelvic Radiation for Locally Advanced Cervical Cancer (II-IVA)

Number of Patients with Adverse Events in Phase 1 Study of Nelfinavir + Cisplatin + Pelvic Radiation Therapy

Maximum tolerable Phase II dose of Nelfinavir in combination with Cisplatin and Pelvic Radiation Therapy.

To determine the levels of Akt activity (and downstream effectors such as pGSK3, pEBP1) and p16INK4A in addition to the presence of Human Papilloma Virus (HPV) 16 and18,and E6/E7 RNA in cervical biopsy specimens of patients at three different time points (1. pre-nelfinavir, pre-radiation, 2. while on nelfinavir, pre-radiation, 3. at completion of radiation therapy), and correlate the levels of these markers to serum Nelfinavir levels from blood drawn at the day of the biopsy.

Tumor response to protocol therapy will be measured using Response Evaluation Criteria In Solid Tumors (RECIST) criteria.

Progression-Free Survival is the period from start of treatment until documented disease progression or death from any cause. For surviving patients without progression, progression-free survival will be censored at the last date of documented progression-free status.

Survival is the observed length of life from start of treatment to death. For surviving patients, follow-up will be censored at the date of last contact.

papilloma/дијареја

Safety Study of Nelfinavir + Cisplatin + Pelvic Radiation Therapy to Treat Cervical Cancer

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