Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Radiosensitizing Effect of Nelfinavir in Locally Advanced Carcinoma of Cervix (NELCER)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03256916
Recruitment Status : Recruiting
First Posted : August 22, 2017
Last Update Posted : March 19, 2020
Sponsor:
Information provided by (Responsible Party):
Supriya Sastri (chopra), Tata Memorial Hospital

Tracking Information
First Submitted Date  ICMJE July 31, 2017
First Posted Date  ICMJE August 22, 2017
Last Update Posted Date March 19, 2020
Actual Study Start Date  ICMJE January 10, 2018
Estimated Primary Completion Date September 30, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 21, 2017)
Improvement in 3 year disease free survival [ Time Frame: 3 years ]
Improvement in 3 year disease free survival by the addition of Nelfinavir to patients with advanced carcinoma of cervix and receiving standard chemoradiation (Cisplatin and Radiotherapy).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 21, 2017)
  • Change in locoregional control rates at 3 years [ Time Frame: 3 years ]
    Change in locoregional control rates at 3 years by the addition of Nelfinavir to patients with advanced carcinoma of cervix and receiving standard chemoradiation (Cisplatin and Radiotherapy).
  • Overall survival at 5 years [ Time Frame: 5 years ]
    Overall survival at 5 years in test and control arms.
  • Incidence of grade 3/4 adverse events [ Time Frame: 5 years ]
    Incidence of grade 3/4 adverse events in patients with advanced carcinoma of cervix and receiving Nelfinavir along with standard chemoradiation (Cisplatin and Radiotherapy)
  • Changes in Akt levels in the tumor [ Time Frame: 5 years ]
    Changes in Akt levels in the tumor from pre Nelfinavir to post EBRT.
  • Change in tumour hypoxia using multifunctional PET/ MRI. [ Time Frame: 5 years ]
    Change in tumour hypoxia using multifunctional PET/ MRI.
  • Interindividual variability of Volume of distribution [ Time Frame: 5 years ]
    Cmax (Maximum concentration) will be estimated
  • Interindividual variability of Clearance of nelfinavir. [ Time Frame: 5 years ]
    Clearence (litres per hour)
  • Interindividual variability of Clearence of Nelfinavir [ Time Frame: 5 years ]
    Half Life (hrs)
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Radiosensitizing Effect of Nelfinavir in Locally Advanced Carcinoma of Cervix
Official Title  ICMJE A Phase III Randomized Clinical Trial to Study the Radiosensitizing Effect of Nelfinavir in Locally Advanced Carcinoma of Uterine Cervix.
Brief Summary

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).

Detailed Description

The trial is a single centre open label randomized unblinded phase-III study to evaluate the efficacy of an investigational drug (Nelfinavir) in combination with standard therapy consisting of weekly cisplatin and pelvic EBRT in cohort of patients diagnosed with stage IIIB Carcinoma cervix.

Patient registration / randomization procedure

300 Patients will be accrued from the Gynaec Oncology Service of Tata Memorial Centre, Mumbai. A study coordinator at TMC will coordinate the accrual and study process and ensure prompt accrual and proper documentation. Eligibility will be checked based on the selection criteria and written informed consent will be obtained prior to randomization. Patients will be given appropriate time to decide for participation. Randomization will be based on a chart prepared with the help of software using a random sorting algorithm. A screening log will be maintained and include the details of all patients screened.

There are two study arms. In Experimental arm (Nelfinavir arm) 150 patients will be accrued & in Control arm (Standard Arm) 150 patients will be accrued.

If patient is randomized to standard arm patient will receive concurrent chemoradiation and brachytherapy. If patient is randomized to nelfinavir arm then nelfinavir will be started at the dose of 1250 mg bid 5-7 days prior to standard treatment (chemoradiation & brachytherapy)

Therapeutic regimens

Cisplatin

Cisplatin will be administered on a weekly basis with a dose of 40 mg/m2 by IV infusion over a period of 1 hour 2-4 hours prior to start of EBRT. Patient will be premedicated with I.V Ondansetron to prevent emesis. Pre chemotherapy and post chemotherapy, patient will be administered IV fluids for effective renal clearance of cisplatin.

Nelfinavir

Nelfinavir will be taken orally with food, because the bioavailability increases under the influence of food. Treatment will start 5-7 days before start of chemo radiation and will continue for the duration of external beam radiotherapy ( no Nelfinavir on weekends or radiation breaks). We will be using a dose of 1250mg BID along with weekly cisplatin, 40mg /m2. All patients will undergo blood sugar evaluation, ECG and Lipid Profile at baseline, treatment completion and at 6 months of follow up. Blood sugars will also be monitored at every 2 weeks while on chemoradiation.

Administration of Pelvic EBRT and Brachytherapy

All patients will undergo baseline MRI of abdomen and pelvis (T2+ T1 with and without contrast+ diffusion and perfusion MRI). Extra sequence acquisition as part of research (like BOLD MRI will be performed on only 60 patients ( 30 in each arm). As MRI will be used for response assessment and brachytherapy planning, in addition to axial images saggital and coronal images will be obtained at each examination. Pelvic EBRT will delivered by standard 4 field technique using 6MV/15 MV photon beams. Prior to delivery of radiation, patients will be simulated by CT simulator for planning the beam arrangements. Total dose of pelvic EBRT will be 46Gy/23 #/4.5 weeks. The prescribed dose will be specified according to ICRU 50 guidelines. All patients will be treated with 3D conformal external radiation with target delineation and multileaf collimator leaf shaping. Biopsies will be performed at two different time points. One prior to treatment initiation and another before last dose of concurrent cisplatin. Patients will be evaluated by the concerned investigators on a weekly basis during radiation therapy and all the toxicities will be documented according to the CTCAE V4.0.

All patients will undergo image based brachytherapy. Standard guidelines for reporting or prescription will be followed.

Translational research studies

Five ml blood sample and tumor biopsies will be taken prior to nelfinavir use, and after EBRT on the day of 1st ICRT. Phosphorylated Akt and total Akt will be determined using flowcytometry/western blot method, as a marker of penetration of the drug into the tumor. The level of phosphorylated Akt will be correlated with tumour response as measured by PET/CT & MRI (changes in SUV max as measured by PET and perfusion changes in the tumour as measured by CT scan and tumour reduction in MRI). Akt levels will be measured in the first 60 patients (30 patient cohorts in each arm) both in the lymphocytes and in the tumour tissue.

Multi functional PET and MRI will be done in the first 30 patients of each arm to gain insight in changes in tumor SUV max and hypoxia following treatment with nelfinavir.

This trial represents a unique opportunity to test various hypotheses in the context of future translational research hence tumour biopsy samples will be stored in the clinical biology lab at ACTREC for future biomarker studies. To test various hypothesis we will require frozen tissues prior to and after treatment. In this case each patient will be her own control. Therefore during the time of the first biopsy we will keep some frozen material in liquid nitrogen.

Pharmacokinetic studies

Population pharmacokinetics of nelfinavir will be studied in the group of patients receiving Nelfinavir. For this, sparse sampling strategy will be followed. A random grouping table will be generated by the epidemiology and clinical trials unit and patient will be allotted to one of the groups for pharmacokinetic sampling. Patients will be allotted to one of the five groups sequentially. Four blood samples will be collected from each patient 7-10 days after the start of Nelfinavir. Timing of Blood sample would be based on the group in which the patient is. The sampling time points are so selected to cover the interval of drug administration. In addition one more blood sample will be collected before the last dose of administration of Cisplatin.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
There will be two study arms. If patient is randomized to standard arm patient will receive concurrent chemoradiation and brachytherapy. If patient is randomized to nelfinavir arm then nelfinavir will be started at the dose of 1250 mg bid 5-7 days prior to standard treatment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Carcinoma Cervix, Stage III
Intervention  ICMJE
  • Drug: Nelfinavir
    Nelfinavir (HIV protease inhibitor) targets proteasome and inhibits AKT phosphorylation and plays an important role in radiosensitization of tumour cells.Nelfinavir will be given to the patient orally with food, because the bioavailability increases under the influence of food.
  • Drug: Cisplatin
    Cisplatin will be administered on a weekly basis with a dose of 40 mg/m2 by IV infusion over a period of 1 hour 2-4 hours prior to start of EBRT. Patient will be premedicated with I.V Ondansetron to prevent emesis. Pre chemotherapy and post chemotherapy, patient will be administered IV fluids for effective renal clearance of cisplatin.
  • Radiation: Pelvic EBRT and Brachytherapy
    Pelvic EBRT will delivered by standard 4 field technique using 6MV/15 MV photon beams. Prior to delivery of radiation, patients will be simulated by CT simulator for planning the beam arrangements. Total dose of pelvic EBRT will be 46Gy/23 #/4.5 weeks. The prescribed dose will be specified according to ICRU 50 guidelines. All patients will be treated with 3D conformal external radiation with target delineation and multileaf collimator leaf shaping.
Study Arms  ICMJE
  • Experimental: Nelfinavir Arm

    If patient is randomized to nelfinavir arm then nelfinavir will be given orally with food at the dose of 1250 mg bid 5-7 days prior to start of chemoradiation.

    Then Pelvic EBRT (46Gy /23#/4.5weeks) + Weekly cisplatin 40mg/m2 & ICRT 7Gy X4 # will be given.

    Interventions:
    • Drug: Nelfinavir
    • Drug: Cisplatin
    • Radiation: Pelvic EBRT and Brachytherapy
  • Standard Arm

    If patient is randomized to standard arm (Cisplatin +Pelvic EBRT and Brachytherapy).

    In this patient will receive Pelvic EBRT (46Gy /23#/4.5weeks) + Weekly cisplatin 40mg/m2 & ICRT 7Gy X4 #

    Interventions:
    • Drug: Cisplatin
    • Radiation: Pelvic EBRT and Brachytherapy
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 21, 2017)
300
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 30, 2025
Estimated Primary Completion Date September 30, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria

  • ECOG 0 to 2
  • FIGO Stage III B Carcinoma Cervix
  • No previous irradiation to the pelvis or chemotherapy
  • Age 18 - 65 years
  • 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

  • Diabetes Mellitus.
  • 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Gender Based Eligibility: Yes
Gender Eligibility Description: Females with Carcinoma of cervix Stage IIIB
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Dr. Supriya J Sastri, MD 9930958309 supriyasastri@gmail.com
Contact: Dr. Jayant Goda, MD 24177000 ext 7027 godajayantsastri@gmail.com
Listed Location Countries  ICMJE India
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03256916
Other Study ID Numbers  ICMJE TMH Project 1543
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Supriya Sastri (chopra), Tata Memorial Hospital
Study Sponsor  ICMJE Tata Memorial Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Dr. Supriya J Sastri, MD Tata Memorial Centre
PRS Account Tata Memorial Hospital
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP