<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03256916</url>
  </required_header>
  <id_info>
    <org_study_id>TMH Project 1543</org_study_id>
    <nct_id>NCT03256916</nct_id>
  </id_info>
  <brief_title>Radiosensitizing Effect of Nelfinavir in Locally Advanced Carcinoma of Cervix</brief_title>
  <acronym>NELCER</acronym>
  <official_title>A Phase III Randomized Clinical Trial to Study the Radiosensitizing Effect of Nelfinavir in Locally Advanced Carcinoma of Uterine Cervix.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Tata Memorial Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Tata Memorial Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The primary aim of the trial is to study the impact of nelfinavir on 3 year disease free&#xD;
      survival in patients with advanced carcinoma of cervix receiving standard chemoradiation&#xD;
      (Cisplatin and Radiotherapy).&#xD;
&#xD;
      There will be two study groups. One group will receive standard treatment (concurrent&#xD;
      chemoradiation and brachytherapy) &amp; other group will receive nelfinavir 5-7 days prior to&#xD;
      standard treatment (chemoradiation &amp; brachytherapy).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The trial is a single centre open label randomized unblinded phase-III study to evaluate the&#xD;
      efficacy of an investigational drug (Nelfinavir) in combination with standard therapy&#xD;
      consisting of weekly cisplatin and pelvic EBRT in cohort of patients diagnosed with FIGO 2018&#xD;
      stage III Carcinoma cervix.&#xD;
&#xD;
      Patient registration / randomization procedure&#xD;
&#xD;
      348 Patients will be accrued from the Gynaec Oncology Service of Tata Memorial Centre,&#xD;
      Mumbai. A study coordinator at TMC will coordinate the accrual and study process and ensure&#xD;
      prompt accrual and proper documentation. Eligibility will be checked based on the selection&#xD;
      criteria and written informed consent will be obtained prior to randomization. Patients will&#xD;
      be given appropriate time to decide for participation. Randomization will be based on a chart&#xD;
      prepared with the help of software using a random sorting algorithm. A screening log will be&#xD;
      maintained and include the details of all patients screened.&#xD;
&#xD;
      There are two study arms. In Experimental arm (Nelfinavir arm) 174 patients will be accrued &amp;&#xD;
      in Control arm (Standard Arm) 174 patients will be accrued.&#xD;
&#xD;
      If patient is randomized to standard arm patient will receive concurrent chemoradiation and&#xD;
      brachytherapy. If patient is randomized to nelfinavir arm then nelfinavir will be started at&#xD;
      the dose of 1250 mg bid 5-7 days prior to standard treatment (chemoradiation &amp; brachytherapy)&#xD;
&#xD;
      Therapeutic regimens&#xD;
&#xD;
      Cisplatin&#xD;
&#xD;
      Cisplatin will be administered on a weekly basis with a dose of 40 mg/m2 by IV infusion over&#xD;
      a period of 1 hour 2-4 hours prior to start of EBRT. Patient will be premedicated with I.V&#xD;
      Ondansetron to prevent emesis. Pre chemotherapy and post chemotherapy, patient will be&#xD;
      administered IV fluids for effective renal clearance of cisplatin.&#xD;
&#xD;
      Nelfinavir&#xD;
&#xD;
      Nelfinavir will be taken orally with food, because the bioavailability increases under the&#xD;
      influence of food. Treatment will start 5-7 days before start of chemo radiation and will&#xD;
      continue for the duration of external beam radiotherapy ( no Nelfinavir on weekends or&#xD;
      radiation breaks). We will be using a dose of 1250mg BID along with weekly cisplatin, 40mg&#xD;
      /m2. All patients will undergo blood sugar evaluation, ECG and Lipid Profile at baseline,&#xD;
      treatment completion and at 6 months of follow up. Blood sugars will also be monitored at&#xD;
      every 2 weeks while on chemoradiation.&#xD;
&#xD;
      Administration of Pelvic EBRT and Brachytherapy&#xD;
&#xD;
      All patients will undergo baseline MRI of abdomen and pelvis (T2+ T1 with and without&#xD;
      contrast+ diffusion and perfusion MRI). Extra sequence acquisition as part of research (like&#xD;
      BOLD MRI will be performed on only 60 patients ( 30 in each arm). As MRI will be used for&#xD;
      response assessment and brachytherapy planning, in addition to axial images saggital and&#xD;
      coronal images will be obtained at each examination. Pelvic EBRT will delivered by standard 4&#xD;
      field technique using 6MV/15 MV photon beams. Prior to delivery of radiation, patients will&#xD;
      be simulated by CT simulator for planning the beam arrangements. Total dose of pelvic EBRT&#xD;
      will be 45- 50Gy/23-25 #/5 weeks, and involved nodes will receive a total EBRT dose of 55 -&#xD;
      60Gy. The prescribed dose will be specified according to ICRU 50 guidelines. All patients&#xD;
      will be treated with 3D conformal external radiation with target delineation and multileaf&#xD;
      collimator leaf shaping. Biopsies will be performed at two different time points. One prior&#xD;
      to treatment initiation and another before last dose of concurrent cisplatin. Patients will&#xD;
      be evaluated by the concerned investigators on a weekly basis during radiation therapy and&#xD;
      all the toxicities will be documented according to the CTCAE V4.0.&#xD;
&#xD;
      All patients will undergo image based brachytherapy. Standard guidelines for reporting or&#xD;
      prescription will be followed.&#xD;
&#xD;
      Translational research studies&#xD;
&#xD;
      Five ml blood sample and tumor biopsies will be taken prior to nelfinavir use, and after EBRT&#xD;
      on the day of 1st ICRT. Phosphorylated Akt and total Akt will be determined using&#xD;
      flowcytometry/western blot method, as a marker of penetration of the drug into the tumor. The&#xD;
      level of phosphorylated Akt will be correlated with tumour response as measured by PET/CT &amp;&#xD;
      MRI (changes in SUV max as measured by PET and perfusion changes in the tumour as measured by&#xD;
      CT scan and tumour reduction in MRI). Akt levels will be measured in the first 60 patients&#xD;
      (30 patient cohorts in each arm) both in the lymphocytes and in the tumour tissue.&#xD;
&#xD;
      Multi functional PET and MRI will be done in the first 30 patients of each arm to gain&#xD;
      insight in changes in tumor SUV max and hypoxia following treatment with nelfinavir.&#xD;
&#xD;
      This trial represents a unique opportunity to test various hypotheses in the context of&#xD;
      future translational research hence tumour biopsy samples will be stored in the clinical&#xD;
      biology lab at ACTREC for future biomarker studies. To test various hypothesis we will&#xD;
      require frozen tissues prior to and after treatment. In this case each patient will be her&#xD;
      own control. Therefore during the time of the first biopsy we will keep some frozen material&#xD;
      in liquid nitrogen.&#xD;
&#xD;
      Pharmacokinetic studies&#xD;
&#xD;
      Population pharmacokinetics of nelfinavir will be studied in the group of patients receiving&#xD;
      Nelfinavir. For this, sparse sampling strategy will be followed. A random grouping table will&#xD;
      be generated by the epidemiology and clinical trials unit and patient will be allotted to one&#xD;
      of the groups for pharmacokinetic sampling. Patients will be allotted to one of the five&#xD;
      groups sequentially. Four blood samples will be collected from each patient 7-10 days after&#xD;
      the start of Nelfinavir. Timing of Blood sample would be based on the group in which the&#xD;
      patient is. The sampling time points are so selected to cover the interval of drug&#xD;
      administration. In addition one more blood sample will be collected before the last dose of&#xD;
      administration of Cisplatin.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">January 16, 2018</start_date>
  <completion_date type="Anticipated">September 30, 2025</completion_date>
  <primary_completion_date type="Anticipated">September 30, 2025</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <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</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Improvement in 3 year disease free survival</measure>
    <time_frame>3 years</time_frame>
    <description>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).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in locoregional control rates at 3 years</measure>
    <time_frame>3 years</time_frame>
    <description>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).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival at 5 years</measure>
    <time_frame>5 years</time_frame>
    <description>Overall survival at 5 years in test and control arms.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of grade 3/4 adverse events</measure>
    <time_frame>5 years</time_frame>
    <description>Incidence of grade 3/4 adverse events in patients with advanced carcinoma of cervix and receiving Nelfinavir along with standard chemoradiation (Cisplatin and Radiotherapy)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Akt levels in the tumor</measure>
    <time_frame>5 years</time_frame>
    <description>Changes in Akt levels in the tumor from pre Nelfinavir to post EBRT.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in tumour hypoxia using multifunctional PET/ MRI.</measure>
    <time_frame>5 years</time_frame>
    <description>Change in tumour hypoxia using multifunctional PET/ MRI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Interindividual variability of Volume of distribution</measure>
    <time_frame>5 years</time_frame>
    <description>Cmax (Maximum concentration) will be estimated</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Interindividual variability of Clearance of nelfinavir.</measure>
    <time_frame>5 years</time_frame>
    <description>Clearence (litres per hour)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Interindividual variability of Clearence of Nelfinavir</measure>
    <time_frame>5 years</time_frame>
    <description>Half Life (hrs)</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">348</enrollment>
  <condition>Carcinoma Cervix,Stage III</condition>
  <arm_group>
    <arm_group_label>Nelfinavir Arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.&#xD;
Then Pelvic EBRT (45-50 Gy/23-25 #/5weeks) + Weekly cisplatin 40mg/m2 &amp; ICRT 7Gy X4 # will be given.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard Arm</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>If patient is randomized to standard arm (Cisplatin +Pelvic EBRT and Brachytherapy).&#xD;
In this patient will receive Pelvic EBRT (45-50 Gy/23-25 #/5weeks) + Weekly cisplatin 40mg/m2 &amp; ICRT 7Gy X4 #</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nelfinavir</intervention_name>
    <description>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.</description>
    <arm_group_label>Nelfinavir Arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cisplatin</intervention_name>
    <description>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.</description>
    <arm_group_label>Nelfinavir Arm</arm_group_label>
    <arm_group_label>Standard Arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Pelvic EBRT and Brachytherapy</intervention_name>
    <description>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 45- 50Gy/23-25 #/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.</description>
    <arm_group_label>Nelfinavir Arm</arm_group_label>
    <arm_group_label>Standard Arm</arm_group_label>
    <other_name>Radiation Therapy</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria&#xD;
&#xD;
          -  ECOG 0 to 2&#xD;
&#xD;
          -  FIGO 2018 Stage IIIA (TNM stage T3a N0 M0) FIGO 2018 Stage IIIB (TNM stage T3b N0 M0)&#xD;
             FIGO 2018 Stage IIIC (TNM stage Any T N1 M0)&#xD;
&#xD;
          -  No previous irradiation to the pelvis or chemotherapy&#xD;
&#xD;
          -  Age 18 years and above&#xD;
&#xD;
          -  Ability to tolerate full course of pelvic radiotherapy and brachytherapy&#xD;
&#xD;
          -  Adequate bone marrow, liver, and kidney function defined as neutrophil count ≥ 1500&#xD;
             platelet count ≥ 100,000, total bilirubin less than 1.5 x upper limit of normal (ULN),&#xD;
             AST and ALT ≤ 2.5 x ULN, and creatinine less than 1.5 upper limit of normal or&#xD;
             Creatinine clearance greater than 60 mL/min/1.73 m2&#xD;
&#xD;
          -  No recent (less than 3 months) severe cardiac disease (arrhythmia, congestive heart&#xD;
             failure, infarction)&#xD;
&#xD;
          -  Ability to understand and the willingness to sign an informed consent document&#xD;
&#xD;
          -  Should be willing to undergo extra biopsy and blood collection for pharmacokinetic&#xD;
             studies&#xD;
&#xD;
        Exclusion criteria&#xD;
&#xD;
          -  Patients with newly diagnosed diabetes , uncontrolled DM (patient with HbA1c of &amp;gt;&#xD;
             6.5% or FBS value or BSF&amp;gt;=126 mg/dL respectively on primary evaluation)&#xD;
&#xD;
          -  Pts on any drugs which has pharmacological interaction with nelfinavir:&#xD;
&#xD;
               -  Terfenadine, cisapride, sildenafil, lovastatin or simvastatin and medication that&#xD;
                  are metabolized by the CYP3A4 isoenzyme.&#xD;
&#xD;
               -  Antiarrhythmics (amiodarone, quinidine).&#xD;
&#xD;
               -  Neuroleptics (pimozide).&#xD;
&#xD;
               -  Sedative/Hypnotic agents (midazolam, triazolam).&#xD;
&#xD;
               -  Ergot derivatives.&#xD;
&#xD;
               -  HMG-CoA reductase inhibitors (atorvastatin).&#xD;
&#xD;
               -  Rifampicin, Rifabutin.&#xD;
&#xD;
               -  Felodipine, Nifedipine.&#xD;
&#xD;
          -  Pregnant or lactating&#xD;
&#xD;
          -  Active co existing malignancy.&#xD;
&#xD;
          -  HIV positive patients will be excluded.&#xD;
&#xD;
          -  Patients with hemophilia.&#xD;
&#xD;
          -  Patients with reduced creatinine clearance ( less than 50 ml/ min) or unilateral or&#xD;
             bilateral hydronephrosis will be excluded.&#xD;
&#xD;
          -  History of psychological, familial, sociological or geographical condition potentially&#xD;
             hampering compliance with the study protocol and follow-up schedule.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Females with Carcinoma of cervix Stage IIIB</gender_description>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Dr. Supriya J Sastri, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Tata Memorial Centre</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Dr. Supriya J Sastri, MD</last_name>
    <phone>9930958309</phone>
    <email>supriyasastri@gmail.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Dr. Jayant Goda, MD</last_name>
    <phone>24177000</phone>
    <phone_ext>7027</phone_ext>
    <email>godajayantsastri@gmail.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Tata Memorial Centre</name>
      <address>
        <city>Mumbai</city>
        <state>Maharashtra</state>
        <zip>400012</zip>
        <country>India</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Supriya J Sastri, MD</last_name>
      <phone>9930958309</phone>
      <email>supriyasastri@gmail.com</email>
    </contact>
    <contact_backup>
      <last_name>Jayant Goda, MD</last_name>
      <phone>24177000</phone>
      <phone_ext>7027</phone_ext>
      <email>godajayantsastri@gmail.com</email>
    </contact_backup>
    <investigator>
      <last_name>Supriya J Sastri, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Jayant Goda, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>India</country>
  </location_countries>
  <link>
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  <verification_date>February 2022</verification_date>
  <study_first_submitted>July 31, 2017</study_first_submitted>
  <study_first_submitted_qc>August 21, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 22, 2017</study_first_posted>
  <last_update_submitted>February 18, 2022</last_update_submitted>
  <last_update_submitted_qc>February 18, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">February 21, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Tata Memorial Hospital</investigator_affiliation>
    <investigator_full_name>Supriya Sastri (chopra)</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Cervical cancer</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nelfinavir</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03256916
org study id: TMH Project 1543
nct id: NCT03256916
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
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).
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 FIGO 2018
      stage III Carcinoma cervix.

      Patient registration / randomization procedure

      348 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) 174 patients will be accrued &
      in Control arm (Standard Arm) 174 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 45- 50Gy/23-25 #/5 weeks, and involved nodes will receive a total EBRT dose of 55 -
      60Gy. 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.
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
primary purpose: Treatment
masking: None (Open Label)
measure: Improvement in 3 year disease free survival
time frame: 3 years
description: 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).
measure: Change in locoregional control rates at 3 years
time frame: 3 years
description: 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).
measure: Overall survival at 5 years
time frame: 5 years
description: Overall survival at 5 years in test and control arms.
measure: Incidence of grade 3/4 adverse events
time frame: 5 years
description: Incidence of grade 3/4 adverse events in patients with advanced carcinoma of cervix and receiving Nelfinavir along with standard chemoradiation (Cisplatin and Radiotherapy)
measure: Changes in Akt levels in the tumor
time frame: 5 years
description: Changes in Akt levels in the tumor from pre Nelfinavir to post EBRT.
measure: Change in tumour hypoxia using multifunctional PET/ MRI.
time frame: 5 years
description: Change in tumour hypoxia using multifunctional PET/ MRI.
measure: Interindividual variability of Volume of distribution
time frame: 5 years
description: Cmax (Maximum concentration) will be estimated
measure: Interindividual variability of Clearance of nelfinavir.
time frame: 5 years
description: Clearence (litres per hour)
measure: Interindividual variability of Clearence of Nelfinavir
time frame: 5 years
description: Half Life (hrs)
arm group label: Nelfinavir Arm
arm group type: Experimental
description: 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 (45-50 Gy/23-25 #/5weeks) + Weekly cisplatin 40mg/m2 & ICRT 7Gy X4 # will be given.
arm group label: Standard Arm
arm group type: Other
description: If patient is randomized to standard arm (Cisplatin +Pelvic EBRT and Brachytherapy).
In this patient will receive Pelvic EBRT (45-50 Gy/23-25 #/5weeks) + Weekly cisplatin 40mg/m2 & ICRT 7Gy X4 #
intervention type: Drug
intervention name: Nelfinavir
description: 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.
arm group label: Nelfinavir Arm
intervention type: Drug
intervention name: Cisplatin
description: 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.
arm group label: Nelfinavir Arm
arm group label: Standard Arm
intervention type: Radiation
intervention name: Pelvic EBRT and Brachytherapy
description: 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 45- 50Gy/23-25 #/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.
arm group label: Nelfinavir Arm
arm group label: Standard Arm
other name: Radiation Therapy
criteria: 
gender: Female
gender based: Yes
gender description: Females with Carcinoma of cervix Stage IIIB
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Dr. Supriya J Sastri, MD
role: Principal Investigator
affiliation: Tata Memorial Centre
last name: Dr. Supriya J Sastri, MD
phone: 9930958309
email: supriyasastri@gmail.com
last name: Dr. Jayant Goda, MD
phone: 24177000
phone ext: 7027
email: godajayantsastri@gmail.com
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
investigator: 
country: India
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description: A Phase I Trial of the HIV Protease Inhibitor Nelfinavir with Concurrent Chemoradiotherapy (CT-RT) for Unresectable Stage IIA/IIIB NSCLC: A Report of Toxicities and Clinical Response. J Thoracic Oncol. ; 7(4): 709-715(2012).
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description: Ma, Y.Y., et al. PIK3CA as an oncogene in cervical cancer. Oncogene 19, 2739-2744 (2000).
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responsible party type: Principal Investigator
investigator affiliation: Tata Memorial Hospital
investigator full name: Supriya Sastri (chopra)
investigator title: Principal Investigator
mesh term: Carcinoma
mesh term: Nelfinavir
sharing ipd: No