Clinical Trials /

Low-cost Enabling Technology for Image-guided Photodynamic Therapy (PDT) of Oral Cancer Cancer.

NCT03638622

Description:

Oral cancer in India affects mostly those from the lower socioeconomic groups, due to a higher exposure to risk factors such as the use of tobacco, zarda, khaini, chewing gutka, mawa, and kharra, which are all dry mixtures of flavorings, areca nut flakes and powdered tobacco. Earlier detection of oral cancer offers the best chance for long-term survival and has the potential to improve treatment outcomes and make healthcare affordable. Current treatment options, primarily surgery and/or radiation, can be curative if cancer or dysplasia is caught at a sufficiently early stage. Though even in these cases treatment may be disfiguring with significant impact upon quality of life, and many patients do not seek medical attention until the disease has progressed to a point where radical operation is required (Stage III/IV), often entailing block dissection and removal of the entire lymphatic drainage of the neck. Despite the radical operation, disease still recurs, leading to an overall survival rate of less than 70% of these cases. The present proposal makes the case that photodynamic therapy (PDT)-based treatment of oral cancer, already shown to be effective in the traditional clinical setting, is inherently conducive to adaptation into a low-cost battery-powered platform that addresses the requirements for LMIC implementation.

Related Conditions:
  • Malignant Buccal Mucosa Neoplasm
  • Malignant Floor of the Mouth Neoplasm
  • Malignant Gingival Neoplasm
  • Malignant Tongue Neoplasm
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Low-cost Enabling Technology for Image-guided Photodynamic Therapy (PDT) of Oral Cancer Cancer.
  • Official Title: Low-cost Enabling Technology for Image-guided Photodynamic Therapy (PDT) of Oral

Clinical Trial IDs

  • ORG STUDY ID: 2015P001855
  • SECONDARY ID: 5UH3CA189901-04
  • NCT ID: NCT03638622

Conditions

  • Oral Cancer

Purpose

Oral cancer in India affects mostly those from the lower socioeconomic groups, due to a higher exposure to risk factors such as the use of tobacco, zarda, khaini, chewing gutka, mawa, and kharra, which are all dry mixtures of flavorings, areca nut flakes and powdered tobacco. Earlier detection of oral cancer offers the best chance for long-term survival and has the potential to improve treatment outcomes and make healthcare affordable. Current treatment options, primarily surgery and/or radiation, can be curative if cancer or dysplasia is caught at a sufficiently early stage. Though even in these cases treatment may be disfiguring with significant impact upon quality of life, and many patients do not seek medical attention until the disease has progressed to a point where radical operation is required (Stage III/IV), often entailing block dissection and removal of the entire lymphatic drainage of the neck. Despite the radical operation, disease still recurs, leading to an overall survival rate of less than 70% of these cases. The present proposal makes the case that photodynamic therapy (PDT)-based treatment of oral cancer, already shown to be effective in the traditional clinical setting, is inherently conducive to adaptation into a low-cost battery-powered platform that addresses the requirements for LMIC implementation.

Detailed Description

      Study Facility:

      Pre-study Screening: Patients come to ENT/Oral and Maxillofacial/Plastic and Reconstructive
      surgery outpatient facilities. Typically, an ENT specialist handles early cases (biopsy
      proven malignancies), while ENT and plastic surgeons jointly deal with advanced cases.
      Patients screening will take place in outpatient departments. The investigator/s will
      interview each subject to develop a brief, relevant medical history and determine that all
      selection criteria are met. The subject will receive an explanation of the study objectives,
      possible risks and benefits of the study. After history evaluation of the patients, Blood
      work will be done to check liver functions Test. After the blood report and inclusion and
      exclusion criteria, the consultant will discuss and educate the patients about
      photosensitization and PDT therapy. If patients are willing to take part in the study,
      co-investigator will obtain a signed consent form. After obtaining a signed consent form, the
      consultant will schedule an appointment for PDT therapy.

      Procedure after enrollment: Investigators plan to enroll 30 patients with oral cancer in this
      study. The study will take place at JNMC, Aligarh. This timeline of procedures considers that
      many patients may need to travel from remote rural areas with poor access to transportation,
      so it cannot be assumed that patients have convenient access to return to the clinic for
      multiple repeated biopsies.

      ALA preparation and administration: The FDA-approved ALA from DUSA Pharmaceuticals, Inc.,
      Wilmington, MA will be used in powder form. Patients will initially receive a baseline
      ultrasound of the oral cavity prior to ALA administration. In case of potentially
      childbearing women serum pregnancy test will be performed before ALA administration by SD
      Bioline kit(Standard Diagnostic Inc, India). One hour prior to ALA administration, analgesic
      (Aceclofenac, HIFENAC-SR (200mg);Intas Pharmaceuticals, India) and antiemetic (Domperidone,
      Domperon, 10mg; Cadila Pharmaceuticals, Inc., India) will be given to patients orally to
      avoid nausea and pain. ALA, totaling 60 mg/kg, will be administered orally via three repeated
      doses of 20 mg/kg of ALA dissolved in either orange juice or a soft drink, which lowers the
      pH of the solution, at 0, 1 and 2 hours.

      Day One: Baseline imaging; Fluorescence measurement: PpIX fluorescence will be recorded using
      405nm excitation light delivered from an LED source powered by a smartphone. This is a
      non-invasive system. The PpIX fluorescence will be photographed using the camera embedded in
      the smartphone. The advantage of this step is that in the long term it will obviate the need
      for biopsies to establish PpIX concentrations and could allow for online dosimetry customized
      to individual patients. Three photographs will be taken in each subject: first photograph
      will be taken prior to given ALA to the patients, second photograph after 2-3 hours of ALA
      incubation, and third photograph will be taken immediately after PDT treatment.

      Imaging Procedure before treatment: After allowing 2-3 hours for PpIX conversion and
      accumulation in the malignant tissue, a baseline image of the tumor will be obtained using
      the smartphone PpIX imaging approach. In this clinical validation study, these PpIX
      fluorescence images will be used to make treatment decisions beyond visual guidance for
      applicator placement on the lesion.

      PDT Procedure: Immediately after the brief imaging session (approximately 5 minutes), the PDT
      treatment will proceed. Depending on the exact fractionation schedule determined, a total
      fluence of 100J/cm2 at the lesion surface will be delivered with an area of applicators or
      compressed applicator in for approximately 30-45 minutes. Placement will be such that the
      full extent of the lesion falls within a 1mm margin of the applicator area. Every 10 minutes,
      a 2-3 minute break is provided to the patient and the study personal will check for the
      correct placement of the probe. The clinician will conduct applicator placement with the
      assistance of a nurse as needed so that it fits tightly in contact with the active surface
      facing the lesion. Care will be required when pressing an applicator tipped light delivery
      system hard against tissue. If one presses too hard and the tissue is rendered temporarily
      hypoxic, there will be no PDT effect. During therapy patients will leave their mouth closed
      around the optical fiber. Depending on the exact orientation of the lesion within the oral
      cavity a mouth guard may be used to aid applicator positioning, or if this improves patient
      comfort. Also, to aid in stabilization of the fiber and improve patient comfort, an ergonomic
      external positioning mount may be employed to help maintain the optical fiber in position.
      Provided that care is taken that no incidental body movements during irradiation lead to
      significant shifting of movement of the applicator, patients will be able to read a magazine,
      watch TV (if available) or other similar activities from a seated position. Small lesions may
      receive a complete treatment in this time interval, while (as noted above), larger lesions
      may require one or more additional applications. Patients will receive analgesic Aceclofenac,
      HIFINAC-SR (200 mg); Intas Pharmaceuticals, India to avoid pain. Appropriate Laser safety
      glasses will also be provided to the patients during irradiation.

      Post-treatment imaging: At the conclusion of the PDT treatment, the light delivery fiber will
      be removed and a follow-up smartphone fluorescence image will be obtained for later analysis
      of PpIX photo bleaching. Patients will receive guidance on resumption of normal activities.
      After the procedure, patient will be advised to avoid foods that are spicy, hot or oily for
      at least 6 hours and advised to take analgesic as needed Aceclofenac, HIFENAC-SR (200 mg);
      Intas Pharmaceuticals, India. to avoid pain. Patients will also be advised to stop smoking,
      and chewing tobacco product.

      Day Two to Three: Routine complete blood investigations including a liver function test (LFT)
      will be performed at 1 to 2 days following ingestion of ALA. If abnormalities are noted,
      follow-up blood work will be conducted that includes a renal function test (blood urea, serum
      creatinine, uric acid) and blood electrolytes measurement.

      Day Seven to Ten: At a follow-up examination, 7 days after treatment, ultrasound of the oral
      cavity will be conducted to assess treatment response by lesion area (cm2) and depth (mm). As
      part of this study, ALA will also be re-administered (unless a particular patient had an
      adverse reaction to ALA in the initial treatment) so that follow-up fluorescence imaging can
      also be conducted. Again, at this stage, fluorescence imaging is included for validation of
      the procedure itself, not to decide the next steps in treatment for this patient cohort.
      However, the follow-up ultrasound will be a decision point to determine whether a given
      patient needs to undergo surgical excision of residual tumor (possibly with additional radio-
      and/or chemotherapy as determined by the clinician team), or if no residual disease is
      present, a biopsy will be conducted at the original disease site for histological
      confirmation of treatment response, and/or disease progression (development of invasive
      disease). If the radiologist reports residual tumor after the ultrasound procedure, an ENT
      surgeon will perform biopsy and the tissue will be preserved in formalin and sent for
      histopathology assessment. The depth of necrosis evaluated from the histopathology will serve
      as end point for evaluating the technology. This histopathology data will also be used for
      validation of imaging to establish fluorescence contrast agreement with histologically
      confirmed malignant tissue.

      Follow-up Model: Patients who have good response to PDT will not need to undergo surgery,
      which would compromise the excellent healing of the mucosa that has been reported with this
      modality. At the same time, patients whose disease has partial or no response to PDT will
      still receive the same standard of care (surgical excision, chemo/radiation) they would have
      if they had not enrolled in the study. It is also possible that the PDT treatment, even if
      response was not complete, could reduce the scope of excision required in these subjects.
      Therefore at the end of the study we will have established the utility of this technology
      without interrupting the flow of treatment/management of the patients whose disease has
      partial or no response to PDT. Regardless of the flow of this study, additional follow-up on
      all patients will be carried out at 1 month,3 months, 6 months, 9 months,12 months and 2
      years after treatment. All patient data obtained will be appropriately de-identified as per
      local institutional guidelines before off-site analysis, which will continue throughout the
      study.

      The clinical validation study will also serve as an opportunity to gather patient data that
      will be invaluable in two capacities 1) to obtain important information immediately relevant
      to individual patient care and 2) with a mind toward sustainability, investigators will seek
      to understand cultural barriers to acceptance or compliance with the proposed PDT treatment
      that will be accounted for in outreach and training plans. The present validation study is
      not powered to make comparison between different interventions, but rather to provide a
      validation that the safety and efficacy of the low cost approach is equivalent to previous
      reports of PDT treatment for oral cancer in traditional medical settings at JNMC.
    

Trial Arms

NameTypeDescriptionInterventions
TreatmentExperimentalaminolevulinic acid and photodynamic therapy Patients receive aminolevulinic acid orally with orange juice in 3 fractions at 0,1,2 hours before undergoing photodynamic therapy using LED based Device on day one.

    Eligibility Criteria

            Inclusion Criteria:
    
              1. Age above 21 years, males or females
    
              2. Subject has read and signed a written informed consent form
    
              3. Subject is willing to have ALA administered and wait for 2-3 hours
    
              4. Subject is willing to receive red light irradiation in the mouth via the fiber
                 probe/applicator and is willing to have the fiber probe/applicator in the mouth for a
                 maximum time of 1 hour
    
              5. Subject is willing to allow investigators to take measurements using smart phone
                 imaging before, during and after light treatment
    
              6. After the procedure, the subject is willing to avoid spicy, hot, or oily foods for at
                 least 6 hours
    
              7. Subject willing to wear full sleeve shirt and full-length garments for couple of hours
    
            Exclusion Criteria:
    
              1. Pregnancy or nursing (ALA is a drug that belongs to FDA pregnancy category C).
    
              2. History of photosensitivity diseases (e.g., lupus erythematosus, porphyrias).
    
              3. Therapy with any photosensitizing medication, e.g., thiazides (for the treatment of
                 high blood pressure), fluoroquinolones, griseofulvin, or sulfonamides (for the
                 treatment of infections), sulfonylureas (for the treatment of diabetes),
                 phenothiazines (for the treatment of emotional problems), and other medications
                 reported to cause photosensitivity within the last 6 months.
    
              4. Subject is unable or unwilling to comply with the study requirements.
    
              5. Subject has any conditions or scars within the location of the test sites that may
                 interfere with the treatment or evaluation.
    
              6. Allergy to porphyrins or ALA.
    
              7. Subject has received laser treatment within 6 months in the area of the treatment.
    
              8. Subject is participating in other potentially confounding research, e.g., currently
                 enrolled in a clinical study of any other unapproved investigational drug or device.
    
              9. Any other condition or laboratory value that would, in the professional opinion of the
                 investigator, potentially affect response or participation in this clinical study.
    
             10. Subject has inadequate organ function.
    
             11. Subject has co-morbid systemic illnesses or severe concurrent disease.
    
             12. Subject is being treated for vascular disease.
    
             13. Subject is an employee of the participating sites directly supervised by the
                 investigator.
    
             14. Subject with invasive deep carcinoma evaluated by biopsy.
    
             15. Subject is currently being treated for other cancers with medical or radiation
                 therapy.
    
             16. Subject has AIDS or other infectious diseases, including tuberculosis, hepatitis or
                 herpetic lesions (oral herpes).
    
             17. Subject has oral submucous fibrosis (OSF) resulting in patient inability to
                 comfortably hold the light applicator in mouth.
    
             18. Subject has HPV positive tumor.
    
             19. Subject has the tumor at Oropharynx area.
    
             20. We will excludes the patients of the all other oral lesions at sites except: the
                 gingivobuccal sulcus, cheek, floor of the mouth and tongue.
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:21 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Tumor response
    Time Frame:3-12 months
    Safety Issue:
    Description:Ultrasound of the oral cavity will be repeated to assess treatment response by lesion area (cm2) and depth (mm). Imaging at followup will be used to inform whether the patient needs full surgical excision of residual tumor by ENT surgeon and continued management as per standard of care (possibly with additional radio- and/or chemotherapy as determined by the clinical team). If no residual disease is detected, a biopsy will be conducted at the original disease site for histological confirmation of treatment response, and/or disease progression (development of invasive disease). Regardless of the flow of this study, additional follow-up on all patients will be carried out at 3 months, 6 months, 9 months and 1 year after treatment. All patient data obtained will be appropriately de-identified as per local institutional guidelines before off-site analysis, which will continue throughout the study

    Details

    Phase:Phase 1/Phase 2
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Massachusetts General Hospital

    Trial Keywords

    • Oral cancer, Photodynamic Therapy, Photosensitizer, ALA

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