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SBRT + Immunomodulating Systemic Therapy for Inoperable, Recurrent H&N

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ClinicalTrials.gov Identifier: NCT03402737
Recruitment Status : Recruiting
First Posted : January 18, 2018
Last Update Posted : August 6, 2018
Sponsor:
Information provided by (Responsible Party):
Radiotherapie, University Hospital, Ghent

Brief Summary:
To derive the maximum tolerated dose of hypofractionated stereotactic body radiotherapy (SBRT) using dose painting by numbers with immunomodulating systemic therapy in patients that are reirradiated for recurrent squamous cell carcinoma of the head and neck.

Condition or disease Intervention/treatment Phase
Head and Neck Neoplasm Radiation: Stereotactic body radiotherapy Not Applicable

Detailed Description:

The standard treatment in inoperable locally or regionally recurrent head and neck cancer has long been palliative systemic therapy using the so-called EXTREME-scheme: a combination of cisplatin, 5-fluorouracil and cetuximab. This therapy remains without realistic chances of cure. More recently, immunotherapy using nivolumab has demonstrated to result in long-term disease control of 1-2 year in cisplatin-refractory recurrent or metastatic head and neck cancer, however only in a small portion of patients (13%).

Fractionated high-dose local or regional re-irradiation is mostly given in a 6-7 weeks scheme. Using stereotactic body radiotherapy (SBRT), high radiotherapy doses can be given in a short time span. Severe late adverse events have been reported using SBRT but seem less frequent than in patients re-treated with conventional schedules. A possible solution to be able to administer higher doses is combining SBRT with dose painting, thus giving these high doses on small subvolumes only.

Addition of concomitant therapy to reirradiation may further improve outcomes due to radiosensitization and direct cytotoxicity. Therefore the investigator aims to combine high doses with concomitant therapy in the proposed study.

The immunomodulatory effect caused by radiation has been demonstrated both in animal models and clinical trials and leads to an enhanced local control as well as to eradication of distant metastasis. This so-called abscopal effect is reached through a systemic immune response evoked by the release of damage-associated molecular patterns (DAMPs) by the dying tumor-cells, also called immunogenic cell death (ICD).

The investigator hypothesizes that an abscopal effect could be present for patients presenting locoregional recurrent disease with asymptomatic distant metastases, thereby offering at least symptom control at the primary site while palliative systemic treatment could be postponed.

The proposed protocol focuses on patients with bad prognosis, as determined by a short timespan between primary therapy and recurrence (defined as 6-24 months after the end of the primary radiotherapy). It would bring the practical advantage of only 2-3 patient visits for the radiotherapy instead of ± 30-35 visits over 6-7 weeks. This shorter treatment schedule is expected to result in a direct gain in quality-of-life due to locoregional symptom control. It can also be expected that rescue systemic therapy will be postponed to a later stage of disease development, thereby prolonging overall survival.

The combination with systemic agents that are involved in immunogenic cell death bear the potential to result in a higher number of patients with longer periods of disease control and survival. The current standard of care, i.e. the combined systemic treatment with cisplatin - 5-fluorouracil - cetuximab, or nivolumab in case of former cisplatin use, can be used as a rescue regimen in case of therapy failure. In that sense, better overall survival from time of diagnosis of the index locoregional recurrent disease is expected.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Intervention Model: Sequential Assignment
Intervention Model Description:

The range of dose-painting will be escalated in following levels:

  • 2x 6-8Gy
  • 3x 6-8Gy

The standard "3+3" design will be used for the this trial. To obtain more precise toxicity rate of the MTD we will double the number of patients at the first dose prescription that gives totally 6 patients. The 3 remaining dose levels will include 3 patients each. Thus, fifteen (6+3+3+3) patients will be included in this radiotherapy dose finding study investigating the MTD.

The number of patients will be doubled in case of 2 DLTs at the dose prescription I and 1 DLT at dose prescriptions II-IV with DLT in a maximum of 10 out of 30 patients.

  • 3x 6-10Gy
  • 3x 6-12Gy
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Combined Hypofractionated Stereotactic Body Radiotherapy With Immunomodulating Systemic Therapy for Inoperable Recurrent Head and Neck Cancer: Detection of the Maximum Tolerated Dose.
Actual Study Start Date : July 31, 2017
Estimated Primary Completion Date : January 31, 2020
Estimated Study Completion Date : January 31, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Stereotactic body radiotherapy + IM
Single arm phase I trial with 3 Stereotactic Body Radiation Therapy dose-escalation arms.
Radiation: Stereotactic body radiotherapy

The range of dose-painting will be escalated in following levels:

  • 2x 6-8Gy (day 1-4)
  • 3x 6-8Gy (day 1-4-7)
  • 3x 6-10Gy (day 1-4-7)
  • 3x 6-12Gy (day 1-4-7)

Patients will take cyclophosphamide orally 50 mg tablets, 1 tablet a day from the first day of irradiation for 8 consecutive weeks.

Nivolumab will be considered as standard therapy in patients with cisplatin refractory locoregional disease recurrence. Nivolumab will be administered as per current standard of care. In case patients that are treated with nivolumab will be included in the trial, they will not be treated with cyclophosphamide.





Primary Outcome Measures :
  1. maximum tolerated dose [ Time Frame: 3 months after radiotherapy ]
    maximum tolerated dose of hypofractionated stereotactic body radiotherapy (SBRT) using dose painting by numbers with immunomodulating systemic therapy in patients that are reirradiated for recurrent squamous cell carcinoma of the head and neck


Secondary Outcome Measures :
  1. symptom palliation - pain [ Time Frame: through study completion, an average of 12 months ]
    reduction in pain

  2. symptom palliation - dysphagia [ Time Frame: through study completion, an average of 12 months ]
    reduction in grade of dysphagia

  3. local control [ Time Frame: 3 months after SBRT and thereafter through study completion, an average of 12 months ]

    Assessment of:

    1. diameter of target lesion of SBRT (and, if present, non-target lesions) in mm
    2. tumor response according to recist criteria

  4. Overall survival [ Time Frame: through study completion, an average of 12 months ]
    To estimate overall survival

  5. Progression free survival [ Time Frame: through study completion, an average of 12 months ]
    To estimate progression-free survival

  6. grade ≥ 3 toxicity-free survival [ Time Frame: through study completion, an average of 12 months ]
    To estimate grade ≥ 3 toxicity-free survival (anemia, febrile neutropenia, fatigue, dysphagia, oral mucositis, laryngeal mucositis, pharyngeal mucositis, pharyngeal hemorrhage, pharyngeal necrosis, pharyngeal stenosis, pharyngolaryngeal pain, dry mouth)

  7. QOL - general [ Time Frame: before therapy, week 3, week 6, week 10, week 14 ]
    To assess quality-of-life: EORTC QLQ

  8. QOL - H&N specific [ Time Frame: before therapy, week 3, week 6, week 10, week 14 ]
    To assess quality-of-life: H&N35

  9. topographic distribution of recurrence [ Time Frame: through study completion, an average of 12 months ]
    To assess the topographic distribution of recurrence (inside/outside FDG-avid GTV)

  10. time to further treatment [ Time Frame: through study completion, an average of 12 months ]
    To assess time to further treatment

  11. immune response [ Time Frame: using serum taken before treatment and at each fraction of SBRT, at weeks 6-14 ]
    To assess the immune response



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed local, regional or combined locoregional recurrence of squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx or larynx or cancer of unknown primary (CUP) in the neck in previously irradiated tissue, with former irradiation with curative intent.
  • Patients with non-symptomatic distant metastases and local, regional or combined locoregional recurrence can be included.
  • In case of non-metastatic disease, the recurrence must be primarily unresectable recurrence and/or patients refused surgery.
  • Time interval 6-24 months after the end of the initial radio(chemo)therapy for primary head and neck cancer.
  • Decision of the Head and Neck Tumor Boards at the recruiting centre to offer salvage radio(chemo)therapy, palliative chemotherapy or anti-PD-1 antibody treatment with nivolumab for cisplatin-refractory locoregional recurrent head and neck squamous cell carcinoma.
  • Karnofsky performance status ≥ 70.
  • Age ≥ 18 years old.
  • Informed consent obtained, signed and dated before specific protocol procedures.

Exclusion Criteria:

  • Previous radiotherapy was for cT1-2 cN0 M0 glottic cancer.
  • Grade ≥ 4 late toxicity after the initial radio(chemo)therapy.
  • Brachytherapy as treatment for second primary / recurrence.
  • Previous (combination with) immunotherapy for the primary or the recurrent squamous cell carcinoma.
  • Impossibility of oral intake of cyclophosphamide.
  • For patients receiving cyclophosphamide: necessary intake during therapy of allopurinol, amiodarone, digoxin, hydrochlorothiazide, indomethacin, phenobarbital, phenytoin, warfarin. clopidogrel, ticlopidine, carbamazepine, efavirenz, rifampicin, ritonavir
  • High risk for arterial blow-out: 1 of following criteria is sufficient to exclude patients:

    1. soft tissue necrosis
    2. skin invasion of the recurrent cancer
    3. circumferential involvement of > 180° of a carotid artery
  • Symptomatic distant metastases.
  • Other uncontrolled second primary tumors.
  • Pregnant or lactating women.
  • Mental condition rendering the patient unable to understand the nature, scope, and possible consequences of the study.
  • Patient unlikely to comply with protocol, i.e. uncooperative attitude, inability to return for follow-up visits, and unlikely to complete the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03402737


Contacts
Contact: An Spiessens, MSc 93320871 ext 0032 an.spiessens@uzgent.be

Locations
Belgium
Radiotherapy department, University Hospital Ghent Recruiting
Ghent, Oost-Vlaanderen, Belgium, 9000
Contact: Wilfried De Neve, MD, PhD    +32 9 332 30 15    wilfried.deneve@uzgent.be   
Contact: Fréderic Duprez, MD, PhD    +32 9 332 30 15    frederic.duprez@uzgent.be   
Principal Investigator: Wilfried De Neve, MD, PhD         
Sub-Investigator: Fréderic Duprez, MD, PhD         
Sub-Investigator: Katrien Vandecasteele, MD, PhD         
Sub-Investigator: Sylvie Rottey, MD, PhD         
UZ Leuven Recruiting
Leuven, Belgium
Contact: Sandra Nuyts, MD, PhD         
CHU Namur Recruiting
Namur, Belgium
Contact: Jean-François Daisne, MD         
Sponsors and Collaborators
University Hospital, Ghent
Investigators
Principal Investigator: Wilfried De Neve, MD, PhD Gent University

Responsible Party: Radiotherapie, Principal Investigator, University Hospital, Ghent
ClinicalTrials.gov Identifier: NCT03402737     History of Changes
Other Study ID Numbers: EC/2017/0636
2017-000133-31 ( EudraCT Number )
First Posted: January 18, 2018    Key Record Dates
Last Update Posted: August 6, 2018
Last Verified: August 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Radiotherapie, University Hospital, Ghent:
Stereotactic body radiotherapy
Immunomodulating systemic therapy

Additional relevant MeSH terms:
Head and Neck Neoplasms
Neoplasms by Site
Neoplasms