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Cisplatin + Radiotherapy vs Durvalumab + Radiotherapy Followed by Durvalumab vs Durvalumab + Radiotherapy Followed by Tremelimumab + Durvalumab in Intermediate-Risk HPV-Positive Oropharyngeal SCC

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ClinicalTrials.gov Identifier: NCT03410615
Recruitment Status : Recruiting
First Posted : January 25, 2018
Last Update Posted : November 9, 2021
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
Canadian Cancer Trials Group

Tracking Information
First Submitted Date  ICMJE January 9, 2018
First Posted Date  ICMJE January 25, 2018
Last Update Posted Date November 9, 2021
Actual Study Start Date  ICMJE January 31, 2018
Estimated Primary Completion Date January 31, 2026   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 17, 2018)
3 year event-free survival [ Time Frame: 3 years ]
Event-free survival (EFS), is defined as the time from randomization to the time when a failure event is observed. Failure is define by Local-regional progression or recurrence, Distant metastasis, Non-protocol RT, chemotherapy, Surgery or death.
Original Primary Outcome Measures  ICMJE
 (submitted: January 18, 2018)
3 year event-free survival [ Time Frame: 3 years ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 2, 2019)
  • Functional Assessment of Cancer Therapy-Head and Neck Version (FACT-HN) score. [ Time Frame: 6 years ]
    The FACT-H&N is a multidimensional, self-report QoL instrument specifically designed for use with head and neck cancer patients (1-3). It consists of 27 core items which assess patient function in four domains: Physical, Social/Family, Emotional, and Functional well-being, which is further supplemented by 12 site specific items to assess for head and neck related symptoms. Each item is rated on a 0 to 4 Likert type scale, and then combined to produce subscale scores for each domain, as well as an global QoL score. Higher scores represent better QoL.
  • Local regional failure [ Time Frame: 6 years ]
    Locoregional control defined as time from randomization to the time of first documented local (primary site) or regional (lymph node) recurrence
  • Distant metastasis-free survival [ Time Frame: 6 years ]
    Distant metastasis-free survival defined as time from randomization to the time of first documented distant metastasis or death from any cause
  • Overall survival [ Time Frame: 6 years ]
    Overall Survival defined as time from randomization to the time of death from any cause
  • Cost-effectiveness of immunotherapy-based treatment arm vs standard of RT and cisplatin in patients with intermediate risk LA-OSC using the EQ-5D-5L [ Time Frame: 6 years ]
  • Number and severity of adverse events [ Time Frame: 6 years ]
  • Cost-utility will be used to abstract indirect costs at the end of RT and at 6 and 12 months post RT [ Time Frame: 6 & 12 months ]
  • Lost productivity questionnaire will be used to abstract indirect costs at the end of RT and at 6 and 12 months post RT [ Time Frame: 6 & 12 months ]
  • Incidence of second cancer [ Time Frame: 6 years ]
  • PRO-CTCAE baseline, last week of treatment, 3 months, 6 months and 12, 24 and 36 months from the end of RT [ Time Frame: 3, 6, 12, 24 and 36 months ]
  • Dysphagia: PSS-HN swallowing subscale at 36 months from the end of RT [ Time Frame: 36 months ]
  • Dysphagia: using MDADI Global at 36 months from the end of RT [ Time Frame: 36 months ]
  • Number and severity of radiation-related late toxicity at 3 months, 6 months and 1 year from the end of RT [ Time Frame: 3 months, 6 months & 1 year ]
Original Secondary Outcome Measures  ICMJE
 (submitted: January 18, 2018)
  • Functional Assessment of Cancer Therapy-Head and Neck Version (FACT-HN) score. [ Time Frame: 3 years ]
    The FACT-H&N is a multidimensional, self-report QoL instrument specifically designed for use with head and neck cancer patients (1-3). It consists of 27 core items which assess patient function in four domains: Physical, Social/Family, Emotional, and Functional well-being, which is further supplemented by 12 site specific items to assess for head and neck related symptoms. Each item is rated on a 0 to 4 Likert type scale, and then combined to produce subscale scores for each domain, as well as an global QoL score. Higher scores represent better QoL.
  • Locoregional control defined as time from randomization to the time of first documented local (primary site) or regional (lymph node) recurrence [ Time Frame: 5.5 years ]
  • Distant metastasis-free survival defined as time from randomization to the time of first documented distant metastasis or death from any cause [ Time Frame: 5.5 years ]
  • Overall Survival defined as time from randomization to the time of death from any cause [ Time Frame: 5.5 years ]
  • Number and severity of adverse events [ Time Frame: 5.5 years ]
  • Incidence of second cancer [ Time Frame: 5.5 years ]
  • Dysphagia: PSS-HN swallowing subscale [ Time Frame: 3 years ]
    at 36 months from the end of RT
  • Dysphagia: MDADI Global [ Time Frame: 3 years ]
  • PRO-CTCAE [ Time Frame: 3 years ]
    baseline, last week of treatment, 3 months, 6 months and 12, 24 and 36 months from the end of RT
  • Number and severity of Radiation related late toxicity [ Time Frame: 3 years ]
    at 3 months, 6 months and 1 year from the end of RT
  • Cost effectiveness of the 2 immunotherapy-based experimental treatment arms vs. the standard of RT and cisplatin in patients with intermediate risk LA-OSC using the EQ 5D 5L [ Time Frame: 5.5 years ]
  • Cost utility and lost productivity calculated from EQ-5D-5L [ Time Frame: 5.5 years ]
    Aquality adjusted life years (QALYs) will be assessed as the area under the preference-weighted survival curve. The mean overall cost per patient for each of the study groups will be calculated to determine the costs per life-year gained.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Cisplatin + Radiotherapy vs Durvalumab + Radiotherapy Followed by Durvalumab vs Durvalumab + Radiotherapy Followed by Tremelimumab + Durvalumab in Intermediate-Risk HPV-Positive Oropharyngeal SCC
Official Title  ICMJE Randomized Phase II Study of Cisplatin Plus Radiotherapy Versus Durvalumab Plus Radiotherapy Followed by Adjuvant Durvalumab Versus Durvalumab Plus Radiotherapy Followed by Adjuvant Tremelimumab and Durvalumab in Intermediate Risk HPV-Positive Locoregionally Advanced Oropharyngeal Squamous Cell Cancer (LA-OSCC)
Brief Summary Sometimes, cancer patients receive an initial treatment, followed by additional treatment to lower the chance of cancer coming back. The standard or usual treatment for this type of disease is initially having radiation therapy at the same time as chemotherapy (with a drug called cisplatin), with no additional therapy afterwards
Detailed Description

This study is looking at whether a type of drug called durvalumab can be used with radiation during the initial treatment, (instead of cisplatin) and also afterwards as additional therapy. Durvalumab is an immunotherapy drug . It has been tested in many different types of cancers. Durvalumab works by allowing the immune system to detect the cancer and reactivate the immune response. This may help to slow down the growth of cancer or may cause cancer cells to die. Durvalumab has been shown to shrink tumours in animals. It has been studied in more than 5000 people, approved for use in other cancers and seems promising.

This clinical trial will also test another type of immunotherapy drug called tremelimumab, which would also be given as additional treatment. Tremelimumab works in a different way to durvalumab to enhance the immune system reaction against cancer cells and may improve the effect of durvalumab. Tremelimumab may also help slow the growth of the cancer cells or may cause cancer cells to die. It has been shown to shrink tumours in animals. Tremelimumab has been studied in over 1200 people, approved for use in other cancers and seems promising.

As of February 2019, tremelimumab will no longer be tested with new participants joining the study.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
This is a non-comparative, randomized, phase II study of cisplatin plus radiotherapy or durvalumab plus radiotherapy followed by adjuvant durvalumab or durvalumab plus radiotherapy followed by adjuvant tremelimumab and durvalumab in intermediate risk, HPV-positive, locoregionally advanced oropharyngeal squamous cell cancer (LA-OSCC) of the head and neck.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Oropharyngeal Squamous Cell Carcinoma
Intervention  ICMJE
  • Radiation: Radiation
    70 Gy in 35 fractions over 7 weeks (i.e. 2 Gy per fraction)
  • Drug: Cisplatin
    100 mg/m2 days 1, 22, 43 concurrently with RT
  • Drug: Durvalumab
    Given in concurrent and adjuvant phase
  • Drug: Tremelimumab
    ARM CLOSED TO ACCRUAL - 2019
Study Arms  ICMJE
  • Active Comparator: Radiation/Cisplatin

    All patients will receive standard fractionation radiation therapy (RT) scheme: 70 Gy in 35 fractions over 7 weeks (i.e. 2 Gy per fraction)

    Cisplatin IV 100 mg/m2 days 1, 22, 43 concurrently with RT

    Interventions:
    • Radiation: Radiation
    • Drug: Cisplatin
  • Experimental: Radiation/Durvalumab + Adjuvant Durvalumab

    All patients will receive standard fractionation radiation therapy (RT) scheme: 70 Gy in 35 fractions over 7 weeks (i.e. 2 Gy per fraction)

    Concurrent Phase: Durvalumab IV 1500 mg, days -7 and 22 (the second dose is given concurrently with RT).

    Adjuvant Phase (to start 4 weeks after completion of concurrent phase): Durvalumab IV 1500 mg q4 weekly for 6 doses.

    Interventions:
    • Radiation: Radiation
    • Drug: Durvalumab
  • Experimental: Radiation/Durvalumab + Adjuvant Durvalumab/Tremelimumab
    ARM CLOSED TO ACCRUAL WITH AMENDMENT #1
    Interventions:
    • Radiation: Radiation
    • Drug: Durvalumab
    • Drug: Tremelimumab
Publications * Not Provided

*   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: February 14, 2019)
180
Original Estimated Enrollment  ICMJE
 (submitted: January 18, 2018)
240
Estimated Study Completion Date  ICMJE July 31, 2026
Estimated Primary Completion Date January 31, 2026   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Histologically and/or cytologically confirmed (primary lesion or regional lymph nodes) squamous cell carcinoma of the oropharynx (OSCC) which is locoregionally advanced, intermediate risk and non-metastatic (M0) as defined by the following (UICC/AJCC 8th Edition staging)

    • T1-2 N1 (smoking ≥ 10 pack years);
    • T3 N0-N1 (smoking ≥ 10 pack years);
    • T1-3 N2 (any smoking hx).
  • Human papillomavirus (HPV)-related as determined by positive p16 immunohistochemical staining on any tumour specimens. Positive p16 expression is defined as strong and diffuse nuclear and cytoplasmic staining in 70% or more of the tumour cells. Local testing is acceptable; testing will not be done centrally in real-time.
  • Must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (see Appendix I) and a body weight of > 30 kg.
  • The following radiological investigations must be done within 8 weeks of randomization:

    • CT or MRI of the neck (with PET-CT and head imaging as indicated);
    • CT chest or x-ray, other radiology tests as clinically indicated.
  • Women/men of childbearing potential must have agreed to use a highly effective contraceptive method.
  • Patient must consent to provision of, and investigator(s) must confirm location and commit to obtain a representation of formalin fixed paraffin block, of non-cytology tissue samples in order that the specific correlative mark assays may be conducted.
  • Patient must consent to provision of samples of blood, saliva and oropharyngeal swab in order that the specific correlative marker assays may be conducted
  • Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life and health economics questionnaires in the languages provided.
  • Patients must be accessible for treatment and follow-up. Patients registered on this trial must be treated and followed at the participating centre
  • In accordance with CCTG policy, protocol treatment (cisplatin/RT or durvalumab) is to begin within 1 week of randomization.
  • The patient is not receiving anti-cancer therapy in a concurrent clinical study testing new treatments or treatment strategies and the patient agrees not to participate in other clinical studies during their participation in this trial while on study treatment.
  • Adequate normal organ and marrow function as defined below (must be done within 14 days prior to randomization): Absolute neutrophils - ≥ 1.5 x 10^9/L; Platelets ≥100 x 10^9; Hemoglobin ≥90 g/L; Bilirubin ≤ 1.5 x UNL; AST and ALT ≤2.5 x UNL; Creatine clearance ≥ 60 mL/min.
  • Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements
  • Patients must be assessed by a radiation oncologist and medical oncologist and deemed suitable for study participation including administration of radiotherapy, cisplatin and durvalumab as outlined in the protocol.

Exclusion Criteria:

  • Patients with a history of other malignancies, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for ≥ 5 years.
  • Current history of other non-OSCC malignancies of the head and neck.
  • Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab, or an anti-CTLA4, including tremelimumab.
  • Any previous cisplatin or carboplatin chemotherapy.
  • Any previous induction chemotherapy for current SCCHN.
  • Any previous surgical treatment of the current cancer (except for a diagnostic biopsy) and no major surgery within 28 days prior to randomization.
  • Any previous radiation to the head and neck region that would result in overlap of fields for the current study.
  • History of allergic or hypersensitivity reactions to any study drug or their excipients.
  • Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥ 470 msec in screening ECG measured using standard institutional method or history of familial long QT syndrome.
  • History of primary immunodeficiency, history of allogenic organ transplant that requires therapeutic immunosuppression and the use of immunosuppressive agents within 28 days of randomization* or a prior history of severe (grade 3 or 4) immune mediated toxicity from other immune therapy or grade ≥ 3 infusion reaction
  • Current or prior use of immunosuppressive medication within 28 days of study entry, with the exceptions of intranasal and inhaled corticosteroids or systemic chronic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Corticosteroids used on study for anti-emetic purpose are allowed. Corticosteroids as premedication for hypersensitivity reactions (e.g. computed tomography [CT] scan premedication) are allowed.
  • Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease (e.g. colitis or Crohn's disease), diverticulitis with the exception of diverticulosis, celiac disease (controlled by diet alone) or other serious gastrointestinal chronic conditions associated with diarrhea), systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangiitis), rheumatoid arthritis, hypophysitis, uveitis, etc., within the past 3 years prior to the start of treatment. The following are exceptions to this criterion:
  • Patients with vitiligo or alopecia;
  • Patients with Grave's disease, vitiligo or psoriasis not requiring systemic treatment (within the last 2 years);
  • Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement;
  • Any chronic skin condition that does not require systemic therapy.
  • Patients with active or uncontrolled intercurrent illness including, but not limited to:

    • cardiac dysfunction (symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia);
    • active peptic ulcer disease or gastritis;
    • active bleeding diatheses;
    • psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent;
    • known history of previous clinical diagnosis of tuberculosis;
    • known active human immunodeficiency virus infection (positive HIV 1/2 antibodies); HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible;
    • known active hepatitis B infection (positive HBV surface antigen (HBsAg). Patients with a past or resolved HBV infection (defined as presence of hepatitis B core antibody (anti-HBc) and absence of HBsAg) are eligible;
    • known active hepatitis C infection. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
  • History of interstitial lung disease e.g. pneumonitis or pulmonary fibrosis or evidence of interstitial lung disease on baseline CT scan.
  • Receipt of live attenuated vaccination (examples include, but are not limited to, vaccines for measles, mumps, and rubella, live attenuated influenza vaccine (nasal), chicken pox vaccine, oral polio vaccine, rotavirus vaccine, yellow fever vaccine, BCG vaccine, typhoid vaccine and typhus vaccine) within 30 days prior to randomization.
  • Pregnant or lactating women
  • Any active disease condition which would render the protocol treatment dangerous or impair the ability of the patient to receive protocol therapy.
  • Any condition (e.g. psychological, geographical, etc.) that does not permit compliance with the protocol
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Wendy Parulekar 613-533-6430 wparulekar@ctg.queensu.ca
Listed Location Countries  ICMJE Belgium,   Canada,   Italy,   Spain
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03410615
Other Study ID Numbers  ICMJE HN9
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Canadian Cancer Trials Group
Study Sponsor  ICMJE Canadian Cancer Trials Group
Collaborators  ICMJE AstraZeneca
Investigators  ICMJE
Study Chair: Anna Spreafico UNH/Princess Margaret Cancer Centre, Toronto ON Canada
Study Chair: Khalil Sultanem The Jewish General Hospital, Montreal QC, Canada
PRS Account Canadian Cancer Trials Group
Verification Date November 2020

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