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Radiotherapy With Double Checkpoint Blockade of Locally Advanced HNSCC

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ClinicalTrials.gov Identifier: NCT03426657
Recruitment Status : Recruiting
First Posted : February 8, 2018
Last Update Posted : June 21, 2019
Sponsor:
Information provided by (Responsible Party):
University of Erlangen-Nürnberg Medical School

Brief Summary:
First-line treatment of locally advanced HNSCC with double checkpoint blockade and radiotherapy dependent on intratumoral CD8+ T cell Infiltration.

Condition or disease Intervention/treatment Phase
Locally Advanced Head and Neck Squamous Cell Carcinoma Combination Product: Durvalumab + Tremelimumab + RT Phase 2

Detailed Description:

This is a single arm, open-label, prospective, non-randomized Phase II clinical trial of locally advanced HNSCC with double checkpoint blockade and radiotherapy dependent on intratumoral CD8+ T cell Infiltration.

All patients will initially be treated with the PD-L1 inhibitor Durvalumab and the CTLA-4 Inhibitor Tremelimumab and one cycle with Cisplatin (30mg/m² d1-3) and Docetaxel (75mg/m² d1). Treatment response will be evaluated clinically by endoscopy with biopsy. Changes of the CD8+ T cell density in the second biopsy compared to the first one before therapy will be used for patient selection. Patients with a stable or decreased CD8+ tumor infiltrating immune cell density or clinical progressive disease will receive standard CRT outside the trial. For these patients toxicity will be monitored until the first dose of the subsequent standard CRT. Patients with an increased CD8+ tumor infiltrating immune cell density and at least clinically stable disease will receive radioimmunotherapy with the PD-L1 Inhibitor Durvalumab and the CTLA4-Inhibitor Tremelimumab (altogether 4 doses q4w including the induction dose) followed by maintenance therapy with Durvalumab (8 additional doses q4w). The primary endpoint is feasibility. Feasibility criteria are receiving the protocol treatment until cycle 6 of antibody treatment and absence of any of the DLT defined in the protocol. A feasibility rate of ≥80% is expected. The efficacy of radioimmunotherapy and predictive character of changes of CD8+ tumor infiltrating immune cells after induction chemo-immunotherapy are further endpoints. The follow up period will be two years after the completion of radiotherapy.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Prospective, Open-Label, Non-Randomized
Masking: None (Open Label)
Masking Description: Open Label
Primary Purpose: Treatment
Official Title: First-line Treatment of Locally Advanced HNSCC With Double Checkpoint Blockade and Radiotherapy Dependent on Intratumoral CD8+ T Cell Infiltration (CheckRad-CD8, EudraCT NUMBER: 2017-003226-33)
Actual Study Start Date : September 20, 2018
Estimated Primary Completion Date : April 2021
Estimated Study Completion Date : April 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Durvalumab

Arm Intervention/treatment
Experimental: Durvalumab + Tremelimumab + RT
Durvalumab (1500 mg,q4W) + Tremelimumab (75 mg, q4W) for up to a maximum of 4 doses/cycles combined with radiotherapy (35 x 2.0/1.8/1.6 Gy) followed by durvalumab monotherapy 1500mg via IV infusion q4W, starting 4 weeks after the last infusion of the combination, for up to a maximum of 8 additional durvalumab doses.
Combination Product: Durvalumab + Tremelimumab + RT
Patients with an increased CD8+ tumor infiltrating immune cell density and at least clinically stable disease will receive radioimmunotherapy with the PD-L1 Inhibitor Durvalumab and the CTLA4-Inhibitor Tremelimumab (altogether 4 doses q4w including the induction dose) followed by maintenance therapy with Durvalumab (8 additional doses q4w).




Primary Outcome Measures :
  1. Assessment of the number of participants receiving the protocol treatment until cycle 6 of antibody treatment [ Time Frame: At the end of cycle 6 of antibody treatment (each cycle is 4 weeks) ]
    Feasibility means the number of participants receiving the protocol treatment

  2. Assessment of the predictive character of changes of CD8+ tumor infiltrating immune cells after induction chemo-immunotherapy [ Time Frame: At Baseline and week 4 ]
    Changes of the CD8+ T cell density in the second biopsy compared to the first one before therapy will be used for patient selection.

  3. Assessment of the absence of any dose-limiting toxicities [ Time Frame: At the time of cycle 1 (week 2) to the last cycle 5-12 (up to 2 years) ]
    Feasibility means the number of dose-limiting toxicities of Grade 3 or higher toxicity that occurs during the trial


Secondary Outcome Measures :
  1. Progression free survival [ Time Frame: 12 weeks after completion of radiotherapy ]
    All patients will receive tumor imaging (CT or MRI) 12 weeks after completion of radiotherapy and panendoscopy with biopsy.

  2. Pathologically confirmed response [ Time Frame: 12 weeks after completion of radiotherapy ]
    All patients will receive tumor imaging (CT or MRI) 12 weeks after completion of radiotherapy and panendoscopy with biopsy.

  3. Overall survival [ Time Frame: 12 weeks after completion of radiotherapy ]
    All patients will receive tumor imaging (CT or MRI) 12 weeks after completion of radiotherapy and panendoscopy with biopsy.


Other Outcome Measures:
  1. Assessment of predictive value of different tumor infiltrating immune cells and immunological tumor markers. [ Time Frame: Baseline (week 0), each cycle is 4 weeks, at the end of cycle 1 (week 2), cycle 2 (week 6), cycle 3 (week 10), cycle 4 (week 14), cycle 5-12 (up to 2 years) ]
    Longitudinal analysis of the immune phenotype in the peripheral blood.

  2. Assessment of predictive changes of different tumor infiltrating immune cells and immunological tumor markers. [ Time Frame: Baseline (week 0), each cycle is 4 weeks, at the end of cycle 1 (week 2), cycle 2 (week 6), cycle 3 (week 10), cycle 4 (week 14), cycle 5-12 (up to 2 years) ]
    Longitudinal analysis of the immune phenotype in the peripheral blood.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Written informed consent and any locally-required authorization (e.g., HIPAA in the USA, EU Data Privacy Directive in the EU) obtained from the subject prior to performing any protocol-related procedures, including screening Evaluations.
  • Age > 18 years at time of study entry
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (amend based on specific study)
  • Locally advanced HNSCC, UICC stage III-IVB (oral cavity, oropharynx, hypopharynx, supraglottic larynx)
  • Histological confirmation of HNSCC (regardless if p16 positive or negative)
  • Measureable CD8 density in provided archival tumor tissue
  • Body weight >30kg
  • Adequate normal organ and marrow function as defined: Haemoglobin ≥ 9.0 g/dL; White blood cells (WBC) ≥ 3,000 per mm3; Platelet count >100,000 per mm3
  • Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).
  • AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal (ULN)
  • Creatinine Clearance >40ml/min (calculated from serum creatinine or cystatin C, alternatively 24h urine possible)
  • Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:

Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).

Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).

  • Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.

Exclusion Criteria:

  • Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
  • Participation in another clinical study with an investigational product during the last 4 weeks
  • Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
  • Distant metastases
  • Prior systemic anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumour embolization, monoclonal antibodies) of the locally advanced HNSCC
  • Any other concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment, except the induction chemotherapy in the protocol. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable
  • Prior radiotherapy of HNSCC
  • Radiotherapy to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug
  • Major surgical procedure of the current locally advanced HNSCC (as defined by the Investigator). Note: Local surgery of isolated lesions for palliative intent is acceptable.
  • History of allogenic organ transplantation.
  • 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], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion:

    • Patients with vitiligo or alopecia areata
    • Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
    • Any chronic skin condition that does not require systemic therapy
    • Patients without active disease in the last 5 years may be included but only after consultation with the study physician
    • Patients with celiac disease controlled by diet alone
  • Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
  • History of another primary malignancy except for

    • Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence
    • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
    • Adequately treated carcinoma in situ without evidence of disease
  • History of active primary immunodeficiency
  • Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
  • Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab. The following are exceptions to this criterion:

    • Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra articular injection)
    • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
    • Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
  • Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.
  • Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy or180 days after the last dose of durvalumab + tremelimumab combination therapy.
  • Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
  • Prior randomisation or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment.
  • Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease.
  • Judgment by the investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements.
  • Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 180 days after the last dose of durvalumab + tremelimumab combination therapy or 90 days after the last dose of durvalumab monotherapy, whichever is the longer time period
  • Known allergy or hypersensitivity to durvalumab, tremelimumab, cisplatin/carboplatin, docetaxel or any excipient
  • Cisplatin/carboplatin induced polyneuropathy or hearing disorder

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): NCT03426657


Contacts
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Contact: Sandra Rutzner, M.Sc. ++49(0)9131-85-33968 sandra.rutzner@uk-erlangen.de
Contact: Markus Hecht, M.D. ++49(0)9131-85-33968 markus.hecht@uk-erlangen.de

Locations
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Germany
Klinik Chemnitz gGmbH Recruiting
Chemnitz, Germany, 09116
Contact: Gunther Klautke, M.D    +49 371 333 ext 42550    g.klautke@skc.de   
Contact: Ute Hintzen, M.D.    +49 371 333 ext 42550    u.hintzen@skc.de   
Dresden, Onkologische Gemeinschaftspraxis Recruiting
Dresden, Germany, 01307
Contact: Thomas Illmer, M.D.    +49351/4472340    illmer@onkologie-dresden.net   
Contact: Lutz Jacobasch, M.D.    +49 351 44000 ext 22    jacobasch@onkologie-dresden.net   
Düsseldorf, Universitätsklinikum, Klinik für Strahlentherapie und Radiologische Onkologie Not yet recruiting
Düsseldorf, Germany, 40225
Contact: Bálint Tamaskovics, M.D.    +49221/81 16894    balint.tamaskovics@med.uni-duesseldorf.de   
Contact: Wilfried Budach, Prof.    +49 21181 ext 17991    wilfried.budach@med.uni-duesseldorf.de   
Erlangen, Universitätsklinikum Strahlenklinik Recruiting
Erlangen, Germany, 91054
Contact: Rainer Fietkau, Prof.    +499131-85-33405    rainer.fietkau@uk-erlangen.de   
Contact: Markus Hecht, M.D.    +49 9131 85 ext 33968    markus.hecht@uk-erlangen.de   
Frankfurt, Universitätsklinikum, Klinik für Strahlentherapie und Onkologie Recruiting
Frankfurt, Germany, 60590
Contact: Claus Rödel, Prof.    +4969/6301 ext 5130    Claus.Roedel@kgu.de   
Contact: Jens von der Grün, M.D.    +49 69 6301 ext 5130    jens.vonderGruen@kgu.de   
Magdeburg, Universitätsklinikum Recruiting
Magdeburg, Germany, 39120
Contact: Thomas Brunner, Prof.    +493916715791    thomas.brunner@med.ovgu.de   
Contact: Peter Hass, M.D.    +49 39167 ext 15795    peter.hass@med.ovgu.de   
Regensburg, Universitätsklinikum, Klinik für Strahlentherapie Recruiting
Regensburg, Germany, 93042
Contact: Matthias Hautmann, M.D.    +49941/9447610    matthias.hautmann@ukr.de   
Contact: Oliver Kölbl, Prof.    +49 941944 ext 7601    oliver.koelbl@ukr.de   
Universitätsklinikum Ulm Recruiting
Ulm, Germany, 89075
Contact: Simon Laban, M.D.    +49 731 500 ext 59548    simon.labana@uniklinik-ulm.de   
Contact: Thomas Wiegel, Prof.    +49 731 500 ext 56101    thomas.wiegel@uniklinik-ulm.de   
Sponsors and Collaborators
University of Erlangen-Nürnberg Medical School
Investigators
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Principal Investigator: Rainer Fietkau, Prof. Universitätsklinikum Erlangen, Strahlenklinik
Study Chair: Wilfried Budach, Prof. Universitätsklinikum Düsseldorf
Study Chair: Claus Rödel, Prof. Universitätsklinikum Frankfurt
Study Chair: Markus Hecht, M.D. Universitätsklinikum Erlangen
Study Chair: Udo Gaipl, Prof. Universitätsklinikum Erlangen

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Responsible Party: University of Erlangen-Nürnberg Medical School
ClinicalTrials.gov Identifier: NCT03426657    
Other Study ID Numbers: CheckRad-CD8
First Posted: February 8, 2018    Key Record Dates
Last Update Posted: June 21, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Squamous Cell Carcinoma of Head and Neck
Carcinoma, Squamous Cell
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Head and Neck Neoplasms
Neoplasms by Site
Durvalumab
Tremelimumab
Antineoplastic Agents, Immunological
Antineoplastic Agents