Radiotherapy With Double Checkpoint Blockade of Locally Advanced HNSCC

NCT03426657 | Completed Phase 2 DMC

• 1 other identifier: CheckRad-CD8
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 7

Brief Summary

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

Conditions

Locally Advanced Head and Neck Squamous Cell Carcinoma

Outcome Measures

Primary Outcomes (3)

• Assessment of the number of participants receiving the protocol treatment until cycle 6 of antibody treatment

  Feasibility means the number of participants receiving the protocol treatment

  At the end of cycle 6 of antibody treatment (each cycle is 4 weeks)

• Assessment of the predictive character of changes of CD8+ tumor infiltrating immune cells after induction chemo-immunotherapy

  Changes of the CD8+ T cell density in the second biopsy compared to the first one before therapy will be used for patient selection.

  At Baseline and week 4

• Assessment of the absence of any dose-limiting toxicities

  Feasibility means the number of dose-limiting toxicities of Grade 3 or higher toxicity that occurs during the trial

  At the time of cycle 1 (week 2) to the last cycle 5-12 (up to 2 years)

Secondary Outcomes (3)

• Progression free survival

  12 weeks after completion of radiotherapy

• Pathologically confirmed response

  12 weeks after completion of radiotherapy

• Overall survival

  12 weeks after completion of radiotherapy

Other Outcomes (2)

• Assessment of predictive value of different tumor infiltrating immune cells and immunological tumor markers.

  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)

• Assessment of predictive changes of different tumor infiltrating immune cells and immunological tumor markers.

  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)

Study Arms (1)

Durvalumab + Tremelimumab + RT

EXPERIMENTAL

Durvalumab (1500 mg,q4W) + Tremelimumab (75 mg, q4W / since Amendment 3: 300 mg absolute dose d5) 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

Interventions

Durvalumab + Tremelimumab + RT COMBINATION_PRODUCT

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).

Durvalumab + Tremelimumab + RT

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Erlangen-Nürnberg Medical School: lead

Study Sites (7)

Klinik Chemnitz gGmbH

Chemnitz, 09116, Germany

Location

Dresden, Onkologische Gemeinschaftspraxis

Dresden, 01307, Germany

Location

Düsseldorf, Universitätsklinikum, Klinik für Strahlentherapie und Radiologische Onkologie

Düsseldorf, 40225, Germany

Location

Erlangen, Universitätsklinikum Strahlenklinik

Erlangen, 91054, Germany

Location

Frankfurt, Universitätsklinikum, Klinik für Strahlentherapie und Onkologie

Frankfurt, 60590, Germany

Location

Universitätsklinikum Regensburg

Regensburg, 93042, Germany

Location

Universitätsklinikum Ulm

Ulm, 89075, Germany

Location

Related Publications (2)

• Beck M, Hartwich J, Eckstein M, Schmidt D, Gostian AO, Muller S, Rutzner S, Gaipl US, von der Grun J, Illmer T, Hautmann MG, Klautke G, Doscher J, Brunner T, Tamaskovics B, Hartmann A, Iro H, Kuwert T, Fietkau R, Hecht M, Semrau S. F18-FDG PET/CT imaging early predicts pathologic complete response to induction chemoimmunotherapy of locally advanced head and neck cancer: preliminary single-center analysis of the checkrad-cd8 trial. Ann Nucl Med. 2022 Jul;36(7):623-633. doi: 10.1007/s12149-022-01744-6. Epub 2022 May 10.

  PMID: 35534690 DERIVED

• Hecht M, Eckstein M, Rutzner S, von der Grun J, Illmer T, Klautke G, Laban S, Hautmann MG, Brunner TB, Tamaskovics B, Hinke A, Zhou JG, Frey B, Donaubauer AJ, Becker I, Semrau S, Hartmann A, Balermpas P, Budach W, Gaipl US, Iro H, Gostian AO, Fietkau R. Induction chemoimmunotherapy followed by CD8+ immune cell-based patient selection for chemotherapy-free radioimmunotherapy in locally advanced head and neck cancer. J Immunother Cancer. 2022 Jan;10(1):e003747. doi: 10.1136/jitc-2021-003747.

  PMID: 35078923 DERIVED

MeSH Terms

Interventions

durvalumab; tremelimumab

Study Officials

• Rainer Fietkau, Prof.

  Universitätsklinikum Erlangen, Strahlenklinik

  STUDY CHAIR

• Wilfried Budach, Prof.

  University Düsseldorf

  STUDY CHAIR

• Claus Rödel, Prof.

  Johann Wolfgang Goethe University Hospital

  STUDY CHAIR

• Markus Hecht, M.D.

  Universitätsklinikum Erlangen

  PRINCIPAL INVESTIGATOR

• Udo Gaipl, Prof.

  Universitätsklinikum Erlangen

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Masking Details: Open Label
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Prospective, Open-Label, Non-Randomized

Study Record Dates

• First Submitted: January 24, 2018
• First Posted: February 8, 2018
• Study Start: September 20, 2018
• Primary Completion: September 16, 2021
• Study Completion: February 29, 2024
• Last Updated: April 11, 2024

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will not share

Locations

DE (7)