Clinical Trials /

Feasibility & Efficacy of Durvalumab+Tremelimumab+RT and Durvalumab+RT in Non-resect. Locally Advanced HPVnegativ HNSCC

NCT03624231

Description:

Phase II trial evaluating to assess the feasibility and efficacy as first-line therapy for patients with non-resectable locally advanced HPV negative HNSCC of Durvalumab a PDL1-Inhibitor plus Tremelimumab a CTLA-4- Inhibitor in combination with radiotherapy and Durvalumab in combination with radiotherapy as first-line therapy. 2-arm, randomized, multicenter, phase II. Step 1 is Registration. All patients need to sign the informed consent form for registration. Tumor tissue then be send to the central lab for defining the HPV status. If the patient is HPV negative the site will be notified if they can further proceed to patient randomization. Step 2 is Randomization of all eligible patients with a centrally diagnosed, HPV negative tumor in one of the two arms (Durvalumab plus Tremelimumab + radiotherapy; Durvalumab + radiotherapy) after signing the informed consent form for step 2.

Related Conditions:
  • Head and Neck Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Feasibility & Efficacy of Durvalumab+Tremelimumab+RT and Durvalumab+RT in Non-resect. Locally Advanced HPVnegativ HNSCC
  • Official Title: Ph II Trial to Assess Feasibility+Efficacy of Treatment w Durva+Treme+Radiation and Treatment w Durva+Radiation as First-line Therapy for Patients w Non-resectable Locally Advanced HPV-HNSCC- a Comparision With a Historical Control Group

Clinical Trial IDs

  • ORG STUDY ID: DURTRE-RAD
  • NCT ID: NCT03624231

Conditions

  • Squamous Cell Carcinoma of the Head and Neck

Interventions

DrugSynonymsArms
DurvalumabMEDI4736Arm 1
TremelimumabArm 1

Purpose

Phase II trial evaluating to assess the feasibility and efficacy as first-line therapy for patients with non-resectable locally advanced HPV negative HNSCC of Durvalumab a PDL1-Inhibitor plus Tremelimumab a CTLA-4- Inhibitor in combination with radiotherapy and Durvalumab in combination with radiotherapy as first-line therapy. 2-arm, randomized, multicenter, phase II. Step 1 is Registration. All patients need to sign the informed consent form for registration. Tumor tissue then be send to the central lab for defining the HPV status. If the patient is HPV negative the site will be notified if they can further proceed to patient randomization. Step 2 is Randomization of all eligible patients with a centrally diagnosed, HPV negative tumor in one of the two arms (Durvalumab plus Tremelimumab + radiotherapy; Durvalumab + radiotherapy) after signing the informed consent form for step 2.

Detailed Description

      The primary objective is to explore the feasibility and efficacy in terms of treatment
      discontinuation due to toxicity and in terms of 1-year progression free survival of a
      PDL1-Inhibitor plus a CTLA-4 Inhibitor in combination with radiotherapy and a PDL1-Inhibitor
      in combination with radiotherapy as first-line therapy for patients with non-resectable
      locally advanced HNSCC in the poor prognostic subgroup.

      Secondary objectives are to investigate the benefit of the addition of a CTLA-4 Inhibitor
      and/or a PDL1-Inhibitor to radiotherapy in terms of overall progression free survival,
      overall survival and to investigate the approach in terms of safety, chronic toxicity and
      quality of life.
    

Trial Arms

NameTypeDescriptionInterventions
Arm 1ExperimentalPatients in arm 1 will receive a single dose of durvalumab of 1500 mg administered on day 1, 14 days prior to initiation of the radiotherapy. Radiotherapy with 35 fractions over 7 weeks (administered as daily fractions of 2 Gy given 5 days every week for 7 weeks) will start on day 14. On week 5, 9, 13 and 17 patients will receive durvalumab (1500 mg) and tremelimumab (75 mg) for up to 4 doses/cycles and then continue 1500 mg durvalumab q4w starting on week 21 to complete a total of 12 months of therapy (overall 9 single doses durvalumab including the initial dose on day 1).
  • Durvalumab
  • Tremelimumab
Arm 2ExperimentalPatients in arm 2 will receive durvalumab (1500 mg) q4w starting on day 1. Radiotherapy with 35 fractions over 7 weeks (administered as daily fractions of 2 Gy given 5 days every week for 7 weeks) will start on day 14. Overall patients will receive treatment with durvalumab mono up to a total of 12 months (up to 13 doses in total).
  • Durvalumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with locally advanced histopathologically confirmed HNSCC not candidate for
             primary surgical treatment

          -  No distant metastasis (M0)

          -  Tumor tissue available for central testing Patient with HPV/p16 negative disease (≤70%
             positively stained cells) as determined by central testing

          -  Adequate normal organ and marrow function

          -  Measurable tumor according to RECIST

          -  Patients must be expected to complete the treatment.

          -  Age > 18 years at time of study entry

          -  Female patients must either be of non-reproductive potential or must have a negative
             serum pregnancy test upon study entry and be willing to use adequate contraceptive
             measurements as described in the protocol

          -  Non-sterilized males who are sexually active with a female partner of childbearing
             potential must be willing to use adequate contraceptive measurements as described in
             the protocol section 6.5.4

        Exclusion Criteria:

          -  Participation in another clinical study with an investigational product during the
             last 3 months

          -  Prior or current anticancer treatment to the head and neck area (e.g. radical
             attempted or tumor reductive surgery, neo-adjuvant chemotherapy, EGFR inhibitors or
             radiotherapy).

          -  Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an
             anti-CTLA4, including tremelimumab

          -  Active or prior documented autoimmune or inflammatory disorders (including
             inflammatory bowel disease [eg, 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

               -  Patients with hypothyroidism (eg, 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 History of primary
                  immunodeficiency

          -  History of allogeneic organ transplant

          -  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 hypersensitivity to durvalumab and/or tremelimumab or any excipient

          -  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

          -  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.

          -  Any condition that, in the opinion of the investigator, would interfere with
             evaluation of study treatment or interpretation of patient safety or study results

          -  Female patients who are pregnant or breastfeeding or male or female patients of
             reproductive potential who are not willing to employ effective birth control as
             described in the protocol 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

          -  Distant metastasis

          -  Patients who are institutionalised by official order

          -  Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3
             electrocardiograms (ECGs) using Fredericia's Correction

          -  Receipt of live attenuated vaccination within 30 days prior to study entry step 2 or
             within 30 days of receiving durvalumab or tremelimumab
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Efficacy- 1-year progression free survival (PFS)
Time Frame:1 year
Safety Issue:
Description:1-year progression free survival (PFS) depicted as the 1-year in-field-progression-free survival and 1-year distant metastasis free survival

Secondary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:From date of randomization until the date of death, assessed up to 3 years
Safety Issue:
Description:defined as the time from patient inclusion to the date of death or date of last follow-up news
Measure:Safety - Number of participants with treatment-related adverse events as assessed by CTCAE v4.03
Time Frame:From date of randomization until the date of study assessed up to 3 years
Safety Issue:
Description:defined as event possibly related to study treatment and fulfills the criteria using CTCAE Version 4.03
Measure:Chronic toxicity -Number of participants with treatment-related adverse Events Lasting longer than 3 months as assessed by CTCAE v4.03 and/or RTOG/EORTC Late Radiation Morbidity Scoring Schema
Time Frame:From date of randomization until the date of study assessed up to 3 years
Safety Issue:
Description:defined as event lasting longer than 3 months and possibly related to study treatment and fulfills the criteria using CTCAE Version 4.03 and/or and/or RTOG/EORTC Late Radiation Morbidity Scoring Schema
Measure:Quality of life (QoL) - measured by EORTC QLQ-H&N35 and EORTC QLQ-C30)
Time Frame:From date of randomization until the date of study assessed up to 3 years
Safety Issue:
Description:defined as assessment for evaluation of medical and psychosocial interventions

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Ulrich Keilholz

Trial Keywords

  • Squamous Cell Carcinoma of the Head and Neck

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