Clinical Trials /

FRAIL-IMMUNE (GORTEC 2018-03) - Combination of Durvalumab With Carboplatin/Paclitaxel

NCT03723967

Description:

The primary objective of the phase II trial is to determine the efficacy and safety of a combination of Durvalumab with the Carboplatin/Paclitaxel as first line treatment in patients with recurrent/metastatic SCCHN not eligible to standard chemotherapy.

Related Conditions:
  • Hypopharyngeal Squamous Cell Carcinoma
  • Laryngeal Squamous Cell Carcinoma
  • Oral Cavity Squamous Cell Carcinoma
  • Oropharyngeal Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: FRAIL-IMMUNE (GORTEC 2018-03) - Combination of Durvalumab With Carboplatin/Paclitaxel
  • Official Title: Multicenter Prospective Single Arm Phase II Study Evaluating Efficacy & Safety of Durvalumab With Carboplatin/Paclitaxel as First Line Treatment in Patients With Recurrent/Metastatic SCCHN Not Eligible to Standard Chemotherapy

Clinical Trial IDs

  • ORG STUDY ID: ET18-023 FRAIL-IMMUNE
  • NCT ID: NCT03723967

Conditions

  • Squamous Cell Carcinoma of the Head and Neck

Interventions

DrugSynonymsArms
Durvalumab with Carboplatin/PaclitaxelCombination of Durvalumab with Carboplatin/PaclitaxelDurvalumab with Carboplatin/Paclitaxel

Purpose

The primary objective of the phase II trial is to determine the efficacy and safety of a combination of Durvalumab with the Carboplatin/Paclitaxel as first line treatment in patients with recurrent/metastatic SCCHN not eligible to standard chemotherapy.

Detailed Description

      For recurrent or metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN), the
      standard first-line treatment is chemotherapy by cisplatin-fluorouracil and cetuximab which
      allows a median overall survival of 10.1 months. Due to its toxicity, this combination could
      be proposed only to patients younger than 70 years, good PS (ECOG PS0 or PS1) and adequate
      renal function.

      In routine practice it is estimated that the proportion of eligible patients is about two
      third. One third of patients were ineligible to first-line chemotherapy by
      cisplatin-fluorouracil-cetuximab. Among them, 25% due to PS2 and the others for various
      reasons (older than 70 years, renal insufficiency….). For these ineligible patients, an
      alternative chemotherapy should be proposed. The carboplatin-paclitaxel scheme with weekly
      paclitaxel is safe for poor population and demonstrated efficacy in head and neck cancers
      with overall survival varying from 4.9 months to 12.8 months in first line. The response rate
      varies from 20% to 52% and is about 25% in our experience. Even for frail patients it should
      be a safe and active treatment.

      Nivolumab, a monoclonal antibody targeting PD1 demonstrated survival benefit compared with
      chemotherapy in patients with SCCHN who progressed after platinum-based first line (median OS
      of 7.5 months versus 5.1 months and 12-month OS rate of 36.0% versus 16.6%). Safety data
      confirm these antibodies are of interest in a population of frail patients. Only 58.9% of
      patients experienced treatment-related adverse events with nivolumab arm and 13% of grade
      3/4. Durvalumab, an anti-PDL1 antibody is currently tested in SCCHN with promising results.

      Head and neck cancers are rapidly progressive and due to the delayed action of immunotherapy,
      and the recent demonstration that immunotherapy with anti-PD1 or anti-PDL1 can be responsible
      of hyperprogression, patients will probably benefit from addition of chemotherapy to
      immunotherapy, mostly for patients unfit for cisplatin-fluorouracil because their poor
      condition is often related to the cancer and a rapid response is needed.

      This trial proposes to study the addition of Durvalumab to chemotherapy in first line
      treatment for frail patients with recurrent/metastatic SCCHN.

      Prior to this evaluation, a run-in tolerance study in a limited number of patients to ensure
      that the experimental treatment combination is safe.
    

Trial Arms

NameTypeDescriptionInterventions
Durvalumab with Carboplatin/PaclitaxelExperimentalCombination of Durvalumab with Carboplatin/Paclitaxel as first line treatment in patients with recurrent/metastatic SCCHN not eligible to standard chemotherapy
  • Durvalumab with Carboplatin/Paclitaxel

Eligibility Criteria

        Inclusion Criteria:

          1. Age ≥ 18 years at the time of study entry;

          2. Histological or cytological confirmation of the diagnosis of Squamous Cell Carcinoma
             of the Head and Neck;

          3. Primary tumor located in one of the following : oral cavity, larynx, oropharynx or
             hypopharynx (NB: sinuses and nasopharynx locations are not allowed; isolated cervical
             lymphnodes with unknown primary site may be discussed with the coordinating
             investigator on a case by case basis)

          4. Archival tumor sample available at the time of inclusion with sufficient material to
             achieve the translational research program. Archival material must have been collected
             3 months before inclusion at the latest, unless a new tumor sample must be collected.

          5. Disease must be in metastatic (Stage IVc) or recurrent setting;

          6. Documented progression of measurable disease as per the RECIST (NB: in case of a
             single metastatic lesion, the tumor size must be > 20mm to allow tumor biopsy)

          7. Patients must fulfil at least one of the following frailty criteria:

               -  Age > 70 years

               -  Creatinine clearance (CrCl) : 40 < CrCl < 60ml/min

               -  Any severe comorbidity rendering the patient ineligible to standard chemotherapy,
                  as per investigator's judgment.

          8. Eastern Cooperative Oncology Group performance status of 0, 1 or 2

          9. Must have a life expectancy of at least 12 weeks

         10. Body weight > 30Kg;

         11. Adequate organ and marrow function as defined below:

               -  Hemoglobin ≥ 9.0 g/dl

               -  Absolute Neutrophils Count (ANC) ≥ 1.0 x 109/L

               -  Platelet count ≥ 100 x 109/L

               -  Creatinine clearance ≥ 40 ml/min using the following appropriate formulae:

                    -  Cockroft-Gault formula for female : 0.85 x weight (Kg) x (140-age) / 72 x
                       serum creatinine (mg/dL)

                    -  Cockroft-Gault formula for male : weight (Kg) x (140-age) / 72 x serum
                       creatinine (mg/dL)

                    -  MDRD for patients older than 65 years: 186.3 x (serum creatinine (µmol/L /
                       88.4) -1.154 x Age -0.203 x (0.742 if female) x (1.212 if black patient
                       [African origin]).

               -  AST/ALT ≤2.5 x institutional upper limit of normal unless liver metastases are
                  present, in which case it must be ≤5 x ULN

               -  Serum total bilirubin ≤ 1.5 x ULN (in the absence of Gilbert's syndrome)

               -  Coagulation panel : INR or PT ≤ 1.5 x ULN

         12. 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).

         13. Patient using a highly effective contraception as defined in appendix 9. Prior to
             dispensing study drugs, the investigator must confirm and document the patient's (and
             his/her partner) use of highly effective contraceptive methods, dates of negative
             pregnancy tests, and confirm the patient's understanding of the teratogenic potential
             of study drugs.

         14. Patient 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.

         15. Covered by a medical insurance.

         16. Signed and dated informed consent document indicating that the patient has been
             informed of all the pertinent aspects of the trial prior to enrolment

        Exclusion Criteria:

          1. 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

          2. Prior anticancer therapy in metastatic or recurrent setting In case patient received
             neoadjuvant or adjuvant anti-cancer treatment, it must have been completed for at
             least 6 months prior to study drugs initiation and patient must have no unresolved
             toxicity NCI CTCAE Grade ≥2 with the exception of alopecia, vitiligo and laboratory
             values defined as inclusion criteria.

             Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after
             consultation with the coordinating investigator.

             Patients with irreversible toxicity not reasonably expected to be exacerbated by
             treatment with durvalumab may be included only after consultation with the
             coordinating investigator.

          3. Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab.

          4. Patient whom tumor lesion is hemorrhagic or at risk of bleeding

          5. Patient whom disease progressed within 6 months after the start date of the previous
             chemotherapy (faster progressors)

          6. Symptomatic or active leptomeningial or parenchymal brain metastases. Patients whose
             brain metastases have been treated may participate provided they show radiographic
             stability (defined as 2 brain images, both of which are obtained after treatment ot
             the brain metastases; these Imaging scans should both be obtained at least 4 weeks
             apart and show no evidence of intracranial progression). In addition, any neurologic
             symptoms that developed either as a result of the brain metastases or their treatment
             must have resolved or be stable either, without the use of steroids, or are stable on
             a steroid dose of <=10mg/day of prednisone or its equivalent and anticonvulsant for at
             least 14 days prior to the start of treatment.

             with previously treated brain metastases (either by surgery, radiotherapy or
             radiosurgery) may be enrolled if stable, off steroids, on imaging and clinically, for
             at least 4 weeks.

          7. Active or prior/history of disease/medical condition listed below:

               -  Documented autoimmune or inflammatory disease (including inflammatory bowel
                  disease [e.g., Crohn's disease, ulcerative colitis], diverticulitis, systemic
                  lupus erythematosus, sarcoidosis syndrome or Wegener syndrome, granulomatosis
                  with polyangitis, Grave's disease, rheumatoid arthritis, hypophysitis, uveitis,
                  etc) within the past 2 years except for autoimmune hypothyroidism on a stable
                  dose of thyroid supplementation and patients with type 1 diabetes mellitus on a
                  stable dose of insulin.

        Note: Subjects with alopecia, vitiligo, Grave's disease, or psoriasis not requiring
        systemic treatment (within the past 2 years) or chronic skin condition that does not
        require systemic therapy, are not excluded, as well as patients without active disease in
        the last 5 years (after consultation with the study physician) and patients with celiac
        disease controlled by diet alone.

          -  Mean QT interval corrected for heart rate (QTc) ≥470 ms using Fredericia's Correction.

          -  Clinically significant cardiac disease or congestive heart failure > New York Heart
             Association (NYHA) class 2. Patients must not have unstable angina (anginal symptoms
             at rest) or new-onset angina within the last 3 months or myocardial infarction within
             the past 6 months.

          -  History of primary immunodeficiency

          -  Allogeneic organ transplantation

          -  Documented hypersensitivity to the active substance or excipient of the study drugs

          -  Any uncontrolled intercurrent illness including, but not limited to:

             o Ongoing or active infection, including tuberculosis (clinical evaluation that
             includes clinical history, physical examination and radiographic findings, and
             tuberculosis 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.

             o Active peptic ulcer disease or gastritis,

               -  Active bleeding diatheses including any subject known to have evidence of acute,

               -  Serious chronic gastrointestinal conditions associated with diarrhea

          -  Any psychiatric illness/social situations that would limit compliance with study
             requirements or compromise the ability of the subject to give written informed consent

             8. Current or prior use, or need for the following concomitant
             medications/interventions not permitted during the study treatment period :

          -  Any concurrent chemotherapy or radiotherapy treatment 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 (except palliative radiotherapy on a non-target lesion after discussion with the
             coordinating investigator), immunotherapy, biologic or hormonal therapy for cancer
             treatment, other than any stated in the protocol (Note: concurrent use of hormonal
             therapy for non-cancer-related conditions (e.g. hormone replacement therapy) is
             acceptable)).

          -  Current or prior use of immunosuppressive medication within 14 days before the first
             dose of durvalumab including, but not limited to systemic corticosteroids at doses
             exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, and TNF-α
             blockers. Use of immunosuppressive medications for the management of investigational
             product-related AEs or in subjects with contrast allergies is acceptable.

          -  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).

               -  Strong inhibitors and inducers of CYP3A4

               -  Major surgical procedure (as defined by the Investigator) within 28 days prior to
                  the first dose of IP. Note: Local surgery of isolated lesions for palliative
                  intent is acceptable.

                  8. Participation in another clinical study with an investigational product during
                  the last 28 days prior to first study drug administration

                  9. 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

                  10. Pregnant or breastfeeding women (Women of childbearing potential are required
                  to have a negative serum pregnancy test within 72 hours prior to study treatment
                  start. A positive urine test must be confirmed by a serum pregnancy test).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Evaluation of efficacy and safety of Durvalumab with the Carboplatin/Paclitaxel as first line treatment in patients with recurrent/metastatic SCCHN not eligible to standard chemotherapy
Time Frame:12 months after study treatment initiation
Safety Issue:
Description:Number of patients still alive 12 months after the first study drug administration (overall survival)

Secondary Outcome Measures

Measure:Progression-Free Survival
Time Frame:12 months after study treatment initiation
Safety Issue:
Description:Defined as the time from the date of the first study drug administration to the date of first documented progression or death due to any cause
Measure:Time to Treatment Failure
Time Frame:12 months after study treatment initiation
Safety Issue:
Description:Defined as the time from the date of inclusion to the date of permanent study treatment discontinuation
Measure:Objective Response Rate
Time Frame:12 months after study treatment initiation
Safety Issue:
Description:Defined as the proportion of patients with a best overall response of Complete or Partial Response
Measure:Best Response Rate
Time Frame:12 months after study treatment initiation
Safety Issue:
Description:Defined as proportion of patients who achieve a best response of CR, PR, SD or PD
Measure:Duration of response
Time Frame:12 months after study treatment initiation
Safety Issue:
Description:Defined as the time from the date of first documented response (CR or PR) to the date of the first documented subsequent progression or death due to any cause
Measure:Quality of life using European Organisation for Research and Treatment of Cancer (EORTC) questionnaire
Time Frame:12 months after study treatment initiation
Safety Issue:
Description:Using the EORTC QLQ-C30 (Quality of Life Questionnaire) - Scale range: 1 (better outcome) to 4 (worse outcome) for 28 variables and from 1 (better outcome) to 7 (worse outcome) for 2 variables
Measure:Quality of life using European Organisation for Research and Treatment of Cancer (EORTC) questionnaire
Time Frame:12 months after study treatment initiation
Safety Issue:
Description:Using the EORTC QLQ-H&N35 questionnaire (Quality of Life Questionnaire) - Scale range: 1 (better outcome) to 4 (worse outcome) for 30 variables and from 1 (better outcome) to 2 (worse outcome) for 5 variables
Measure:Tolerance profile: Incidence of treatment emergent adverse events and serious adverse events
Time Frame:12 months after study treatment initiation
Safety Issue:
Description:Incidence of Treatment Emergent Adverse Events, Serious Adverse Events (SAE) and death assessed according to the NCI-CTC AE version 5

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Centre Leon Berard

Trial Keywords

  • Squamous Cell Carcinoma of the Head and Neck
  • Recurrent / metastatic SCCHN
  • Frail patients
  • GORTEC

Last Updated

January 6, 2020