Clinical Trials /

Metronomic Oral Vinorelbine Plus Anti-PD-L1/Anti-CTLA4 ImmunothErapy in Patients With Advanced Solid Tumours

NCT03518606

Description:

This is a phase I/II national, multicentre, multiple cohort, prospective open-label, non-randomised and non-comparative study, to evaluate the safety and activity of metronomic oral vinorelbine associated with durvalumab + tremelimumab combination immunotherapy for the treatment of advanced solid tumours.

Related Conditions:
  • Breast Carcinoma
  • Cervical Carcinoma
  • Head and Neck Carcinoma
  • Malignant Solid Tumor
  • Prostate Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Metronomic Oral Vinorelbine Plus Anti-PD-L1/Anti-CTLA4 ImmunothErapy in Patients With Advanced Solid Tumours
  • Official Title: A Phase I/II Basket Trial Evaluating a Combination of Metronomic Oral Vinorelbine Plus Anti-PD-L1/Anti-CTLA4 ImmunothErapy in Patients With Advanced Solid Tumour

Clinical Trial IDs

  • ORG STUDY ID: UC-101/1709
  • NCT ID: NCT03518606

Conditions

  • Advanced Solid Tumours
  • Breast Cancer
  • Head and Neck Cancer
  • Cervix Cancer
  • Prostate Cancer

Interventions

DrugSynonymsArms
Durvalumab + Tremelimumab + metronomic VinorelbineBreast cancer cohort

Purpose

This is a phase I/II national, multicentre, multiple cohort, prospective open-label, non-randomised and non-comparative study, to evaluate the safety and activity of metronomic oral vinorelbine associated with durvalumab + tremelimumab combination immunotherapy for the treatment of advanced solid tumours.

Detailed Description

      Methodology:

      The study divided in two parts:

        -  Phase I part: dose escalation study of metronomic oral vinorelbine associated with
           durvalumab + tremelimumab combination immunotherapy,

        -  Phase II part: activity study of metronomic oral vinorelbine associated with durvalumab
           + tremelimumab combination immunotherapy.

      Indication:

      Patient eligible to the study are patients with histologically confirmed locally advanced or
      metastatic solid tumours, resistant to conventional therapies, and candidate to experimental
      therapy by local clinical board, from the following primary tumours: head and neck, prostate,
      cervix, and breast cancers, as well as miscellaneous malignancies with high mutational load.
    

Trial Arms

NameTypeDescriptionInterventions
Breast cancer cohortExperimentalPatients presenting advanced refractory breast cancer
  • Durvalumab + Tremelimumab + metronomic Vinorelbine
Head and neck cohortExperimentalPatients presenting advanced refractory head and neck cancer
  • Durvalumab + Tremelimumab + metronomic Vinorelbine
Cervix cohortExperimentalPatients presenting advanced refractory cervix cancer
  • Durvalumab + Tremelimumab + metronomic Vinorelbine
Prostate cohorteExperimentalPatients presenting advanced refractory prostate cancer
  • Durvalumab + Tremelimumab + metronomic Vinorelbine
Miscellaneous cohorteExperimentalPatients presenting advanced refractory solid tumour with high mutational load
  • Durvalumab + Tremelimumab + metronomic Vinorelbine

Eligibility Criteria

        Inclusion Criteria:

          1. Patient must have signed a written informed consent form prior to any study specific
             procedures.

          2. Histologically confirmed locally advanced or metastatic solid tumours, resistant to
             conventional therapies, and candidate to experimental therapy by local clinical board,
             from the following primary tumours:

               -  Head and neck squamous cell carcinomas,

               -  Breast cancer,

               -  Prostate cancer,

               -  Cervical cancer,

               -  Miscellaneous primary tumours (except melanoma, non-small cell lung cancer
                  [NSCLC], and renal cell cancer) with a high mutational load, as defined by a
                  molecular clinical board after next-generation sequencing (comprehensive cancer
                  gene panel or whole genome/exome sequencing) analysis.

          3. Patients aged ≥18 years at registration.

          4. Life expectancy ≥3 months.

          5. Measurable disease according to RECIST v1.1.

          6. ECOG performance status ≤1.

          7. Body weight >30 kg.

          8. Normal haematological function (ANC ≥1.5 x 109/L; platelets count ≥100 x 109/L;
             haemoglobin ≥9.0 g/dL).

          9. Normal hepatic function: total bilirubin ≤1.5 upper limit of normal (ULN) (unless
             documented Gilbert's syndrome); ASAT and ALAT ≤2.5 ULN (≤5 ULN in the presence of
             liver metastases).

         10. Normal cardiac function: LVEF ≥50% (any assessment method).

         11. Measured Creatinine clearance (Cockcroft and Gault) ≥40 mL/min OR creatinine ≤1.5
             times ULN.

         12. Evidence of post-menopausal status or negative urinary or serum pregnancy test for
             female pre-menopausal patients (urine within 72 h, or serum pregnancy test within 14
             days prior to enrolment).

         13. Patient willing and able to comply with the protocol for the duration of the study
             including: treatment and scheduled visits during the treatment phase, and visits
             during follow up.

         14. Patient is willing to comply with a baseline tumour biopsy (unless an archived biopsy
             of a secondary or a primary site of the current disease-collected within 3 months
             prior enrolment is available for research ; bone metastasis are accepted only when
             predominant extra-bone tissue is available), and with a series of blood samples
             throughout the study.

         15. Patient must be affiliated to a social health insurance.

        Exclusion Criteria:

          1. Other concurrent malignancies, except adequately treated cone-biopsied in situ
             carcinoma of the cervix, or basal cell or squamous cell carcinoma of the skin.
             Patients who have had potentially curative therapy for a prior malignancy are eligible
             provided there has been no evidence of disease for ≥5 years and the risk of recurrence
             is considered low.

          2. Active brain metastases, spinal cord compression, or leptomeningeal disease. Patients
             whose brain metastases have been treated may participate if the brain metastases are
             stable by imagery (defined as 2 brain images, both obtained after treatment of the
             brain metastases and at least four weeks apart, and showing no evidence of
             intracranial progression). In addition, any neurologic symptoms caused by the brain
             metastases or their treatment must be resolved or stable, without steroidal treatment
             or with a dose of steroid ≤10 mg/day of prednisone or its equivalent and an
             anticonvulsants, for at least 14 days prior to the start of treatment.

          3. Previous treatment with an anti-PD1/PD-L1 including durvalumab or an anti-CTLA-4
             therapy including tremelimumab or vinorelbine.

          4. Patients with known allergy or severe hypersensitivity to any of the study treatments
             or any of the study treatment excipients.

          5. History of active primary immunodeficiency.

          6. 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.

               -  Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on
                  hormone replacement therapy.

               -  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.

          7. History of allogeneic organ transplantation.

          8. History or evidence of active, non-infectious pneumonitis.

          9. 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.

         10. 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 (e.g., intra
                  articular injection)

               -  Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or its
                  equivalent (see APPENDIX 7)

               -  Steroids as premedication for hypersensitivity reactions (e.g., CT scan
                  premedication)

         11. Uncontrolled intercurrent illness, including but not limited to, symptomatic
             congestive heart failure, uncontrolled hypertension, unstable angina pectoris,
             clinically significant cardiac arrhythmia, interstitial lung disease, serious chronic
             gastrointestinal conditions associated with diarrhoea, or psychiatric illness/social
             situations that would limit compliance with study requirement, substantially increase
             risk of incurring adverse events, or compromise the ability of the patient to give
             written informed consent

         12. Patients who have received a live vaccine within 30 days of the planned start of the
             study treatment(s).

         13. Prior anticancer therapy, within the last 3 weeks. It includes radiotherapy
             (concurrent palliative radiotherapy is allowed), endocrine therapy, immunotherapy,
             chemotherapy (2 weeks for weekly schedule, 6 weeks for nitrosoureas and mitomycin C),
             or other investigational agents.

         14. Major surgery within 28 days prior to the first dose of study treatment. Note: Local
             surgery of isolated lesions for palliative intent is acceptable.

         15. Malabsorption syndrome or disease significantly affecting gastro-intestinal function
             or major resection of the stomach or proximal small bowel that could affect absorption
             of oral vinorelbine

         16. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the
             exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
             criteria

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

               -  Patients with irreversible toxicity not reasonably expected to be exacerbated by
                  treatment with durvalumab or tremelimumab may be included only after consultation
                  with the Study Coordinator.

         17. Patients enrolled in another clinical study with an investigational product within 30
             days of inclusion.

         18. 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

         19. Female patients who are pregnant or breastfeeding. Male or female patients of
             reproductive potential who are not willing to employ highly effective methods of
             contraception from screening to 180 days after receipt of the final dose of durvalumab
             and tremelimumab in combination or 90 days after the last dose of durvalumab
             monotherapy or vinorelbine.

         20. Persons deprived of their liberty or under protective custody or guardianship.

         21. Patients with any psychological, family, sociological or geographical problem
             potentially hampering compliance with the study protocol and follow-up schedule.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD) and the phase II recommended dose (RP2D)
Time Frame:9 months
Safety Issue:
Description:Phase I

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:UNICANCER

Trial Keywords

  • Advanced solid tumours
  • Durvalumab
  • Tremelimumab
  • Metronomic vinorelbine
  • High mutational load malignancies
  • Immunotherapy
  • Early phase
  • Combination study

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