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.
Conditions
Interventions
Trade Name: NAVELBINE
Pharmaceutical Form: Capsule, soft
Product Name: Durvalumab
Product Code: MEDI4736
Pharmaceutical Form: Solution for injection
INN or Proposed INN: DURVALUMAB
Other descriptive
Sponsors
UNICANCER
Eligibility
Sex/Gender
All
Inclusion 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, ? 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. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 130 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 29
Exclusion criteria
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 ? Steroids as premedication for hypersensitivity reactions 11. Uncontrolled intercurrent illness or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring adverse events, or compromise the ability of
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: - Phase I To determine the maximum tolerated dose (MTD) and the recommended dose for phase II (RP2D) of metronomic oral vinorelbine associated with durvalumab + tremelimumab combination immunotherapy for the treatment of advanced solid tumours: head and neck, prostate, cervix, and breast cancers, as well as miscellaneous malignancies with high mutational load. - Phase II To assess the antitumour activity of metronomic oral vinorelbine associated with durvalumab + tremelimumab combination immunotherapy for the treatment of advanced solid tumours: head and neck, prostate, cervix, and breast cancers, as well as miscellaneous malignancies with high mutational load, using the clinical benefit rate (CBR) according to RECIST v1.1.;Secondary Objective: - Phase I ? The tolerance and safety profile according to NCI CTCAE v4.0, ? The clinical benefit rate (CBR) according to RECIST, ? The objective response rate (ORR) according to RECIST v1.1, ? The duration of overall response (DoR) according to RECIST v1.1. - Phase II To evaluate in the study arms: ? The tolerance and safety profile according to NCI CTCAE v4.0, ? The clinical benefit rate (CBR) according to iRECIST, ? The objective response rate (ORR) according to RECIST v1.1 and iRECIST, ? The duration of overall response (DoR) according to RECIST v1.1 and iRECIST, ? The progression-free survival (PFS) according to RECIST v1.1 and iRECIST, ? The overall survival (OS). Of note: Patients included at RP2D during phase I will be considered as evaluable for phase II.;Primary end point(s): - Phase I: The primary analysis endpoint of the phase I is to determine the Maximum Tolerated Dose (MTD) and the phase II recommended dose (RP2D) of metronomic oral vinorelbine associated with fixed dose of durvalumab + tremelimumab combination in patient with advanced solid tumour. Toxicities are to be graded according to the National Cancer Institute Common Terminalogy Criteria (NCI CTC, version 4.0) The Dose Limiting Toxicity | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): ORR, iORR, the iCBR24 will be presented with the associated 95% confidence intervals (CIs). PFS, iPFS, OS, DoR, and iDoR will be estimated using the Kaplan-Meier method and will be described in terms of medians with the associated 95% CIs. The safety will be evaluated using the incidence of treatment emergent adverse events (TEAE), serious adverse Events (SAE), and deaths. Tolerance will be assessed by NCI-CTCAE v4.0 scale. Descriptive statistics will be provided for characterising and assessing patient tolerance to treatment. ;Timepoint(s) of evaluation of this end point: _ | — |
Countries
France
Contacts
Public ContactProject Leader
UNICANCER
Outcome results
None listed