| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| 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. |
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| E.1.1.1 | Medical condition in easily understood language |
| Patients with locally advanced or metastatic solid tumours |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
- 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. |
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| E.2.2 | Secondary objectives of the trial |
- 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. |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
- To evaluate potential immune biomarkers in baseline and on-treatment blood (T cells, T regs, MDSC, NK cells), plasma (soluble PD-L1), and tissue (PD-L1, T cells, CD8+Tcells, innate effectors) samples, with respect to efficacy and resistance.
- To evaluate germinal polymorphisms of genes regulating immune response (VEGFA, chemokine receptors such as CX3CR1, CCR8, CXCR6, CCR3, CCR2, CCR5, CCRL2, Fc receptors) in baseline blood samples as potential biomarkers for efficacy and toxicity.
- To evaluate genomic and transcriptomic features (copy number alteration status by a CGH, mutational status by NGS, gene expression profiling) in baseline and on-treatment samples as potential biomarkers for efficacy and resistance.
- To generated and validate a PK and PD models generated by computational pharmacology. |
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| E.3 | Principal 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. |
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| E.4 | Principal 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 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.
14. Major surgery within 28 days prior to the first dose of study treatment.
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
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.
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| E.5 End points |
| E.5.1 | 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 (DLT) is defined in section 5.3.4 of the protocol.
All patients who receive any study treatment are monitored for toxicity and included in the safety analysis. To be evaluable for DLT, a patient must either be observed for a full phase I duration period, i.e. 4-week DLT evaluation period from the treatments initiation, or have experienced DLT.
- Phase II:
The primary analysis endpoint of the phase II is the CBR defined as the rate of complete response (CR), partial response (PR), or SD lasting at least 24 weeks according to RECIST v1.1 and will be evaluated based on the best response status obtained until 24 weeks after starting treatment.
Analysis of the primary endpoint will be carried out sequentially with interim analyses planned after 24 weeks of follow up of the first 10 patients of each cohort and then every 5 patients. At each analysis the Bayesian model will be updated and:
• Bayesian estimation of the mean CBR given each prior distribution will be provided with the associated 95% credibility interval (precision of the Bayesian estimation).
• If the stopping criterion for inefficacy is fulfilled for 2 out of 3 prior distributions, then the trial stop will be recommended
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | 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.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
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| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 62 |
| E.8.9.1 | In the Member State concerned days | |
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