A basket Phase I/II study evaluating the combination of a Metronomic oral chemotherapy given with a combination of immunotherapy in patients with advanced solid tumors.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Unicancer

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

27 Jun 2018 → 20 Dec 2024

Decision date (initial)

2024-10-29

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

INCa · Pierre Fabre · Astra Zeneca

External identifiers

EU CT number

2024-518151-29-00

EudraCT number

2017-001857-14

ClinicalTrials.gov

NCT03518606

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

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 and/or MSI-High.
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 and/or MSI-High, using the clinical benefit rate (CBR) according to RECIST v1.1.

Secondary objectives 10

1. Phase I_The tolerance and safety profile according to NCI CTCAE v5.0,
2. Phase I_The clinical benefit rate (CBR) according to RECIST
3. Phase I_The objective response rate (ORR) according to RECIST v1.1
4. Phase I_The duration of overall response (DoR) according to RECIST v1.1
5. Phase II_The tolerance and safety profile according to NCI CTCAE v5.0
6. Phase II_The clinical benefit rate (CBR) according to iRECIST
7. Phase II_The objective response rate (ORR) according to RECIST v1.1 and iRECIST
8. Phase II_The duration of overall response (DoR) according to RECIST v1.1 and iRECIST
9. Phase II_The progression-free survival (PFS) according to RECIST v1.1 and iRECIST
10. Phase II_The overall survival (OS).

Conditions and MedDRA coding

Patients with locally advanced or metastatic solid tumours

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

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, treated with a maximum of 2 lines of chemotherapy in metastatic setting ✓ Prostate cancer, Tumeur Groupe Tumeur d’UNICANCER: MEDECINE PERSONNALISEE N° de Protocole : UC-0101/1709 N° EudraCT : 2017-001857-14 Protocole MOVİE n°: UC-0101/1709 - Version n°8.0 – 03 June 2024 Page 6 / 146 DOC43_Protocole ME_FR_v3.2 - 06-03-2017 ✓ Cervical cancer, ✓ Miscellaneous primary tumours (except melanoma, non-small cell lung cancer [NSCLC], and renal cell cancer) with o 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. OR o Microsatellite instability (MSI) or mismatch repair (MMR) deficient as determined locally by immunohistochemistry AND polymerase chain-reaction.
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 21

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 (except local meningeal disease due to local recurrence). 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 (in advanced setting).
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 21 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Phase I: Determine 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. 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 full phase I duration period, i.e. 4-week DLT evaluation period from the treatment initiation,or have experienced DLT
2. Phase2: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

Secondary endpoints 3

1. ORR, iORR, the iCBR24 will be presented with the associated 95% confidence intervals (CIs).
2. 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.
3. 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 v5.0 scale. Descriptive statistics will be provided for characterising and assessing patient tolerance to treatment.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Unicancer

Sponsor organisation

Unicancer

Address

101 Rue De Tolbiac

City

Paris

Postcode

75013

Country

France

Scientific contact point

Organisation

Unicancer

Contact name

Nourredine AIT RAHMOUNE

Public contact point

Organisation

Unicancer

Contact name

Nourredine AIT RAHMOUNE

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 7 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications