Phase 1 study of a Propranolol (HEMANGIOL®) and oral metronomic Vinorelbine (NAVELBINE®) combination on children and teenagers With Refractory/Relapsing Solid Tumors - PROVIN

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Regional De Marseille

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

4 May 2020 → ongoing

Decision date (initial)

2024-09-05

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

DGOS (PHRCK 2017)

External identifiers

EU CT number

2024-517185-42-00

EudraCT number

2019-001772-10

ClinicalTrials.gov

NCT02897986

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Dose response

To determine the maximal tolerated dose of oral navelbine given 3 times a week with daily oral propanolol

Secondary objectives 7

1. To determine the dose limiting toxicities and tolerance of treatment with single agent metronomic navelbine
2. To determine the toxicity and tolerance of treatment with oral metronomic vinorelbine and daily propanolol
3. To determine the recommmended dose of vinorelbine combined with fixed dose of propanolol
4. To establish PK of oral navelbine given 3 times a week during the first cycle of treatment and in combination with propanolol during the second cycle
5. To evaluate PFS after 2, 4, 6, 12, 18 and 24 months in the entire study population and in each cohort during the extension phase
6. To determine response rates after 2, 4, 6,12,18 and 24 months in the whole study population and in each cohort during the exttension phase.
7. To determie the overall survival after 6, 12, 18 and 24 months in the whole study population and in each cohort during the extension phase.

Conditions and MedDRA coding

Children and teenagers with refractory/relapsing solid tumor

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. Histological diagnosis of malignancy or typical radiological appearance of a low-grade glial tumor not warranting biopsy or surgery, and desmoid tumors
2. Refractory or relapsed disease, in therapeutic failure despite standard treatments, or for which there is no effective standard therapy
3. Measurable lesions according to RECIST, INSS or WHO criteria depending on histological type
4. Age > or = 4 years and <24 years
5. Lansky score >50 or Karnofsky>50
6. Hematological conditions: neutrophils > 1 x 109/l and platelets > 75 x 109/l
7. Creatinine < 1.5 x upper limit of normal for age (ULN) or Schwarz clearance > 70 ml/ mn/1.73 m2
8. Liver function: Total Bilirubin < 1.5 LNS and SGOT and SGPT <3 LNS except in the case of liver metastases: Total Bilirubin < 3LNS and SGOT and SGPT <5 LNS
9. Absence of other organ toxicity (Grade < 2 according to NCI-CTC v5.0)
10. No known allergy to any of the compounds in the experimental treatment
11. Able to swallow softgels and oral suspension or tablets
12. Life expectancy > 3 months
13. Affiliation to a social security scheme
14. Effective contraception (if applicable) throughout the treatment period. Women of childbearing potential must use effective contraception during treatment, and at least until 7 months after treatment. Men treated with Navelbine must be warned not to conceive a child during treatment, and must use effective contraception during treatment and at least until 4 months after treatment.
15. Having signed the informed consent form. For unemancipated minors, authorization will be given by the holders of parental authority. Minors will receive information adapted to their ability to understand.

Exclusion criteria 12

1. Chemotherapy within 21 days prior to D1 of the start of study treatment. This period may be shortened in the case of vincristine treatment (2 weeks) and extended to 6 weeks in the case of nitrosourea treatment or 5 half-lives in the case of targeted therapies or metronomic chemotherapy.
2. Organ toxicity grade > 2 according to NCI-CTCAE scale version 5.0
3. Active infection
4. Inability to undergo medical follow-up for geographical, social or psychological reasons
5. Radiotherapy within 3 months prior to D1 of the start of study treatment. RT on a non-target lesion is permitted up to 3 weeks before inclusion.
6. Previous treatment with oral or IV vinorelbine in a metronomic regimen
7. High blood pressure during treatment.
8. None hypersensibility to any of the investigational drugs, including their respective excipients
9. Contraindications to propranolol (asthma or history of bronchospasm, Prinzmetal's angina, severe peripheral arterial disorders, Raynaud's syndrome, arterial hypotension (age-dependent limits), second- or 3rd-degree AVB, sinus disease including sino-auricular block, bradycardia with age-dependent limits, cardiogenic shock, heart failure not controlled by treatment, diabetes/predisposition to hypoglycemia, untreated pheochromocytoma, chronic obstructive bronchitis, history of anaphylactic reaction, as part of primary and secondary prevention of digestive bleeding in cirrhotics: advanced liver failure with hyperbilirubinemia, massive ascites, hepatic encephalopathy)
10. Contraindications to navelbine: pathologies affecting absorption of the treatment, notably a history of surgical resection of the stomach, patients on long-term oxygen therapy, vaccination against yellow fever
11. Inflammatory bowel disease
12. Pregnant or breast-feeding women

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Maximum tolerated dose (MTD) assessed over the first two treatment cycles (D1 to D56) according to the NCI-CTC v5.0 scale and defined as follows: - Grade 3 or 4 neutropenia requiring treatment deferral of more than 7 days - Grade 3 or 4 thrombocytopenia requiring transfusions for more than 7 days - Grade 3 or 4 non-hematological toxicity, with the exception of : - nausea and vomiting - grade 3 fever, - grade 3 liver toxicity reversible after 14 days

Secondary endpoints 3

1. Tolerance judged using NCI-CTC v5.0 scale
2. PK performed by liquid chromatography coupled with either mass spectrometry (LCMSMS) or UV detection
3. Efficacy: Progression-free survival 2, 4, 6, 12, 18 and 24 months of treatmentand overall survival after 6, 12, 18 and 24 months of treatment, and response rate according to RECIST, SIOPEN or WHO criteria. PFS will be calculated from study entry to the date of progression or death (if related to tumor or treatment toxicities). Overall survival will be calculated from study entry to date of death.

Investigational products

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

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Regional De Marseille

Sponsor organisation

Centre Hospitalier Regional De Marseille

Address

80 Rue Brochier

City

Marseille

Postcode

13005

Country

France

Scientific contact point

Organisation

Centre Hospitalier Regional De Marseille

Contact name

Prof. Nicolas ANDRE

Public contact point

Organisation

Centre Hospitalier Regional De Marseille

Contact name

Prof. Nicolas ANDRE

Locations

1 EU/EEA country · 7 investigational sites

By country

Investigational sites

Country notifications

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

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 1 · Art. 52 CTR

Urgent safety measures 1 · Art. 54 CTR

Application history

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