MEPENDAX: Phase I/II study of axitinib (Inlyta®) and oral metronomic etoposide for pediatric children and AYA with refractory/relapsing medulloblastoma and ependymoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux 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

19 Nov 2024 → ongoing

Decision date (initial)

2024-10-07

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

DGOS - PHRC-K 2022 · Ligue contre le Cancer · Fondation Flavien · Gouvernement de Monaco

External identifiers

EU CT number

2023-509585-38-00

ClinicalTrials.gov

NCT06485908

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Safety, Therapy, Efficacy, Pharmacokinetic

First stage (Escalation part): to determine the MTD of axitinib when combined to a fixed dose of oral metronomic etoposide
Second stage (Extension part): to estimate the efficacy of axitinib when used at the dose determined during the escalating part of the study, in combination with the fixed dose of oral metronomic etoposide in terms of progression-free survival (PFS), in children and AYA with refractory / relapsing medulloblastoma or ependymoma.

Secondary objectives 10

1. First stage (Escalation part): to evaluate the safety profile of the combination in children and AYA with refractory/relapsing medulloblastoma or ependymoma
2. First stage (Escalation part):to determine the PK of oral axitinib combined with etoposide
3. First stage (Escalation part): to evaluate the PFS after 2, 4, 6, 12 and 24 months in the whole population and in each sub-group (medulloblastoma and ependymoma)
4. First stage (Escalation part): to determine the response rates after 2, 4, 6, 12 and 24 months in the whole population (RAPNO criteria)
5. First stage (Escalation part): to determine the Overall Survival (OS) after 6, 12 and 24 months in the whole population
6. Second stage (Extension part): to confirm the safety of the drug combination
7. Second stage (Extension part): to evaluate the PFS after 2, 4, 6, 12 and 24 months in the whole population and in each cohort (medulloblastoma and ependymoma) during the extension phase
8. Second stage (Extension part): to determine the response rates after 2, 4, 6, 12 and 24 months in the population and in each cohort (medulloblastoma and ependymoma) during the extension phase
9. Second stage (Extension part): to determine the OS after 6, 12 and 24 months in the population and in each cohort (medulloblastoma and ependymoma) during the extension phase.
10. Ancillary study : To explore a plasma/cerebrospinal fluid (LCR) signature predictive of treatment efficacy using the redundant cytokines of the VEGF signaling pathway for the promotion of angiogenesis and lymphangiogenesis

Conditions and MedDRA coding

Ependymoma

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

1. Histologically proven diagnosis of ependymoma or medulloblastoma.
2. Methyloma classification performed or available material for methyloma analysis
3. Confirmed progressive or refractory disease despite standard therapy, or for which no effective standard therapy exists
4. Male and female subjects with > 4 to ≤ 25 years of age at inclusion
5. Weight > 20 kg
6. Evaluable target lesion(s) according to RAPNO
7. Performance status: Karnofsky performance status (for patients >12 years of age) or Lansky Play score (for patients ≤12 years of age) ≥ 70%. Patients who are unable to walk because of paralysis or stable neurological disability, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
8. Life expectancy ≥ 3 months
9. No known allergy to any of the compounds in the experimental treatment
10. Able to take oral treatments
11. Adequate organ function: Hematologic criteria:
 - Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3 (unsupported) 
 - Platelet count ≥ 100,000/mm3 (unsupported) - Hemoglobin ≥ 8.0 g/dL (transfusion is allowed) Cardiac function : - Shortening fraction (SF) >29% and left ventricular ejection fraction (LVEF) ≥50% at baseline, as determined by echocardiography (mandatory only for patients who have received cardiotoxic therapy). Renal and hepatic function: - Serum creatinine < 1.5 x upper limit of normal (ULN) for age - Total bilirubin < 1.5 x ULN - Alanine aminotransferase (ALT)/ Aspartate aminotransferase (AST)/ < 2.5 x ULN
12. Able to comply with scheduled follow-up and with management of toxicity.
13. Females of child bearing potential must have a negative serum pregnancy test within 7 days prior to initiation of treatment.
14. Sexually active patients must agree to use adequate and appropriate contraception (in accordance with Clinical Trials Facilitation and Coordination Group (CTFG) recommendations) while on study drug and for 6 months after stopping the study drug.
15. Patient able to comfortably swallow capsules.
16. Written informed consent from parents/legal representative, patient, and age-appropriate assent before any study-specific screening procedures are conducted according to local, regional or national guidelines.
17. Patient affiliated to a social security regimen or beneficiary of the same according to local requirements.

Exclusion criteria 14

1. Chemotherapy within 21 days of day 1 from the start of study treatment. This period can be shortened in the case of treatment with vincristine (2 weeks) and extended to 6 weeks in the case of treatment with nitrosureas. The period is set to 5 half-lives in the case of targeted therapies or metronomic chemotherapy. The period is set to 2 weeks after bevacizumab administration.
2. Evidence of > Grade 1 recent CNS hemorrhage on the baseline MRI scan
3. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter drug absorption of oral drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome).
4. Clinically significant, uncontrolled heart disease (including history of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality within 12 months of screening)
5. Known active viral hepatitis or known human immunodeficiency virus (HIV) infection or any other uncontrolled infection.
6. Known congenital immune-deficiency
7. Presence of any NCI-CTCAE v5 grade ≥ 2 treatment-related extra-hematological toxicity with the exception of alopecia, ototoxicity or peripheral neuropathy.
8. Radiotherapy within the 2 months preceding D1 of the start of study treatment. Palliative RT on a non-target lesion is allowed up to 1 weeks before beginning of treatment.
9. Invasive procedure/surgery during the last 15 days.
10. Bleeding disorder
11. Inability to undergo medical monitoring of the trial for geographic, social or psychological reasons Known hypersensitivity to any study drug or component of the formulation.
12. Hypersensitivity to any study drug or component of the formulation.
13. Absence of effective contraception in patients of childbearing age
14. Pregnant or nursing (lactating) females.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. First stage: The Dose-Limiting Toxicity (DLT) will be assessed over the first 28-day cycles, according to the NCI CTCAE V5
2. Second stage: Progression-free survival (PFS) computed as the time interval from the date of beginning of treatment to the date of centrally-assessed progression or death from any cause. The progression will be based on the RAPNO criteria. A central review of all imaging will evaluate tumor response and progressions at end of dose escalation phase and at end of expansion phase. PFS will be censored at the date of last visit.

Secondary endpoints 6

1. Adverse events (type, grade) graded according to the NCI CTCAE V5, per 28-day cycle and over the whole treatment duration. All AE occurring during treatment or in the 28 days after end of treatment will be reported, regardless of reported causal relationship, except symptoms related to the underlying disease or disease progression.
2. Tumor response during treatment, centrally assessed using RAPNO criteria. The best overall response will be defined as the best response recorded from beginning of treatment until disease progression
3. Overall survival, computed as the time interval from the date of beginning of treatment to the date of death from any cause. Survival of patients alive at last follow-up will be censored at the date of last visit.
4. Relative dose-intensity of the different drugs, estimated for each drug as the ratio between the computed dose-intensity (cumulative dose expressed in mg/m² divided by the study duration and expressed in mg/m²/week) and the protocol dose-intensity.
5. First stage: Calculate PK parameters of oral axitinib combined with etoposide
6. Ancillary study: exploration of molecular signature in blood or CSF - Progression-free survival, defined as the time from randomization to recurrence, development of second primary cancer, or death from any cause. Overall survival defined as the time from randomization to death from any cause.

Investigational products

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

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Marseille

Sponsor organisation

Assistance Publique Hopitaux De Marseille

Address

80 Rue Brochier

City

Marseille

Postcode

13005

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Marseille

Contact name

Professor Nicolas ANDRE

Public contact point

Organisation

Assistance Publique Hopitaux De Marseille

Contact name

Professor 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

Urgent safety measures 1 · Art. 54 CTR

Results and documents

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

Documents 18 files

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

Application history

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