Phase Ib study of the combination of regorafenib with conventional chemotherapy for the treatment of newly diagnosed patients with multimetastatic Ewing sarcoma - REGO-INTER-EWING1

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Gustave Roussy

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

Trial duration

16 Jun 2023 → ongoing

Decision date (initial)

2024-07-31

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

European Science Foundation (Fight Kids Cancer 2021 Call)

External identifiers

EU CT number

2023-503322-39-00

EudraCT number

2022-002874-10

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

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

To determine the recommended Phase 2 dose (RP2D) of regorafenib in combination with standard backbone chemotherapy of VDC/IE in patients with newly diagnosed metastatic (other than lungs and/or pleura only) Ewing sarcoma.

Secondary objectives 4

1. To assess the toxicity of the combination of regorafenib and VDC/IE chemotherapy
2. To evaluate the radiological response of primary tumor, regional lymph nodes and/or other metastases.
3. To evaluate the primary tumor histological response
4. To assess the survival outcome (PFS, OS)

Conditions and MedDRA coding

Newly diagnosed patients with metastatic (other than lung/pleura metastases only) Ewing sarcoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Any histologically and genetically confirmed Ewing sarcoma of bone or soft tissue, or round cell sarcomas which are ‘Ewing’s-like’ but negative for EWSR1 gene rearrangement
2. Metastatic disease
3. Age ≥2 years and <50 years (from second birthday to 49 years 364 days)
4. Patient assessed as medically fit to receive the Ewing sarcoma standard multimodal treatment and regorafenib, including: - Absolute Neutrophil Count (ANC) ≥ 0.75x109/L, platelets ≥ 75x109/L. - Alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤ 5×ULN - Bilirubin ≤ 2×ULN - Creatinine < 2x ULN or creatinine clearance >60 ml/min/1.73 m2 - International normalized ratio (INR)/ Partial thromboplastin time (PTT) INR and PTT ≤ 1.5 x ULN INR & PTT ≤ 1.5xULN
5. Adequate cardiac function as evidenced by left ventricular ejection fraction (LVEF) ≥50%) at baseline, as determined by echocardiography
6. Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as: a BP <95th percentile for sex, age, and height at screening (as per National Heart Lung and Blood Institute [NHLBI] guidelines) and no change in antihypertensive medications within 1 week prior to Cycle 1 Day 1. Patients >18 years old should have BP ≤ 150/90 mm Hg.
7. No prior treatment for Ewing sarcoma other than surgery
8. Negative pregnancy test for female patients of childbearing potential within 7 days prior to study registration
9. Patient agrees to use highly effective contraception during therapy and for 12 months after last trial treatment (females) or 6 months after last trial treatment (males), where applicable
10. Subject must be able to swallow and retain oral medication.
11. Written informed consent from the patient and/or the parent/legal guardian, according to local, regional or national regulation prior to any study specific procedures.
12. Patients must be affiliated to a social security system or beneficiary of the same, as per local regulatory requirements (France only)

Exclusion criteria 16

1. Localized tumor or metastatic disease to lung/pleura only.
2. Major surgical procedure or significant traumatic injury within 28 days before starting study treatment
3. Non-healing wound, ulcer or bone facture.
4. Uncontrolled systemic or local infection requiring systemic tratement
5. Interstitial lung disease with ongoing signs and symptoms.
6. Known prior history of HBV, HCV, HIV
7. Any other medical or other condition that, in the opinion of the investigator(s), would preclude the subject’s participation in this clinical study
8. Contra-indication to the Ewing sarcoma standard multimodal treatment
9. Pregnant or breastfeeding women or intending to become pregnant during the study.
10. Follow-up not possible due to social, geographic or psychological reasons
11. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter absorption of oral drugs
12. A clinically significant ECG abnormality, including a marked prolonged QTcF interval (eg, a repeated demonstration of a QTcF interval >480 msec) Clinically significant, uncontrolled heart disease (including history of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality, unstable angina, active coronary artery disease and myocardial infarction within 6 months before randomization.) Uncontrolled hypertension (systolic pressure >150 mm Hg or diastolic pressure > 90 mm Hg on repeated measurement) despite optimal medical management
13. Previous arterial or venous thromboembolisms Grade ≥ 3 per CTCAE v5.0
14. Hypersensitivity to any active substance or to any excipients
15. Radiographic evidence of encasement or invasion of a major blood vessel or of intratumoral cavitation
16. Any anticoagulant therapy

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 5

1. Dose-limiting toxicity (DLT) -DLT will be defined as any of the following haematological and non-haematological events (CTCAE v5.0) that occur during the DLT assessment period (4 weeks after the start of treatment = cycle 1) and are at least possibly related (possibly, probably, or definitely) attributable to VDC/IE + regorafenib
2. Any grade ≥ 3 (hematological or non-hematological) toxicity leading to delay of start of day 15 by > 7 days (i.e: starting > day 21) or day 1 of cycle 2 by > 14 days ((i.e: starting > day 42)
3. Any dose interruption or reduction due to toxicity which results in administration of less than 80% of the planned dosage of regorafenib or 75% of the planned dosage of chemotherapy in the first cyle of 28 days of treatment.
4. Any grade ≥ 3 toxicity resulting in permanent discontinuation of the regorafenib
5. Any grade 5 toxicity related to study treatment (death)

Secondary endpoints 4

1. Overall Survival (OS) and progression-free survival (PFS)
2. Adverse events and toxicity, defined by CTCAE v5.0
3. Histological response of the primary tumor to induction chemotherapy if surgery is performed as local control
4. Radiological response of primary tumor, regional lymph nodes and/or metastases

Investigational products

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

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut Gustave Roussy

Sponsor organisation

Institut Gustave Roussy

Address

114 Rue Edouard Vaillant

City

Villejuif

Postcode

94800

Country

France

Scientific contact point

Organisation

Institut Gustave Roussy

Contact name

Regulatory affairs officer

Public contact point

Organisation

Institut Gustave Roussy

Contact name

Regulatory affairs officer

Locations

5 EU/EEA countries · 12 investigational sites

By country

Investigational sites

Country notifications

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

Application history

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