A Phase I Dose Finding Study in Children With Solid Tumors Recurrent or Refractory to Standard Therapy

NCT ID: NCT02085148

Last Updated: 2024-04-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 62 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-04-11
• Study Completion Date: 2024-03-13

Brief Summary

Dose escalation phase of the study :

To define the safety profile, maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of regorafenib administered orally as a single agent in a 3-weeks-on/1- week-off schedule in repeating cycles of 28 days in pediatric subjects with solid malignant tumors recurrent or refractory to standard therapy. To characterize the pharmacokinetics (PK) of regorafenib The dose escalation phase of the study has been completed.

Expansion phase:

To define the safety profile, MTD and the RP2D of regorafenib administered orally in combination with backbone chemotherapy (vincristine and irinotecan) at relapse in pediatric subjects with rhabdomyosarcoma (RMS) and other solid malignant tumors recurrent or refractory to standard therapy.

Detailed Description

Expansion Phase of the study:

Subjects must have relapsed/refractory RMS or a solid malignant tumor (Ewing sarcoma, hepatoblastoma, neuroblastoma and Wilms tumor).

Conditions

Pediatric Oncology

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: OTHER
• Blinding Strategy: NONE

Study Groups

Sequential dosing schedule

Expansion phase: Schedule B - Sequential dosing schedule: Of a 21-day cycle, regorafenib will be dosed sequentially, following administration of VI: Vincristine：intravenous bolus, 1.5 mg/m2 (0.05 mg/kg for subjects ≤ 10 kg), Day 1 and Day 8. Irinotecan: intravenously over 1 hour, 50mg/m2/day, Day 1 to Day 5. Regorafenib: orally, at a starting dose level of 72 mg/m2 (subjects 2 to less than 18 years old) or 60 mg/m2 (subjects 6 to less than 24 months old) once daily, Day 8 to Day 21.

Group Type: EXPERIMENTAL

Regorafenib (BAY73-4506)

Intervention Type: DRUG

Regorafenib will be given orally once a day, across cycles of 21 days each. During each cycle regorafenib is taken for 2 weeks followed by one week off the drug. Doses of the study drug used in this study are age-dependent and the children's dose will been adjusted based on the age and the body surface area and given either as tablets or granulate.

Vincristine (Cellcristin®)

Intervention Type: DRUG

Vincristine will be given at a dose of 1.5 mg/m2 (0.05 mg/kg for subjects ≤ 10 kg, maximum 2.0 mg) on Day 1 and Day 8 in 21-day cycles.

Irinotecan (Irinotecan Cell pharm®)

Intervention Type: DRUG

Irinotecan will be administered at a starting dose of 50 mg/m2/day from Day 1 to Day 5, in 21 day cycles.

Concomitant dosing schedule

Expansion phase: Schedule A - Concomitant dosing schedule: Of a 21-day cycle, regorafenib will be concomitantly administered with vincristine and irinotecan (VI): Vincristine: intravenous bolus, 1.5 mg/m2 (0.05 mg/kg for subjects ≤ 10 kg), Day 1 and Day 8. Irinotecan: intravenously over 1 hour, 50 mg/m2/day, Day 1 to Day 5. Regorafenib: orally, at a starting dose level of 72 mg/m2 (subjects 2 to less than 18 years old) or 60 mg/m2 (subjects 6 to less than 24 months old) once daily, Day 1 to Day 14.

Group Type: EXPERIMENTAL

Regorafenib (BAY73-4506)

Intervention Type: DRUG

Regorafenib will be given orally once a day, across cycles of 21 days each. During each cycle regorafenib is taken for 2 weeks followed by one week off the drug. Doses of the study drug used in this study are age-dependent and the children's dose will been adjusted based on the age and the body surface area and given either as tablets or granulate.

Vincristine (Cellcristin®)

Intervention Type: DRUG

Vincristine will be given at a dose of 1.5 mg/m2 (0.05 mg/kg for subjects ≤ 10 kg, maximum 2.0 mg) on Day 1 and Day 8 in 21-day cycles.

Irinotecan (Irinotecan Cell pharm®)

Intervention Type: DRUG

Irinotecan will be administered at a starting dose of 50 mg/m2/day from Day 1 to Day 5, in 21 day cycles.

Dose escalation

Dose escalation phase: This phase of the study has been completed

Group Type: EXPERIMENTAL

Regorafenib (BAY73-4506)

Intervention Type: DRUG

Regorafenib will be given orally once a day, across cycles of 21 days each. During each cycle regorafenib is taken for 2 weeks followed by one week off the drug. Doses of the study drug used in this study are age-dependent and the children's dose will been adjusted based on the age and the body surface area and given either as tablets or granulate.

Interventions

Regorafenib (BAY73-4506)

Regorafenib will be given orally once a day, across cycles of 21 days each. During each cycle regorafenib is taken for 2 weeks followed by one week off the drug. Doses of the study drug used in this study are age-dependent and the children's dose will been adjusted based on the age and the body surface area and given either as tablets or granulate.

Intervention Type: DRUG

Vincristine (Cellcristin®)

Vincristine will be given at a dose of 1.5 mg/m2 (0.05 mg/kg for subjects ≤ 10 kg, maximum 2.0 mg) on Day 1 and Day 8 in 21-day cycles.

Intervention Type: DRUG

Irinotecan (Irinotecan Cell pharm®)

Irinotecan will be administered at a starting dose of 50 mg/m2/day from Day 1 to Day 5, in 21 day cycles.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Signed Informed Consent Form by subjects and/or subjects' parents/legal guardians and age appropriate Assent Form by the subjects obtained before any study specific procedure
• Age: from 6 months to less than 18 years old
• Diagnosis, Dose escalation phase of the study: subjects must have had histologic verification of solid malignancy at original diagnosis. Subjects with recurrent or refractory solid tumors are eligible, including primary central nervous system (CNS) tumors or subjects with known CNS metastases. Subject's current disease state must be one for which there is no known effective therapy or therapy proven to prolong survival with an acceptable quality of life. Effective therapy may include surgery, radiation therapy, chemotherapy or any combination of these modalities.

Dose expansion phase of the study: subjects must have relapsed/refractory RMS or a solid malignant tumor (Ewing sarcoma, hepatoblastoma, neuroblastoma and Wilms tumor) in which treatment with vincristine/irinotecan is considered backbone chemotherapy at relapse and a scientific rationale to combine vincristine/irinotecan with regorafenib exists.

• Subjects must have at least one measurable or evaluable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. For the neuroblastoma subjects with osteomedullary disease, the SIOPEN (International Society of Pediatric Oncology Europe Neuroblastoma Group) score will be used. Bone scans (if clinically indicated) should be obtained ≤12 weeks prior to the start of treatment.
• Life expectancy of at least 12 weeks from the time of signing informed consent/assent.
• Performance level: Karnofsky ≥ 70% for subjects > 12 years of age or Lansky ≥ 70% for subjects ≤ 12 years of age
• Adequate hematological function assessed by the following laboratory requirements conducted within 7 days before starting study treatment:

Peripheral absolute neutrophil count (ANC): ≥ 1.0 x 10*9/L Platelet count : ≥ 100 x 10*9/L (transfusion independent) Hemoglobin: ≥ 8.0 g/dL

-Adequate hepatic function defined as:

• Aspartate aminotransferase/alanine aminotransferase (AST/ALT) ≤ 3.0* ULN
• Bilirubin (sum of conjugated and unconjugated) ≤ 1.5 * ULN

Exclusion Criteria

• Prior treatment with regorafenib. Subjects permanently withdrawn from study participation will not be allowed to re-enter the study.
• Dose expansion phase of the study only: Subjects with brain tumors or subjects with known CNS metastases are excluded.
• Subjects with uncontrolled baseline hypertension higher than Grade 1 NCICTCAE v. 4.0
• Subjects with evidence or history of disorders of coagulation or thrombosis
• Cardiac abnormalities and cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted)
• History of organ allograft (including allogeneic bone marrow transplant)
• Any other malignant disease treated prior to study entry
• Pregnancy or breast feeding
• Significant gastrointestinal disorders with diarrhea as a major symptom e.g., Crohn's disease or any malabsorption condition
• Close affiliation with the investigational site, e.g. a close relative of the investigator or a dependent person (e.g. employee or student of the investigational site)
• Unresolved toxicity higher than NCI-CTCAE v. 4.0 Grade 1 attributed to any prior therapy/procedure (excluding alopecia, chemotherapy-induced ototoxicity, Grade 2 chemotherapy-induced neuropathy and, as per above eligibility criteria, anemia with hemoglobin ≥ 8 mg/dL and ANC ≥ 1.0 x 10 9/L ).
• Any other malignant disease treated prior to the study

• Minimum Eligible Age: 6 Months
• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Bayer

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Bayer Study Director

Role: STUDY_DIRECTOR

Bayer

Locations

Lyon, , France

Marseille, , France

Paris, , France

Villejuif, , France

Genoa, Liguria, Italy

Milan, Lombardy, Italy

Madrid, , Spain

Valencia, , Spain

Sutton, Surrey, United Kingdom

Newcastle upon Tyne, Tyne and Wear, United Kingdom

Birmingham, West Midlands, United Kingdom

Manchester, , United Kingdom

Countries

France; Italy; Spain; United Kingdom

References

Casanova M, Bautista F, Campbell-Hewson Q, Makin G, Marshall LV, Verschuur AC, Canete Nieto A, Corradini N, Ploeger BA, Brennan BJ, Mueller U, Zebger-Gong H, Chung JW, Geoerger B. Regorafenib plus Vincristine and Irinotecan in Pediatric Patients with Recurrent/Refractory Solid Tumors: An Innovative Therapy for Children with Cancer Study. Clin Cancer Res. 2023 Nov 1;29(21):4341-4351. doi: 10.1158/1078-0432.CCR-23-0257.

Reference Type: DERIVED

PMID: 37606641 (View on PubMed)

Geoerger B, Morland B, Jimenez I, Frappaz D, Pearson ADJ, Vassal G, Maeda P, Kincaide J, Mueller U, Schlief S, Teufel M, Ploeger BA, Cleton A, Agostinho AC, Marshall LV. Phase 1 dose-escalation and pharmacokinetic study of regorafenib in paediatric patients with recurrent or refractory solid malignancies. Eur J Cancer. 2021 Aug;153:142-152. doi: 10.1016/j.ejca.2021.05.023. Epub 2021 Jun 20.

Reference Type: DERIVED

PMID: 34157616 (View on PubMed)

Related Links

https://clinicaltrials.bayer.com/

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Other Identifiers

2013-003579-36

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

15906

Identifier Type: -

Identifier Source: org_study_id