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

NCT02085148 | Completed Phase 1

• 2 other identifiers: 159062013-003579-36
• Study Type: interventional
• Target: 62
• Locations: 4 countries
• Sites: 12

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.

Conditions

Pediatric Oncology

Keywords

Pediatric cancer; Rhabdomyosarcoma,; Ewing sarcoma; Hepatoblastoma; Neuroblastoma; Wilm's tumor

Outcome Measures

Primary Outcomes (4)

• Safety: Maximum Tolerated Dose

  MTD is defined as the dose level at which none or 1 of 6 participants experiences dose-limiting toxicity (DLT), when at least 2 of 3-6 participants experience a DLT at the next highest dose

  approximately after 21 months

• Safety: Recommended Phase II Dose

  In order to establish a RP2D, the MTD cohort will be expanded to have at least 12 evaluable subjects to confirm the RP2D. It is expected that at least 15 subjects evaluable for DLTs will be necessary to establish the RP2D of the combination"

  approximately after 21 months

• Number of participants with Adverse Events

  Individual listings of adverse events will be provided. The incidence of treatment-emergent adverse events and drug-related adverse events, respectively, will be summarized by worst NCI-CTCAE v 4.0 grade and by dose level

  Dose escalation phase:approximately after 21 months; Expansion Phase: approximately after 21 months

• AUC(0-24)md based on nominal dosing

  Dose escalation phase has been completed

  Dose escalation phase:Cycle 1 Day 1, Day 15 and Day 21

Secondary Outcomes (10)

• Overall survival

  Dose escalation phase: approximately 21 months; Expansion phase: approximately 21 months

• Time to progression

  Dose escalation phase: approximately 21 months; Expansion phase: approximately 21 months

• Tumor response: tumor assessment by RECIST v. 1.1

  Dose escalation phase: approximately 21 months; Expansion phase: approximately 21 months

• Taste and texture questionnaire of the regorafenib formulations

  Dose escalation phase: Cycle 1; Expansion phase:Concomitant: Cycle 1 Day 1;Sequential: Cycle 1 Day 8

• AUC(0-24)md based on nominal dosing

  Expansion Phase:Cycle 1 Day1, Day 15 and Day 21

Study Arms (3)

Sequential dosing schedule

EXPERIMENTAL

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.

Drug: Regorafenib (BAY73-4506); Drug: Vincristine (Cellcristin®); Drug: Irinotecan (Irinotecan Cell pharm®)

Concomitant dosing schedule

EXPERIMENTAL

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.

Drug: Regorafenib (BAY73-4506); Drug: Vincristine (Cellcristin®); Drug: Irinotecan (Irinotecan Cell pharm®)

Dose escalation

EXPERIMENTAL

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

Drug: Regorafenib (BAY73-4506)

Interventions

Regorafenib (BAY73-4506) 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.

Concomitant dosing schedule; Dose escalation; Sequential dosing schedule

Vincristine (Cellcristin®) 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.

Concomitant dosing schedule; Sequential dosing schedule

Irinotecan (Irinotecan Cell pharm®) 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; Sequential dosing schedule

Eligibility Criteria

• Age: 6 Months - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Bayer: lead

Study Sites (12)

Unknown Facility

Lyon, 69008, France

Location

Unknown Facility

Marseille, 13005, France

Location

Unknown Facility

Paris, 75248, France

Location

Unknown Facility

Villejuif, 94805, France

Location

Unknown Facility

Genoa, Liguria, 16147, Italy

Location

Unknown Facility

Milan, Lombardy, 20133, Italy

Location

Unknown Facility

Madrid, 28009, Spain

Location

Unknown Facility

Valencia, 46026, Spain

Location

Unknown Facility

Sutton, Surrey, SM2 5PT, United Kingdom

Location

Unknown Facility

Newcastle upon Tyne, Tyne and Wear, NE1 4LP, United Kingdom

Location

Unknown Facility

Birmingham, West Midlands, B4 6NH, United Kingdom

Location

Unknown Facility

Manchester, M13 9WL, United Kingdom

Location

Related Publications (2)

• 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.

  PMID: 37606641 DERIVED

• 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.

  PMID: 34157616 DERIVED

Related Links

• Click here to find information for studies related to Bayer products. To find this study enter the ClinicalTrials.gov identifier (NCT) number or Bayer Study Identifier (ID) in the search field.

MeSH Terms

Conditions

Neoplasms; Rhabdomyosarcoma; Sarcoma, Ewing; Hepatoblastoma; Neuroblastoma; Wilms Tumor

Interventions

regorafenib; Vincristine; Irinotecan

Condition Hierarchy (Ancestors)

Myosarcoma; Neoplasms, Muscle Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Sarcoma; Osteosarcoma; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Complex and Mixed; Neuroectodermal Tumors, Primitive, Peripheral; Neuroectodermal Tumors, Primitive; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplastic Syndromes, Hereditary; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Camptothecin

Study Officials

• Bayer Study Director

  Bayer

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 7, 2014
• First Posted: March 12, 2014
• Study Start: April 11, 2014
• Primary Completion: May 5, 2019
• Study Completion: March 13, 2024
• Last Updated: April 22, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will not share

Locations

IT (2); ES (2); FR (4); GB (4)