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

A Multi-center, Open-label, Non-randomized, Phase I Dose Escalation Study of Regorafenib (BAY 73-4506) in Pediatric Subjects With Solid Malignant Tumors That Are Recurrent or Refractory to Standard Therapy

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.

Study Overview

• Status: Completed
• Conditions: Pediatric Oncology
• Intervention / Treatment: Drug: Regorafenib (BAY73-4506); Drug: Vincristine (Cellcristin®); Drug: Irinotecan (Irinotecan Cell pharm®)

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).

• Study Type: Interventional
• Enrollment (Actual): 62
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Lyon, France, 69008
  • Marseille, France, 13005
  • Paris, France, 75248
  • Villejuif Cedex, France, 94805
• Italy
  • Liguria
    • Genova, Liguria, Italy, 16147
  • Lombardia
    • Milano, Lombardia, Italy, 20133
• Spain
  • Madrid, Spain, 28009
  • Valencia, Spain, 46026
• United Kingdom
  • Manchester, United Kingdom, M13 9WL
  • Surrey
    • Sutton, Surrey, United Kingdom, SM2 5PT
  • Tyne And Wear
    • Newcastle Upon Tyne, Tyne And Wear, United Kingdom, NE1 4LP
  • West Midlands
    • Birmingham, West Midlands, United Kingdom, B4 6NH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: 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.; 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.; 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.
Experimental: 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.	Drug: 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.; 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.; 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.
Experimental: Dose escalation; Dose escalation phase: This phase of the study has been completed	Drug: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Expansion phase Dose escalation phase	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	Expansion Phase:Cycle 1 Day1, Day 15 and Day 21
Cmax(0-24)md based on individual dosing	Expansion phase	Expansion Phase:Cycle 1 Day1, Day 15 and Day 21
Cav(0-24)md based on individual dosing	Expansion phase Dose escalation phase	Expansion phase:Cycle 1 Day1, Day 15 and Day 21; Dose escalation phase:Cycle 1 Day1, Day 15 and Day 21
t1/2eff,md based on individual dosing	Expansion phase Dose escalation phase	Expansion phase:Cycle 1 Day1, Day 15 and Day 21; Dose escalation phase:Cycle 1 Day1, Day 15 and Day 21
AUC(0-24)md based on individual dosing	Expansion phase	Expansion Phase:Cycle 1 Day1, Day 15 and Day 21
Clearance of irinotecan and SN-38	Expansion phase	Expansion Phase:Cycle 1 Day1, Day 15 and Day 21

Collaborators and Investigators

• Sponsor: Bayer
• Investigators: Study Director: Bayer Study Director, Bayer

Publications and helpful links

General Publications

• 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.

Helpful 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.

Study record dates

Study Major Dates

• Study Start (Actual): April 11, 2014
• Primary Completion (Actual): May 5, 2019
• Study Completion (Actual): March 13, 2024

Study Registration Dates

• First Submitted: March 7, 2014
• First Submitted That Met QC Criteria: March 7, 2014
• First Posted (Estimated): March 12, 2014

Study Record Updates

• Last Update Posted (Actual): April 22, 2024
• Last Update Submitted That Met QC Criteria: April 19, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Ewing sarcoma; Neuroblastoma; Hepatoblastoma; Wilm's tumor; Pediatric cancer; Rhabdomyosarcoma,
• Additional Relevant MeSH Terms: Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Topoisomerase Inhibitors; Topoisomerase I Inhibitors; Irinotecan; Vincristine
• Other Study ID Numbers: 15906; 2013-003579-36 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

IPD Plan Description

Availability of this study's data will later be determined according to Bayer's commitment to the EFPIA/PhRMA "Principles for responsible clinical trial data sharing". This pertains to scope, timepoint and process of data access. As such, Bayer commits to sharing upon request from qualified researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the US and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014.

Interested researchers can use www.vivli.org to request access to anonymized patient-level data and supporting documents from clinical studies to conduct research. Information on the Bayer criteria for listing studies and other relevant information is provided in the member section of the portal.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No