A Phase 1 interventional study of Regorafenib (BAY73-4506) and Vincristine (Cellcristin®) in Pediatric Oncology, sponsored by Bayer. Completed at 12 sites in 4 countries. Open to participants aged 6 Months to 18 Years. Per ClinicalTrials.gov, last updated 2024-04-22.
Sponsored by Bayer · Phase 1, Interventional, and Other
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.
Expansion Phase of the study:
Subjects must have relapsed/refractory RMS or a solid malignant tumor (Ewing sarcoma, hepatoblastoma, neuroblastoma and Wilms tumor).
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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.
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:
Exclusion Criteria:
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®)
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 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.
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 will be administered at a starting dose of 50 mg/m2/day from Day 1 to Day 5, in 21 day cycles.
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
Time frame: 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"
Time frame: 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
Time frame: 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
Time frame: Dose escalation phase:Cycle 1 Day 1, Day 15 and Day 21
Overall survival
Time frame: Dose escalation phase: approximately 21 months; Expansion phase: approximately 21 months
Time to progression
Time frame: Dose escalation phase: approximately 21 months; Expansion phase: approximately 21 months
Tumor response: tumor assessment by RECIST v. 1.1
Time frame: Dose escalation phase: approximately 21 months; Expansion phase: approximately 21 months
Taste and texture questionnaire of the regorafenib formulations
Expansion phase Dose escalation phase
Time frame: 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
Time frame: Expansion Phase:Cycle 1 Day1, Day 15 and Day 21
Cmax(0-24)md based on individual dosing
Expansion phase
Time frame: Expansion Phase:Cycle 1 Day1, Day 15 and Day 21
Cav(0-24)md based on individual dosing
Expansion phase Dose escalation phase
Time frame: 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
Time frame: 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
Time frame: Expansion Phase:Cycle 1 Day1, Day 15 and Day 21
Clearance of irinotecan and SN-38
Expansion phase
Time frame: Expansion Phase:Cycle 1 Day1, Day 15 and Day 21
Plan to share: No — 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.
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