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

Pediatric Oncology Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02085148
• Other study ID #: 15906
• Secondary ID: 2013-003579-36
• Status: Completed
• Phase: Phase 1
• Start date: April 11, 2014
• Est. completion date: March 13, 2024

Study information

• Verified date: April 2024
• Source: Bayer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

Expansion Phase of the study:

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 62
• Est. completion date: March 13, 2024
• Est. primary completion date: May 5, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Months to 18 Years

Eligibility

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

Related Conditions & MeSH terms

• Neoplasms
• Pediatric Oncology

Intervention

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 (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.
• 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.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Bayer

Countries where clinical trial is conducted

France,  Italy,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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	Overall survival		Dose escalation phase: approximately 21 months; Expansion phase: approximately 21 months
Secondary	Time to progression		Dose escalation phase: approximately 21 months; Expansion phase: approximately 21 months
Secondary	Tumor response: tumor assessment by RECIST v. 1.1		Dose escalation phase: approximately 21 months; Expansion phase: approximately 21 months
Secondary	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
Secondary	AUC(0-24)md based on nominal dosing	Expansion phase	Expansion Phase:Cycle 1 Day1, Day 15 and Day 21
Secondary	Cmax(0-24)md based on individual dosing	Expansion phase	Expansion Phase:Cycle 1 Day1, Day 15 and Day 21
Secondary	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
Secondary	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
Secondary	AUC(0-24)md based on individual dosing	Expansion phase	Expansion Phase:Cycle 1 Day1, Day 15 and Day 21
Secondary	Clearance of irinotecan and SN-38	Expansion phase	Expansion Phase:Cycle 1 Day1, Day 15 and Day 21

External Links

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