Clinical trial NCT02085148: A Phase I Dose Finding Study in Children With Solid Tumors Recurrent or Refractory to Standard Therapy
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Pediatric Oncology
Keywords: Pediatric cancer
Rhabdomyosarcoma,
Ewing sarcoma
Hepatoblastoma
Neuroblastoma
Wilm's tumor
Lead sponsor: Bayer
Sponsor class: INDUSTRY
First posted: 2014-03-12
Enrollment: 62
Sex: ALL
Minimum age (years): 6
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

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).

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

Primary outcomes:
measure: Safety: Maximum Tolerated Dose
timeFrame: approximately after 21 months
measure: Safety: Recommended Phase II Dose
timeFrame: approximately after 21 months
measure: Number of participants with Adverse Events
timeFrame: Dose escalation phase:approximately after 21 months; Expansion Phase: approximately after 21 months
measure: AUC(0-24)md based on nominal dosing
timeFrame: Dose escalation phase:Cycle 1 Day 1, Day 15 and Day 21
Secondary outcomes:
measure: Overall survival
timeFrame: Dose escalation phase: approximately 21 months; Expansion phase: approximately 21 months
measure: Time to progression
timeFrame: Dose escalation phase: approximately 21 months; Expansion phase: approximately 21 months
measure: Tumor response: tumor assessment by RECIST v. 1.1
timeFrame: Dose escalation phase: approximately 21 months; Expansion phase: approximately 21 months
measure: Taste and texture questionnaire of the regorafenib formulations
timeFrame: Dose escalation phase: Cycle 1; Expansion phase:Concomitant: Cycle 1 Day 1;Sequential: Cycle 1 Day 8
measure: AUC(0-24)md based on nominal dosing
timeFrame: Expansion Phase:Cycle 1 Day1, Day 15 and Day 21
measure: Cmax(0-24)md based on individual dosing
timeFrame: Expansion Phase:Cycle 1 Day1, Day 15 and Day 21
measure: Cav(0-24)md based on individual dosing
timeFrame: Expansion phase:Cycle 1 Day1, Day 15 and Day 21; Dose escalation phase:Cycle 1 Day1, Day 15 and Day 21
measure: t1/2eff,md based on individual dosing
timeFrame: Expansion phase:Cycle 1 Day1, Day 15 and Day 21; Dose escalation phase:Cycle 1 Day1, Day 15 and Day 21
measure: AUC(0-24)md based on individual dosing
timeFrame: Expansion Phase:Cycle 1 Day1, Day 15 and Day 21
measure: Clearance of irinotecan and SN-38
timeFrame: Expansion Phase:Cycle 1 Day1, Day 15 and Day 21
Other outcomes:
Locations:
city: Lyon
country: France
city: Marseille
country: France
city: Paris
country: France
city: Villejuif Cedex
country: France
city: Genova
country: Italy
state: Liguria
city: Milano
country: Italy
state: Lombardia
city: Madrid
country: Spain
city: Valencia
country: Spain
city: Sutton
country: United Kingdom
state: Surrey
city: Newcastle Upon Tyne
country: United Kingdom
state: Tyne And Wear
city: Birmingham
country: United Kingdom
state: West Midlands
city: Manchester
country: United Kingdom
Study officials:
affiliation: Bayer
name: Bayer Study Director
role: STUDY_DIRECTOR
References:
citation: 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.