| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| RMS and other solid malignant tumors (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 irinotecan with regorafenib exists. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Pediatric patients with cancer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065147 |
| E.1.2 | Term | Malignant solid tumor |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| - To define the safety profile, maximum tolerated dose (MTD) and recommended phase II dose (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 |
|
| E.2.2 | Secondary objectives of the trial |
- To characterize the pharmacokinetics (PK) of regorafenib in combination with vincristine and irinotecan
- To evaluate the anti-tumor activity of regorafenib in combination with vincristine and irinotecan
- To characterize the pharmacokinetics (PK) of irinotecan
- To evaluate pharmacodynamic parameters of regorafenib in
combination with vincristine and irinotecan
- Acceptability and palatability of the regorafenib formulations - tablets and granulates
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Dose Expansion Phase:
- 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
- Pediatric subjects who are able to swallow tablets
- Diagnosis: 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.
- Sexually active females of childbearing potential and sexually active males must agree to use adequate contraception before entering the program until at least 3 months after the last study drug administration. Abstinence is considered an adequate contraception method. For sexually active females, 2 forms of highly effective contraception are mandatory. The investigator or a designated associate is requested to advise the subject on how to achieve an adequate birth control. Adequate contraception is defined in the study as any medically recommended method (or combination of methods) as per standard of care. Male patients after puberty onset are advised not to father a child during and up to 6 months after vincristine treatment; for all male patients after puberty onset, prior to study treatment, advice should be sought for conserving sperm due to the chance of irreversible infertility as a consequence of vincristine treatment.
- Female subjects of childbearing potential must have a pregnancy test performed a maximum of 7 days before start of study treatment, and a negative result must be documented before start of study treatment.
- Subjects must have at least one measurable or evaluable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. For 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 and Lansky ≥ 70% for subjects ≤ 12 years of age. Note the performance level should not be considered
reduced by limitations to movement or play caused by motor paresis or paralysis due to
disease. Any neurological deficits must have been stable for a minimum of 1 week prior to first dose of study treatment.
- Adequate hematological function assessed by the following laboratory requirements conducted within 7 days before starting study treatment:
o Peripheral absolute neutrophil count (ANC): ≥ 1.0 x 10 9/L
o Platelet count : ≥ 100 x 109/L (transfusion independent)
o Hemoglobin : ≥ 8.0 g/ dL
- Adequate renal function defined as creatinine clearance based on Schwartz Estimate ≥ 70 ml/min/1.73 m2
- International normalized ratio (INR) ≤ 1.5 and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN
- Lipase ≤ 1.5 x ULN
- Adequate hepatic function defined as:
o Aspartate aminotransferase/alanine aminotransferase (AST/ALT) ≤3.0 x ULN
o Total bilirubin (sum of conjugated and unconjugated) ≤ 1.5 ULN
- Alkaline phosphatase limit ≤ 2.5 x ULN for age (≤ 5 x ULN for subjects with bone tumors) |
|
| E.4 | Principal exclusion criteria |
Dose Expansion Phase
- Prior treatment with regorafenib. Subjects permanently withdrawn from study participation will not be allowed to re-enter the study.
- Subjects with brain tumors or subjects with known CNS metastases
- Active or uncontrolled infection (> National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE] Grade 2 at screening).
- Active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiviral therapy
- Known history of human immunodeficiency virus (HIV) infection
- Major surgical procedure or significant traumatic injury within 28 days before start of study medication. Bone marrow biopsy and central lines will not be considered as a major surgical procedure.
- Non-healing wound, ulcer, or bone fracture
- Seizure disorder requiring medication with: carbamazepine, phenobarbital, phenytoin, ethosuximide, valproic acid, tiagabine, felbamate, tiagabine, zomisamide and lamotrigine. Subjects with history of seizures controlled with levetiracetam or gabapentin are allowed to enter the study.
- Subjects with uncontrolled baseline hypertension higher than Grade 1 NCICTCAE v.4.0 (recurrent or persistent [≥24 hours] blood pressure [BP] >ULN: BP > the 95th percentile for age, height, and gender measured as described in Appendix 14.5). Additional information about hypertension is provided in Appendix 14.6.
- Clinically significant bleeding (NCI-CTCAE v. 4.0 Grade 3 or higher) within 30 days before start of study medication
- Arterial or venous thrombotic or embolic events such as deep vein thrombosis or pulmonary embolism within 6 months before start of study medication (except for adequately treated catheter-related venous thrombosis occurring more than 1 month before the start of study treatment)
- Subjects with evidence or history of disorders of coagulation or thrombosis
- Cardiac abnormalities such as congestive heart failure (Modified Ross Heart Failure Classification for Children ≥ class 2) and cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted)
- History of organ allograft (including allogeneic bone marrow transplant)
- Unresolved toxicity higher than NCI-CTCAE v. 4.0 Grade 1 attributed to any prior therapy/procedure (excluding alopecia, chemotherapy-induced ototoxicity, and, as per above eligibility criteria, anemia with hemoglobin ≥ 8 mg/dL and ANC ≥ 1.0 x 10 9/L )
- Pleural effusion or ascites that causes respiratory compromise (NCI-CTCAE v. 4.0 Grade 2 dyspnea)
- Any other malignant disease treated prior to study entry
- Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation
- Pregnancy or breast feeding
- Significant gastrointestinal disorders with diarrhea as a major symptom e.g., Crohn’s disease or any malabsorption condition
- Interstitial lung disease with ongoing signs and symptoms at the time of screening
- Any other serious or unstable illness, or medical, psychological or social condition, that could jeopardize the safety of the subject and/or his/her compliance with study procedures, or may interfere with the subject’s participation in the study or evaluation of the study results
- 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 investigation site).
Prohibited prior therapy
- Other anticancer treatment is prohibited, including any investigational new drugs within 28 days or 5
drug half-lives (if drug half-life in subjects is known), whichever is shorter (or within 6 weeks for mitomycin C), before start of study treatment. In the dose expansion phase, prior treatment with vincristine and/or irinotecan is permitted but subject must undergo proper washout (5 drug half-lives)
- Hematopoietic growth factors: within the past 21 days before start of study treatment
-Radiation therapy: ≤ 4 weeks prior to start of study treatment (≤ 2 weeks if limited field
radiation therapy); ≥ 6 months must have elapsed if ≥ 50% radiation of pelvis; 3 months
must have elapsed for cranial-spinal irradiation.
- Autologous stem cell transplant (without total body irradiation) or stem cell rescue
within 3 months prior to start of treatment
- Therapeutic anticoagulation within 3 weeks prior to start of study treatment. Prophylactic anticoagulation of venous or arterial access devices is allowed provided that the requirements for prothrombin time (PT), INR and PTT are met.
- Strong CYP3A4 inhibitors or CYP3A4 within 2 weeks or 5 drug half-lives whichever is longer, before start of study treatment
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| - To define the safety profile, maximum tolerated dose (MTD) and recommended phase II dose (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 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- To characterize the pharmacokinetics (PK) of regorafenib in combination with vincristine and irinotecan
- To evaluate the anti-tumor activity of regorafenib in combination with vincristine and irinotecan
- To characterize the pharmacokinetics (PK) of irinotecan
- To evaluate pharmacodynamic parameters of regorafenib in combination with vincristine and irinotecan
- Acceptability and palatability of the regorafenib formulations - tablets and granulates |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Tumor evaluation is conducted every 8 weeks.
-Pharamcodynamic parameters evaluated during screening phase and end of treatment
- Taste and texture questionnaire is collected during cycle 1. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Phase I dose escalation in pediatric subjects |
|
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 14 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 14 |
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