E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Solid tumors are masses of abnormal tissue growth that originate in organs or soft tissues |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10065252 |
E.1.2 | Term | Solid tumor |
E.1.2 | System Organ Class | 100000020962 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
•To evaluate the safety and tolerability of cobimetinib in children and young adults, including estimation of the maximum-tolerated dose (MTD) or the maximum administered dose (MAD) and characterization of dose-limiting toxicities (DLTs) |
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E.2.2 | Secondary objectives of the trial |
•To characterize the pharmacokinetics (PK) of cobimetinib in children and young adults
•To evaluate the anticancer activity of cobimetinib in children and young adults with solid or brain tumors, as measured by objective response rate (ORR), progression-free survival (PFS), duration of objective response (DOR), and overall survival (OS)
•To identify recommended Phase II doses for cobimetinib tablet and suspension formulations in pediatric patients on the basis of safety, PK, and efficacy outcome measures |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Signed informed consent form or child's informed assent, when appropriate as determined by patient's age and individual site and country standards
- For dose-escalation stage, tablets: age >=6 years to <18 years; dose-escalation stage, suspension: age >=6 months to < 18 years
- For expansion stage: age >=6 months (>=6 years if suspension is not available to <30 years
- Able to comply with the study protocol, in the investigator’s judgment
- Histologically or cytologically confirmed tumor from the list below, but not limited to, for which prior treatment has proven to be ineffective (i.e., relapsed or refractory) or intolerable or for which no standard therapy exists. Tumor with known or expected RAS/RAF/MEK/ERK pathway involvement. Patients must have had histologic or cytologic confirmation of malignancy at the time of diagnosis or relapse:
• Gliomas, including high- and low-grade gliomas, and diffuse intrinsic pontine glioma (DIPG)
• Soft tissue sarcomas, including rhabdomyosarcoma
• Neuroblastoma
• Melanoma
• Neurofibromatosis (NF)-associated tumors (including plexiform neurofibroma, malignant peripheral nerve sheath tumors, and schwannoma)
• Any solid tumor or brain tumor that occurs in a patient with a RASopathy (such as NF1 or Noonan syndrome)
• Rhabdoid tumors, including anaplastic teratoid/rhabdoid tumor (ATRT)
• Any solid or brain tumor that has been molecularly profiled and shown to have RAS/RAF/MEK/ERK pathway activation, with approval of Medical Monitor
- Current disease state for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life
- Disease that is measurable as defined by the modified International Neuroblastoma Response Criteria (mINRC), Response Assessment in Neuro-Oncology (RANO) criteria or Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or evaluable by nuclear medicine techniques, immunocytochemistry techniques, tumor markers, or other reliable measures
- Availability of tumor tissue at study enrollment is mandatory. Archival tumor tissue block or 15 freshly cut unstained, serial slides available for submission, and/or willingness to undergo a core or excisional biopsy prior to enrollment
- Lansky Performance Status or Karnofsky Performance Status >= 50%
- Life expectancy >=3 months, in the investigator's judgment
- Adequate hematologic and end organ function, defined by the following laboratory results obtained within 28 days prior to initiation of study drug:
• Absolute neutrophil count (ANC) >= 0.75 × 10^9/Liter (L) (unsupported)
• Platelet count >=75 × 10^9/L (unsupported)
• Hemoglobin >=8 gram/deciliter (g/dL) (transfusion is acceptable to meet this criterion)
• Bilirubin <=1.5 × upper limit of normal (ULN) for age
• Aspartate aminotransferase (AST) and alanine transaminase (ALT) <=2.5 × ULN for age
• Serum creatinine <=1.5 × ULN for age or creatinine clearance (or radioisotope glomerular filtration rate) > 70 milliliter per minute (mL/min) /1.73 meter (m)^2
- Fractional shortening (FS) >= 30% and left ventricular ejection fraction (LVEF) >= 50% at baseline, as determined by echocardiography within 28 days prior to initiation of study drug
- Must be able to swallow liquid suspension
- Female patients of childbearing potential and male patients with a female partner of childbearing potential must agree with the required contraceptive methods as defined in the protocol
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E.4 | Principal exclusion criteria |
- Prior treatment with cobimetinib or other MEK inhibitor. Prior sorafenib use is permissible
- Treatment with high-dose chemotherapy and stem-cell rescue (autologous stem cell transplant) within 3 months prior to initiation of study drug
- Treatment with chemotherapy or differentiation therapy or immunotherapy within 4 weeks prior to initiation of study drug or, if treatment included nitrosoureas, within 6 weeks prior to initiation of study drug
- Treatment with thoracic or mediastinal radiotherapy within 6 weeks prior to initiation of study drug
- Treatment with hormonal therapy (except hormone replacement therapy or oral contraceptives), immunotherapy, biologic therapy, or herbal cancer therapy within 4 weeks or < 5 half-lives, whichever is shorter, prior to initiation of study drug
- Treatment with a long-acting hematopoietic growth factor within 2 weeks prior to initiation of study drug or a short-acting hematopoietic growth factor within 1 week prior to initiation of study drug
- Treatment with investigational therapy (with the exception of cancer therapies as described above) within 4 weeks prior to initiation of study drug
- Requirement for initiation of corticosteroids or an increase in the dose of corticosteroids within 1 week prior to initiation of study drug
- Treatment with St. John's wort or hyperforin or drugs that are strong inhibitors or inducers of CYP3A within 1 week prior to initiation of study drug
- Ingestion of grapefruit juice within 1 week prior to initiation of study drug
- Any toxicity (excluding alopecia and ototoxicity) from prior treatment that has not resolved to Grade <= 1 (per National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] version 4.0) at screening except as permitted in the exclusion criteria
- Major surgical procedure or significant traumatic injury within 4 weeks prior to initiation of study drug, or anticipation of need for major surgical procedure during the course of the study. Placement of a vascular access device or minor surgery is permitted if the site has healed prior to initiation of study drug
- Known active infection (excluding fungal infection of the nail beds) within 28 days prior to initiation of study drug that has not completely resolved
- History of Grade ≥ 2 CNS hemorrhage
- History of CNS hemorrhage within 28 days of study entry. This criterion may be waived at the investigator’s request if the CNS hemorrhage was asymptomatic, with approval of the Medical Monitor
- For brain tumor patients, use of anticoagulants within 1 week of study drug initiation
- History or evidence of retinal pathology on ophthalmologic examination that is considered to be a risk factor for or indicative of neurosensory retinal detachment, Central Serous Chorioretinopathy (CSCR), neovascular retinopathy, or retinopathy of prematurity
- Known hypersensitivity to any component of the study drug
- Inability to swallow oral medications
- Impaired gastrointestinal absorption
- Prior allogenic bone marrow transplantation or prior solid organ transplantation
- Any other disease, metabolic or psychological dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or places the patient at unacceptable risk from treatment complications
- Current drug or alcohol use or dependence that would interfere with adherence to study requirements, in the opinion of the investigator
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E.5 End points |
E.5.1 | Primary end point(s) |
1.Incidence of DLTs
2.Number of patients with adverse events, adverse events of special interest and serious adverse events
3.Changes in vital signs, physical findings, and clinical laboratory results
4.Change from baseline in growth patterns and development patterns
5.Pharmacokinetics following single and multiple doses
6.Objective response (complete or partial response)
7.Progression free survival
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1-4: Up to 5 years
5: At dosing and at 2, 4, 6, and 24 hours after dosing on Days 1 and 21 of Cycle 1, and prior to dosing on Day 1 of Cycle 2
6-7: Up to 5 years
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E.5.2 | Secondary end point(s) |
1.Duration of Response
2.Overall survival
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
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 |
first in paediatric population |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
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.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 41 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
Denmark |
France |
Germany |
Ireland |
Israel |
Italy |
Netherlands |
Spain |
Switzerland |
United Kingdom |
United States |
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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
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The end of this study is defined as the date when the last patient, last visit (LPLV) occurs, or 5 years after the last patient is enrolled, whichever occurs first. The Sponsor reserves the right to present interim data to health authorities for compliance purposes.
For an individual patient the completion of the study (i.e., the last visit) will occur when the patient withdraws consent, has completed follow-up, has been lost to follow-up, dies, or when the trial is stopped.
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 15 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 3 |