Safety (Primary) ObjectiveThe primary objective for this study is as follows:- 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…
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Synonym
Health condition
solide tumoren
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety Outcome Measures
The safety outcome measures for this study are as follows:
- Incidence and nature of DLTs
- Nature, frequency, severity, and timing of adverse events, including serious
adverse events and adverse events of special interest
- Changes in vital signs, physical findings, and clinical laboratory results
during and following cobimetinib administration
- Growth patterns (relative to age-specific standards for height and weight)
accounting for baseline growth of the patient
- Development patterns (relative to onset of menarche [for females] and
pubertal changes) accounting for baseline development of the patient
Pharmacokinetic Outcome Measure
The PK outcome measure for this study is as follows:
- To characterize cobimetinib PK in pediatric patients, the following PK
parameters following single and multiple doses will be estimated: maximum
plasma concentration observed, time to maximum concentration, total exposure
(area under the concentration-time curve from 0 to 24 hours [AUC0-24]), and
apparent clearance.
Efficacy Outcome Measures
The co-primary efficacy outcome measures for this study are as follows:
- ORR, defined as the percentage of patients with a complete or partial
response for patients with measurable disease or neuroblastoma patients with
evaluable disease at baseline, or a complete response for patients with
non*measurable but evaluable disease at baseline (except neuroblastoma
patients), on two consecutive occasions * 4 weeks apart, as determined by the
investigator using mINRC for patients with neuroblastoma, RANO criteria for
patients with HGG, and RECIST v1.1 for patients with other tumors
- PFS, defined as the time from initiation of study drug to the first
documented occurrence of disease progression, as determined by the investigator
using mINRC for patients with neuroblastoma, RANO criteria for patients with
HGG, and RECIST v1.1 for patients with other tumors, or death from any cause,
whichever occurs first
Secondary outcome
The secondary efficacy outcome measures for this study are as follows:
- DOR, defined as the time from the first tumor assessment that supports the
patient*s objective response to the time of disease progression, as determined
by the investigator using mINRC for patients with neuroblastoma, RANO criteria
for patients with HGG, and RECIST v1.1 for patients with other tumors, or death
from any cause, whichever occurs first
- OS, defined as the time from initiation of study drug to death from any cause
Exploratory Outcome Measures
The exploratory outcome measures for this study are as follows:
- Levels of potential PD biomarkers (including but not limited to p-MEK, p ERK,
and Ki67) measured in tumor tissue collected at baseline, on treatment, and at
the time of disease progression
- Correlation between non-inherited and inherited biomarkers in plasma
(including but not limited to BRAF mutations, BRAF fusions, RAS mutations, and
NF1) and safety, PK, or efficacy outcome measures
- To explore potential relationships between cobimetinib pharmacokinetics and
other outcome measures (such as safety or efficacy outcome measures)
- Diffusion activity in tumors before and after cobimetinib treatment, as
demonstrated on available MRI scans
- Metabolic activity in tumors before and after cobimetinib treatment, as
demonstrated on available PET scans
- Acceptability Survey
Background summary
see protocol version 3 (05 August 2015), section 1.3 "study rationale and
benefit-risk assessment", pages 45-46
Study objective
Safety (Primary) Objective
The primary objective for this study is as follows:
- 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)
Pharmacokinetic Objective
The pharmacokinetic (PK) objective for this study is as follows:
- To characterize the pharmacokinetics of cobimetinib in children and young
adults
Efficacy Objective
The efficacy objective for this study is as follows:
- 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)
Dose-Finding Objective
An additional objective for this study is as follows:
- 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
Exploratory Objectives
The exploratory objectives for this study are as follows:
- To explore the relationship between cobimetinib exposure and changes in
levels of pharmacodynamic (PD) biomarkers in children and young adults
- To explore non-inherited biomarkers that may be predictive of response to
cobimetinib (i.e., predictive biomarkers), may be associated with progression
to a more severe disease state (i.e., prognostic biomarkers), acquired
resistance to cobimetinib, or susceptibility to developing adverse events, may
provide evidence of cobimetinib activity, or may increase the knowledge and
understanding of disease biology
- To explore inherited biomarkers (i.e., variants in germline DNA) that may be
predictive of response to cobimetinib (i.e., predictive biomarkers), may be
associated with progression to a more severe disease state (i.e., prognostic
biomarkers), acquired resistance to cobimetinib, or susceptibility to
developing adverse events, or may increase the knowledge and understanding of
disease biology
- To explore potential relationships between PK parameters for cobimetinib and
other outcome measures (such as safety or efficacy outcome measures)
- To evaluate tumor characteristics before and after treatment on the basis of
available magnetic resonance imaging (MRI) and positron emission tomography
(PET) scans
- To evaluate specific aspects of the acceptability of the cobimetinib
formulations
Study design
This is a Phase I/II, multicenter, open-label, dose-escalation study designed
to evaluate the safety, tolerability, pharmacokinetics, and preliminary
efficacy of cobimetinib in pediatric and young adult patients with solid tumors
with known or potential RAS/RAF/MEK/ERK pathway activation for which standard
therapy has proven to be ineffective (i.e., relapsed or refractory tumors) or
intolerable or for which no curative standard-of-care treatment options exist.
Patients will be enrolled via an interactive web response system in two
stages: a dose escalation stage and an expansion stage at the recommended
dose. During the dose escalation stage, cohorts of 3-6 pediatric patients (age
* 6 months to < 18 years) will be evaluated at escalating dose levels to
determine the MTD or MAD of cobimetinib in pediatric patients with advanced
solid tumors. The MTD or MAD of each cobimetinib formulation (tablet or
suspension) will be determined in separate dose escalations. Once the MTD or
MAD has been established, pediatric patients (age * 6 months to < 18 years)
will be enrolled in the expansion stage and treated at the recommended dose,
which will be at or below the MTD or MAD, as determined by the Sponsor; adult
patients * 18 years of age with pediatric tumor types can be enrolled on this
study but only during the expansion stage; these adult patients will be treated
at the adult flat dose.
Intervention
The test product (investigational drug) for this study is cobimetinib 20 mg
tablets. Cobimetinib will be taken orally once daily on Days 1-21 of each
28-day treatment cycle (21/7 dosing schedule) according to the guidance
provided in Appendix 9 until the occurance of disease progression as determined
by the investigator, death, unacceptable toxicity, or patient or investigator
decision to discontinue treatment. Patients will be assigned to dose levels in
the order in which they are enrolled. The starting dose for tablets will be
0.6 mg/kg in the dose-escalation stage. Pediatric patients (< 18 years of age)
enrolled in the expansion stage will be treated at or below the MTD or MAD, as
determined by the sponsor. Adult patients (* 18 years of age) enrolled in the
expansion stage will be treated with the adult recommended dose of 60 mg
daily. Cobimetinib should be taken at approximately the same time each day, no
earlier than 1 hour before and no later than 4 hours after the usual dosing
time.
Patients under 6 years of age or weighing < 20 kg are only eligible to receive
the drug in suspension.
Any overdose or incorrect administration of study drug should be noted on the
Study Drug Administration electronic Case Report Form (eCRF). Adverse events
associated with an overdose or incorrect administration of study drug should be
recorded on the Adverse Event eCRF.
Study burden and risks
An overview of the risks can be found in the informed consent form, Annex 5.
Study procedures can be found in the informed consent form, on page 2 under
header "How will the study be conducted", and in the protocol under study
procedures.
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Listed location countries
Age
Inclusion criteria
Patients must meet the following criteria for study entry:
- Signed Informed Consent Form
- Signed Child's Informed Assent, when appropriate as determined by patient's age and individual site and country standards
- For dose-escalation stage, tablets: Age at study entry * 6 years to < 18 years
- For dose-escalation stage, suspension: age at study entry * 6 months to < 18 years
Patients <1 year of age will not be enrolled until * 6 patients *1 year to <18 years of age have received at least one cycle of therapy with suspension and until safety and PK assessment of these patients has been conducted.
- For expansion stage: Age at study entry * 6 months (* 6 years if suspension is not available) to < 30 years
Patients * 6 months to < 1 year of age may not be enrolled until * 6 patients *1 year to <18 years of age have received at least one cycle of therapy with suspension in the dose-escalation phase and until safety and PK assessment of these patients has been conducted.
In exceptional cases of relapsed pediatric tumors in patients * 30 years of age, the Sponsor will consider waiving the age requirement with approval of the Medical Monitor. This waiver is restricted to patients with pediatric-specific diseases (e.g., neuroblastoma) for whom clinical trials are unlikely to be available, and will not be extended to patients with tumors that typically occur both in children and adults (e.g., HGG). The Sponsor may decide to stop enrollment of patients * 18 years of age at any time during the study to ensure adequate enrollment of patients < 18 years of age.
- Able to comply with the requirements of the study protocol, in the investigator*s judgment
- Tumor 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. Diagnosis MUST be one of the following tumor types:
Central nervous system gliomas, including high- and low-grade gliomas, and diffuse intrinsic pontine glioma (DIPG)
Embryonal rhabdomyosarcoma and other non-rhabdomyosarcoma soft tissue sarcomas
Neuroblastoma
Melanoma
Malignant peripheral nerve sheath tumor
Rhabdoid tumors, including atypical teratoid/rhabdoid tumor
Tumors from the following groups that, in the judgment of the investigator, are life threatening, resulting in severe symptoms (including severe pain), or are in close proximity to vital structures:
Neurofibromatosis 1 (NF1)-associated tumors (including plexiform neurofibroma)
Schwannoma
Any solid tumor or brain tumor that occurs in a patient with another RASopathy (such as Noonan syndrome)
Any solid or brain tumor that has been molecularly profiled and shown to have RAS/RAF/MEK/ERK pathway activation, with approval of the Medical Monitor.
- Tumor diagnosis must be histologically or cytologically confirmed either at the time of diagnosis or at the time of relapse, except in the following scenario:
DIPG and optic pathway gliomas do not require histologic confirmation if radiographic findings are sufficient to make diagnosis and institutional standard of care does not mandate biopsy for diagnosis.
- 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 mINRC, RANO criteria, or RECIST v1.1 (as appropriate) 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 (fine-needle aspiration, brush biopsy, and lavage samples are not acceptable)
For patients submitting archival tissue, a minimum of 15 slides are required. Patients with fewer than 15 slides available may be eligible for study entry following approval of the Medical Monitor.
- Lansky Performance Status or Karnofsky Performance Status * 50%
- Life expectancy * 3 months, in the investigator's judgment
- For female patients of childbearing potential: Agreement to remain abstinent or use single or combined contraceptive methods that result in a failure rate of <1% per year during the treatment period and for at least 3 months after the last dose of study drug
True abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
Examples of contraceptive methods with a failure rate of <1% per year include, hormonal implants, established, proper use of combined oral or injected hormonal contraceptives, and certain intrauterine devices. Alternatively, two methods (e.g., two barrier methods such as a condom and a cervical cap) may be combined to achieve a failure rate of < 1% per year. Barrier methods must always be supplemented with the use of a spermicide.
- For male patients with a female partner of childbearing potential or a pregnant female partner: Agreement to remain abstinent or use a condom during the treatment period and for at least 3 months after the last dose of study drug
True abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
- For male patients: agreement to refrain from donating sperm during the treatment period and for at least 3 months after the last dose of study drug
- Adequate hematologic and end organ function, defined by the following laboratory results obtained within 28 days prior to initiation of study drug:
ANC * 0.75 x 10 9/L (unsupported)
Platelet count * 75 x 10 9/L (unsupported)
Hemoglobin * 8 g/dL (transfusion is acceptable to meet this criterion)
Bilirubin * 1.5 x the upper limit of normal (ULN) for age
AST and ALT * 2.5 x ULN for age
Serum creatinine * 1.5 x ULN for age or creatinine clearance (or radioisotope glomerular filtration rate) > 70 mL/min/1.73 m2
- Fractional shortening (FS) * 30% and left ventricular ejection fraction (LVEF) * 50% at baseline, as determined by echocardiography or multigated acquisition scan within 28 days prior to initiation of study drug
Depending on institutional standard, either FS or LVEF is adequate for enrollment if only one value is measured; if both values are measured, then both values must meet criteria above.
- Body weight must be * 20 kg if suspension is not available
Exclusion criteria
Patients who meet any of the following criteria will be excluded from study entry:
- Pregnant or lactating, or intending to become pregnant during the study
Females of childbearing potential must have a negative serum pregnancy test result within 1 week prior to initiation of study drug.
- 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 (other than high-dose chemotherapy as described above) or differentiation therapy (such as retinoic acid) or immunotherapy (such as anti-GD2 antibody treatment) within 4 weeks prior to initiation of study drug or, if treatment included nitrosoureas, within 6 weeks prior to initiation of study drug. This requirement may be waived at the investigator*s request if the patient has recovered from therapeutic toxicity to the degree specified in the protocol, with approval of the Medical Monitor.
- 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 NCI CTCAE v4.0) at screening except as otherwise permitted in the inclusion/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, 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
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-004685-25-NL |
| ClinicalTrials.gov | NCT02639546 |
| CCMO | NL52503.078.16 |