PRIMARY OBJECTIVES:
I. To estimate the maximum tolerated dose (MTD) and recommend a phase II dose of volitinib
(savolitinib) administered orally daily in children with refractory, progressive or recurrent
primary CNS tumors.
II. To define and describe the toxicities of savolitinib in children with refractory,
progressive, or recurrent primary CNS tumors.
III. To characterize the pharmacokinetics of savolitinib in children with refractory,
progressive, or recurrent primary CNS tumors.
SECONDARY OBJECTIVES:
I. To preliminarily define the antitumor activity of savolitinib within the confines of a
phase I study.
II. To perform a genomic analysis within the confines of a phase I study to investigate
correlation between response to treatment (as measured by objective response or progression
free survival [PFS]) and the presence of specific genomic alterations (e.g. MET
amplification, chromosome 7q aneuploidy, MET mutation, or HGF amplification) and/or specific
subgroups of disease.
OUTLINE: This is a dose-escalation study.
Patients receive volitinib orally (PO) once daily (QD). Treatment repeats every 28 days for
up to 39 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, then periodically
for up to 2 years.
Inclusion Criteria:
- Patients with a histologically confirmed diagnosis of a primary CNS tumor
(medulloblastoma, high-grade glioma, or diffuse intrinsic pontine glioma [DIPG]) that
is recurrent, refractory, or progressive. All tumors must have histologic verification
at either the time of diagnosis or recurrence except patients with diffuse intrinsic
brain stem tumors. These patients must have radiographic or clinical evidence of
progression. Patients with a recurrent, progressive, or refractory primary CNS tumor
with evidence of genetic activation of the MET pathway, regardless of histology, are
also eligible to the Phase I component of this study
- Note: Refractory disease is defined as the presence of persistent abnormality on
conventional magnetic resonance imaging (MRI) imaging that is further
distinguished by histology (biopsy or sample of lesion) or advanced imaging, OR
as determined by the treating physician and discussed with the primary
investigator prior to enrollment
- Efficacy Expansion Cohort: Patients must have a recurrent, progressive, or refractory
primary CNS tumor with evidence of genetic activation of the MET pathway, regardless
of histology. The submitted specimen can be from diagnosis or recurrence and there is
no time limit from when the specimen was obtained to enrollment onto the efficacy
expansion cohort. The assessment will be performed in a Clinical Laboratory
Improvement Act (CLIA) certified laboratory. MET pathway activation status must be
confirmed using Food and Drug Administration (FDA) approved testing prior to
enrollment. MET pathway activation is defined as:
- MET kinase domain mutations, allelic frequency >= 5% OR
- MET or HGF amplification, >= 6 copies OR
- Chromosome 7 gain OR
- MET fusion
- If a MET aberration is identified using local testing at a Pediatric Brain
Tumor Consortium (PBTC) institution, final confirmation for eligibility to
the efficacy cohort will be confirmed using Memorial Sloan Kettering Cancer
Center's (MSKCC's) FDA approved IMPACT (Integrated Mutation Profiling of
Actionable Cancer Targets) panel. Alternatively, if a MET aberration is
identified at a PBTC site using another FDA approved panel (Foundation
Medicine or Oncomine), the result will be considered sufficient for
eligibility following study chair review
- Recurrent or refractory primary malignant CNS tumor patients must have adequate
pre-trial frozen or formalin-fixed paraffin-embedded (FFPE) tumor material available
for the required correlative studies. If target amounts of tissue or number of slides
are not available, the site must obtain study chair/co-chair approval for adequacy of
submitted tumor samples and prioritization of studies to be performed, prior to
patient enrollment
- Patients with DIPG who have pre-trial tumor tissue available are requested to
submit tissue; however, this is not required for eligibility
- Patients must have evaluable disease to be eligible. Evaluable disease is defined as
the presence of at least one lesion that can be measured accurately in at least 2
(two) dimensions
- Patients must be > 5 years and =< 21 years of age at the time of study enrollment
- Body surface area (BSA)
- Patients enrolled on 75 mg/m^2/day (dose level 0) must have a BSA >= 1.00 m^2
- Patients enrolled on 150 mg/m^2/day (dose level 1) must have a BSA >= 0.55 m^2
- Patients enrolled on 240 mg/m^2/day (dose level 2) must have a BSA >= 0.67
m^2
- Patients enrolled on 350 mg/m^2/day (dose level 3) must have a BSA >= 0.73 m^2
and =< 2.10 m^2 (the upper BSA restriction for dose level 3 applies during the
dose finding phase only)
- Patients must have failed prior standard therapy for their tumor. Patients with
medulloblastoma must have received radiation therapy in addition to platinum and
alkylator-based chemotherapy. Patients with high-grade glioma (HGG) and DIPG must have
at least received radiation therapy. Patients must have recovered from the acute
treatment related toxicities (defined as =< grade 1 if not defined in eligibility
criteria) of all prior chemotherapy, immunotherapy, radiotherapy or any other
treatment modality prior to entering this study
- Patients must have received their last dose of known myelosuppressive anticancer
therapy at least 21 days prior to enrollment or at least 42 days if it included
nitrosourea
- Biologic or investigational agent (anti-neoplastic):
- Patients must have recovered from any acute toxicity potentially related to the
agent and received their last dose of the investigational or biologic agent >= 7
days prior to study enrollment
- For agents that have known adverse events occurring beyond 7 days after
administration, this period must be extended beyond the time during which
adverse events are known to occur
- Monoclonal antibody treatment and agents with known prolonged half-lives:
- Patients must have recovered from any acute toxicity potentially related to
the agent and received their last dose of the agent >= 28 days prior to
study enrollment
- Patients must have had their last fraction of:
- Craniospinal irradiation or total body irradiation or radiation to >= 50% of
pelvis > 3 months prior to enrollment
- Focal irradiation > 4 weeks prior to enrollment
- Patients must be:
- >= 6 months since allogeneic stem cell transplant prior to enrollment with no
evidence of active graft versus (vs.) host disease
- >= 3 months since autologous stem cell transplant prior to enrollment
- Both males and females of all races and ethnic groups are eligible for this study
- Neurologic Status
- Patients with neurological deficits should have deficits that are stable for a
minimum of 1 week prior to enrollment. A baseline detailed neurological exam
should clearly document the neurological status of the patient at the time of
enrollment on the study
- Patients with seizure disorders may be enrolled if seizures are well controlled
- Patients must be able to swallow whole tablets to be eligible for study
enrollment
- Karnofsky performance scale (KPS for > 16 years of age) or Lansky performance score
(LPS for =< 16 years of age) assessed within two weeks of enrollment must be >= 50
- Patients who are unable to walk because of neurologic deficits, but who are up in
a wheelchair, will be considered ambulatory for the purpose of assessing the
performance score
- Absolute neutrophil count >= 1.0 x 10^9 cells/ L
- Platelets >= 100 x 10^9 cells/ L (unsupported, defined as no platelet transfusion
within 7 days prior to enrollment)
- Hemoglobin >= 8 g/dL (hemoglobin should be unsupported, i.e., red blood cell
transfusions are not allowed within 14 days prior to enrollment)
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x the upper
limit of normal (ULN) with total bilirubin =< 1x ULN OR total bilirubin > ULN - =< 1.5
x ULN with ALT and AST =< 1 x ULN
- Albumin >= 2 g/dL
- Serum creatinine based on age/gender. Patients that do not meet the criteria below but
have a 24 hour creatinine clearance or glomerular filtration rate (GFR) (radioisotope
or iothalamate) >= 70 mL/min/1.73 m^2 are eligible
- Age: Maximum serum creatinine (mg/dL)
- 2 to < 6 years: 0.8 (male and female)
- 6 to < 10 years: 1 (male and female)
- 10 to < 13 years: 1.2 (male and female)
- 13 to < 16 years: 1.5 (male), 1.4 (female)
- >= 16 years: 1.7 (male), 1.4 (female)
- International normalized ratio (INR) < 1.5 x ULN and activated partial thromboplastin
time (aPTT) < 1.5 x ULN unless patients are receiving therapeutic anti-coagulation
which affects these parameters
- Patients with known tumor thrombus or deep vein thrombosis are eligible if clinically
stable on low molecular weight heparin for >= 2 weeks
- Cardiac function:
- Mean resting corrected QT interval (QTc) =< 450 msec on screening obtained from 3
electrocardiograms (EKGs)
- Oxygen saturation as measured by pulse oximetry is > 93% on room air
- Patients who are receiving corticosteroids must be on a stable or decreasing dose for
at least 1 week prior to enrollment
- Patients must be off all colony-stimulating factor(s) (e.g., filgrastim, sargramostim
or erythropoietin) for at least 1 week prior to enrollment. Two (2) weeks must have
elapsed if patients received polyethylene glycol (PEG) formulations
- Pregnancy Prevention
- Patients of childbearing or child fathering potential must be willing to use a
medically acceptable form of birth control, which includes abstinence, while
being treated on this study
- Women of child-bearing potential should use effective contraception from the time
of enrollment until 4 weeks after discontinuing study treatment
- Male study participants should use a condom with female partners of child-bearing
potential during the study and for 4 weeks after discontinuing study treatment
- If the female partner of a male study participant is not using effective
contraception, men must use a condom during the study and for 6 months after
discontinuing study treatment
- Male study participants should avoid fathering a child and refrain from sperm
donation from study start to 6 months after discontinuing study treatment
- The patient or parent/guardian is able to understand the consent and is willing to
sign a written informed consent document according to institutional guidelines
Exclusion Criteria:
- Pregnant women or nursing mothers are excluded from this study. Female patients of
childbearing potential must have a negative serum or urine pregnancy test within 24
hours prior to receiving the first dose of study medication. If the urine test is
positive or cannot be confirmed as negative, a serum pregnancy test will be required.
Pregnant women are excluded from this study because there are unknown but potential
risks to an unborn baby from savolitinib. Because there is an unknown but potential
risk for adverse events in nursing infants secondary to treatment of the mother with
savolitinib, breastfeeding should be discontinued if the mother is treated with
savolitinib
- Patients with a known serious active infection including, but not limited to, viral
hepatitis, human immunodeficiency virus, tuberculosis
- Patients with any clinically significant unrelated systemic illness or significant
cardiac, pulmonary, hepatic or other organ dysfunction), that in the opinion of the
investigator would compromise the patient's ability to tolerate protocol therapy, put
them at additional risk for toxicity or would interfere with the study procedures or
results
- Patients with uncontrolled hypertension (i.e., a blood pressure [BP] > 95th percentile
for age, height, and gender, patients with values above these levels must have their
blood pressure controlled with medication prior to starting study drug)
- The normal blood pressure by height, age and gender tables can be assessed in the
Generic Forms section of the PBTC member's webpage
- Patients with any of the following cardiac diseases
- Congestive heart failure (New York Heart Association >= grade 2)
- Clinically significant cardiac arrhythmia
- Mean resting corrected QT interval (QTc) > 450 msec on screening obtained from 3
electrocardiograms (EKGs) or
- Factors that may increase the risk of QTc prolongation such as chronic
hypokalemia not correctable with supplements, congenital or familial long QT
syndrome, or
- Family history of unexplained sudden death under 40 years of age in first-degree
relatives or
- Any concomitant medication known to prolong the QT interval and cause Torsade de
Pointes. These drugs must have been discontinued prior to the start of
administration of study treatment in accordance with guidance
- Any clinically important abnormalities in rhythm, conduction or morphology of
resting EKG, e.g., complete left bundle branch block, third degree heart block,
second degree heart block, PR interval > 250 msec.
- Patients with a prior or concurrent malignancy whose natural history or treatment has
the potential to interfere with the safety or efficacy assessment of the
investigational regimen for this trial
- Concurrent Therapy
- Patients who are receiving any other anticancer or investigational drug therapy
- Patients receiving strong inducers of CYP3A4, strong inhibitors of CYP3A4 or
CYP1A2 or CYP3A4 substrates with a narrow therapeutic index within 2 weeks of the
first dose of savolitinib (3 weeks for St John's Wort). Strong inducers of CYP3A4
and CYP3A4 substrates which have a narrow therapeutic range or CYP3A4 sensitive
substrates should not be used during the trial or used with caution. Because the
lists of these agents are constantly changing, it is important to regularly
consult a frequently-updated medical reference. Patient drug information handout
and wallet card should be provided to patients
- Prior or current treatment with a MET inhibitor (e.g., foretinib, crizotinib,
cabozantinib, or onartuzumab)
- Patient is currently receiving any of the following herbal preparations or medications
and cannot be discontinued 1 week (7 days) prior to enrollment (3 weeks for St. John's
wort). These herbal medications include, but are not limited to: cannabis products,
St. John's wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone
(DHEA), yohimbe, saw palmetto, and ginseng
- Patient has undergone major surgical procedure =< 28 days prior to beginning study
drug or a minor surgical procedure =< 7 days prior to beginning study drug. No waiting
is required following port-a-cath placement
- Patients who in the opinion of the investigator are unwilling or unable to return for
required follow-up visits or obtain follow-up studies required to assess toxicity to
therapy or to adhere to drug administration plan, other study procedures, and study
restrictions
- Patients with a history of allergic reactions attributed to compounds of similar
chemical or biologic composition
- Prisoners will be excluded from this study
