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Volitinib in Treating Participants With Recurrent or Refractory Primary CNS Tumors

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ClinicalTrials.gov Identifier: NCT03598244
Recruitment Status : Recruiting
First Posted : July 25, 2018
Last Update Posted : August 22, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase I trial studies the best dose and side effect of volitinib in treating participants with primary central nervous system (CNS) tumors that have come or does not respond to treatment. Volitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or disease Intervention/treatment Phase
MET Fusion Gene Positive MET Gene Mutation Primary Central Nervous System Neoplasm Recurrent Diffuse Intrinsic Pontine Glioma Recurrent Malignant Glioma Recurrent Medulloblastoma Refractory Diffuse Intrinsic Pontine Glioma Refractory Malignant Glioma Refractory Medulloblastoma Drug: Savolitinib Phase 1

Detailed Description:

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.

Participants receive volitinib orally (PO) once daily (QD). Treatment repeats every 28 days for up to 39 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up at 30 days, then periodically for up to 2 years.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study of Savolitinib in Recurrent, Progressive or Refractory Primary CNS Tumors
Actual Study Start Date : October 15, 2018
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : December 31, 2020


Arm Intervention/treatment
Experimental: Treatment (volitinib)
Participants receive volitinib PO QD. Treatment repeats every 28 days for up to 39 courses in the absence of disease progression or unacceptable toxicity.
Drug: Savolitinib
Given PO
Other Names:
  • AZD 6094
  • AZD6094
  • HMPL-504
  • Volitinib




Primary Outcome Measures :
  1. Maximum tolerated dose of volitinib defined as the highest dose level at which six patients have been treated with at most one patient experiencing a dose limiting toxicity and the next higher dose level has been determined to be too toxic [ Time Frame: Up to 30 days post treatment ]
  2. Recommend a phase II dose [ Time Frame: Up to 30 days post treatment ]

Secondary Outcome Measures :
  1. Objective responses (complete response + partial response) [ Time Frame: Up to 2 years ]
    Will be described by dose and by histology. Prolonged stable diseases will also be reported in a descriptive fashion.

  2. Molecular analyses of tumors [ Time Frame: Up to 2 years ]
    Will be reported descriptively.

  3. Pharmacokinetic Parameters [ Time Frame: Up to 2 years ]
    Will be presented in tabular and graphical form. Pharmacokinetic parameters of interest, such as apparent volume of the central compartment (Vc/F), elimination rate constant (Ke), half-life (t1/2), apparent oral clearance (CL/F), and area under the plasma concentration time curve (AUC) will be estimated using compartmental methods. Dose proportionality in pharmacokinetic parameters will be investigated by performing one-way analysis of variance (ANOVA) on dose-normalized parameters.

  4. Population parameters [ Time Frame: Up to 2 years ]
    Will be estimated using nonlinear mixed effects modeling methods (NONMEM). This method estimates the population parameters and both the inter- and intra-subject variability. Once the population parameters and corresponding covariance matrix are estimated, individual estimates can be obtained using post hoc analysis.



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Ages Eligible for Study:   6 Years to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

    • 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 (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 principal investigator (PI) 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) who weigh < 50 kg must have a BSA >= 0.63 m^2 but =< 2.00 m^2
    • Patients enrolled on 240 mg/m2/day (dose level 2) who weigh >= 50 kg must have a BSA >= 0.63 m^2
  • 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):

    • Patient 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: At least three half-lives must have elapsed prior to enrollment

      • Note: A list of the half-lives of commonly used monoclonal antibodies is available on the PBTC webpage under Generic Forms and Templates
  • 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
  • Patient 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 tablets as a whole 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 - =< 1.5x ULN with ALT and AST =< 1x 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:

    • Left ventricular ejection fraction > 55% on echocardiogram (ECHO)
    • Mean resting corrected QT interval (QTc) =< 470 msec
  • 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. 2 (two) weeks must have elapsed if patients received polyethylene glycol (PEG) formulations
  • Female patients of childbearing potential must not be pregnant or breast-feeding. Female patients of childbearing potential must have a negative serum or urine pregnancy test
  • 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:

  • Female patients who are breast-feeding
  • Patients with a known serious active infection including, but not limited to, viral hepatitis, human immunodeficiency virus, tuberculosis, or 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
    • Any factors that increased 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
  • Patients with a history of any other malignancy, except patients with a secondary brain tumor if the patient's first malignancy has been in remission for at least 5 years from the end of treatment
  • 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)
  • Patients 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03598244


Locations
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United States, Colorado
Children's Hospital Colorado Suspended
Aurora, Colorado, United States, 80045
United States, Illinois
Lurie Children's Hospital-Chicago Recruiting
Chicago, Illinois, United States, 60611
Contact: Site Public Contact    773-880-4562      
Principal Investigator: Stewart Goldman         
United States, New York
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Site Public Contact    212-639-7592      
Principal Investigator: Stephen W. Gilheeney         
United States, Ohio
Cincinnati Children's Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229
Contact: Site Public Contact    513-636-2799    cancer@cchmc.org   
Principal Investigator: Ralph Salloum         
United States, Pennsylvania
Children's Hospital of Pittsburgh of UPMC Recruiting
Pittsburgh, Pennsylvania, United States, 15224
Contact: Site Public Contact    412-692-8570    jean.tersak@chp.edu   
Principal Investigator: Alberto Broniscer         
United States, Tennessee
St. Jude Children's Research Hospital Suspended
Memphis, Tennessee, United States, 38105
United States, Texas
Texas Children's Hospital Recruiting
Houston, Texas, United States, 77030
Contact: Site Public Contact    888-823-5923    ctsucontact@westat.com   
Principal Investigator: Patricia A. Baxter         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Ralph Salloum Pediatric Brain Tumor Consortium

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03598244     History of Changes
Other Study ID Numbers: NCI-2018-01499
NCI-2018-01499 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
PBTC-049 ( Other Identifier: Pediatric Brain Tumor Consortium )
PBTC-049 ( Other Identifier: CTEP )
UM1CA081457 ( U.S. NIH Grant/Contract )
First Posted: July 25, 2018    Key Record Dates
Last Update Posted: August 22, 2019
Last Verified: May 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Glioma
Medulloblastoma
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neuroectodermal Tumors, Primitive
Neoplasms by Site
Nervous System Diseases