Clinical Trials /

Volitinib in Treating Participants With Recurrent or Refractory Primary CNS Tumors

NCT03598244

Description:

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.

Related Conditions:
  • Diffuse Intrinsic Pontine Glioma
  • Glioma
  • Medulloblastoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Volitinib in Treating Participants With Recurrent or Refractory Primary CNS Tumors
  • Official Title: A Phase I Study of Savolitinib in Recurrent, Progressive or Refractory Primary CNS Tumors

Clinical Trial IDs

  • ORG STUDY ID: NCI-2018-01499
  • SECONDARY ID: NCI-2018-01499
  • SECONDARY ID: PBTC-049
  • SECONDARY ID: PBTC-049
  • SECONDARY ID: UM1CA081457
  • NCT ID: NCT03598244

Conditions

  • MET Fusion Gene Positive
  • MET Gene Mutation
  • Primary Central Nervous System Neoplasm
  • Progressive Medulloblastoma
  • Recurrent Diffuse Intrinsic Pontine Glioma
  • Recurrent Malignant Glioma
  • Recurrent Medulloblastoma
  • Refractory Diffuse Intrinsic Pontine Glioma
  • Refractory Malignant Glioma
  • Refractory Medulloblastoma

Interventions

DrugSynonymsArms
SavolitinibAZD6094, HMPL-504Treatment (volitinib)

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (volitinib)ExperimentalParticipants receive volitinib PO QD. Treatment repeats every 28 days for up to 39 courses in the absence of disease progression or unacceptable toxicity.
  • Savolitinib

Eligibility 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
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:6 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Objective responses (complete response + partial response)
Time Frame:Up to 2 years
Safety Issue:
Description:Will be described by dose and by histology. Prolonged stable diseases will also be reported in a descriptive fashion.
Measure:Molecular analyses of tumors
Time Frame:Up to 2 years
Safety Issue:
Description:Will be reported descriptively.
Measure:Pharmacokinetic Parameters
Time Frame:Up to 2 years
Safety Issue:
Description: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.
Measure:Population parameters
Time Frame:Up to 2 years
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

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