Clinical Trials /

AXL Inhibitor BGB324 in Treating Participants With Recurrent Glioblastoma Undergoing Surgery

NCT03965494

Description:

This phase I trial studies how well AXL inhibitor BGB324 works in treating participants with glioblastoma that has come back who are undergoing surgery. AXL inhibitor BGB324 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Glioblastoma
  • Gliosarcoma
Recruiting Status:

Recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: AXL Inhibitor BGB324 in Treating Participants With Recurrent Glioblastoma Undergoing Surgery
  • Official Title: Pilot Surgical PK Study of BGB324 in Recurrent Glioblastoma Patients

Clinical Trial IDs

  • ORG STUDY ID: ABTC-1701
  • SECONDARY ID: IRB00184546
  • SECONDARY ID: UM1CA137443
  • NCT ID: NCT03965494

Conditions

  • Brain and Central Nervous System Tumors

Interventions

DrugSynonymsArms
BGB 324 (before surgery)AXL Inhibitor BGB324, BemcentinibAXL inhibitor BGB324 then surgery
BGB 324 (after surgery)AXL Inhibitor BGB324, BemcentinibSurgery then AXL inhibitor BGB324

Purpose

This phase I trial studies how well AXL inhibitor BGB324 works in treating participants with glioblastoma that has come back who are undergoing surgery. AXL inhibitor BGB324 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Evaluate the penetration of AXL inhibitor BGB324 (BGB324) across the blood brain barrier
      measured by pharmacokinetics/drug concentration of 1.0 uM in tissue resected from a contrast
      enhancing region of the tumor in 60% of recurrent glioblastoma patients.

      SECONDARY OBJECTIVES:

      I. Determine AXL expression, phosphorylation state (AXL phosphospecific antibody if AXL is
      inhibited), and circulating soluble AXL levels.

      II. Determine the BGB324 concentration in tissue resected from a contrast non-enhancing
      region of the tumor.

      III. Characterize the steady state pharmacokinetics of BGB324 in patients with recurrent
      glioblastoma.

      IV. Estimate safety and tolerability of BGB324 for recurrent glioblastoma. V. Assess the
      progression-free and overall survival of patients with recurrent glioblastoma.

      OUTLINE: Participants are assigned to 1 of 2 groups.

      GROUP A: Participants receive AXL inhibitor BGB324 orally (PO) once daily (QD) on days 1-5,
      then undergo surgery 3-6 hours after last dose. Within 45 days, participants receive AXL
      inhibitor BGB324 PO QD on days 1-21. Courses repeat every 21 days in the absence of disease
      progression or unacceptable toxicity.

      GROUP B: Participants undergo surgery, then within 45 days receive AXL inhibitor BGB324 PO QD
      on days 1-21. Courses repeat every 21 days in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, participants are followed up at 30 days.
    

Trial Arms

NameTypeDescriptionInterventions
AXL inhibitor BGB324 then surgeryExperimentalParticipants receive AXL inhibitor BGB324 PO QD on days 1-5, then undergo surgery 3-6 hours after last dose. Within 45 days, participants receive AXL inhibitor BGB324 PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • BGB 324 (before surgery)
Surgery then AXL inhibitor BGB324ExperimentalParticipants undergo surgery, then within 45 days receive AXL inhibitor BGB324 PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • BGB 324 (after surgery)

Eligibility Criteria

        Inclusion Criteria:

          -  Must have histologically confirmed glioblastoma (GBM) that is progressive or recurrent
             following radiation therapy +/- chemotherapy. Patients with previous low-grade glioma
             who progressed after radiation therapy (RT)/chemotherapy and are biopsied and found to
             have GBM/gliosarcoma (GS) are eligible

          -  Patients must have measurable, supratentorial contrast-enhancing progressive or
             recurrent glioblastoma or gliosarcoma by magnetic resonance imaging (MRI) within 21
             days of starting treatment. Patient must be able to tolerate MRIs

          -  May have had treatment for no more than 2 prior relapses

          -  Must have a tumor tissue form indicating availability of archived tissue from initial
             resection at diagnosis of GBM or GS, completed and signed by a pathologist. Sites must
             agree to provide this form within 14 days after treatment start. Availability of
             tissue is not a requirement for study participation

          -  The following intervals from previous treatments are required to be eligible:

               -  12 weeks from the completion of radiation

               -  6 weeks from a nitrosourea chemotherapy or mitomycin C

               -  3 weeks from a non-nitrosourea chemotherapy

               -  4 weeks from any investigational (not Food and Drug Administration
                  [FDA]-approved) agents

               -  2 weeks from administration of a non-cytotoxic, FDA-approved agent, e.g.,
                  erlotinib, hydroxychloroquine, etc.)

               -  4 weeks from prior antiangiogenesis therapy (approved or investigational) (e.g.,
                  bevacizumab, aflibercept, ramucirumab, cediranib, cabozantinib, etc.)

               -  4 weeks from any immunotherapy intervention

          -  Patients must be undergoing surgery that is clinically indicated as determined by
             their care providers. Patients must be eligible for surgical resection according to
             the following criteria:

             * Expectation that the surgeon is able to resect 0.05-0.10 cm^3 (50-100 mg) of tumor
             from enhancing tumor and at least 0.05-0.10 cm^3 (50-100 mg) from non-enhancing tumor
             with low risk of inducing neurological injury

          -  Must have a Karnofsky performance status >= 60% (i.e. the patient must be able to care
             for himself/herself with occasional help from others)

          -  Absolute neutrophil count >= 1,500/uL

          -  Platelets >= 100,000/uL

          -  Hemoglobin >= 9 g/dL

          -  Total bilirubin < 1.5 x upper limit of normal (ULN)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             < 2.5 x institutional upper limit of normal

          -  Creatinine =< institutional upper limit of normal OR creatinine clearance >= 60
             ml/min/1.73m^2 for patients with creatinine levels above institutional normal

          -  Activated partial thromboplastin time (APTT)/partial thromboplastin time (PTT) =< 1.5
             x institutional upper limit of normal

          -  Must have a 12-lead electrocardiogram with a measurable corrected QT using
             Fridericia's correction formula (QTcF) =< 450 msec

          -  Must be able to provide written informed consent

          -  Women of childbearing potential must have a negative serum pregnancy test prior to
             study entry. Women of child-bearing potential and men must agree to use adequate
             contraception (hormonal or barrier method of birth control; abstinence) prior to study
             entry and for the duration of study participation, and through 4 months after the last
             dose of study drug. Should a woman become pregnant or suspect she is pregnant while
             she or her partner is participating in this study, she should inform her treating
             physician immediately. Men treated or enrolled on this protocol must also agree to use
             adequate contraception prior to the study, for the duration of study participation,
             and 4 months after completion of BGB324 administration

          -  Must have no concurrent malignancy except curatively treated basal or squamous cell
             carcinoma of the skin or carcinoma in situ of the cervix, breast, or bladder. Patients
             with prior malignancies must be disease-free for >= five years

          -  Must be able to swallow whole capsules

        Exclusion Criteria:

          -  Patients receiving any other investigational agents are ineligible

          -  Patients with a history of allergic reactions attributed to compounds of similar
             chemical or biologic composition to BGB324 are ineligible. The investigator brochure
             can be referenced for more information

          -  Patients on enzyme-inducing anti-epileptic drugs (EIAED) are not eligible for
             treatment on this protocol. Patients may be on non-enzyme inducing anti-epileptic
             drugs or not be taking any anti-epileptic drugs. Patients previously treated with an
             EIAED may be enrolled if they have been off the EIAED for 10 days or more prior to
             treatment start

          -  Patients with a history of bleeding diathesis are ineligible

          -  Patients who have not recovered to < Common Terminology Criteria for Adverse Events
             (CTCAE) grade 2 toxicities related to prior therapy are ineligible

          -  Patients considered at risk of QTc induced arrhythmias or uncontrolled or significant
             cardiovascular disease, including, but not limited to, any of the following are
             ineligible:

               -  Abnormal left ventricular ejection fraction on echocardiography (less than the
                  lower limit of normal for a subject of that age at the treating institution or <
                  45%)

               -  History of an ischemic cardiac event including myocardial infarction within 3
                  months of study entry

               -  Congestive cardiac failure of > grade 2 severity according to the New York Heart
                  Association as defined by symptomatic at less than ordinary levels of activity

               -  Unstable cardiac disease including unstable angina or hypertension as defined by
                  the need for change in medication within the last 3 months

               -  History or presence of bradycardia (=< 60 beats per minute [bpm]) or history of
                  symptomatic bradycardia, left bundle branch block, cardiac pacemaker or
                  significant atrial tachyarrhythmias as defined by the need for treatment

               -  Current treatment with any agent known to cause torsade de points which cannot be
                  discontinued at least two weeks prior to treatment

               -  Known family or personal history of long QTc syndrome or ventricular arrhythmias
                  including ventricular bigeminy

               -  Previous history of drug-induced QTc prolongation

               -  Screening 12-lead electrocardiogram (ECG) with a measurable QTcF > 450 ms

          -  Patients with uncontrolled intercurrent illness including, but not limited to, ongoing
             or active infection, symptomatic congestive heart failure, clinically significant
             cardiac disease, unstable angina pectoris, cardiac arrhythmia, or psychiatric
             illness/social situations that would limit compliance with study requirements, are
             ineligible

          -  Pregnant women are excluded from this study because the effects of BGB324 on a fetus
             are unknown. Because there is an unknown but potential risk for adverse events in
             nursing infants secondary to treatment of the mother with BGB324, breastfeeding should
             be discontinued if the mother is treated with BGB324

          -  Patients positive for human immunodeficiency virus (HIV) are NOT excluded from this
             study, but HIV-positive patients must have:

               -  A stable regimen of highly active anti-retroviral therapy (HAART) not containing
                  a strong inducer or inhibitor of CYP2C9

               -  No requirement for concurrent antibiotics or antifungal agents for the prevention
                  of opportunistic infections

               -  A CD4 count above 250 cells/uL and an undetectable HIV viral load on standard
                  polymerase chain reaction (PCR)-based test
      
Maximum Eligible Age:120 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Proportion of patients who achieve a drug concentration at >= 1.0 uM level in contrast enhancing tumor tissue
Time Frame:Up to 1 year
Safety Issue:
Description:Will be estimated using binomial distribution along with 90% confidence interval.

Secondary Outcome Measures

Measure:Change in AXL expression level
Time Frame:Up to 1 year
Safety Issue:
Description:Change in AXL expression level (ng/mL) from baseline (before intervention) to post-intervention.
Measure:Pharmacokinetics as measured by plasma maximum concentration (Cmax) (ug/mL)
Time Frame:up to 30 days post-treatment
Safety Issue:
Description:Samples for pharmacokinetic analysis will be collected at baseline, prior to dose on day of surgery, at 2, 4, 8, 12, 16, 20, and 24 hours after dosing; on course (C)1 day (D)1, at 2, 4, 6 and 24 hours on C1D15, C2D8, C2D15, prior to starting each course and 30 days post-treatment
Measure:Pharmacokinetics as measured by plasma minimum concentration (Cmin) (ug/mL)
Time Frame:up to 30 days post-treatment
Safety Issue:
Description:Samples for pharmacokinetic analysis will be collected at baseline, prior to dose on day of surgery, at 2, 4, 8, 12, 16, 20, and 24 hours after dosing; on course (C)1 day (D)1, at 2, 4, 6 and 24 hours on C1D15, C2D8, C2D15, prior to starting each course and 30 days post-treatment
Measure:Pharmacokinetics as measured by area under the curve (AUC) (ug/mL*hr)
Time Frame:up to 30 days post-treatment
Safety Issue:
Description:Samples for pharmacokinetic analysis will be collected at baseline, prior to dose on day of surgery, at 2, 4, 8, 12, 16, 20, and 24 hours after dosing; on course (C)1 day (D)1, at 2, 4, 6 and 24 hours on C1D15, C2D8, C2D15, prior to starting each course and 30 days post-treatment
Measure:Toxicity as assessed by number of participants experiencing of adverse events
Time Frame:Up to 1 year
Safety Issue:
Description:Number of participants experiencing of adverse events grade 3 or higher as defined by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0)
Measure:Overall survival
Time Frame:up to 1 year
Safety Issue:
Description:Time until death or the time of last known alive if lost to follow-up. Survival probability and a median time of survival will be estimated using Kaplan-Meier method along with 95% confidence interval.
Measure:Progression-free survival
Time Frame:up to 1 year
Safety Issue:
Description:Median time of progression-free survival will be estimated using Kaplan-Meier method along with 95% confidence interval. Tumor assessment will be conducted per Response Assessment in Neuro-Oncology (RANO): Complete Response (CR)= no change in size of T1-gadolinium-enhancing (T1-Gd+) disease, stable or reduced T2/FLAIR signal, no new lesion, no corticosteroid use, and stable or improved clinical status; Partial Response (PR)= ≥50% change in size of T1-Gd+ disease, stable or reduced T2/FLAIR signal, no new lesion, stable or reduced corticosteroid use, and stable or improved clinical status; Stable Disease (SD)= <50% reduction to <25% increase size of T1-Gd+ disease, stable or reduced T2/FLAIR signal, no new lesion, stable or reduced corticosteroid use, and stable or improved clinical status; Progressive Disease (PD)= ≥25% increase size of T1-Gd+ disease, or increased T2/FLAIR signal, or presence of new lesion, or worsening clinical status

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Trial Keywords

  • adult glioblastoma

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