Clinical Trials /

STAT3 Inhibitor WP1066 in Treating Patients With Recurrent Malignant Glioma or Progressive Metastatic Melanoma in the Brain

NCT01904123

Description:

This phase I trial studies the side effects and best dose of STAT3 inhibitor WP1066 in treating patients with malignant glioma that has come back or melanoma that has spread to the brain and is growing, spreading, or getting worse. STAT3 inhibitor WP1066 may stop the growth of tumor cells and modulate the immune system.

Related Conditions:
  • Malignant Glioma
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: STAT3 Inhibitor WP1066 in Treating Patients With Recurrent Malignant Glioma or Progressive Metastatic Melanoma in the Brain
  • Official Title: A Phase I Trial of WP1066 in Patients With Recurrent Malignant Glioma and Brain Metastasis From Melanoma

Clinical Trial IDs

  • ORG STUDY ID: 2012-0358
  • SECONDARY ID: NCI-2015-00163
  • SECONDARY ID: 2012-0358
  • SECONDARY ID: P30CA016672
  • SECONDARY ID: P50CA127001
  • SECONDARY ID: P50CA093459
  • NCT ID: NCT01904123

Conditions

  • Metastatic Malignant Neoplasm in the Brain
  • Metastatic Melanoma
  • Recurrent Brain Neoplasm
  • Recurrent Glioblastoma
  • Recurrent Malignant Glioma

Interventions

DrugSynonymsArms
STAT3 Inhibitor WP1066WP1066Treatment (STAT3 inhibitor WP1066)

Purpose

This phase I trial studies the side effects and best dose of STAT3 inhibitor WP1066 in treating patients with malignant glioma that has come back or melanoma that has spread to the brain and is growing, spreading, or getting worse. STAT3 inhibitor WP1066 may stop the growth of tumor cells and modulate the immune system.

Detailed Description

      PRIMARY OBJECTIVES; I. Identify the maximum tolerated dose (MTD) of STAT3 inhibitor WP1066
      (WP1066) in patients with recurrent malignant glioma (glioblastoma, anaplastic glioma), and
      melanoma patients with progressive brain metastasis.

      II. Assess the safety and tolerability of WP1066 in patients with recurrent malignant glioma
      and melanoma patients with progressive brain metastasis using the National Cancer Institute
      (NCI) Common Toxicity Criteria (CTC) with special attention directed at determining whether
      any induced autoimmune reactions occur.

      SECONDARY OBJECTIVES:

      I. Pharmacokinetic analysis of the in vivo bioavailability of WP1066. II. Assess overall
      response rate (ORR) in patients with recurrent malignant gliomas and progressive metastatic
      melanoma to the brain.

      III. Assess immunological response in patients with recurrent malignant glioma and melanoma
      patients with progressive brain metastasis treated with WP1066.

      IV. Assess time to radiographically assessed progression and/or response in patients treated
      with WP1066.

      V. Assess progression-free survival (PFS) and overall survival (OS) in patients treated with
      WP1066.

      VI. Estimate the proportion of patients treated with WP1066 who develop additional melanoma
      metastatic lesions, including those in the central nervous system (CNS).

      OUTLINE: This is a dose-escalation study.

      Patients receive STAT3 inhibitor WP1066 orally (PO) twice daily (BID) on Monday, Wednesday,
      and Friday of weeks 1 and 2. Courses repeat every 28 days in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 1 and 2 months.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (STAT3 inhibitor WP1066)ExperimentalPatients receive STAT3 inhibitor WP1066 PO BID on Monday, Wednesday, and Friday of weeks 1 and 2. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • STAT3 Inhibitor WP1066

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically confirmed progressive brain metastases from melanoma
             or recurrent/progressive malignant glioma (glioblastoma, anaplastic glioma), for which
             standard curative or palliative measures, with the exception of surgery, do not exist
             or are no longer effective

          -  Patients must have measurable disease in the brain, defined as at least one lesion
             that can be accurately measured in at least one dimension as >= 10 mm by brain
             magnetic resonance imaging (MRI); MRI of the brain (with and without gadolinium
             enhancement) is to be performed using standard 5-mm slices with 2.5-mm spacing for
             comparison to subsequent MRI scans

          -  In the case of malignant glioma patients, they must have previously undergone
             standard-of-care treatment including surgery, radiation, and first line adjuvant
             chemotherapy prior to the experimental treatment (WP1066); in the case of melanoma
             patients with brain metastasis, they may have previously undergone a resection (with
             radiographic evidence of progression), have undergone gamma knife radiosurgery (with
             radiographic evidence of progression), or have been treated with other systemic
             therapies that failed

          -  Karnofsky performance scale score >= 60%

          -  Leukocytes >= 3,000/mcL

          -  Absolute neutrophil count >= 1,000/mcL

          -  Platelets >= 75,000/mcL

          -  Total bilirubin =< 1.6

          -  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 within normal institutional limits OR creatinine clearance >= 60
             mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

          -  Prothrombin time (PT)/partial thromboplastin time (PTT) < 1.5 x normal institutional
             standard

          -  Ability to understand and the willingness to sign a written informed consent document

          -  Melanoma patients must be intolerant of, or have disease that has proven refractory to
             approved therapies such as BRAF or MEK inhibitors for BRAF-positive metastatic
             melanoma and/or checkpoint blockade with either anti-PD1 or anti-CTLA-4 for metastatic
             melanoma

          -  Willing and able to tolerate brain MRI's with contrast

          -  Patients with stable seizures (e.g., no seizures for >= 14 days and not requiring
             escalation or addition of anti-epileptic drugs for 14 days from starting treatment)
             will be eligible

          -  Patients who are eligible for the surgical expansion cohort are identified by the
             clinical team who have made the independent decision that the patient would benefit
             from non-emergent palliative surgical resection (i.e. they are not a candidate for
             gamma knife or other type of standard therapy)

        Exclusion Criteria:

          -  Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
             nitrosoureas) prior to entering the study or those who have not recovered from adverse
             events due to agents administered more than 4 weeks earlier; biological agents, immune
             modulators, and targeted therapeutic approaches require a 2-week washout window

          -  Patients who are receiving any other investigational agents require a 4 week washout
             period; patients who have received cellular or gene therapy at any time are not
             eligible

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to WP1066

          -  The enzymatic metabolism profile of WP1066 is unknown; patients who are receiving
             drugs that significantly interact with the cytochrome P450 (CYP450) enzyme(s) are
             ineligible; however, if they are switched to other medications with a 2-week washout
             window, they will be eligible; patients are also excluded if they have been exposed
             within 7 days of planned first study treatment day to medications that are
             predominantly cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6),
             cytochrome P450, family 2, subfamily C, polypeptide 9 (2C9) or cytochrome P450, family
             2, subfamily C, polypeptide 19 (2C19) substrates, strong inhibitors or inducers, and
             sensitive substrates of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)
             with narrow therapeutic range; patients requiring escalation of the corticosteroid
             dose will be excluded, but patients receiving a stable or decreasing dose for at least
             one week will be eligible

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

          -  No single lesion can be larger than 3 cm in maximal diameter; there may not be midline
             shift exceeding 5 mm or hydrocephalus

          -  Pregnant women are excluded from this study because WP1066 could potentially be
             teratogenic or have abortifacient effects; breastfeeding should be discontinued if the
             mother is treated with WP0166; female subjects of childbearing potential should be
             willing to use 2 methods of birth control prior to study entry, during the study, and
             for 2 months after the last dose of the study drug or be surgically sterile; subjects
             of childbearing potential are those who have not been surgically sterilized or have
             not been free from menses for > 1 year; 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 WP1066 administration

          -  Human immunodeficiency virus (HIV)-positive patients receiving combination
             antiretroviral therapy are ineligible because of the potential for pharmacokinetic
             interactions with WP1066

          -  Patients who have received bevacizumab, Gliadel, or are on active therapy with Optune
             are not eligible

          -  The potential for further hemorrhaging with the use of WP1066 is unknown; furthermore,
             because brain melanoma metastases commonly hemorrhage, toxicity may be inappropriately
             attributed to WP1066 in this setting; it will be at the principal investigator's (PIs)
             discretion to enroll a patient who has a small, asymptomatic brain hemorrhage, but
             patients who have had symptomatic hemorrhages will be excluded

          -  Patients with uncontrolled seizures or seizure requiring escalation or addition of
             anti-epileptic drugs will be excluded

          -  Because one of the secondary objectives is PFS based on radiographic volumetric
             analysis of the tumor, the presence of diffuse leptomeningeal disease will be an
             exclusion criterion for this study; this is secondary to the inadequacy of measuring
             the extent of the tumor burden within this setting and the very poor prognosis of
             these patients

          -  The cardiac toxicities of WP1066 are unknown; thus, patients who have a corrected QT
             (QTc) interval > 450 ms at base line will be excluded; concomitant use of agents that
             prolong the QT interval will be avoided

          -  Malignant glioma patients within 12 weeks of completion of radiation concurrent
             temozolomide will be excluded

          -  Melanoma patients with large or symptomatic brain metastasis, and in whom
             neurosurgical removal is indicated will not be eligible for this trial
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) of JAK2 inhibitor WP1066, defined as the dose level at which 0/6 or 1/6 patients experience a dose limiting toxicity (DLT) with at least 2 patients experiencing DLT at the next higher dose level
Time Frame:28 days
Safety Issue:
Description:A DLT will be defined as an adverse event or an abnormal laboratory value assessed as being at least possibly related to the investigation agent that occurs during the first 28 days after administration of the first dose of JAK2 inhibitor WP1066 and will be assigned a grade based on National Cancer Institute (NCI) Common Terminology Criteria (CTC). Any grade toxicity at least possibly related to WP1066 that leads to dose delay of >= 2 weeks will be considered a DLT.

Secondary Outcome Measures

Measure:Pharmacokinetic analysis of the in vivo bioavailability of JAK2 inhibitor WP1066
Time Frame:Days 1, 2, 14, and 15 of course 1
Safety Issue:
Description:
Measure:Proportion of patients reaching complete response or partial response
Time Frame:Up to 2 months after the last study drug dose
Safety Issue:
Description:Estimated with a 95% confidence interval.
Measure:Duration of response
Time Frame:Up to 2 months after the last study drug dose
Safety Issue:
Description:Estimated using Kaplan-Meier survival curves. Cox proportional hazards regression methodology may be used to assess the association between duration of response or survival and clinical and demographic characteristics of interest.
Measure:Overall survival
Time Frame:Up to 2 months after the last study drug dose
Safety Issue:
Description:Estimated using Kaplan-Meier survival curves. Cox proportional hazards regression methodology may be used to assess the association between duration of response or survival and clinical and demographic characteristics of interest.
Measure:Progression free survival
Time Frame:Up to 2 months after the last study drug dose
Safety Issue:
Description:Estimated using Kaplan-Meier survival curves. Cox proportional hazards regression methodology may be used to assess the association between duration of response or survival and clinical and demographic characteristics of interest.
Measure:The proportion of patients who develop additional melanoma metastatic lesions
Time Frame:Up to 2 months after the last study drug dose
Safety Issue:
Description:Estimated with a 95% confidence interval.
Measure:Change in regulatory T cell numbers
Time Frame:Baseline up to 2 months after the last study drug dose
Safety Issue:
Description:Tested using paired t-tests or Wilcoxon signed-rank tests, as appropriate. The longitudinal analysis for all markers will be similar using generalized linear mixed-effects (GLMM) models to assess the significance of the changing values over time and estimating the trajectory.
Measure:Change in the number of peripheral blood mononuclear cells expressing phosphorylated STAT3
Time Frame:Baseline up to 2 months after the last study drug dose
Safety Issue:
Description:Tested using paired t-tests or Wilcoxon signed-rank tests, as appropriate. The longitudinal analysis for all markers will be similar using GLMM models to assess the significance of the changing values over time and estimating the trajectory.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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