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JAK2 Inhibitor WP1066 in Treating Patients With Recurrent Malignant Glioma or Progressive Metastatic Melanoma in the Brain

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ClinicalTrials.gov Identifier: NCT01904123
Recruitment Status : Recruiting
First Posted : July 22, 2013
Last Update Posted : February 19, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
This phase I trial studies the side effects and best dose of janus kinase 2 (JAK2) 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. JAK2 inhibitor WP1066 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or disease Intervention/treatment Phase
Metastatic Malignant Neoplasm in the Brain Metastatic Melanoma Recurrent Brain Neoplasm Recurrent Glioblastoma Recurrent Malignant Glioma Drug: JAK2 Inhibitor WP1066 Other: Laboratory Biomarker Analysis Other: Pharmacological Study Phase 1

Detailed Description:

PRIMARY OBJECTIVES; I. Identify the maximum tolerated dose (MTD) of WP1066 (JAK2 inhibitor 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 JAK2 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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 33 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Trial of WP1066 in Patients With Recurrent Malignant Glioma and Brain Metastasis From Melanoma
Actual Study Start Date : July 13, 2018
Estimated Primary Completion Date : July 31, 2021
Estimated Study Completion Date : July 31, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Experimental: Treatment (JAK2 inhibitor WP1066)
Patients receive JAK2 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.
Drug: JAK2 Inhibitor WP1066
Given PO
Other Name: WP1066

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Pharmacological Study
Correlative studies




Primary Outcome Measures :
  1. 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 ]
    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.

  2. Incidence of adverse events assessed using NCI CTC [ Time Frame: Up to 2 months after the last study drug dose ]

Secondary Outcome Measures :
  1. Pharmacokinetic analysis of the in vivo bioavailability of JAK2 inhibitor WP1066 [ Time Frame: Days 1, 2, 14, and 15 of course 1 ]
  2. Proportion of patients reaching complete response or partial response [ Time Frame: Up to 2 months after the last study drug dose ]
    Estimated with a 95% confidence interval.

  3. Duration of response [ Time Frame: Up to 2 months after the last study drug dose ]
    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.

  4. Overall survival [ Time Frame: Up to 2 months after the last study drug dose ]
    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.

  5. Progression free survival [ Time Frame: Up to 2 months after the last study drug dose ]
    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.

  6. The proportion of patients who develop additional melanoma metastatic lesions [ Time Frame: Up to 2 months after the last study drug dose ]
    Estimated with a 95% confidence interval.

  7. Change in regulatory T cell numbers [ Time Frame: Baseline up to 2 months after the last study drug dose ]
    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.

  8. 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 ]
    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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have histologically confirmed progressive brain metastases from melanoma or recurrent 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 B-Raf proto-oncogene, serine/threonine kinase (BRAF) or mitogen-activated protein kinase kinase 1 (MEK1) inhibitors for BRAF-positive metastatic melanoma and/or checkpoint blockade with either anti-programmed cell death 1 (PD1) or anti-cytotoxic T-lymphocyte-associated protein 4 (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) 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
  • 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
  • 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; 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
  • Patients who have received bevacizumab, Gliadel, or are on active therapy with Optune are not eligible.
  • 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 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
  • 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
  • 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
  • Patients with uncontrolled seizures or seizure requiring escalation or addition of anti-epileptic drugs will be excluded

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): NCT01904123


Contacts
Contact: Amy Heimberger 713-563-8717 aheimber@mdanderson.org

Locations
United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Amy B. Heimberger    713-563-8717      
Principal Investigator: Amy B. Heimberger         
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
Principal Investigator: Amy Heimberger M.D. Anderson Cancer Center

Additional Information:
Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT01904123     History of Changes
Other Study ID Numbers: 2012-0358
NCI-2015-00163 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2012-0358 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
P50CA127001 ( U.S. NIH Grant/Contract )
P50CA093459 ( U.S. NIH Grant/Contract )
First Posted: July 22, 2013    Key Record Dates
Last Update Posted: February 19, 2019
Last Verified: February 2019

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

Additional relevant MeSH terms:
Neoplasms
Melanoma
Glioblastoma
Glioma
Brain Neoplasms
Neoplasms, Second Primary
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Nevi and Melanomas
Astrocytoma
Neoplasms, Neuroepithelial
Neoplasms, Glandular and Epithelial
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tyrphostins
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action