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Trial of WP1066 in Patients With Recurrent Malignant Glioma and Brain Metastasis From Melanoma

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ClinicalTrials.gov Identifier: NCT01904123
Recruitment Status : Recruiting
First Posted : July 22, 2013
Last Update Posted : July 25, 2018
Sponsor:
Collaborators:
National Institutes of Health (NIH)
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:

The goal of this clinical research study is to find the highest tolerable dose of WP1066 that can be given to patients with recurrent (has returned after treatment) cancerous brain tumors or melanoma that has spread to the brain. The safety of this drug will also be studied.

WP1066 is designed to target the STAT3 pathway in cancer cells, which makes these cells divide, increases new blood vessels to the tumor, causes the cancer cells to move throughout the body and brain, and avoids them being detected by the immune system. Targeting this pathway may cause the immune system to kill the cancer cells.

This is the first study using WP1066 in humans.

This is an investigational study. WP1066 is not FDA approved or commercially available. It is currently being used for research purposes only.

Up to 33 participants will be enrolled in this study. All will take part at MD Anderson.


Condition or disease Intervention/treatment Phase
Brain Cancer Central Nervous System Neoplasms Melanoma Solid Tumors Drug: WP1066 Procedure: Advanced Brain Tumor Imaging (ABTI) Procedure: Surgical Resection Phase 1

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 33 participants
Allocation: Non-Randomized
Intervention Model: Parallel 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 2021
Estimated Study Completion Date : July 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Experimental: WP1066

Participants include those with recurrent malignant glioma (glioblastoma, anaplastic glioma), and melanoma patients with progressive brain metastasis.

Each 28 day cycle consists of two weeks of treatment with WP1066 administered twice per day (BID) on Monday, Wednesday, and Friday followed by a two-week cycle of no administration.

Dose escalation proceeds according to an Accelerated Titration Design followed by a 3 + 3 design algorithm.

Part I starting dose of WP1066 6 mg/kg by mouth 2 times per day on Monday, Wednesday, and Friday of Weeks 1 and 2 of each 28-day cycle.

Part II starting dose maximum tolerated dose from Part I.

Drug: WP1066

Part I starting dose: 6 mg/kg by mouth 2 times per day on Monday, Wednesday, and Friday of Weeks 1 and 2 of each 28-day cycle.

Part II starting dose: Maximum tolerated dose from Part I on Monday, Wednesday, and Friday of Weeks 1 and 2 of each 28-day cycle.

Part III starting dose: Maximum tolerated dose from Part II on Monday, Wednesday, and Friday of Weeks 1 and 2 of each 28-day cycle.


Experimental: WP1066 + Tumor Surgery
Cohort includes recurrent malignant glioma participants that are pre-dosed with WP1066 14 (+ 3) days prior to surgery. Part III participants receive maximum tolerated dose from Part II. Each 28 day cycle consists of two weeks of treatment with WP1066 administered twice per day (BID) on Monday, Wednesday, and Friday followed by a two-week cycle of no administration. Participants imaged prior to treatment with WP1066 and within 72 hours of surgical resection. Surgery takes place within 3 working days of last WP1066 dose. Drug administration can restart 2 weeks after surgery, provided participants have recovered from surgery. Participants continue to receive WP1066 after surgery is completed, in the absence of DLT, unacceptable toxicity, or disease progression.
Drug: WP1066

Part I starting dose: 6 mg/kg by mouth 2 times per day on Monday, Wednesday, and Friday of Weeks 1 and 2 of each 28-day cycle.

Part II starting dose: Maximum tolerated dose from Part I on Monday, Wednesday, and Friday of Weeks 1 and 2 of each 28-day cycle.

Part III starting dose: Maximum tolerated dose from Part II on Monday, Wednesday, and Friday of Weeks 1 and 2 of each 28-day cycle.


Procedure: Advanced Brain Tumor Imaging (ABTI)
Participants imaged prior to treatment with WP1066 and within 72 hours of surgical resection, and every 8 weeks postop.
Other Names:
  • ABTI
  • Advanced MRI

Procedure: Surgical Resection
Surgery takes place within 3 working days of last WP1066 dose.
Other Name: Tumor resection




Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) of WP1066 [ Time Frame: 6 months ]
    Maximum tolerated dose (MTD) is dose level at which 0/6 or 1/6 patients experience a dose-limiting toxicity (DLT) with at least 2 patients experiencing DLT at next higher dose level. DLT 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 WP1066 and assigned a grade based on National Cancer Institute (NCI) Common Toxicity Criteria (CTC). Any grade toxicity at least possibly related to WP1066 that leads to dose delay of ≥ 2 weeks considered a DLT.


Secondary Outcome Measures :
  1. Overall Response Rate (ORR) [ Time Frame: Every 8 weeks ]
    Overall response measured from time measurement criteria are met for complete response (CR) or partial response (PR) (whichever is first recorded) until first date that recurrent or progressive disease is objectively documented (taking as a reference for progressive disease the smallest measurements recorded since the treatment started).

  2. Progression Free Survival (PFS) [ Time Frame: Baseline and 30 days after progression noted ]
    PFS defined radiographically as a greater than 25% increase in tumor volume (in malignant glioma) or a greater than 20% increase in tumor volume (in brain melanoma metastasis) on T1-weighted MRI scans compared with the MRI obtained within 4 weeks before enrollment.



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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:

  1. Patients must have histologically confirmed progressive brain metastases from melanoma melanoma or recurrent/progressive malignant glioma (glioblastoma, anaplastic glioma), for which standard curative or palliative measures do not exist or are no longer effective.
  2. 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.
  3. 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), whole brain radiation, or have been treated with other systemic therapies that have failed.
  4. Age >=18 years. Because no dosing or adverse event data are currently available on the use of WP1066 in patients <18 years of age, children are excluded from this study.
  5. ECOG performance status <=2, and Karnofsky Performance Scale score >=60%.
  6. Patients must have normal organ and marrow function as defined below: leukocytes >=3,000/mcL, absolute neutrophil count >=1,000/mcL, platelets >=100,000/mcL, total bilirubin within normal institutional limits, AST(SGOT)/ALT(SGPT) <=2.5 X institutional upper limit of normal, creatinine within normal institutional limits OR, creatinine clearance >=60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal. PT/PTT <1.5 x normal institutional standard
  7. Ability to understand and the willingness to sign a written informed consent document.
  8. 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.
  9. Willing and able to tolerate brain MRI's with contrast.
  10. Patients with stable seizures (e.g., no seizures for >= 14 days and not requiring escalation or addition of anti-epileptic drugs) will be eligible.

Exclusion Criteria:

  1. 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.
  2. 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.
  3. History of allergic reactions attributed to compounds of similar chemical or biologic composition to WP1066.
  4. The enzymatic metabolism profile of WP1066 is unknown. Patients who are receiving drugs that significantly interact with the 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 mediations that are predominantly CYP2D6, 2C9 or 2C19 substrates, strong inhibitors or inducers, and sensitive substrates of CYP3A4 with narrow therapeutic range.
  5. 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.
  6. No single lesion can be larger than 3 cm in maximal diameter. There may not be midline shift exceeding 5 mm or hydrocephalus.
  7. 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.
  8. HIV-positive patients receiving combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with WP1066.
  9. Patients who have received bevacizumab, Gliadel®, or are on active therapy with Optune® are not eligible.
  10. 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 PIs discretion to enroll a patient who has a small, asymptomatic brain hemorrhage, but patients who have had symptomatic hemorrhages will be excluded.
  11. 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.
  12. 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.
  13. The cardiac toxicities of WP1066 are unknown. Thus, patients who have a mean QTc interval >450 ms at base line will be excluded. Concomitant use of agents that prolong the QT interval will be avoided.
  14. Malignant glioma patients within 12 weeks of completion of radiation with concurrent temozolomide will be excluded.
  15. Melanoma patients with large or symptomatic brain metastasis, and in whom neurosurgical removal is indicated will not be eligible for this trial.
  16. 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, MD 713-563-8717 aheimber@mdanderson.org

Locations
United States, Texas
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact       aheimber@mdanderson.org   
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Institutes of Health (NIH)
National Cancer Institute (NCI)
Investigators
Principal Investigator: Amy Heimberger, MD 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
P50CA093459 ( U.S. NIH Grant/Contract )
P50CA127001 ( U.S. NIH Grant/Contract )
NCI-2015-00163 ( Registry Identifier: NCI CTRP )
First Posted: July 22, 2013    Key Record Dates
Last Update Posted: July 25, 2018
Last Verified: July 2018

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

Keywords provided by M.D. Anderson Cancer Center:
Brain cancer
Central nervous system neoplasms
CNS
Melanoma
Glioblastoma Multiforme
GBM
Solid tumors
Metastatic to the brain
WP1066
Recurrent malignant glioma
Glioblastoma
Anaplastic glioma
Advanced Brain Tumor Imaging
ABTI

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