Patient case: 64-year-old male with melanoma; genetic feature: BRAF (V600E)

Clinical trial: A Phase I Trial of WP1066 in Patients With Recurrent Malignant Glioma and Brain Metastasis From Melanoma

Summary: The goal of this clinical research study is to find the highest tolerable dose of WP1066 that can be given to participants with recurrent 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.

Detailed description: Study Groups:
  If participant is found to be eligible to take part in this study, they will be assigned to a study group based on when they join this study. Up to 6 groups of 1-6 participants will be enrolled in Part 1 of the study, and up to 6 participants will be enrolled in Part 2. Up to 12 participants who will have surgery on the tumor during the study will be enrolled in Part 3.
  If participant is enrolled in Part 1, the dose of WP1066 they receive will depend on when they joined this study. The first group of participants will receive the lowest dose level of WP1066. Each new group will receive a higher dose of WP1066 than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of WP1066 is found.
  If participant is enrolled in Part 2 or Part 3, they will receive WP1066 at the highest dose that was tolerated in Part 1.
  If participant is enrolled in Part 3, they will have additional tumor testing and advanced MRIs performed as described below.
  Study Drug Administration:
  Participant will take WP1066 by mouth 2 times per day on Monday, Wednesday, and Friday of Weeks 1 and 2 of each 28-day cycle. For 2 hours before and 2 hours after each dose, participant must fast (have nothing to eat or drink except water).
  If participant misses a dose, they may take it within 24 hours. However, if it has been more than 24 hours since when participant was supposed to take WP1066, they will need to contact the study doctor.
  For the first and last dose of Cycle 1, participant will take WP1066 in the clinic so that timed blood tests can be done. If participant is the first enrolled participant in a study group, they will be watched for 1 hour after their first dose in Cycle 1, and their vital signs will be checked every 15 minutes.
  The study doctor may decide to lower participant's dose of the study drug if they have side effects.
  Participant will write down the times of their doses of WP1066 in a study drug diary that will be given to them. Participant should bring the diary to the clinic at the end of each cycle.
  Study Visits:
  At every visit, participant will be asked about any new drugs they may be taking, including vitamins, herbs, and supplements. Participant will also be asked about any changes in their health, how they feel, and any side effects they may be having.
  On Day 1 of Cycle 1:
  -  Participant will have a physical and neurological exam, including measurement of their vital signs and weight.
  -  Participant's performance status will be recorded.
  -  Blood (up to 6 tablespoons) and urine will be collected for routine tests.
  -  Blood (about 2 teaspoons each time) will be drawn for pharmacokinetic (PK) testing before receiving WP1066 and 8 times during the 10 hours after the dose. PK testing measures the amount of study drug in the body at different time points.
  -  Participant will have an EKG to check their heart function.
  On Day 2 of Cycle 1, blood (about 2 teaspoons) will be drawn for PK testing.
  On Day 8 of Cycle 1, blood (up to 6 tablespoons) will be drawn for routine tests.
  On Day 14 of Cycle 1, blood (about 2 teaspoons each time) will be drawn for PK testing before receiving WP1066 and 8 times during the 10 hours after the dose.
  On Day 15 of Cycle 1, blood (about 6 tablespoons) will be drawn for PK testing and routine tests.
  On Day 22 of Cycle 1 and Days 8, 15, and 22 of Cycle 2, blood (up to 6 tablespoons) will be drawn for routine tests.
  On Day 1 of Cycle 2:
  -  Participant will have a physical and neurological exam, including measurement of their vital signs and weight.
  -  Participant's performance status will be recorded.
  -  Blood (up to 6 tablespoons) and urine will be collected for routine tests.
  -  Participant will have an EKG to check their heart function.
  On Day 1 of Cycles 3 and beyond:
  -  Participant will have a physical and neurological exam, including measurement of their vital signs and weight.
  -  Participant's performance status will be recorded.
  -  Blood (up to 6 tablespoons) will be drawn for routine tests.
  Every 8 weeks, if participant is in Part 1 or Part 2, they will have an MRI to check the status of the disease.
  Every 8 weeks, if participant has melanoma, they will have a CT scan of the chest, abdomen, and pelvis to check the status of the disease.
  If participant is in Part 3, leftover tumor tissue from surgery will be tested for immune responses and to find out if STAT3 is in the tumor. Before surgery, after surgery, and every 8 weeks after that, participant will have an advanced MRI to check the status of the disease. The advanced MRI is a special MRI that takes about an hour and a half longer than usual, and provides very detailed information for studying the area of the brain where the tumor is. These detailed pictures are called "treatment response maps," and can show clear differences between tumor and non-tumor tissues in the brain. Information from the advanced MRI will allow researchers to learn more about brain tumor tissue and how it relates to an immune response in the brain.
  If the study doctor thinks it is needed, certain tests may be repeated at other times.
  If it is more convenient, participant can have their blood and urine collections for routine tests done at their local clinic or lab instead of at MD Anderson.
  Length of Study Drug Dosing:
  Participant may continue taking the study drug for as long as the doctor thinks it is in their best interest. Participant will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if they are unable to follow study directions.
  Patient's participation on the study will be over after the follow-up visits.
  Follow-Up Visits:
  At 1 and 2 months after participant's last study drug dose:
  -  Participant will be asked about any changes in their health, how they feel, and any side effects they may be having.
  -  Participant will have a physical and neurological exam, including measurement of their vital signs and weight.
  -  Participant's performance status will be recorded.
  -  Blood (up to 6 tablespoons) will be drawn for routine tests.
  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.

Eligibility: 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. Eastern Cooperative Oncology Group (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 corrected QT interval (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.

Relevance to patient case: possibly relevant