| Eligibility |
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
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