Inclusion Criteria:
- - Newly diagnosed, histologically confirmed World Health Organization (WHO) glioblastoma
multiforme (GBM), IDH wild-type.
- - External pathology reports are permitted for confirmation of histological
diagnosis.
- - Documentation of isocitrate dehydrogenase (IDH) wild-type status will be by IDH1
R123H immunohistochemistry, except for patients =< age 54 for whom IDH sequencing
will be required to detect noncanonical IDH mutations.
- - Documentation of O6-methylguanine-DNA methyltransferase (MGMT) unmethylated status per
testing at any Clinical Laboratory Improvement Amendment (CLIA) certified laboratory.
- - Cohort 1 only: Patients with prior gross total resection (GTR)
- Cohort 2 only: Patients without prior gross total resection (GTR)
- Cohort 2 only: Measurable disease in the brain (per RANO criteria) on brain magnetic
resonance imaging (MRI) scan conducted within =< 4 weeks prior to initiating trial
therapy.
- - Cohort 2 only: Patients who would benefit from non-emergent, palliative surgical
resection, in the opinion of the local site's tumor board.
- - Able to initiate trial therapy within 8 weeks of the initial brain surgical procedure
(biopsy or resection) that lead to the patient's initial diagnosis of GBM.
- - Karnofsky performance scale score >= 60%
- White blood cell (WBC) count >= 3.0 x 10^9/L (within =< 30 days prior to registration)
(without growth factor support and/or receipt of blood products within =< 14 days
prior to testing)
- Absolute neutrophil count (ANC) >= 1.0 x 10^9/L (within =< 30 days prior to
registration) (without growth factor support and/or receipt of blood products within
=< 14 days prior to testing)
- Platelet count >= 75 x 10^9/L (within =< 30 days prior to registration) (without
growth factor support and/or receipt of blood products within =< 14 days prior to
testing)
- Total bilirubin =< 1.5 x upper limit of normal (ULN) or direct bilirubin =< ULN for
subjects with total bilirubin levels > 1.5 x ULN (within =< 30 days prior to
registration)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =<
2.5 x ULN (within =< 30 days prior to registration)
- Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x
ULN (within =< 30 days prior to registration)
- Creatinine or creatinine clearance within normal institutional limits.
A creatinine
level above the institutional normal limit is acceptable, provided creatinine
clearance (CrCl) is >= 60 mL/min/1.73 m^2 (within =< 30 days prior to registration).
Creatinine clearance should be calculated using the Cockcroft-Gault formula.
- - International normalized ratio (INR) =< 1.5 x ULN or for subjects receiving
anticoagulant therapy, INR must be within the therapeutic range of intended use of
anticoagulants, as determined by the treating investigator (within =< 30 days prior to
registration)
- Activated partial thromboplastin time (aPTT) =< 1.5 x ULN or for subjects receiving
anticoagulant therapy, aPTT must be within the therapeutic range of intended use of
anticoagulants, as determined by the treating investigator (within =< 30 days prior to
registration)
- Willing and able to tolerate brain MRI with contrast.
Patients with any known severe
allergy to contrast agent(s) should not participate in the study. Patients with mild
allergies to contrast agents (e.g., rash only) may participate in the study per
treating investigator discretion; it is recommended that these patients be pretreated
with acetaminophen and diphenhydramine [or other institutional standard combination of
agent(s) for allergy prep] prior to injection of the contrast agent.
- - Willing and able to follow the below contraception requirements:
For Females:
- Female subjects of childbearing potential (defined below) must agree to use adequate
contraception (e.g., abstinence or 2 methods of birth control, such as a barrier
method in combination with hormonal contraception) starting from the time of informed
consent, throughout the duration of treatment with WP1066, and for 2 months after the
last dose of WP1066.
They also must agree to not donate/freeze eggs during the same
timeframe. A female of reproductive potential is any woman (regardless of sexual
orientation, having undergone a tubal ligation, or remaining celibate by choice) who
meets both of the following two criteria:
- - Has not undergone a hysterectomy or bilateral oophorectomy.
- - Has had menses at any time in the preceding 12 consecutive months (and therefore
has not been naturally postmenopausal for > 12 months)
For Males:
- Male subjects must agree to use adequate contraception (e.g., abstinence or 2 methods
of birth control, such as a barrier method in combination with partner's use of
hormonal contraception) starting from the time of informed consent, throughout the
duration of treatment with WP1066, and for 4 months after the last dose of WP1066.
They also must agree to not donate sperm during the same timeframe Note: The effects
of WP1066 on the developing human fetus are unknown. WP1066 could potentially be
teratogenic or have abortifacient effects. 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.
- - Subject (or subject's legally authorized representative if subject has impaired
decision-making capacity) must have the ability to understand and the willingness
to sign a written informed consent document.
- - Both men and women of all races and ethnic groups may participate in this trial.
Exclusion Criteria:
- - Receipt of investigational agents within =< 2 weeks prior to registration.
- - Prior receipt of gene therapy, at any time.
- - Prior receipt of bevacizumab, at any time.
- - Prior receipt of Gliadel, at any time.
- - Patients who are on active therapy with Optune and who are unable to safely
discontinue Optune prior to initiating trial therapy Note: Patients who can safely
discontinue Optune prior to initiating trial therapy may participate.
- - Patients who are on active therapeutic anti-cancer therapy and who are unable to
discontinue the anti-cancer therapy prior to initiating trial therapy Note: Patients
who discontinue anti-cancer therapy prior to initiating trial therapy may participate.
Patients with a prior or concurrent malignancy whose natural history or treatment does
not have the potential to interfere with the safety or efficacy assessment of the
investigational regimen for this trial may participate.
- - History of allergic reactions attributed to compounds of similar chemical or biologic
composition to WP1066 or its excipients.
- - Human immunodeficiency virus (HIV)-positive patients receiving combination
antiretroviral therapy Note: These patients are ineligible because of the potential
for pharmacokinetic interactions with WP1066.
(HIV testing is not required, unless
mandated by a local health authority.)
- - Patients who have received drugs that significantly interact with CYP450 enzyme(s)
within =< 2 weeks prior to planned first study treatment day Note: Patients who are
able to safely discontinue the aforementioned agents > 2 weeks prior to initiating
treatment with WP1066 may participate.
The enzymatic metabolism profile of WP1066 is
unknown. Drugs that have a minor interaction with CYP450 are allowed, and drugs with a
moderate interaction are allowed at the principal investigators (PI's) discretion.
Zofran (ondansetron) is allowed.
- - Patients who have received any of the following agents within 7 days of planned first
study treatment day:
- Agents that are predominantly CYP2D6, 2C9, or 2C19 substrates.
- - Agents that are strong inhibitors or inducers of CYP2D6, 2C9, or 2C19.
- - Agents that are sensitive substrates of CYP3A4 with narrow therapeutic range
Note: Patients who are able to safely discontinue the aforementioned agents > 7
days prior to initiating treatment with WP1066 may participate.
The enzymatic
metabolism profile of WP1066 is unknown. Drugs that are minor CYP2D6, 2C9 or 2C19
substrates; minor inhibitors or inducers of CYP2D6, 2C9, or 2C19; or minor
substrates of CYP3A4 are allowed. Moderate drugs will be allowed per PI's
discretion. Zofran (ondansetron) is allowed.
- - Patients on corticosteroids who require escalation of the corticosteroid dose Note:
Patients receiving a stable or decreasing dose for at least one week may participate.
Zofran (ondansetron) is allowed.
- - History of brain hemorrhage, unless the following exception is met:
- Exception: Small, asymptomatic brain hemorrhage may be permitted, provided
written documentation of PI approval has been obtained Note: The potential for
further hemorrhaging with the use of WP1066 is unknown.
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.
- - Uncontrolled seizures or seizure requiring escalation or addition of anti-epileptic
drug.
- - Lesion(s) larger than 50 mm in maximal diameter on MRI, or with midline shift
exceeding 5 mm, or with hydrocephalus.
- - Diffuse leptomeningeal disease Note: Because one of the objectives is PFS based on
radiographic volumetric analysis of the tumor, the presence of diffuse leptomeningeal
disease is excluded.
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.
- - Corrected QT (QTc) B interval >= 450 ms These patients are excluded because the
cardiac toxicities of WP1066 are unknown.
Concomitant use of agents that prolong the
QT interval should be avoided whenever feasible, or used with caution. Zofran
(ondansetron) is allowed.
- - Subjects who are at increased risk for radiation therapy (RT)-associated toxicities,
such as those with known active collagen vascular disease (e.g., scleroderma,
Sjogren's disease, etc.) or other inherited RT-hypersensitivity syndromes (e.g.,
Gorlin syndrome, Fanconi anemia, ataxia-telangiectasia, etc.)
- For female patients of childbearing potential only:
Patients with a positive serum beta-human chorionic gonadotropin (HCG) pregnancy test
within =< 2 days prior to planned start date for trial therapy or who are immediately
planning to become pregnant.
- - Breastfeeding patients who are unwilling/unable to discontinue breastfeeding while
receiving WP1066 Note: Because there is an unknown but potential risk for adverse
events in nursing infants secondary to treatment of the mother with WP1066,
breastfeeding should be discontinued if the mother is treated with WP1066.
Patients
who discontinue breastfeeding prior to initiating treatment with WP1066 may
participate.
- - Uncontrolled intercurrent illness or condition including, but not limited to any of
the following:
Ongoing or active infection requiring systemic treatment, except uncomplicated urinary
tract infection;
- Symptomatic congestive heart failure.
- - Unstable angina pectoris.
- - Psychiatric illness/social situation that would limit compliance with study
requirements.
- Any other illness or condition that the treating investigator feels would interfere
with study compliance or would compromise the subject's safety or study endpoints
