WP1066 and Radiation Therapy in Newly Diagnosed Glioblastoma Patients
Study Details
Study Description
Brief Summary
This is a phase II, open label, multi-arm trial of radiation therapy in combination with WP1066 in newly diagnosed IDH wild-type, MGMT-unmethylated glioblastoma patients, with multiple cohorts. Patients will be stratified into Cohort 1 versus Cohort 2 based on gross total resection (GTR) status.
Cohort 1: Radiation therapy (RT) + WP1066 in glioblastoma patients with gross total resection Sample size for Cohort 1: Up to 25 patients may be enrolled in order to obtain 21 patients who are evaluable for the primary objective.
Cohort 2: RT + WP1066 ± optional secondary surgical resection post-RT in glioblastoma patients without gross total resection who are candidates for non-emergent palliative surgical resection Sample size for Cohort 2: Up to 14 patients may be enrolled in order to obtain 10 patients who undergo secondary surgical resection.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1/Phase 2 |
Detailed Description
This is a phase II, open label trial of radiation therapy in combination with WP1066 in newly diagnosed IDH wild-type, MGMT-unmethylated glioblastoma patientsThere are two cohorts/treatment arms:
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Cohort 1: Radiation therapy + WP1066 (in patients with prior gross total resection)
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Cohort 2: Radiation therapy + WP1066 ± optional secondary surgical resection (in patients without prior gross total resection who are candidates for non-emergent palliative surgical resection) Radiation therapy is standard of care in this patient population. WP1066 is an oral, small molecule inhibitor of p-STAT3 and is investigational.
A safety lead-lead has been designed, wherein the first 6 subjects in Cohorts 1 or 2 who receive combination therapy with RT + WP1066 will be observed for 10 weeks for dose limiting toxicities (DLTs), in order to ensure the safety of the combination. If an unacceptable frequency of DLTs are observed, a protocol amendment to explore alternate dosing schemes may be considered. If a patient in the safety lead-in permanently discontinues RT or WP1066 prior to completing the intended 6-week regimen of RT + WP1066 for reasons other than having experienced a DLT, then such subject will not be evaluable for the DLT analysis, and an additional subject will be added to the safety lead-in, provided overall accrual to Cohort 1 does not exceed 25 patients, and provided overall accrual to Cohort 2 does not exceed 14 patients.
Cohort 1 Treatment Plan: Radiation therapy + WP1066:
For Cohort 1, patients with prior gross total resection will receive standard of care radiation therapy (2 Gy per fraction x 30 fractions = 60 Gy) over 6 weeks (± 1 week). Patients also will self-administer concurrent WP1066 by mouth (PO), three days a week during the 6-week course of radiation therapy. The starting dose of WP1066 is 8 mg/kg twice daily (BID) on days 1, 3, and 5 of each week, with dose reductions to 6 mg/kg and 4 mg/kg permitted. Upon completion of the 6-week regimen of radiation therapy and WP1066, patients will take a 4-week recovery break during which time no therapy will be administered. Following the 4-week recovery, patients will enter the adjuvant phase of treatment, during which they will resume WP1066 treatment for up to 12 cycles (or longer, per PI discretion). Each cycle of adjuvant WP1066 will be 28-days, and WP1066 will be given BID, on days 1, 3, 5, 8, 10, and 12 of each adjuvant cycle. Trial therapy with WP1066 may continue until Response Assessment in Neuro-Oncology (RANO) disease progression, intolerable toxicity, subject withdrawal, or other discontinuation criterion is met; whichever occurs first.
Cohort 2 Treatment Plan: Radiation therapy + WP1066 ± optional secondary surgical resection:
For Cohort 2, patients without prior gross total resection and who are candidates for non-emergent palliative surgical resection will receive standard of care radiation therapy (2 Gy per fraction x 30 fractions = 60 Gy) over 6 weeks (± 1 week). Patients also will self-administer concurrent WP1066 by mouth (PO), three days a week during the 6-week course of radiation therapy. The starting dose of WP1066 is 8 mg/kg twice daily (BID) on days 1, 3, and 5 of each week, with dose reductions to 6 mg/kg and 4 mg/kg permitted. Upon completion of the 6-week regimen of radiation therapy and WP1066, patients will take a 4-week recovery break. During this recovery period, patients with lesions amenable to surgery will undergo a secondary surgical resection or open biopsy 1 week (± 1 week) after completing radiation therapy. Following the 4-week recovery, patients will enter the adjuvant phase of treatment, during which they will resume WP1066 treatment for up to 12 cycles (or longer, per PI discretion). Each cycle of adjuvant WP1066 will be 28-days, and WP1066 will be given BID on days 1, 3, 5, 8, 10, and 12 of each adjuvant cycle. Trial therapy with WP1066 may continue until RANO disease progression, intolerable toxicity, subject withdrawal, or other discontinuation criterion is met; whichever occurs first.
Safety Lead-In: To exclude prohibitive toxicity, a safety lead-in will be conducted in the first 6 subjects in Cohort 1 or 2. If an unacceptable frequency of DLTs observed, a protocol amendment to explore alternate dosing schemes may be considered.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Radiation therapy + WP1066 in patients with gross total resection Patients with prior gross total resection will receive standard of care radiation therapy (2 Gy per fraction x 30 fractions = 60Gy) over 6 weeks. Patients will self-administer concurrent WP1066 by mouth, three days a week during the 6-week course of radiation therapy. The starting dose of WP1066 is 8 mg/kg twice daily (BID) on days 1,3 and 5 of each week, with dose reductions to 6 mg/kg and 4 mg/kg permitted. Following 4 weeks of recovery, patients will enter the adjuvant phase of treatment, during which they will resume WP1066 treatment for up to 12 cycles. Each cycle of adjuvant WP1066 will be 28-days, and WP1066 will be given BID, on days 1, 3, 5, 8, 10, and 12 of each adjuvant cycle. Trial therapy with WP1066 may continue until RANO disease progression, intolerable toxicity, subject withdrawal, or other discontinuation criterion is met; whichever occurs first. |
Drug: WP1066
Orally administered as an outpatient
Other Names:
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| Experimental: Radiation therapy + WP1066 / optional secondary surgical resection Patients without prior gross total resection and who are candidates for non-emergent palliative surgical resection will receive standard of care radiation therapy (2 Gy per fraction x 30 fractions = 60 Gy) over 6 weeks. Patients also will self-administer concurrent WP1066 by mouth, three days a week during the 6-week course of radiation therapy. The starting dose of WP1066 is 8 mg/kg twice daily (BID) on days 1, 3, and 5 of each week, with dose reductions to 6 mg/kg and 4 mg/kg permitted. During the recovery period, patients with lesions amenable to surgery will undergo a secondary surgical resection or open biopsy 1 week after completing radiation therapy. Thereafter, patients may resume WP1066 treatment for up to 12 cycles. Trial therapy with WP1066 may continue until RANO disease progression, intolerable toxicity, subject withdrawal, or other discontinuation criterion is met; whichever occurs first. |
Drug: WP1066
Orally administered as an outpatient
Other Names:
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Outcome Measures
Primary Outcome Measures
- Progression Free Survival [Through study completion, an average of 1 year]
To determine the progression-free survival (PFS) outcomes of patients with MGMT-unmethylated glioblastoma treated with WP1066 in combination with standard-of-care radiation therapy
Secondary Outcome Measures
- Tumor microenvironment analysis [Through study completion, an average of 1 year]
Ascertain the changes in the tumor microenvironment by the combination of WP1066 + radiation
Eligibility Criteria
Criteria
Inclusion Criteria:
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Newly diagnosed, histologically confirmed World Health Organization (WHO) glioblastoma multiforme (GBM), IDH wild-type (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)
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Documentation of O6-methylguanine-DNA methyltransferase (MGMT) unmethylated status per testing at any Clinical Laboratory Improvement Amendment (CLIA) certified laboratory.
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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
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Willing and able to tolerate brain MRI with contrast.
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Karnofsky Performance Scale score ≥ 60%
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Age ≥ 18 years
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Adequate organ and bone marrow function, as defined in Section 3.1, within ≤30 days prior to registration
Exclusion Criteria:
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Receipt of investigational agents within ≤ 2 weeks prior to registration
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Prior receipt of gene therapy, at any time
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Prior receipt of bevacizumab, at any time
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Prior receipt of Gliadel®, at any time
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Patients who are on active therapy with Optune® and who are unable to safely discontinue Optune® prior to initiating trial therapy. (Patients who can safely discontinue Optune® prior to initiating trial therapy may participate.)
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Patients who are on active therapeutic anti-cancer therapy and who are unable to discontinue the anti-cancer therapy prior to initiating trial therapy. (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.)
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HIV-positive patients receiving combination antiretroviral therapy (These patients are ineligible because of the potential for pharmacokinetic interactions with WP1066.)
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Patients who have received drugs that significantly interact with CYP450 enzyme(s) within ≤ 2 weeks prior to planned first study treatment day.
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Patients who have received any of the following agents within 7 days of planned first study treatment day:
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Agents that are predominantly CYP2D6, 2C9, or 2C19 substrates,
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Agents that are strong inhibitors or inducers of CYP2D6, 2C9, or 2C19,
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Agents that are sensitive substrates of CYP3A4 with narrow therapeutic range.
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Patients on corticosteroids who require escalation of the corticosteroid dose (Patients receiving a stable or decreasing dose for at least one week may participate.)
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Uncontrolled seizures or seizure requiring escalation or addition of anti-epileptic drugs
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Lesion(s) larger than 50 mm in maximal diameter on MRI, or with midline shift exceeding 5 mm, or with hydrocephalus
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Diffuse leptomeningeal disease (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.)
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QTc B interval ≥ 450 ms (These patients are excluded because the cardiac toxicities of WP1066 are unknown.)
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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.)
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Moleculin Biotech, Inc.
- Northwestern University
Investigators
- Principal Investigator: Amy B Heimberger, MD, Northwestern University
Study Documents (Full-Text)
None provided.More Information
Publications
- MB-402