PCI-24781 + Temozolomide for Recurrent Brain Cancer
Recruiting in Palo Alto (17 mi)
Overseen byNicole Shonka, MD
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: University of Nebraska
Must not be taking: Enzyme-inducing antiepileptics, Valproic acid
Disqualifiers: Cardiovascular disease, Active malignancy, HIV, others
No Placebo Group
Approved in 2 Jurisdictions
Trial Summary
What is the purpose of this trial?The goal of this clinical trial is to learn about treatment for a type of brain cancer called glioma. This clinical trial is for people with glioma who have been cancer-free for a period of time but their cancer has come back. The primary goals of this clinical trial are the following:
* To determine the recommended dose of PCI-24781/Abexinostat with metronomic temozolomide
* To evaluate side effects associated with using PCI-24781/Abexinostat with metronomic temozolomide
Will I have to stop taking my current medications?
The trial requires you to stop taking certain medications, including some antiepileptic drugs and specific medications like amiodarone, clarithromycin, and methadone, among others. If you are on these medications, you must discontinue or switch them before enrolling in the study.
What data supports the effectiveness of the drug temozolomide for recurrent brain cancer?
Temozolomide has shown effectiveness in treating various types of brain tumors, including glioblastoma multiforme and anaplastic astrocytoma, and is being studied for other brain cancers. It is known for its ability to treat malignant gliomas and has been used successfully in combination with other treatments.
12345Is the combination of PCI-24781 and Temozolomide safe for humans?
Temozolomide has been shown to have mild to moderate side effects like fatigue, nausea, and low blood cell counts, with severe effects being rare. Safety data for PCI-24781 specifically is not provided, but Temozolomide's safety profile is generally acceptable in humans.
16789What makes the drug Temozolomide unique for treating recurrent brain cancer?
Temozolomide is unique because it is an alkylating agent that works by adding a chemical group to the DNA of cancer cells, which can help stop their growth. It has shown effectiveness in treating various types of brain tumors, including gliomas and pituitary carcinomas, and is often used when other treatments have failed.
13101112Eligibility Criteria
This trial is for adults over 19 with recurrent high-grade glioma who've had prior radiation and temozolomide treatment. They must have good liver, kidney, and bone marrow function, not be pregnant or nursing, and agree to use birth control. Excluded are those with certain heart conditions, other active cancers (except some skin/prostate), specific infections or systemic illnesses that could affect safety.Inclusion Criteria
I have recovered from side effects of previous cancer treatments.
I've had radiation and temozolomide treatment for my cancer.
I am 19 years old or older.
+9 more
Exclusion Criteria
Baseline ECG showing QTc interval prolongation
I have recently used specific medications or therapies.
Lactating or pregnant
+9 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive PCI-24781/Abexinostat and metronomic temozolomide in 28-day cycles until disease progression or intolerance
Up to 25 months
Regular visits every 28 days
Follow-up
Participants are monitored for safety and effectiveness after treatment
Up to 36 months
Extension
Participants with stable or responsive disease may continue therapy until intolerance or progressive disease
Long-term
Participant Groups
The study tests the combination of a drug called PCI-24781 with low-dose Temozolomide in patients whose brain cancer has returned. It aims to find the safest dose of this combo and assess its side effects in treating high-grade gliomas like astrocytoma or glioblastoma.
1Treatment groups
Experimental Treatment
Group I: Single armExperimental Treatment2 Interventions
Patients will receive a combination of PCI-24781/Abexinostat and temozolomide. Patients will receive a loading dose of PCI-24781/Abexinostat prior to the start of Cycle 1; patients will take PCI-24781/Abexinostat by mouth twice a day starting 7 days prior to Cycle 1, Day 1 and ending 4 days prior to Cycle 1, Day 1.
Patients will continue taking PCI-24781/Abexinostat on days 1-4, 8-11, 15-18, and 22-25 of each 28 day cycle, starting with Cycle 1, Day 1. The initial dose level is 60 mg of PCI-2478/Abexinostat 1 by mouth twice daily. The dose level may be escalated based on results of interim data analysis.
Patients will additionally initiate metronomic temozolomide on Cycle 1, Day 1 at a dose of 50 mg/m2, taken by mouth twice daily. Patients will continue the PCI-24781/Abexinostat and metronomic temozolomide regimen until disease progression or intolerance.
Temozolomide is already approved in European Union, United States for the following indications:
🇪🇺 Approved in European Union as Temodal for:
- Newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and subsequently as monotherapy treatment
- Children from the age of three years, adolescents and adults with malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy
🇺🇸 Approved in United States as Temodar for:
- Newly diagnosed glioblastoma concomitantly with radiotherapy and subsequently as monotherapy treatment
- Newly diagnosed or refractory anaplastic astrocytoma
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of Nebraska Medical CenterOmaha, NE
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Who Is Running the Clinical Trial?
University of NebraskaLead Sponsor
Xynomic Pharmaceuticals, Inc.Industry Sponsor
References
Phase II trial of temozolomide in patients with progressive low-grade glioma. [2022]Temozolomide (Temodar; Schering-Plough Corp, Kenilworth, NJ) is an imidazole tetrazinone that undergoes chemical conversion to the active methylating agent 5-(3-methyltriazen-1yl)imidazole-4-carboximide under physiologic conditions. Previous studies have confirmed activity of Temodar in the treatment of progressive and newly diagnosed malignant gliomas. We have extended these results, and now we report results of a phase II trial of Temodar for patients with progressive, low-grade glioma.
A multicenter prospective observational study of the conformity of temozolomide prescriptions in France. [2018]Temozolomide (TMZ) is approved for the treatment of high-grade gliomas such as glioblastoma (GBM) multiforme and refractory anaplastic astrocytoma, but it is also used in indications not mentioned in the summary of product characteristics (SPC). The main objective of this study was to evaluate the conformity of TMZ prescriptions to the French SPC and prescription guidebook.
Phase II study of first-line chemotherapy with temozolomide in recurrent oligodendroglial tumors: the European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971. [2022]Oligodendroglial tumors are chemotherapy-sensitive tumors, with two thirds of patients responding to combination chemotherapy with procarbazine, lomustine, and vincristine (PCV). Temozolomide (TMZ), a new alkylating and methylating agent, has demonstrated high response rates in patients with recurrent anaplastic astrocytoma. We investigated TMZ as first-line chemotherapy in recurrent oligodendroglial tumors (OD) and mixed oligoastrocytomas (OA) after surgery and radiation therapy.
Economic evaluation of temozolomide in the treatment of recurrent glioblastoma multiforme. [2018]Temozolomide (TMZ) is an oral alkylating agent with demonstrated efficacy as therapy for glioblastoma multiforme (GBM) and anaplastic astrocytoma. TMZ has widely replaced the procarbazine, lomustine plus vincristine (PCV) combination for the treatment of malignant brain tumours as a result of its oral administration and favourable toxicity profile.
Future directions for temozolomide therapy. [2019]Although the initial indications of temozolomide (Temodar in the United States, Temodal globally; Schering Corporation, Kenilworth, NJ) therapy are for refractory central nervous system malignancies (anaplastic astrocytoma in the United States and Europe, glioblastoma multiforme in Europe), a number of clinical trials are planned or ongoing to evaluate the efficacy and safety of temozolomide in newly diagnosed glioma, oligodendroglioma, pediatric glioma, brain metastases, metastatic melanoma, and other systemic tumors. Also under investigation are modifications to the temozolomide dosing schedule, other routes of administration, and treatment regimens that include temozolomide in combination with other chemotherapeutic and biologic agents. Temozolomide has the potential to be a useful agent in the treatment of a variety of cancers.
Bioequivalence study of 20-mg and 100-mg temozolomide capsules (TOZ309 and Temodal®) in glioma patients in China. [2021]Label="BACKGROUND">Temozolomide is an alkylating agent approved by the U.S. Food and Drug Administration in 1999 for the treatment of patients with primary brain tumors. The aim of this study was to confirm the bioequivalence and safety of two strengths (20-100 mg) of generic temozolomide in the form of TOZ039 and Temodal® capsules administered to brain tumor patients.
Role of temozolomide in pediatric brain tumors. [2022]FEATURES OF TEMOZOLOMIDE: Temozolomide (TMZ) belongs to the imidazotetrazine class and it is a DNA-methylating agent that has a good antitumor activity. Despite of dacarbazine, TMZ is spontaneously converted into its active metabolite 5-(3-methyltriazen-l-yl)imidazole-4-carboxamide at physiologic pH, so it is not required in enzymatic demethylation in the liver. TMZ is able to cross the blood brain barrier and is stable at gastric acid pH so it has almost 100% oral bioavailability and is rapidly absorbed after it is taken orally.
Temozolomide for the treatment of recurrent supratentorial glioma: results of a compassionate use program in Belgium. [2022]Temozolomide (TMZ) has demonstrated activity and acceptable toxicity for the treatment of recurrent high-grade gliomas in prospective phase II studies. Limited information is available on TMZ when prescribed outside a clinical trial. We conducted a retrospective study to evaluate the activity and safety of TMZ that was prescribed for the treatment of recurrent glioma in the context of a compassionate use program in Belgium. Data were obtained on 117 adult patients (from five hospitals) who received TMZ as first or second line chemotherapy. The recommended starting dose of TMZ was 200 mg/m2 x5d q28d for chemonaive patients and 150 mg/m2 x5d q28d for pre-treated patients. Toxicity was generally mild. Thrombocytopenia was the most frequent treatment related adverse event (grade 3/4 in 17% of patients). Its occurrence was correlated with a starting dose of 200 mg/m2/d and stresses the need to monitor toxicity. The overall objective response rate (complete and partial response) was 29 and 34% of patients achieved an objective disease stabilization. The median progression-free survival was 104 days (95% CI: 85-123) and the median overall survival was 215 days (95% CI: 161 269). In multivariate analysis a 'deep localization' of the glioma (as opposed to a cortico-subcortical localization) and 'the preceding history of a low-grade glioma' were respectively identified as a negative and positive independent prognostic variable for survival. No significant difference in terms of response or median survival was observed between patients with anaplastic astrocytoma or oligo-astrocytoma and chemonaive glioblastoma multiforme. This retrospective study indicates that the reported activity and toxicity profile of TMZ for the treatment of patients with recurrent glioma is reproducible outside the setting of a prospective clinical trial.
Temozolomide-induced aplastic anaemia: Case report and review of the literature. [2022]Temozolomide (TMZ) is an oral alkylating agent principally indicated for neurological malignancies including glioblastoma (GBM) and astrocytoma. Most common side effects are mild to moderate, and include fatigue, nausea, vomiting, thrombocytopenia and neutropenia. Severe or prolonged myelosuppression, causing delayed treatment or discontinuation, is uncommon. Major haematological adverse effects such as myelodysplastic syndrome or aplastic anaemia (AA) have rarely been reported.
Temozolomide-induced shrinkage of a pituitary carcinoma causing Cushing's disease--report of a case and literature review. [2021]Temozolomide (TMZ) is an alkylating chemotherapeutic agent that has recently been used in some cases as a new therapeutic tool for pituitary carcinomas and aggressive pituitary adenomas. In this report, we present the case of effective TMZ treatment in a 42-year-old man with ACTH-secreting carcinoma. The tumor grew progressively over 4 years, from 2.2 to 31.1 cm³, despite three surgical approaches and γ-knife treatment. Ki-67 increased from 2 to 18%. An intradural metastasis at the foramen magnum was detected by MRI after the third operation. Thereafter, four cycles of 5-day TMZ administration (200 mg/m²/day during the first, and 150 mg/m²/day during the following cycles) induced dramatic tumor size reduction (>90%). Clinical conditions improved progressively and, after 17 months from the beginning of TMZ administration, the patient is still alive. The treatment was well tolerated except for a transient thrombocytopenia (grade 4 WHO).
Temozolomide as second-line chemotherapy for relapsed gliomas. [2019]Temozolomide, an imidazotetrazine prodrug has shown activity in phase II studies in patients with high-grade glioma at first recurrence. We assessed the efficacy of temozolomide as second-line therapy following failure of PCV chemotherapy in patients with recurrent/progressive gliomas.
Biochemical changes associated with a multidrug-resistant phenotype of a human glioma cell line with temozolomide-acquired resistance. [2022]Temozolomide (TMZ) is a newly approved alkylating agent for the treatment of malignant gliomas. To investigate resistance mechanisms in a multidrug therapeutic approach, a TMZ-resistant human glioma cell line, SF188/TR, was established by stepwise exposure of human SF188 parental cells to TMZ for approximately 6 months. SF188/TR showed 6-fold resistance to TMZ and cross-resistance to a broad spectrum of other anticancer agents that included 3-5-fold resistance to melphalan (MEL), gemcitabine (GEM), paclitaxel (PAC), methotrexate (MTX), and doxorubicin (DOX), and 1.6-2-fold resistance to cisplatin (CDDP) and topotecan (TPT). Alkylguanine alkyltransferase (AGT) activity was increased significantly in the resistant cell line compared with the parental cell line (P