Refractory Anaplastic Astrocytoma Research Articles

UV spectroscopic method for estimation of temozolomide: Application in stability studies in simulated plasma pH, degradation rate kinetics, formulation design, and selection of dissolution media

Temozolomide (TMZ) is a broad spectrum alkylating agent found effective in the treatment of glioblastoma multiforme, refractory anaplastic astrocytoma, and metastatic melanoma. The major drawback associated with TMZ is pH-dependent stability and short half-life. At physiological pH, it undergoes conversion to MTIC (methyltriazine imidazole carboxamide) and AIC (amino imidazole carboxamide), resulting in only 20–30% brain bioavailability. There is a need for an analytical method for the estimation of TMZ in stability samples and nanoformulations. In this research study, analytical methods were developed for the estimation of TMZ using two media pH 1.2 (0.1 N HCl) and pH 4.5 acetate buffer, which were validated for linearity, range, precision, accuracy, limit of detection, limit of quantification, and specificity as per ICH guidelines. The % RSD was found to be <2% indicating the reliability of the method. Further, the application of the developed methods was explored. The stability of TMZ in three pH conditions (1.2, 4.5, and 7.4) and the respective degradation rate kinetics was studied. Conversion of TMZ was found to follow first order kinetics with the conversion rate of 0.0011, 0.0011, and 0.0453 h−1 in pH 1.2, 4.5, and 7.4 respectively. The developed methods accurately estimated the TMZ concentration in lipid nanoformulation (liposomes) indicated by ~100% recovery. Acetate buffer (pH 4.5) was found to be an appropriate dissolution media for TMZ loaded lipid nanoformulations. The developed methods were found to be suitable for routine analysis, for the determination of drug stability and estimation of temozolomide in lipid nanoformulations.

Should CD4 Levels be Monitored in a Patient on Temozolomide?

Temozolomide is an alkylating agent, indicated in the treatment of refractory anaplastic astrocytoma and newly diagnosed glioblastoma. We describe a case of Salmonella typhimurium bacteraemia associated with septic arthritis in the setting of concurrent temozolomide use. A 67-year-old woman presented with acute onset of bilateral knee pain and swelling. She had a medical history of glioblastoma multiforme treated with temozolomide. Synovial fluid analysis and blood cultures revealed S. typhimurium, confirming a diagnosis of S. typhimurium bacteraemia associated with septic arthritis. We conclude that chemotherapy with temozolomide and corticosteroid use will increase an individual's susceptibility to a wide variety of opportunistic infections akin to HIV-associated acquired immunodeficiency syndrome (AIDS). Furthermore, we hypothesize a possible benefit of monitoring CD4 levels and prophylaxis against opportunistic infections (based on the CD4 levels) in individuals receiving temozolomide-based chemotherapy, similar to HIV-AIDS. Chemotherapy with temozolomide and corticosteroid use will increase an individual's susceptibility to a wide variety of opportunistic infections akin to HIV-associated acquired immunodeficiency syndrome (AIDS).There may be a benefit in monitoring CD4 levels in patients who are receiving temozolomide.Given selective CD4 lymphopenia while on temozolomide, there may be a possible benefit of prophylaxis against opportunistic infections in individuals based on their CD4 levels, similar to HIV-AIDS (current guidelines recommend considering Pneumocystis jirovecii pneumonia prophylaxis for patients receiving concomitant radiotherapy and temozolomide, and high-dose steroids).

SAT-477 Pituitary Carcinoma Arising from a Macroprolactinoma

Background: Pituitary carcinomas make up 0.2% of all pituitary carcinomas and remain a challenging diagnosis to make with few effective treatment options. Clinical Case: A 73-year old man with a past medical history of a pan-hypopituitarism secondary to a prolactinoma who had undergone multiple resections in 1969 and 1992 presented to the emergency room with worsening headache and progressive vision loss for two weeks. He was doing well until symptoms recurred in 2017 and he subsequently underwent another resection in July of 2018 at an outside hospital. Five weeks post-resection his MRI showed rapid progression of his disease and at this time he presented to our facility. On presentation, his prolactin level was 41,890 ng/mL while on cabergoline 0.25mg three times weekly. His other laboratory results were consistent with pan-hypopituitarism and he was on treatment with hydrocortisone and levothyroxine. Initially, cabergoline was increased to 0.5mg three times weekly but prolactin levels remained persistently high. Repeat imaging showed a local invasive 5.6 x 4.8 x 4.0 cm left anterior skull base mass. The patient then underwent another resection in August of 2018. Pathology was significant for strong nuclear immunoreactivity of p53, a Ki-67 index greater than 20%, high mitotic activity with 16/10hpf, and strong prolactin reactivity. Temozolomide therapy alongside radiation therapy was recommended. A systematic review by Almalki et al., showed around a 60% response in patient with aggressive pituitary tumors with Temozolomide.1 Unfortunately, the patient developed meningitis post-operatively and has required repeated re-admissions for altered mental status. He has now started radiation therapy, but Temozolomide therapy remains on hold. Conclusion: Prolactinomas are usually well-controlled by dopamine agonists. Refractory forms are rare and can rapidly progress making treatment very challenging. An initially large size mass with invasion, associated systemic metastasis or recurrence should raise suspicion for malignancy. Any delays in the initiation of therapy should be avoided, which can include surgery, external beam radiotherapy, radiosurgery, various chemotherapeutic approaches such as temozolomide, an alkylating agent, which is currently only approved for glioblastoma multiforme and refractory anaplastic astrocytoma. 1Almalki MH, Aljoaib NN, Alotaibi MJ, Aldabas BS, Wahedi TS, Ahmad MM, et al. Temozolomide therapy for resistant prolactin-secreting pituitary adenomas and carcinomas: a systematic review. Hormones. 2017;16(2):139–49.

Abstract 599: Secondary malignancies in temozolomide-treated metastatic pancreatic neuroendocrine tumors

Abstract Purpose: To determine the incidence of secondary malignancies in patients treated with temozolomide (TMZ) for metastatic pancreatic neuroendocrine tumors (PNET). Background: TMZ is an oral alkylating agent used to treat glioblastoma multiforme (GBM), refractory anaplastic astrocytoma (AA), and metastatic PNET. This imidazotetrazine analog of dacarbazine lacks the ability to directly crosslink DNA and is thought to be less leukemogenic than other alkylators. Given either alone, or in combination with other therapies, TMZ is associated with improved clinical outcomes. However, serious hematologic adverse events (HAEs) like agranulocytosis, lymphopenia and aplastic anemia are not uncommon. Until recently, metastatic PNET was primarily managed with somatostatin-analogs, but with more reports demonstrating therapeutic activity of TMZ-based regimens, it is anticipated that more patients with metastatic PNET will be exposed to TMZ. Methods: To determine the incidence of secondary malignancy in TMZ-treated PNET, a systematic review of all known clinical trials, case reports, and other relevant literature regarding PNET and TMZ published before September 2017 was conducted using PubMed, Embase, Cochrane Library, and the FDA database. Results: Twenty-one publications, including clinical trials, meta-analyses, case reports, and cohort studies were analyzed. HAEs ranged from agranulocytosis to myelodysplastic syndrome. No publications reported any secondary malignancies. Incidentally, at the University of Kansas Medical Center, 3 patients with TMZ-treated PNET developed hematologic malignancies. A 29-year-old female with metastatic PNET was treated with TMZ and subsequently developed acute myeloid leukemia (AML) with cytogenetics consistent with therapy-related leukemia. The second patient with TMZ-treated metastatic PNET developed diffuse large B-cell lymphoma. These two patients both had aggressive disease that was not responsive to multiple rounds of treatment. They succumbed to their hematologic malignancy, and not from metastatic PNET. The third patient is a 29-year-old who was recently diagnosed with high-grade T-cell lymphoblastic lymphoma and is currently undergoing treatment for his lymphoma. Conclusion: This review did not find any cases of secondary malignancy in TMZ-treated metastatic PNET. Yet, at our own institution we have identified 3 cases of secondary hematologic malignancies in patients treated with TMZ for PNET. We believe that the leukemogenic potential of TMZ is underreported and anticipate increased reports of secondary malignancy as the use of TMZ increases. It is important for treatment guidelines to address this risk in the decision to pursue TMZ treatment. Appropriate dosing, proper follow-up and surveillance, especially in patients who are able to live long enough to develop these hematologic cancers, is crucial. Citation Format: Nicole Balmaceda, Sunil Abhyankar, Tyler Mouw, Joaquina Baranda. Secondary malignancies in temozolomide-treated metastatic pancreatic neuroendocrine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 599.

Acute Liver Injury during Co-treatment with Levetiracetam and Temozolomide

Drug-induced liver injury (DILI) accounts for approximately 10 percent of all cases of acute hepatitis. The patterns of acute injury include any form of hepatic injury, but the most common problems are cholestasis, hepatocellular damage, or a mixed type. DILI is often re- versible, and discontinuation of the offending agent usually results in a complete recovery; however, some cases may lead to chronic liver injury, cirrhosis, and even death. Temozolomide (TMZ) is an alkylating, anti-neoplastic agent used for the treatment of refractory anaplastic astrocytoma, newly-diagnosed Glioblastoma multiforme (GBM) and metastatic melanoma. Levetiracetam (LEV) is an established second-generation antiepileptic drug and is most com- monly approved as adjunctive treatment of partial-onset seizures with or without secondary generalization. When administered separately each of these drugs is considered to be relatively safe and only few cases of severe liver injury can be found throughout the literature; however, LEV and TMZ are commonly used together in the treatment of brain malignancies. We report three patients who presented with jaundice during treatment with TMZ and LEV, and propose a mechanism for liver sensitization by LEV for TMZ-induced injury.

Refractory anaplastic astrocytoma responsive to PCV in combination with bevacizumab.

We present a patient with anaplastic astrocytoma who had recurrent disease after treatment with surgery, radiation, procarbazine, lomustine (CCNU) and vincristine (PCV) over one year followed by poor response to second line treatment with temozolomide, irinotecan with bevacizumab, Novocure TTF therapy successively over a four year period after her initial treatment who then responded to PCV in combination with bevacizumab as third line therapy. This is the first report demonstrating benefit of concurrent PCV and bevacizumab treatment in a highly treatment refractory tumor.

Salvage therapy with lomustine for temozolomide refractory recurrent anaplastic astrocytoma: a retrospective study

There is no standard therapy for recurrent anaplastic astrocytoma (AA). Assess response and toxicity of lomustine (CCNU) in recurrent AA following prior surgery, radiotherapy and TMZ in a retrospective case series. Thirty-five adults (18 males; 17 females: median age 42.5 years) with TMZ refractory recurrent AA were treated with lomustine. Seven patients were treated at 1st recurrence and 28 patients were treated at 2nd recurrence. Prior salvage therapy included re-resection in 19, TMZ in 20 and radiotherapy in 7. A cycle of lomustine was defined as 110 mg/m(2) on day 1 only administered once every 6-8 weeks. Success of treatment was defined as progression free survival at 6 months of 40 % or better. Grade 3 or 4 toxicities included anemia (14 patients), constipation (1), fatigue (4), lymphopenia (5), nausea/vomiting (2), neutropenia (8) and thrombocytopenia (10). No grade five toxicities were seen. The median number of cycles of therapy was 3 (range 1-6). Best radiographic response was progressive disease in 14 (40 %), stable disease in 19 (54 %) and partial response in 2 (5.7 %). Median progression free survival (PFS) was 4.5 months (range 1.5-12 months), 6-month PFS was 40 % and 12 month PFS was 11.4 %. Median survival after onset of CCNU was 9.5 months (range 2.5-15 months). Median overall survival was 2.7 years (range 1.7-4.3). In this small retrospective series of patients with recurrent AA refractory to TMZ, lomustine appears to have modest single agent with manageable toxicity. Confirmation in a larger series of similar patients is required.

A multicenter prospective observational study of the conformity of temozolomide prescriptions in France

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. We conducted a prospective observational study of all consecutive patients treated with TMZ in 21 French hospitals between September 2006 and February 2007, accounting for 39% of total TMZ consumption in France. The conformity of TMZ prescriptions was evaluated in terms of the indication, dosage, treatment duration, and combination with other treatments, with respect to the SPC and prescription guidebook. We enrolled 831 patients (median age, 56 years) who received a total of 5982 TMZ treatment cycles. TMZ was mainly prescribed to patients with newly diagnosed GBM (384 patients), GBM in progression/relapse (28 patients), or anaplastic astrocytoma in progression/relapse (19 patients). Prescriptions conformed to the SPC in 51.9% of cases and to the prescription guidebook in 91.5% of cases. Global conformity with the SPC, in terms of the dosage, treatment duration, and combination with other treatments, was 62% for newly diagnosed GBM treated with radiotherapy plus TMZ, 72% for TMZ maintenance monotherapy, and 66% for GBM and anaplastic astrocytoma in progression/relapse. In France, routine TMZ prescriptions conform to the SPC and practice guidebook. This is one of the largest studies of drug use in neuro-oncology in terms of the number of patients and cycles analyzed.

Trabedersen to target transforming growth factor- : when the journey is not the reward, in reference to Bogdahn et al. (Neuro-Oncology 2011;13:132-142)

Trabedersen to target transforming growth factor- : when the journey is not the reward, in reference to Bogdahn et al. (Neuro-Oncology 2011;13:132-142)

Emergence of Cytomegalovirus Disease in Patients Receiving Temozolomide: Report of Two Cases and Literature Review

Temozolomide chemotherapy has become part of the therapy used to treat glioblastoma multiforme and refractory anaplastic astrocytoma. Temozolomide frequently produces profound lymphopenia. We report 2 cases of cytomegalovirus disease that occurred in patients receiving temozolomide therapy and review 4 additional cases reported in the literature. Narrow monitoring with cytomegalovirus antigenemia assay should be considered for recommendation.

Treatment of malignant gliomas with TGF-β2 antisense oligonucleotides

Antisense oligodeoxynucleotides (AS-ODNs) have been widely used to determine gene function, validate drug targets and as novel therapeutics for human diseases. In this review, we describe the development of AS-ODNs, including their modifications, pharmacokinetics and toxicity in animal models and humans, and their preclinical and clinical development in the therapy of human high-grade gliomas. The most advanced AS-ODN for the therapy of high-grade gliomas is a phosphorothioate-modified AS-ODN, AP 12009 (trabedersen), which targets mRNA encoding TGF-β2. AP 12009 is administered intratumorally using convection-enhanced delivery. A series of Phase I and II clinical trials have evaluated the toxicity profile and optimal dose of the substance. A randomized, controlled international Phase III study was initiated in March 2009 and will compare trabedersen 10 µM versus conventional alkylating chemotherapy in patients with recurrent or refractory anaplastic astrocytoma after standard radio- and chemotherapy.

The safety of temozolomide in the treatment of malignancies

Background: Temozolomide (TMZ) has demonstrated clinical antitumor activity. In the US and the EU, TMZ is licensed for the treatment of glioblastoma multiforme concurrently with radiation followed by a maintenance treatment, and for refractory anaplastic astrocytoma or glioblastoma multiforme. TMZ is also approved for metastatic melanoma in > 20 countries worldwide. Objectives: To ascertain the safety profile of TMZ. Methods: Synthesis of evidence from published clinical trials and the investigator's brochure of the manufacture. Conclusion: For a cytotoxic cancer-treatment agent, TMZ has an acceptable safety profile. Lymphopenia is common in patients treated with all doses and schedules of TMZ. All patients receiving TMZ should be observed for lymphopenia and potential opportunistic infections, particularly when it is combined with other immune suppressive therapies.

Temozolomide with radiation therapy in high grade brain gliomas: pharmaceuticals considerations and efficacy; a review article.

Malignant gliomas (glioblastoma multiforme and anaplastic astrocytoma) which have a combined incidence of 5–8/100,000 population, represent the most common primary central nervous system tumors. The treatment outcomes even with aggressive approach including surgery, radiaton therapy and chemotherapy are dismal with median reported survival is less than 1 year. Temozolomide is a new drug which has shown promise in treating malignant gliomas and other difficult-to-treat tumors. This drug is a per os (p.o) imidazotetrazine second-generation alkylating agent which represents the leading compound in a new class of chemotherapeutic agents that enter the cerebrospinal fluid and do not require hepatic metabolism for activation. The efficacy of temozolomide was tested in vitro studies and has demonstrated schedule-dependent antitumor activity against highly resistant malignancies, including high-grade glioma (HGG). In addition, in clinical studies, temozolomide consistently demonstrates reproducible linear pharmacokinetics with approximately 100% p.o. bioavailability, noncumulative minimal myelosuppression that is rapidly reversible, and activity against a variety of solid tumors in both children and adults. Moreover, preclinical studies have evaluated the combination of temozolomide with other alkylating agents and inhibitors of the DNA repair protein O6-alkylguanine alkyltransferase to overcome resistance to chemotherapy in malignant glioma and malignant metastatic melanoma. At the present time temozolomide is approved in the United States for the treatment of adult patients with refractory anaplastic astrocytoma and, in the European Union, for treatment of glioblastoma multiforme showing progression or recurrence after standard therapy. Temozolomide’s characteristics which make it a candidate for a wide range of clinical testing to evaluate the potential of combination treatments in different tumor types are its predictable bioavailability and minimal toxicity. An overview of the mechanism of action of temozolomide and a summary of results from more important randomized controlled clinical trials in high grade gliomas are presented here.

Salvage chemotherapy with bevacizumab for recurrent alkylator-refractory anaplastic astrocytoma

A retrospective study of bevacizumab only in adults with recurrent temozolomide (TMZ)-refractory anaplastic astrocytoma (AA) with a primary objective of determining progression free survival (PFS). There is no standard therapy for alkylator-resistant AA and hence a need exists for new therapies. Twenty-five patients (15 men; 10 women) ages 26-63 (median 50), with radiographically recurrent AA were treated. All patients had previously been treated with surgery, involved-field radiotherapy, and alkylator-based chemotherapy. Fourteen patients underwent repeat surgery. Patients were treated at second recurrence with bevacizumab (10 mg/kg), once every 2 weeks (defined as a single cycle). Neurological evaluation was performed every 2 weeks and neuroradiographic assessment following the initial two cycles of bevacizumab and subsequently after every four cycles of bevacizumab. All patients were evaluable for toxicity and response. A total of 360 cycles of bevacizumab (median 14 cycles; range 2-40) was administered. Bevacizumab-related toxicity included fatigue (14 patients; 2 grade 3), leukopenia (7; 1 grade 3), deep vein thrombosis (5; 2 grade 3), hypertension (5; 1 grade 3), anemia (4; 0 grade 3) and wound dehiscence (1; 1 grade 3). Sixteen patients (64%) demonstrated a partial radiographic response, 2 (8.0%) stable disease and 7 (28%) progressive disease following two cycles of bevacizumab. Time to tumor progression ranged from 1 to 20 months (median: 7). Survival ranged from 2 to 23 months (median: 9.0). 6-month and 12-month PFS were 60 and 20%, respectively. Bevacizumab demonstrated efficacy and acceptable toxicity in this cohort of adults with recurrent alkylator refractory AA.

Results of a phase Iib active-controlled study with AP 12009 for patients with recurrent or refractory anaplastic astrocytoma

2076 Background: High-grade gliomas (HGG) show an overexpression of TGF-beta 2. AP 12009 is a TGF-beta 2 specific inhibitor, which has been successfully tested in phase I/II studies in patients with recurrent or refractory HGG. Methods: The phase IIb study G004 was an international, open-label, randomized, active-controlled, dose-finding study in patients with recurrent or refractory HGG (WHO grades III and IV). Patients were randomized into 3 treatment groups. Main objective was to compare 2 doses of AP 12009 (10 μM=AP-10 or 80 μM=AP-80) and standard chemotherapy (TMZ or PCV) with regard to response rate, survival, and safety. AP 12009 was administered intratumorally by convection-enhanced delivery with up to 11 treatment cycles (7-d-on, 7-d-off / cycle. Results: Here we report on the subpopulation of patients with recurrent AA (WHO grade III, GBM patients see separate abstract). The AP-10 group showed an overall comparable safety profile as the control group. Although there was a higher incidence of SAEs in the AP 12009 groups, these were often procedure-related and mostly reversible. No drug-related SAEs were observed in any of the 3 treatment groups. The current median of survival times was higher in both AP 12009 groups than in the control group with a remarkable survival benefit of AP-10 over chemotherapy of 12.3 months. Furthermore, more individuals in the AP-10 group experienced long-term clinical benefit (CR+PR) and showed significantly more responders after 14 months. Dose finding was achieved, as efficacy and safety results for the AP-10 group were better than those of the AP-80 group. Conclusions: AP 12009 showed a positive risk-benefit profile and demonstrated an excellent potential as single agent for the treatment of recurrent or refractory AA patients, especially for the AP-10 group. A phase III study in patients with recurrent or refractory AA is planned to start in Q2 2008. Treatment group AP-10 (N=12) AP-80 (N=15) Control (N=12) Incidence of SAEs (%) 67 67 25 Related or possibly related 0 0 0 Current median of survival times (months) 34.0 31.7 21.7 Survival rate at 24 months (%) 83 53 42 Overall response rate (CR+PR) at 14 months (%) 42* 20 0* CR=complete response, PR=partial response, * significant difference between AP-10 and control (p<0.05) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Antisense Pharma Antisense Pharma GmbH Antisense Pharma Antisense Pharma GmbH

A phase IIb actively controlled study with the TGF-beta-2 inhibitor AP 12009 for recurrent or refractory anaplastic astrocytoma

2025 Background: The TGF-β2 antisense phosphorothioate oligonucleotide inhibitor AP 12009 is a targeted anti-tumor therapy for TGF-β2 overexpressing tumors. In three Phase I/II dose escalation studies complete and long-lasting responses were observed in patients with recurrent or refractory anaplastic astrocytoma. Methods: The Phase IIb actively controlled dose finding study G004 is an open-label, randomized trial in adult patients with recurrent or refractory high-grade glioma (HGG) confirmed by central histopathology. 145 patients were randomized into three groups: Low dose AP 12009 (10 μM), high dose AP 12009 (80 μM), or standard chemotherapy, i.e. TMZ (or PCV if TMZ had already failed). Study objective was to compare the efficacy and safety of the three treatment groups. AP 12009 was applied locoregionally by convection- enhanced delivery (CED) with up to 11 treatment cycles (7-day-on, 7-day-off / per cycle). Results: Here we report on patients with recurrent anaplastic astrocytoma (AA, Grade III; GBM patients see separate abstract). 39 AA patients were treated, 12 pts received AP 12009 10 μM (AP-10), 15 pts 80 μM (AP-80), and 12 pts standard chemotherapy (10 pts TMZ, 2 pts PCV). Preliminary safety data reveal no SAEs related to the study drug in the AP-10 and AP-80 groups vs. one in the control group. Survival rates were higher in both AP 12009 groups compared to the chemotherapy group (see table ). In both AP 12009 groups mOS has not yet been reached. Overall survival at present is 28.6 months for the AP-10 group, 24.2 months for the AP-80 group, and 20.2 months for the control group. Dose finding was achieved, as efficacy and safety results for the AP-10 group were superior to those of the AP-80 group (see table ). Conclusion: AP 12009 revealed a positive benefit-risk profile and demonstrated excellent potential as monotherapy for the treatment of recurrent or refractory AA patients, especially for the AP 12009 10 μM group. [Table: see text] [Table: see text]

Phase II Clinical Trial of Didemnin B in Patients with Recurrent or Refractory Anaplastic Astrocytoma or Glioblastoma Multiforme (NSC 325319)

The activity of didemnin B, a natural product derived from the Caribbean Tunic was assessed in 16 patients with Glioblastoma multiforme. Didemnin B was administered intravenously by a short infusion at a dose of 4.3 mg/m2 and subsequently escalated to 6.3 mg/m2. No anti-tumor activity was observed. Toxicity consisted of fatigue, weakness, stomatitis, mild blood count changes, nausea and vomiting and occasional fever. Based on these results further studies with didemnin B in patients with Glioblastoma multiforme are not recommended.