The FDA has approved an investigational new drug application for berubicin for the treatment of patients with glioblastoma multiforme, according to an announcement made by CNS Pharmaceuticals, Inc.

A trial evaluating the efficacy of the product in adults with glioblastoma who have progressed on frontline treatment will be initiated in the first quarter of 2021. The trial has undergone modifications based on communication between the regulatory agency and the pharmaceutical company. For example, now the primary end point of the trial is overall survival (OS).

“Since becoming a public company, our clear focus has been on advancing the clinical development of berubicin. We will now rapidly move to initiate our phase 2 trial of berubicin for adults with glioblastoma and expect to being enrolling patients in the first quarter of next year,” John Climaco, CEO of CNS Pharmaceuticals, stated in the press release.

“The Company will transform within the next several months as berubicin becomes the subject of up to 3 active clinical trials, which include our randomized, controlled phase 2 trial in the United States, and 2 trials planned by our sublicensee WPD in Poland,” Climaco added. 

In the phase 2 trial, investigators will examine the effectiveness of berubicin vs standard-of-care lomustine in patients with glioblastoma multiforme who have progressed on initial treatment for their disease. Participants were randomized 2:1 to either the investigative arm or control arm.

Because the trial has an adaptive design, it allows for an interim analysis of the findings to illustrate differences in efficacy between the approaches; it also allows for an adjustment to the size of the study population for greatest efficacy with regard to time in development. Due to this design, the trial possesses the potential to deliver findings to the FDA that could allow for an accelerated pathway for development.

Data from the first clinical trial examining the agent demonstrated that 44% of participants achieved a clinical response; 1 of these patients experienced a durable complete response (CR).

 The agent has also been shown to improve survival in this population that is known to have a dismal median survival of just 14.6 months from the time of diagnosis.

In the phase 2 trial, investigators set out to identify the maximum-tolerate dose and dose-limiting toxicity of berubicin; they also examined pharmacokinetics, pharmacodynamics, and efficacy in those with primary brain tumors.

In the trial, a total of 35 patients with recurrent or refractory glioblastoma multiforme or other primary brain cancers were given berubicin intravenously over the course of 2 hours for 3 consecutive days every 21 days. The accelerated titration design of the trial evaluated dose escalations, with daily doses that ranged from 1.2 mg/m2 to 9.6 mg/m2.

The maximum-tolerated dose (MTD) of the agent was identified to be 7.5 mg/m2. One of 5 patients who received the agent at the MTD had a DLT. Moreover, 2 of 6 patients who received the agent at the dose of 9.6 mg/m2 reported a DLT. 

The patient who experienced a durable CR proved to still be in remission over 11 years later. Additionally, 2 patients achieved partial or minor responses and 9 patients experienced stable disease. Among the 27 patients determined to be efficacy evaluable, the 12 responses translated to a 44% response rate. Moreover, pharmacokinetic data indicated that there was dose-dependent clearance, with a half-life of 32.3 hours and a large volume of distribution of 1842 L/m2. Additionally, the mean maximum plasma concentration and area under the plasma concentration-time curve seemed to proportionally increase with each escalating dose.

Additionally, the most frequent dose-limiting toxicity (DLT) was myelosuppression, particularly neutropenia. Additionally, nonhematologic adverse effects were reported, with no neurotoxicity or cardiotoxicity observed. 

In June 11, 2020, the FDA granted an orphan drug designation to the anthracycline for the treatment of patients with malignant gliomas.

“We are entering an area with significant unmet medical need since the current treatment paradigm for glioblastoma remains bleak, as this aggressive and currently incurable form of brain cancer continues to claim high mortality rates,”concluded Climaco. “We have a tremendous opportunity ahead of us as we continue our mission to improve patient outcomes for glioblastoma and build on the promising results demonstrated by berubicin in its phase 1 clinical trial.”

1. CNS Pharmaceuticals announces FDA approval of IND application for its brain cancer drug candidate berubicin. News release. CNS Pharmaceuticals, Inc. December 17, 2020. Accessed December 21, 2020. http://prn.to/2KuKRbb.

2. Berubicin. CNS Pharmaceuticals website. Accessed December 21, 2020. http://bit.ly/3pfA9Ec.

This article was originally published on OncLive as, "

FDA Gives Green Light to IND for Berubicin for Glioblastoma Multiforme.

Articles

The FDA has approved an investigational new drug application for berubicin for the treatment of patients with glioblastoma multiforme.

FDA OKs Berubicin for GBM Treatment

AV-GBM-1, a personalized cancer vaccine, demonstrated an improvement in progression-free survival (PFS) in patients with newly diagnosed glioblastoma, according to data from a phase 2 trial (NCT03400917).

Results presented during the 2020 SITC Annual Meeting showed that the vaccine resulted in a PFS rate of 69% at 7 months, which favorably compares with the historical rate of 50% at this time point.2 The median PFS was 10.0 months (95% CI, 8.5-11.5) with the vaccine versus 6.9 months (95% CI, 5.8-8.2) in the landmark study that had established the standard of care for this patient population. This translated to a 38% reduction in the risk of progression or death at 6.9 months of treatment, according to AIVITA Biomedical Inc.

Moreover, the overall survival (OS) rate at 12 months was 72% with AV-GBM-1, which also compares favorably with the historical rate of 61%.

“The improvement in [patients with] glioblastoma who were treated with AV-GBM-1, compared to studies with the standard of care, is a very promising indication that our therapy confers benefit to patients in need,” Robert O. Dillman, MD, chief medical officer, of AIVITA Biomedical, Inc, stated in a press release.

Standard approaches for patients with primary glioblastoma are linked with poor survival outcomes. Investigators hypothesized that adjunctive therapy with patient-specific vaccines could help to improve these outcomes in patients by boosting immune response. AV-GMB-1 is made of autologous dendritic cells that are comprised of autologous tumor antigens from self-renewing tumor-initiating cells.

In the single-arm, phase 2 trial, a total of 57 patients were scheduled to receive up to 8 doses of AV-GBM-1 over the course of 6 months. At the time of the analysis, patients had completed treatment and had been followed for further analysis between 7.2 months and 24.2 months.

Patients were enrolled to the trial after they recovered from surgery and before they began treatment with concurrent temozolomide chemotherapy and radiation. To be eligible for participation, patients had to have a diagnosis of primary glioblastoma, be 70 years of age or younger at the time of tumor resection, have a successful cell culture of cancer cells in serum-free media, have acceptable monocyte collection by leukapheresis, and a Karnofsky performance score (KPS) of 70 or greater following surgical recovery.

Investigators utilized interleukin-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF) to produce dendritic cells from peripheral blood monocytes. Dendritic cells were generated with autologous tumor antigens from the lysate of the cancer cells to manufacture each patient-specific vaccine. Patients began treatment after they recovered from concurrent treatment with chemotherapy and radiation. With each vaccine dose given, GM-CSF was also given at 500 mcg at the time of the injection on weeks 1, 2, 3, 8, 12, 16, 20, and 24.

Investigators collected tumors between August 18, 2018 and January 15, 2020. Patients were enrolled for treatment between October 3, 2018, and February 27, 2020. A total of 80 tumors were received and 71 of 73 were determined to have successful cell lines. Seven patients withdrew while the cell line was in progress. A total of 65 leukapheresis procedures were conducted, but 6 patients withdrew prior to this. Sixty patients were enrolled to the intent-to-treat population. Three patients withdrew before beginning treatment.

The key objectives of the trial include confirmation of the feasibility of producing patient-specific vaccines, the safety of administering these vaccines, survival from the date of enrollment, PFS from date of enrollment, and survival from the date of diagnostic surgical resection.

The median age of study participants was 59 years and the majority, or 70%, were male. Moreover, 72% were white, 17% were Hispanic, 3% were Black, and 2% were Asian. A little more than half of patients, or 52%, did not have MGMT methylation, while 22% did; for 27% of patients, this information was unknown. Twelve percent of patients had tumors that harbored an IDH mutation. Forty-two percent of patients had a KPS of 90, 28% had a score of 80, 23% had a score of 70, and 7% had a score of 100.

Fifty-seven patients received treatment. Of these patients, 39 received all 8 doses, 2 patients completed 7 doses, 5 received 6 doses, 2 received 4 doses, 5 received 3 doses, and 3 completed 2 doses.

Regarding safety, the vaccine was found to be well tolerated. The most commonly reported toxicity was local injection site reactions. Notably, no study participants stopped treatment because of adverse effects. Fifty-four serious toxicities were observed among 28 patients, although none of these effects were determined to be associated with the vaccine.

Many of these toxicities were related to the central nervous system; 10 patients reported falls and/or focal weakness and 3 experienced headaches and/or cerebral edema. One death was reported; this occurred after 2 injections with the vaccine. The patient fell at home, refused to go to the hospital, and died 2 days later.

“This is a major victory against glioblastoma, a devastating disease that has evaded treatment for far too long,” Hans S. Keirstead, PhD, chairman and chief executive officer of AIVITA, added in the release. “We now have excellent results from phase 2 clinical studies in both melanoma and glioblastoma, underscoring the tremendous potential of this personalized cancer immunotherapy.”

The vaccine is under examination in 3 clinical trials in patients with ovarian cancer, melanoma, and glioblastoma. AIVITA announced that they are working on obtaining a conditional commercial approval in Japan for its melanoma treatment.

1. AIVITA Biomedical’s phase 2 glioblastoma trial shows improved progression-free survival. AIVITA Biomedical, Inc. News release. November 17, 2020. Accessed November 17, 2020. https://prn.to/2IKABuF.

2. Bota DA, Piccioni DE, Duma CM, et al. Phase II trial of active specific immunotherapy in primary glioblastoma: antigens from self-renewing autologous tumor cells presented by autologous dendritic cells. Presented at: 2020 SITC Annual Meeting; November 9-14, 2020; Virtual. Abstract 745.

Cancer Vaccine AV-GBM-1 Improves PFS in Newly Diagnosed Glioblastoma

AV-GBM-1 Vaccine Improves Glioblastoma Outcomes

The FDA has granted a fast track designation to paxalisib (formerly GDC-0084) for the treatment of patients with glioblastoma, according to an announcement from Kazia Therapeutics Limited, the developer of the drug.

The indication is specifically for the treatment of patients with newly diagnosed glioblastoma with unmethylated O6-Methylguaninemethyltransferase (MGMT) promotor status who have finished initial radiation with concomitant temozolomide.

“In awarding fast track designation to paxalisib, [the] FDA has recognized the drug’s potential to meaningfully improve outcomes for patients with glioblastoma; this is a very power acknowledgement,” James Garnder, MD, MBA, CEO of Kazia Therapeutics Limited, stated in a press release. “The opportunities that fast track designation creates, as we move toward an new drug application (NDA) filing, are of great value and have the potential to substantially accelerate the commercialization of paxalisib.”

Interim data from an ongoing phase 2 trial (NCT03522298) examining the investigational small molecule inhibitor of the PI3K/mTOR pathway in a total of 30 patients with glioblastoma were presented during the Virtual Scientific Program and showed a median progression-free survival (PFS) of 8.5 months.

 Moreover, the overall survival (OS) was 17.7 months with paxalisib in this population.

The data with paxalisib compare favorably with the current standard of care, which is temozolomide (Temodar), according to Kazia Therapeutics Limited. The PFS benefit observed with the chemotherapy is just 5.3 months, while the OS is 12.7 months.

In the open-label, multicenter, dose-escalation and -expansion phase 2 trial, investigators set out to examine the safety and tolerability, pharmacokinetics, and clinical activity of paxalisib in patients with newly diagnosed glioblastoma with unmethylated MGMT promotor status as adjuvant treatment after surgical resection and initial chemoradiation with temozolomide. Another objective of the trial was to establish the recommended phase 2 dose of the agent.

The trial had a 2-part design. In the first portion, investigators used a standard 3 + 3 design to establish the maximum-tolerated dose (MTD) of paxalisib.

 The agent was initially given at a dose of 60 mg based on phase 1 data and dose levels increased in 15-mg steps. For the dose-escalation portion of the research, investigators assessed the safety, tolerability, and pharmacokinetics of the drug given orally in 28-day treatment cycles.

Following the identification of the MTD, patients continued to receive their protocol-assigned dose levels of paxalisib until disease progression or intolerable toxicity, whichever occurred first.

In the expansion phase of the research, patients were evaluated in a 2-arm, randomized, open-label trial to further understand the safety, tolerability, and pharmacokinetics of the drug and to garner insight into the activity of the agent as a monotherapy in this patient population.

To be eligible for enrollment, patients had to be 18 years of age or older, have a life expectancy of over 12 weeks, have histologically confirmed intracranial unmethylated MGMT promotor status glioblastoma, have undergone maximal surgical resection of their tumor and within 6 weeks of surgery received radiation treatment in conjunction with temozolomide, among others.

If patients received prior radiotherapy to the brain or other cytotoxic therapy in addition to the required postoperative radiation plus temozolomide, or any other investigational therapy directed against the tumor, they were not permitted to participate. Patients who received any previous or had any anticipated concomitant treatment involving a medical device applying tumor treating fields, those with undetermined/indeterminate MGMT status, and those who were diabetic or pre-diabetic, among others, were considered ineligible to enroll.

Overall, a total of 30 patients were enrolled on the trial; 9 patients were included in the dose-escalation cohort and an additional 21 were included in the second portion of the research.

 Previous results showed that in the 9-patient subgroup, the median OS with paxalisib was 17.7 months. In the group of 30 patients, the median PFS was 8.5 months.

Regarding safety, no major toxicities were reported. Hyperglycemia, oral mucositis, and low-grade rash were among the most frequently reported adverse effects that were determined to be associated with the study treatment.

“The ‘rolling review’ process enables Kazia to complete and submit substantial sections of our NDA filing in advance, saving time and reducing risk for the product,” Garner added in the release. “We look forward to working closely with the FDA as we move into the final stage of development for paxalisib.”

In August 2020, the agent was granted a fast track designation by the FDA. Further data are expected in the second half of 2020, with completion expected in early 2021. The agent has been selected to be examined in the international GBM AGILE study that is being done in patients with glioblastoma and investigators expect to start recruiting patients in the second half of 2020.

1. US FDA awards fast track designation (FTD) to paxalisib for glioblastoma. News release. Kazia Therapeutics Limited. August 20, 2020. Accessed August 20, 2020.

2. Kazia presents further paxalisib and cantrixil data at AACR, reinforcing positive efficacy signals for both drugs. News release. Kazia Therapeutics Limited. June 22, 2020. Accessed August 20, 2020. https://prn.to/3hgbCLM.

3. Safety, pharmacokinetics and efficacy of paxalisib (GDC-0084) in newly-diagnosed glioblastoma. ClinicalTrials.gov. Updated June 9, 2020. Accessed August 20, 2020. https://clinicaltrials.gov/ct2/show/NCT03522298.

4. Kazia's paxalisib shows positive overall survival signal in phase II glioblastoma study. News release. Kazia Therapeutics Limited.April 7, 2020. Accessed August 20, 2020. https://yhoo.it/2JP8QOA.

The FDA has granted a fast track designation to paxalisib for the treatment of patients with glioblastoma.

FDA Grants Fast Track Status to Paxalisib for GBM Treatment

The FDA has granted a fast track designation for the PKCβ inhibitor enzastaurin (DB102) for the treatment of patients with newly diagnosed glioblastoma (GBM), according to an announcement from Denovo Biopharma LLC.1

“This fast track designation in GBM is an important milestone in the development of [enzastaurin],” Xiao-Xiong Lu, PhD, chief technical officer at Denovo stated in a recent press release. “We are pleased that the FDA has recognized our innovative biomarker approach to conquer GBM. It potentially accelerates our development of [enzastaurin] in GBM, a difficult-to-treat indication with a significant unmet need and adds value to our DB102 franchise.”

Denovo plans to launch a pivotal phase 3 trial evaluating enzastaurin in combination with temozolomide, both during and following radiation therapy, in patients with newly diagnosed glioblastoma.

The agent is also being evaluated in the phase 3 ENGINE trial (NCT03263026).2 In this trial, investigators set out to enroll 235 patients with CD20-positive diffuse large B-cell lymphoma (DLBCL) and randomize them to receive either enzastaurin added to the standard-of-care of rituximab (Rituxan) plus cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R-CHOP) or R-CHOP alone for 6 cycles during the combination phase.

The primary end point of the trial was overall survival (OS) in patients with DLBCL who test positive for DGM1, with a secondary end point of OS in patients without DGM1. The key objective of the trial is to determine whether the addition of the investigational agent to R-CHOP in the frontline could lead to better outcomes compared with R-CHOP alone, and whether the presence of DGM1 correlates with response to the agent in this setting.

Additionally, in the phase 3 PRELUDE study (NCT00332202), investigators compared the PKCβ inhibitor with placebo in patients with high-risk DLBCL and found no statistically significant difference in disease-free survival at 4 years, at 70% versus 71%, respectively.3 No difference was observed with regard to OS, either (81% vs 82%, respectively). Another effort, the phase 2 S028 trial (NCT00451178), examined the novel agent in the frontline setting, in combination with R-CHOP compared with R-CHOP alone, in patients with intermediate- or high-risk disease. Again, results failed to show added benefit with enzastaurin.

Despite the negative data from PRELUDE and S028, genomic research examining DNA samples collected from study participants have been fruitful in that they led to the discovery of the DGM1 polymorphism. Specifically, following retrospective genotyping of patient samples collected from the PRELUDE trial, investigators found that the biomarker could be predictive of response to the PKCβ inhibitor. Enzastaurin was found to significantly improve OS in patients with DGM1-positive disease versus those without the polymorphism (HR, 0.27; P = .0002).

These data were upheld in a biomarker analysis performed on patient DNA samples collected from the S028 study. Here, enzastaurin was linked with a superior survival benefit in those with high-risk DLBCL who were also positive for DGM1 versus those without the polymorphism (HR, 0.28; P = .018). These efforts supported the initiation of the ENGINE trial, which is being conducted to validate these data.

1. FDA grants fast track designation for DB102 in patients with newly diagnosed glioblastoma (GBM). News release. Denovo Biopharma LLC. July 17, 2020. Accessed July 22, 2020. https://bit.ly/39kp6Tv.

2. Smith S, Zhu J, O’Connor OA, et al. ENGINE: phase III randomized study of enzastaurin/R-CHOP versus placebo/R-CHOP in frontline high-risk diffuse large B-cell lymphoma patients with novel genetic biomarker DGM1. J Clin Oncol. 2019;37(suppl 15; abstr TPS7569). doi:10.1200/JCO.2019.37.15_suppl.TPS7569

3. Luo W, Sun H, Zhu J, Smith SD, Han I, Shazer R. Improved survival with enzastaurin treatment in diffuse large B-cell lymphoma patients with the novel genetic biomarker, DGM1. Blood. s2018;132 (suppl 1):4207. doi:10.1182/blood-2018-99-115807

FDA Grants Fast Track Status to Enzastaurin for Newly Diagnosed Glioblastoma

The FDA has granted a fast track designation for the PKCβ inhibitor enzastaurin for the treatment of patients with newly diagnosed glioblastoma.

FDA Grants Fast Track Status to Enzastaurin to Treat Newly Diagnosed GBM

The FDA has accepted a biologics license application for a proposed biosimilar for bevacizumab (Avastin), according to an announcement by Mylan during its fourth quarter 2019 earnings call.

The company stated that the application is under review by the FDA, with an action date of December 27, 2020.

Mylan and Biocon co-develop the bevacizumab biosimilar MYL-1402O (Abevmy) which was approved by the Drug Controller General of India in November 2017 for all indications of reference bevacizumab, including for the treatment of patients with metastatic colorectal cancer (CRC), non—small cell lung cancer, glioblastoma, ovarian cancer, cervical cancer, and renal cell carcinoma, as part of specific regimens for Indian patients.

The approval was based on results of a comprehensive data package that demonstrated biosimilarity between the biosimilar and reference bevacizumab, including through analytical, pharmacokinetic, and pharmacodynamic studies and an India-specific, randomized, double-blind study in patients with mCRC. The biosimilar is approved in an injection formulation at 100-mg and 400-mg doses.

Results of a single-center, randomized, double-blind, 3-arm, parallel-group study of MYL-1402O were presented at the 2017 ASCO Annual Meeting.

 In 111 healthy male volunteers, investigators sought to establish pharmacokinetic (PK) similarity between the bevacizumab biosimilar (arm A) and EU-sourced bevacizumab (arm B) and US-sourced bevacizumab (arm C), as well as between EU-sourced bevacizumab and US-sourced bevacizumab.

Patients were randomized to receive intravenous treatment in 1 of the 3 arms at a 1-mg/kg dose over 90 minutes. Dosage was selected based on the lower dose in the linear range of PK and acceptable safety.

Bioequivalence was determined if the 90% confidence intervals (CIs) of the ratios were within 80% to 125%. Investigators also evaluated area under the curve (AUC)0-t, Cmax, tmax, elimination rate constant, and half-life were assessed as secondary PK factors.

Results showed that bioequivalence was demonstrated between arms A and B, arms A and C, and between arms B and C. The least squares mean ratios were close to 1, and 90% CIs were within 0.80 to 1.25 for all 3 comparisons. Moreover, the secondary PK parameters were also found to be comparable with the 90% CIs for ratios of AUC0-t and Cmax within 80% to 125%.

Regarding safety, 313 treatment-emergent adverse events (TEAEs), which were grades 1/2 in severity, were reported across all arms: arm A (89%), arm B (78%), and arm C (76%). The majority of the TEAEs were consistent with prior clinical findings of bevacizumab, and no serious or unexpected TEAEs were reported.

Two other bevacizumab biosimilars are approved by the FDA: bevacizumab-awwb (Mvasi) and bevacizumab-bvzr (Zirabev), both of which launched in the United States in 2019. Moreover, a supplemental biologics license application was accepted by the FDA in November 2019 for the bevacizumab biosimilar SB8.

In the fourth quarter 2019 earnings call, Mylan also announced that it had submitted a European application for the bevacizumab biosimilar, adding that it is currently in the validation stage with authorities.

1. Mylan Launches Biosimilar Bevacizumab, ABEVMY, in India [news release]: Bengaluru, India. Published November 27, 2017. https://bit.ly/3anI3Ee. Accessed March 5, 2019.

2. Socinski MA, Hummel M, Bosje T, et al. A bioequivalence study of proposed bevacizumab biosimilar, MYL-1402O (A) vs EU-Avastin (B) and US-Avastin (C). J Clin Oncol. 2017;35(suppl_15). doi: 10.1200/JCO.2017.35.15_suppl.e14034

FDA Accepts BLA for Bevacizumab Biosimilar

Historically, glioblastoma (GBM) is a difficult-to-treat tumor type. Checkpoint inhibition, which has proven successful in multiple other tumor types, has had limited success in patients with GBM to-date—though that could change down the line with the advent of combination therapy, according to recent research presented at the Society for Neuro-Oncology (SNO) annual meeting.

“The early trials of PD-1 inhibition and glioblastoma have had mixed results. By combining something like a standard checkpoint blockade agent with a therapeutic neoantigen vaccine, we're hoping that we can improve the responses we see with these therapies,” said Connor Liu, researcher and medical student at Washington University School of Medicine in St. Louis. “A lot of my work was piloting that combination vaccine plus checkpoint blocking strategy in varying models of glioblastoma.”

 of highly aggressive orthotopic murine GBM with checkpoint blockade and multi-valent neoantigen vaccination. The study is the pre-clinical correlate investigating personalized neoantigens in the tumors of patients with recurrent GBM.

: Can you give an overview of your study?

 The work I did over the past 2 years really focused on identifying new antigens, tumor-specific mutations in these varying models of glioblastoma. The whole idea is that using a genomic approach to identify these tumor-specific mutations and then to hopefully utilize them in a therapeutic setting, like a cancer vaccine. 

We characterized 2 types of glioblastoma that both have different phenotypes and responses to immune therapies. Then we test these combination treatments in both of those models. 

Combination immune treatment, at least in these varying glioblastoma models, [can have] some synergistic interaction between these standard checkpoint blockade agents that are already used in a lot of other tumor types but have not been successful in GBM. There's some synergistic interaction with those agents and personalized new antigen vaccine treatments. 

What is the future for treating these patients? 

Especially with something like an aggressive, historically treatment-resistant tumor like glioblastoma, combination modalities definitely [will be the future]. Figuring out how, especially, all these new immune therapy treatments, like checkpoint blockade, adoptive cell transfer, neoantigen vaccines, whatever it may be, and how those treatments interact on a biologic and immunologic level with the current standard of care therapies like surgical resection, temozolomide, chemotherapy, and things like that. 

Understanding that biology is also going to help us tease apart the actual practical aspect of how to treat a patient with glioblastoma, and using all of these agents we have: the timing of it, the dosing of it, the routes of administration. That's where the field is going: understanding how these combination treatments are going to interact together, and how can we best use the options that we have currently to produce the best benefit for our patients. 

For my pre-clinical studies in these mouse models, we see the significance in the combination vaccine and checkpoint blockade, but the question is: why? What is the underlying biology? Are we increasing the number of these tumor-specific effector immune cells in the brain? How is that interacting with these checkpoint blockade agents? That's the next phase of my experiments—understanding the underlying immunology to better optimize the way that we can give these treatments. 

Glioblastoma is historically difficult to treat, but recent research shows some potential for immunotherapy/vaccine combinations for these patients.

Checkpoint Blockade Plus Vaccines Show Synergy in Early GBM Trials

Single-agent vorasidenib or ivosidenib (Tibsovo) led to brain penetrance and 2-hydroxyglutarate (2-HG) suppression in patients with low-grade glioma who harbor 

 mutations, according to updated data from an ongoing, 2-cohort, perioperative study (NCT03343197) that were presented at the 2019 Society for Neuro-Oncology Annual Meeting.

Findings were available from 42 efficacy-evaluable patients on vorasidenib (n = 21) or ivosidenib (n = 21). Among those who received postoperative vorasidenib at 50 mg, 4 (31%) patients achieved objective tumor responses, which comprised 2 partial responses (PRs) and 2 minor responses, according to the investigator by Response Assessment in Neuro-Oncology for low-grade glioma (RANO-LGG).

The objective response rate was also 31% for patients who received 500 mg of ivosidenib in the postoperative setting, also according to investigator by RANO-LGG. This included 2 PRs and 2 minor responses. Moreover, stable disease was achieved in 15 and 16 patients on vorasidenib and ivosidenib, respectively, which led to respective disease control rates of 90% and 95%.

Vorasidenib is an investigational, oral, selective IDH1/IDH2 inhibitor that is designed to enhance brain penetrance and has been in clinical development in 

Ivosidenib is currently approved by the FDA for the treatment of adult patients with relapsed/refractory 

-mutant acute myeloid leukemia (AML), and for the first-line treatment of adult patients with 

-mutant AML, as detected by an FDA-approved test, who are ≥75 years old or are ineligible to receive intensive induction chemotherapy.

In the ongoing trial, vorasidenib and ivosidenib are being evaluated as single agents in patients with 

-mutant grade 2/3 glioma. Patients are randomized to receive 500 mg of ivosidenib once daily, 50 mg vorasidenib once daily, or the control arm of no treatment in cohort 1. In the second cohort, patients receive either 250 mg of ivosidenib twice daily or 10 mg of vorasidenib once daily. Patients are treated for 4 weeks prior to surgery and can continue postoperative treatment until disease progression.

The primary endpoint is 2-HG concentration in tumors resected following neoadjuvant treatment with vorasidenib and ivosidenib compared with the untreated control tumors.

As of the July 26, 2019, data cutoff, 49 patients were randomized before surgery and 39 remain on treatment. The median duration of postoperative treatment for all doses was 5.42 months (0.9-13.5) for vorasidenib and 6.93 months (1.0-13.2) for ivosidenib.

The baseline characteristics were similar across arms in each cohort. Overall, 88% of patients had World Health Organization classified grade 2 tumors; less than one-third of patients had prior radiation therapy and approximately half of patients previously received systemic therapy.

Results also showed that vorasidenib and ivosidenib each demonstrated brain penetrance. The mean brain-plasma ratios were 3.16, 1.74, 0.13, and 0.10 for the 10-mg vorasidenib, 50-mg vorasidenib, 250-mg ivosidenib, and 500-mg ivosidenib arms, respectively. The mean percent reduction in 2-HG were 92.6% (95% CI, 76.1-97.6) in the 50-mg vorasidenib group and 91.1% (95% CI, 72.0-97.0) in the 500-mg ivosidenib arms, relative to untreated samples.

A safety analysis was conducted for all 49 patients as of the data cutoff, which showed that both vorasidenib and ivosidenib had favorable safety profiles. In the vorasidenib arm, the most common adverse events (AEs) occurring in >25% of patients were diarrhea (29.2%), fatigue (29.2%), and nausea (29.2%). The most common AEs on the ivosidenib arm were headache (32%), diarrhea (28%), and anemia (28%).

A total 8.3% of patients on vorasidenib developed transaminase elevations, including one grade 3 transaminase elevation at 50 mg daily; this was resolved with dose interruption. Grade ≥3 AEs occurred in 6 (25.0%) vorasidenib-treated patients and 4 (16.0%) patients on ivosidenib; the majority of these were related to postoperative complications. No patients discontinued treatment due to AEs.

“Having now demonstrated brain penetrance, robust 2-HG suppression and an encouraging disease-control rate with vorasidenib, we’re confident in our ability to make a difference for patients with 

 mutant low-grade glioma and are on track to initiate the phase III INDIGO study next month.” Chris Bowden, MD, chief medical officer at Agios Pharmaceuticals, Inc., the developer of these agents, stated in the press release.

The double-blind, phase III INDIGO study will randomize 366 patients with 

-mutant, grade 2 non-enhancing glioma 1:1 to receive either 50 mg of vorasidenib once daily or placebo. The primary endpoint of the trial, which is expected to initiate at the end of 2019, is progression-free survival.

A version of this article originally appeared on OncLive

Vorasidenib, Ivosidenib Show Encouraging Activity in IDH1-Mutant Low-Grade Glioma

Agios presents new pharmacodynamic and response data from both cohorts of the perioperative study of vorasidenib and Tibsovo (ivosidenib) in patients with IDH1 mutant positive low-grade glioma. Agios Pharmaceuticals. Published November 22, 2019. https://bit.ly/34lHPL7. Accessed November 25, 2019.

Two new single agents led to brain penetrance and 2-hydroxyglutarate (2-HG) suppression in patients with low-grade glioma who harbor IDH1 mutations, according to updated findings.

New Agents Show Promise in Treating Patients with IDH1-Mutant Low-Grade Glioma

The Food and Drug Administration (FDA) approved bevacizumab-bvzr (Zirabev)—a biosimilar for bevacizumab (Avastin) for the treatment of multiple cancer types:

Unresectable, locally advanced, recurrent or metastatic non-squamous non-small cell lung cancer (NSCLC)

Persistent, recurrent, or metastatic cervical cancer

“Biosimilars like ZIRABEV can help increase access to impactful therapies, driving market competition that may ultimately lower costs and help address the diverse needs of patients living with cancer,” said Andy Schmeltz, global president, Pfizer Oncology, the manufacturer of the biosimilar, in 

. “We are proud to add ZIRABEV to our growing oncology portfolio for U.S. patients living with a wide variety of tumor types.”

In order to gain FDA approval, biosimilars must prove that they are 

. This approval was based on a review of a comprehensive data package, including results from the REFLECTIONS B7391003 clinical comparative study, which proved that bevacizumab-bvzr had no clinically meaningful differences to bevacizumab in patients with advanced non-squamous NSCLC.

Bevacizumab-bvzr and its reference product, work by inhibiting new blood cells from forming by binding to the VEGF protein. The biosimilar has been studied in nearly 400 patients so far.

Across the studies and tumor types, the most common adverse events (AEs) for bevacizumab that occurred in 10% or more of patients were: epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis. AEs led to an 8% to 22% discontinuation rate across studies.

“ZIRABEV represents a welcome addition to the treatment armamentarium in its approved indications, potentially providing physicians with a medicine that has a similar safety profile and efficacy as the reference product,” said Niels Reinmuth, MD, PhD, Department of Thoracic Oncology, Asklepios Lung Clinic, Munich-Gauting, Germany, and lead author of the REFLECTIONS B7391003 study. “The FDA’s approval of ZIRABEV may provide an important new option for the treatment of multiple forms of cancer.”

The Food and Drug Administration approved bevacizumab-bvzr (Zirabev) – a biosimilar for bevacizumab (Avastin) for the treatment of metastatic colorectal cancer; unresectable, locally advanced, recurrent or metastatic NSCLC; recurrent glioblastoma; metastatic renal cell carcinoma; and persistent, recurrent or metastatic cervical cancer.

FDA Approves Bevacizumab Biosimilar for 5 Cancer Types

Health-related quality of life (QOL) is becoming an increasingly important endpoint in cancer clinical trials, explained Giuseppe Lombardi, MD, PhD, a medical oncologist at the Veneto Institute of Oncology in Padua, Italy.

It is important that clinicians can offer patients not only the chance of improved survival, but also to live well in the meantime. This is especially true for patients with glioblastoma, who can have decreased neurologic or physical functioning. To ensure this, cancer treatment centers should assemble multidisciplinary teams that involve psychosocial supports, therapists, and more.

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Health-related quality of life (QOL) is becoming an increasingly important endpoint in cancer clinical trials.

Quality of Life Is an Important Endpoint in Cancer Trials

When Jessica Morris was first diagnosed with glioblastoma, it seemed that there was no consistent way to track symptoms for patients with the disease. So, Morris teamed up with other patients, clinicians and experts in the field to develop the OurBrainBank app, which tracks symptoms and anonymously sends them to brain tumor researchers around the globe.

 recently sat down with Morris to discuss the app, and the hope that it can bring to the brain cancer space.

: How are symptoms traditionally tracked for glioblastoma, and what are some of the limitations to this approach? 

With people like me living with glioblastoma, which is perhaps the worst possible kind of brain cancer, with a median survival of 14 months, our symptoms are not really collected in a systematic way. I speak to other people like me with this condition, not just in the US, but all over the world, and symptom tracking is pretty nonexistent in any methodical way. 

That's one of the reasons why I founded, together with some fantastic physicians and other patients, a nonprofit called Our Brain Bank. What we're doing there is enabling people affected by the disease, both patients and the people who care for us, to everyday take time out and think, 'How does this disease actually feel? How did I sleep last night? How is my nutrition today? How is my depression?' The doctors want that because they want to spot insights and use the data that we're collecting in the form of the free Our Brain Bank app to be more exploratory in looking at how this disease actually relates to the individual experiencing it. They think that there may be some insights there that can lead to ultimately new treatments and a new approach. 

The Our Brian Bank app is a IRB-certified app, and you can download it from the app store or Google Play for free. It's available in the US for the moment, and we're taking it to other countries soon. You register using this code OBB100. Then you can choose up to 10 symptoms to track. They can relate to your own particular situation. Then, you are invited to donate that data anonymously to Our Brain Bank, and we're certified with the IRB, so you can ensure that we've taken every step possible to respect people's privacy. Then [the data] is available to researchers to do whatever they want. 

In less than a year, we've had 3 sponsors of clinical trials come to us saying, “Can we access the data that you're using, because that would be really helpful as we're trying to set up new trials in glioblastoma.” This disease needs more experimental treatments. It needs more research. It needs more clinical trials. The data that we're collecting is helping that pursuit. 

Our mission at Our Brain Bank is to move glioblastoma from terminal to treatable, powered by patients. 

Can you talk about the data available thus far?

We went live with the app in the United States in March last year. In just over a year, with just a few of us hammering out a tweet every now and then and a Facebook post, we've got 400 regular users. We've collected between 7000 and 8000 data points, and that has blown our medical research team away. We've been published by ASCO online and so you can just look up Brain Bank and it will come up. We were invited to present at the Society of Neuro-Oncology in 2018. We had a poster session, and so we're trying to get out into the community. 

What we're getting is very positive feedback from brain tumor researchers. This is new data. We all know that there are some macro trends hitting healthcare: digitalization and greater interest in patient centricity. We're surfing those waves, and we're saying by putting patients first and demonstrating empathy and thinking what is it like to be me, then you get to ask better questions. So, for symptoms, what is it like to experience living with this disease? This starting, we hope, allows medical researchers to ask themselves a different set of questions and think, “How can we use the reality of what it's like to live with the disease to unlock new insights and ultimately a cure?”

What is the biggest takeaway for patients? 

I am a patient. I'm living with this disease. And I'm interacting with hundreds of patients on our app, and all I get back is, “This is giving me hope.” Hope is a very powerful lesson, and it's not just artificial hope. It's real hope. This is an ideologically pragmatic approach to defeating this disease. It's ideological because we want to stay alive; we're more ambitious for that, and it's practical because we've taken advice from some of the finest neuro-oncologists in the world. We have people from Columbia University, the Dana-Farber Cancer Institute, the University of Michigan, Memorial Sloan Kettering Cancer Center, the National Institutes, saying, “Yes this is a great idea.”

In healthcare, the freest agents are patients. The only investment we have is in ourselves and in our families. We don't have to oblige by any regulations, except those that we impose on ourselves. The regulation that I've imposed on myself is to stay alive for as long as possible. I have 3 children, and I love my life, and I love life. That means that I have a determination that is at least, if not perhaps more, as great as the finest doctors in the world. Together, we can do it. 

Patients can track symptoms and anonymously send them to glioblastoma researchers around the world.

Brain Cancer