Temferon, genetically modified Tie2-expressing monocytes (TEMs) targeting interferon a2 (IFNa2), showed the potential to activate the immune system and reprogram the tumor microenvironment in patients with newly diagnosed glioblastoma (GBM), according to preliminary findings from the phase 1/2a TEM-GBM study (NCT03866109)

“These results provide the initial evidence for on-target activity of Temferon in GBM,” said Bernhard Gentner, MD, study coauthor and the leader of the translational stem cell and leukemia research unit at San Raffaele Telethon Institute for Gene Therapy in Milan, Italy, in a presentation of the findings at the 2022 AACR Annual Meeting.

Temferon is an investigational advanced therapy consisting of autologous CD34+ enriched hematopoietic stem and progenitor cells exposed to transduction with a lentiviral vector, driving myeloid-specific IFNa2 expression. Genetically modified TEMs target IFNa2 expression in the GBM tumor microenvironment.

“In order to guarantee stable delivery of genetically engineered TEMs into the tumor, we transduce hematopoietic stem and progenitor cells with a lentiviral vector carrying the IFNa2 transgene transcriptionally regulated by the Tie2 promoter and by post transcriptional elements that guarantee that the transgene is expressed only in myeloid cells that are recruited into the tumor,” Gentner said.

TEM-GBM is an open-label, dose-escalation study evaluating the safety and efficacy of Temferon in up to 21 newly diagnosed patients with GBM harboring an unmethylated MGMT promoter. Following surgical resection, up to 15 patients were assigned to 1 of 3 escalating doses of Temferon and 1 of 2 different conditioning regimens in part A of the trial. In Part B, 6 more patients will receive a single dose of Temferon at the recommended phase 2 dose.

Following completion of radiotherapy, patients received a conditioning regimen consisting of carmustine (BCNU) and thiotepa (Tepadina) in cohorts 1 to 4 or busulfan (Busulfex) and thiotepa in cohort 5 prior to administration of Temferon.

In-patient monitoring occurs until hematological recovery, then patients will undergo regular follow-up for up to 720 days. At that point, patients are invited to participate in a long term follow-up study for an additional 6 years.

Eligible adults aged 18 to 70 years must have an ECOG performance score of 0 to 1, a Karnofsky performance score greater than 70%, and adequate cardiac, renal, hepatic, and pulmonary function. Patients with active autoimmune disease or who have received any oral or parenteral chemotherapy or immunotherapy within 2 years of screening are excluded.

The primary end points of the study are Temferon engraftment over the first 90 days, proportion of patients achieving hematologic recovery 30 days after autologous stem cell transplantation, and short-term tolerability of Temferon as defined by stable blood counts, absence of cytopenias, absence of significant organ toxicities greater than grade 2, and absence of Replication Competent Lentivirus.

By the October 15, 2021, data cutoff, the median follow-up was 267 days (range: 60-749). Patients in cohorts 1 to 3 received a dose 0.5-2.0 x 106/kg Temferon with an average vector copy number of 0.70 and a transduction efficiency of 54%. Those in cohorts 4 and 5 received 2.0 x 106/kg Temferon with an average vector copy number of 0.77 and a transduction efficiency of 49%.

Investigators observed increasing proportions of Temferon-derived differentiated cells, as determined by the presence of vector genomes in the DNA of peripheral blood and bone marrow cells, reaching up to 30% at 1 month in the highest treatment cohort (2.0 x 106/kg). Those differentiated cells persisted at lower levels for up to 18 months.

 Temferon engraftment,” Gentner said. “Engraftment was highest at 1 month, and in many patients resembled pretty much the input fraction. …Engraftment then decreased, stabilizing at 3 to 6 months around 10%.

“Despite the significant proportion of engineered cells, only very low-medium concentrations of interferon alpha were detected in the plasma and in the cerebral spinal fluid, indicating a tight regulation of the vector expression.”

Gentner added that Temferon did not delay hemopoietic recovery, and neutrophil and platelet engraftment were similar to standard autologous stem cell procedure.

Investigators did not detect any dose limiting toxicities. Gentner said that, so far, adverse events have been related to progression or the transplant procedure, not to the IFNa2 itself.

Gentner B, Finocchiaro G, Farina F, et al. Genetically modified Tie-2 expressing monocytes target IFN-α2 to the glioblastoma tumor microenvironment (TME): Preliminary data from the TEM-GBM Phase 1/2a study. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract 5213.

Articles

Preliminary findings from the phase 1/2a TEM-GBM study highlight the potential utility of temferon, genetically modified Tie2-expressing monocytes targeting interferon a2 in treating patients with glioblastoma. 

Temferon Is a Viable Treatment Option in Newly Diagnosed Glioblastoma 

Adjuvant neratinib (Nerlynx) following chemoradiation induced significantly longer progression-free survival (PFS) compared with adjuvant temozolomide among a subset of patients with 

-positive glioblastoma. However, no overall PFS or overall survival (OS) benefit was observed across the general study population, according to data from phase 2 INSIGhT trial (NCT02977780).

Data from the trial, which were presented during the 2021 Society for Neuro-Oncology Annual Meeting, showed that in the 

-positive subgroup (n = 73), the median PFS achieved with neratinib (n = 43) was 6.3 months vs 4.6 months with the control regimen (n = 30; HR, 0.58; log-rank test 

 = .04). However, in this group, neratinib did not significantly improve median OS over the control, at 14.4 months and 15.3 months, respectively (HR, 0.97; 

No statistically significant improvement in PFS or OS was observed with neratinib vs the control in the overall patient population (n = 149). The median PFS in this population was 6.0 months with neratinib and 4.7 months with the control regimen (HR, 0.75; 

= .12). The median OS with neratinib and the control regimen were 13.8 months and 14.7 months, respectively (HR, 1.01; 

There was also no significant improvement in PFS or OS was achieved with neratinib in the 

VIII–mutant subgroup (n = 28). The median PFS with neratinib (n = 16) was 6.2 months vs 5.1 months with the control (n = 12; HR, 0.88; 

= .77). The median OS with neratinib was 16.9 months vs 12.7 months (HR, 0.44; 

“Although preliminary results did not achieve the primary end point, subgroup analyses demonstrated improved PFS in patients with 

 activation and a nonsignificant trend toward improved OS in those with 

 VIII mutations, which could warrant further investigation,” Isabel Arrillaga-Romany, MD, PhD, director of Neuro-Oncology Clinical Trials at Massachusetts General Cancer Center, stated in a press release.2 “Additionally, we are very pleased that this trial reinforced feasibility of randomized Bayesian adaptive platform trials for newly diagnosed glioblastoma.”

 is an intriguing target in glioblastoma, several trials that have been conducted in patients with this disease have demonstrated limited efficacy with EGFR TKIs. INSIGhT is the first biomarker-driven, prospective controlled trial to explore an EGFR small molecule inhibitor in patients with newly diagnosed glioblastoma.

Notably, the trial utilized a Bayesian adaptive approach, which means that investigators utilized an adaptive algorithm to randomize patients to treatment arms and updated randomization probabilities by biomarker grouping each month. Specifically, individual biomarker subsets and the PFS of enrolled patients were leveraged to identify randomization probabilities.

The use of this algorithm was meant to accelerate and provide a competitive advantage to investigative arms linked with promising data early in the study. Notably, new arms can be added, and existing arms can also be dropped with this approach.

To be eligible for enrollment, patients needed to have histologically confirmed intracranial glioblastoma or gliosarcoma, be at least 18 years of age, have a Karnofsky performance status (KPS) of at least 60, and normal organ and marrow function. Patients also needed to have plans to initiate radiation treatment within 14 to 42 days after surgical resection and be negative for 

 R132H mutation on immunohistochemistry. Standard-of-care assays also needed to detect evidence that the MGMT promoter is unmethylated.

Those who received prior therapy apart from surgery, had significant intratumoral hemorrhage, were taking EIAED, received greater than 4 mg of decadron, had uncontrolled intercurrent illness, or impairment of gastrointestinal function, were excluded. Moreover, patients with a history of a different malignancy, unless disease free for at least 2 years and determined by study investigator to be at low risk for recurrence of that malignancy, were also excluded.

After patients with newly diagnosed unmethylated glioblastoma underwent genotyping for biomarker subgrouping, they underwent randomization. In the control arm, patients underwent radiation at 6000 cGy and temozolomide at a daily dose of 75 mg/m2 for 42 days followed by a 4-week break, and adjuvant temozolomide at a once daily dose ranging from 150 mg/m2 to 200 mg/m2 for 5 days and 6 treatment cycles.

There were 3 investigative arms to the trial. In 1 arm, patients received radiation plus temozolomide followed by adjuvant abemaciclib (Verzenio). In another arm, patients were given radiation plus CC-115 followed by adjuvant CC-115. In the last investigative arm, patients were administered radiation plus temozolomide followed by adjuvant neratinib given at a daily dose of 240 mg in 28-day cycles until disease progression or unacceptable toxicity.

The primary objective of the research was to identify whether any of the experimental approaches improved OS in patients with glioblastoma whose tumors harbored unmethylated MGMT promoters vs standard therapy with temozolomide.

Key secondary objectives included determining whether specific a priori defined biomarkers could predict benefit from investigative therapy, assessing the toxicity in investigative arms, evaluating PFS in investigative arms and biomarker subsets, assessing OS in investigative arms and biomarker subsets, and determining the link between PFS and OS effects in the investigative arms.

Data from the neratinib arm were shared during the meeting. The median age of those in the neratinib arm was 60 years (range, 24-78) vs 59 years (range, 24-75) in the control arm. In the investigative and control arms, 46% and 41% of patients, respectively, were male; 74% and 63% were Caucasian; 79% and 65% were non-Hispanic, 31% and 40% had a KPS of 90; 43% and 30% had 

Safety data showed that neratinib was generally well tolerated, with reported toxicities mirroring previously reported data. Notably, no new toxicity signals were identified with the agent, and no patients experienced a grade 4 adverse effect (AE).

Nineteen grade 3 AEs associated with the study drug were reported, and they included colitis (n = 1), diarrhea (n = 6), fatigue (n = 2), sepsis (n = 1), urinary tract infection (n = 1), alanine aminotransferase increased (n = 1), platelet count decreased (n = 1), anorexia (n = 1), dehydration (n = 1), hypokalemia (n = 1), generalized muscle weakness (n = 1), hypertension (n = 1), and surgical and medical procedures (n = 1).

“[These are] the first data demonstrating an effect of neratinib in 

-amplified or -mutated glioblastoma,” Alan H. Auerbach, chief executive officer and president of Puma Biotechnology, added in the press release.2 “While we are not looking to pursue further clinical investigations of neratinib in this indication, we are evaluating the potential to develop a backup compound, HKI-357, which has preclinically demonstrated better 

Arrillaga-Romany I, Trippa L, Fell G, et al. Preliminary results of the neratinib arm in the individualized screening trial of innovative glioblastoma therapy (INSIGhT): a phase II platform trial using Bayesian adaptive randomization. Presented at Society for Neuro-Oncology Annual Meeting; November 17-21, 2021; Boston, MA. Accessed March 2, 2022.

Puma Biotechnology presents data from the neratinib arm of the INSIGhT Trial at the 2021 SNO annual meeting. News release. Puma Biotechnology; November 20, 2021. Accessed March 2, 2022. 

This article was originally published on OncLive as “Adjuvant Neratinib Misses Primary End Point of OS in Glioblastoma, But Significantly Prolongs PFS in EGFR+ Subset”

Although adjuvant neratinib was not found to improve progression-free or overall survival across a population of patients with glioblastoma, the agent yielded promising progression-free survival rates in a subset of patients with EGFR-positive disease. 

Adjuvant Neratinib Does Not Improve Overall Survival in Glioblastoma, Yet May Offer Benefit for EGFR+ Subset 

While there are numerous support services for patients with cancer, far fewer focus on the needs of caregivers. After realizing these needs, a group of researchers at the University of Alabama at Birmingham (UAB) created FamilyStrong, a telehealth support service for caregivers of patients who were recently diagnosed with grade IV brain tumors.

“They’re partners in care and delivering the majority of care in the home setting, and this is a very distressed group, often reporting their own mental and physical health suffering due to the care that they are providing,” said study author J. Nicholas Dionne-Odom, PhD, RN, ACHPN, FAAN, assistant professor at the UAB school of nursing and co-director of the Caregiver and Bereavement Support Services and UAB Center for Palliative and Supportive Care.

Family caregivers enrolled in the program were contacted by a palliative care nurse who performed monthly distress screenings, which were based on National Comprehensive Cancer Network (NCCN) patient screenings, adjusted for caregivers. Based on the results, the nurse would provide emotional, educational, problem-solving, and referral support.

“Providing this type of support is just an extension of what I see patient- and family-centered care,” Dionne-Odom said.

The majority of patients (79.3%) were spouses/partners to patients. Average age was 53.5, and more than half (62.3%) were female.

Common problems that caregivers wanted help addressing were:

Managing their loved one’s health conditions and symptoms (51%)

Planning for the future/advanced care planning (17%)

Dionne-Odom said that FamilyStrong could be applied to other cancers and disease types, as he and his team made it so that it is straightforward, quick, and easy to use by a nurse, social worker, lay navigator, or any other professional along the disease trajectory. In fact, they are now examining the tool in family caregivers of those with Alzheimers and dementia.

“The uptake and scalability is very high for many different cancer centers to quickly implement and not be too burdensome for them to do so,” he said.

Regardless of what disease the patient has, having a healthy and happy caregiver can lead to better outcomes overall.

“In general, data seems to indicate that there is a correlation between a relatively high-functioning, low-distress caregiver, and being able to provide higher quality care to patients,” Dionne-Odom said.

Dionne-Odom JN, Williams GR, Warren PP, et. Al. Implementing a clinic-based telehealth support service (FamilyStrong) for family caregivers of individuals with grade IV brain tumors. 

Caregivers have their own set of issues and anxieties, but a telehealth support service may help. 

Telehealth Program Supports Family Caregivers of Patients With Brain Cancer

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.

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.

Brain Cancer