On June 17, 2019 T Medical Technologies, Inc., a company dedicated to improving the lives of patients with brain tumors, reported the presentation of clinical data from a prospective study of GammaTile Therapy in patients with previously irradiated intracranial neoplasms (brain tumors) at the American Brachytherapy Society (ABS) 2019 Annual Meeting in Miami (Press release, GT Medical Technologies, JUN 17, 2019, View Source [SID1234537120]). These data reinforce the safety profile of GammaTile Therapy, a surgically targeted radiation therapy (STaRT) that is designed to delay tumor regrowth for patients with recurrent intracranial neoplasms (brain tumors).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The company also announced that David Brachman, M.D., co-founder and CTO of GT MedTech, received the prestigious Judith Stitt Best Abstract Award for his abstract Surgically Targeted Radiation Therapy: Safety Profile of Collagen Tile Brachytherapy in 79 Recurrent, Previously Irradiated Intracranial Neoplasms on a Prospective Clinical Trial. Only four abstracts every year – out of hundreds of submissions – are selected by the ABS’s scientific committee for this recognition.

GammaTile is an FDA-cleared therapy for patients with recurrent intracranial neoplasms (brain tumors) including primary (benign or malignant) and metastatic tumors. Placed directly at the site of the tumor cavity during the last few minutes of excision surgery, GammaTile Therapy is a new approach that immediately begins targeting residual tumor cells, before they can replicate. Designed to help protect healthy brain tissue and facilitate rapid, accurate placement during the procedure, the therapy features a bioresorbable, conformable, 3D-collagen tile and uniform radiation source.

The prospective, single-arm study evaluated the safety profile of GammaTile Therapy in combination with tumor resection surgery in 79 recurrent brain tumors of various types, including gliomas, meningiomas, and brain metastases. Results from the study showed that GammaTile Therapy improves local tumor control compared to currently available treatments. The study also showed a low rate of adverse events, with wound infection occurring in 2.5% of tumors and radiation-related brain changes occurring in 8% of treated patients during the follow-up period. These findings suggest that GammaTile Therapy is a viable radiation therapy option for the challenging cohort of patients with recurrent brain tumors.

"These data further support the safety profile and efficacy of GammaTile Therapy for patients with brain tumors," said Dr. Brachman. "This therapy is designed to meet a significant unmet need for patients who may not be candidates for other forms of radiation therapy, or for whom surgery is not a viable option without effective adjuvant therapy. We are encouraged by these data, which build on our body of evidence supporting the safety and efficacy of this therapy."

GammaTile Therapy offers advantages over the most common treatment for patients undergoing surgery for recurrent brain tumors: a course of External Beam Radiation Therapy (EBRT), which requires daily treatments for up to six weeks. Some patients may not be candidates for EBRT. Once the disease has returned, many people with recurrent brain tumors have already received levels of radiation therapy that make the risk of additional external beam radiation outweigh the potential benefits. Additionally, those patients who are potentially candidates for EBRT typically have to wait two weeks or more for surgical wound healing before beginning treatment, giving any residual tumor cells a chance to replicate.

Initial data from this study were published this year in the Journal of Neurosurgery (JNS) demonstrating that GammaTile therapy is a safe and effective new option proven to delay tumor progression in patients with previously treated, aggressive meningiomas, the most common type of primary brain tumor. Additional data from this study supporting the safety and efficacy of GammaTile Therapy for various tumor types were presented in April at the American Association of Neurological Surgeons Annual Meeting, affirming that this therapy could help expand options for brain tumors that are challenging to treat.

About GammaTile Therapy

GammaTile Therapy is an FDA-cleared, surgically targeted radiation therapy (STaRT) that is designed to delay tumor regrowth for patients with brain tumors. Featuring a bioresorbable, conformable, 3D-collagen tile and uniform radiation source, GammaTile Therapy is placed at the end of excision surgery so that it immediately begins to target residual tumor cells while limiting the impact of radiation on healthy brain tissue. Because the therapy is implanted at the end of surgery, patients treated with GammaTile Therapy require no additional trips to the hospital or clinic for radiation therapy.

On June 17, 2019 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly-targeted and immuno-oncology drugs for the treatment of cancer, reported that it has entered into a mutual agreement with Celgene Corporation to terminate the parties’ global collaboration for tislelizumab, BeiGene’s investigational anti-PD-1 antibody, in advance of the pending acquisition of Celgene by Bristol-Myers Squibb (Press release, BeiGene, JUN 17, 2019, View Source [SID1234537119]). In connection with the termination, Celgene has agreed to pay $150 million to BeiGene.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"Our collaboration with Celgene was instrumental for the late-stage clinical development of tislelizumab and has provided us with significant resources to continue our broad clinical program," said John V. Oyler, Co-Founder, Chief Executive Officer, and Chairman of BeiGene. "As we have been leading most of the ongoing Phase 3 or potentially registration-enabling trials with a global development organization of over 800 people, we believe that we are well-positioned to continue the development of tislelizumab. I am proud of the work that we have accomplished in collaboration with Celgene and am excited by the tremendous opportunity that we have ahead now that we’ve regained full global rights to tislelizumab."

Tislelizumab has been dosed in over 2,950 patients globally. With two new drug applications under review in China, BeiGene expects tislelizumab to receive its first regulatory approval later this year.

In July 2017, BeiGene and Celgene announced a global strategic collaboration in which Celgene obtained exclusive rights to develop and commercialize tislelizumab in solid tumor cancers in the United States, Europe, Japan and the rest of world outside of Asia. BeiGene retained rights in hematology indications globally and in solid tumor cancers in Asia (ex-Japan). In connection with that agreement, BeiGene also acquired Celgene’s commercial operations in China and an exclusive license to Celgene’s cancer commercial portfolio in China (ABRAXANE, REVLIMID, VIDAZA). BeiGene’s commercial license from Celgene is not affected by the termination of the tislelizumab agreement. In the almost two years since the transaction, BeiGene has grown its commercial organization in China to more than 600 people.

About Tislelizumab

Tislelizumab (BGB-A317) is an investigational humanized IgG4 anti–PD-1 monoclonal antibody specifically designed to minimize binding to FcγR on macrophages. In pre-clinical studies, binding to FcγR on macrophages has been shown to compromise the anti-tumor activity of PD-1 antibodies through activation of antibody-dependent macrophage-mediated killing of T effector cells. Tislelizumab is the first drug candidate produced from BeiGene’s immuno-oncology biologic program, and is being developed as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid tumor and hematologic cancers.

Tislelizumab is being studied in a broad clinical program. BeiGene has completed a pivotal Phase 2 clinical trial in patients with relapsed or refractory (R/R) classical Hodgkin’s lymphoma (cHL). Ongoing clinical trials of tislelizumab include a Phase 3 clinical trial in patients with second-line or third-line non-small cell lung cancer (NSCLC); a Phase 3 clinical trial in first-line patients with hepatocellular carcinoma (HCC); a Phase 3 clinical trial in second-line patients with esophageal squamous carcinoma (ESCC); a Phase 3 clinical trial in first-line patients with gastric cancer (GC); a Phase 3 clinical trial in first-line patients with ESCC; a Phase 2 clinical trial in second- or third-line patients with HCC; and a Phase 1 clinical trial in patients with R/R NK/T-cell lymphomas. The aforementioned studies are enrolling patients in multiple countries, including the U.S., Europe, and China.

Additionally, BeiGene is conducting a Phase 3 clinical trial in first-line patients with non-squamous NSCLC; a Phase 3 clinical trial in first-line patients with squamous NSCLC; a Phase 3 clinical trial in patients with nasopharyngeal cancer (NPC); a Phase 3 clinical trial in first-line patients with urothelial carcinoma (UC); a pivotal Phase 2 clinical trial in patients with locally advanced or metastatic urothelial cancer; and a pivotal Phase 2 trial in patients with MSI-H or dMMR solid tumors. These studies are enrolling patients in China.

New drug applications (NDA) for tislelizumab in patients with R/R cHL and in patients with locally advanced or metastatic UC have been accepted by the China National Medical Products Administration (NMPA, formerly known as CFDA) and the R/R cHL filing has been granted priority review.

On June 17, 2019 Verastem, Inc. (Nasdaq:VSTM) (Verastem Oncology or the Company), a biopharmaceutical company focused on developing and commercializing medicines seeking to improve the survival and quality of life of cancer patients, reported that two posters highlighting clinical data for COPIKTRA (duvelisib) in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) were presented at the European Hematology Association (EHA) (Free EHA Whitepaper) 2019 Annual Meeting which took place June 13-16, 2019, in Amsterdam (Press release, Verastem, JUN 17, 2019, View Source;p=irol-newsArticle&ID=2401532 [SID1234537118]). One poster describes results from a post-hoc analysis evaluating the effect of COPIKTRA on lymphocytosis in patients with relapsed or refractory CLL/SLL from the Phase 3 DUO study, including patients with high-risk factors. The other poster describes dose modification data from patients with relapsed or refractory CLL/SLL in the DUO study.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

COPIKTRA, a targeted oral inhibitor of phosphoinositide 3-kinase (PI3K), and the first approved dual inhibitor of PI3K-delta and PI3K-gamma, received approval as monotherapy from the U.S. Food and Drug Administration (FDA) in September 2018 for the treatment of patients with relapsed or refractory CLL/SLL after at least two prior therapies.

"Duvelisib is a potent oral dual inhibitor of PI3K-delta and -gamma with clinical activity in patients with CLL/SLL after at least two prior therapies," said Hagop Youssoufian, MSc, M.D., Head of Medical Strategy at Verastem Oncology. "In a post-hoc analysis authored by Dr. Barrientos and colleagues, duvelisib induced rapid and transient lymphocytosis that was associated with a reduction in lymphadenopathy, including in high-risk patients. Notably, duvelisib also resulted in resolution of lymphocytosis at up to 21 weeks, and the majority of patients achieved a lymph node response and also achieved rapid shrinkage of their lymph nodes."

Patterns of Duvelisib-Induced Lymphocytosis in Patients with Relapsed/Refractory CLL/SLL, Including Those with High-Risk Factors

In this study, researchers aimed to characterize the clinical profile and kinetics associated with duvelisib-related lymphocytosis. Lymphocytosis is an increase in the number of lymphocytes (white blood cells) in the blood and is a recognized biological marker of treatment with B-cell receptor pathway inhibitors. Similar to ibrutinib and idelalisib, duvelisib treatment induces lymphocytosis in patients with CLL. This post hoc analysis defined response in patients (n=158) with relapsed or refractory CLL/SLL, including high-risk subgroups, which were characterized by unmutated IGHV (n=110), 17p deletion/TP53 mutation (n=48), 11q deletion (n=38), and bulky disease (n=74).

Of 158 patients treated with duvelisib, 78% experienced lymphocytosis. Median time to onset of lymphocytosis was one week across all patients, including patients in the high-risk subgroups. Median time to resolution of lymphocytosis was 14 weeks, with a 50% reduction from baseline at 21 weeks. Similar results were observed regardless of high-risk status. Rapid shrinkage of lymph nodes was noted, with 86% of patients achieving lymph node response. Among patients who achieved a response with duvelisib at first or second assessment, 78% and 86%, respectively, experienced lymphocytosis; median time to resolution of lymphocytosis in these patients was 12 and 18 weeks, respectively. Prolonged lymphocytosis (for >12 months) occurred in 12 patients (8%). The overall response rate in patients with prolonged lymphocytosis was 83%. Of note, the median PFS was similar among patients with and without prolonged lymphocytosis; 22.1 months (95% CI, 12.9-27.6), compared to 24 months (95% CI, 20.5-NE), respectively. Overall, there were low rates of tumor lysis syndrome (1 patient; 0.6%). These results showed that duvelisib monotherapy induced rapid and transient lymphocytosis temporally associated with a reduction in lymphadenopathy in patients with relapsed or refractory CLL/SLL.

Effect of Dose Modification on Response to COPIKTRA in Patients with Relapsed or Refractory CLL/SLL in the Phase 3 DUO Study

The randomized, multicenter, open-label, Phase 3 DUO study, compared COPIKTRA versus ofatumumab in 319 adult patients with CLL (n=312) or SLL (n=7) after at least one prior therapy. The study randomized patients with a 1:1 ratio to receive either COPIKTRA 25mg twice daily until disease progression or unacceptable toxicity, or ofatumumab, an approved standard of care treatment for use in CLL/SLL, for 7 cycles. This analysis examined dose modification patterns and their impact on response to COPIKTRA. Dose interruptions or dose reductions to 15mg, 10mg or 5mg twice daily were permitted per study protocol to manage treatment-emergent adverse events (TEAEs). Responses were assessed per an Independent Review Committee.

Among the 158 COPIKTRA-treated patients in the DUO study, the median duration of exposure was 11.6 months, versus 5.3 months for patients treated with ofatumumab. The most common cause of dose interruption was diarrhea (23%), followed by neutropenia (12%) and pneumonia or colitis (11% each). Among responders (n=118), median time to first response on COPIKTRA was 1.9 months and the estimated median duration of response was 11.1 months. Median time to first dose interruption was 3.9 months and median duration of dose interruption was 15 days (range 1 to 133 days). Response to COPIKTRA was improved or maintained in most patients evaluated for response who had at least one dose interruption for >1 week (84%) or >2 weeks (82%) followed by at least 3 weeks on COPIKTRA. In a landmark analysis, median PFS was similar in patients with dose interruptions and those without dose interruptions for >1 week (17.8 versus 16.3 months) or >2 weeks (17.8 versus 16.3 months) within the first 3 months. The median time to dose reduction after a complete response or partial response was 5.6 months (n=25) and median duration was 3.4 months. Median time to onset across adverse events of special interest (AESIs) after starting COPIKTRA ranged from 2.2 to 4.3 months. Median time to resolution was within 4 weeks across AESIs. Proportions of patients experiencing AESIs were stable or decreased over time after 3-6 months: 0-3 months, 64%; >3-6 months, 63%; >6-9 months, 47%; >9-12 months, 52%, and seldom led to discontinuation of COPIKTRA (≤10%). These findings support the thesis that dose interruptions or dose reductions may be useful in managing TEAEs with COPIKTRA and that dose interruptions of >1-2 weeks or more did not appear to significantly impact response to COPIKTRA or PFS.

PDF copies of these poster presentations are available here.

Details for the EHA (Free EHA Whitepaper) 2019 poster presentations are as follows:

Title: Effect of dose modifications on response to duvelisib in patients with relapsed/refractory (R/R) CLL/SLL in the DUO trial
Lead author: Paolo Ghia, Università Vita-Salute San Raffaele
Session: 6. Chronic lymphocytic leukemia and related disorders – Clinical
Abstract #: PS1157
Title: Patterns of duvelisib-induced lymphocytosis in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic leukemia including those with high-risk factors treated in the DUO trial
Lead author: Jacqueline Barrientos, Zucker School of Medicine at Hofstra/Northwell
Session: 6. Chronic lymphocytic leukemia and related disorders – Clinical
Abstract #: PS1160
Important Safety Information

WARNING: FATAL AND SERIOUS TOXICITIES: INFECTIONS, DIARRHEA OR COLITIS, CUTANEOUS REACTIONS, and PNEUMONITIS

•Fatal and/or serious infections occurred in 31% of COPIKTRA-treated patients. Monitor for signs and symptoms of infection. Withhold COPIKTRA if infection is suspected.

•Fatal and/or serious diarrhea or colitis occurred in 18% of COPIKTRA-treated patients. Monitor for the development of severe diarrhea or colitis. Withhold COPIKTRA.

•Fatal and/or serious cutaneous reactions occurred in 5% of COPIKTRA-treated patients. Withhold COPIKTRA.

•Fatal and/or serious pneumonitis occurred in 5% of COPIKTRA-treated patients. Monitor for pulmonary symptoms and interstitial infiltrates. Withhold COPIKTRA.

WARNINGS AND PRECAUTIONS

Infections: Serious, including fatal (4%), infections occurred in 31% of patients receiving COPIKTRA (N=442). The most common serious infections were pneumonia, sepsis, and lower respiratory infections. Median time to onset of any grade infection was 3 months, with 75% of cases occurring within 6 months. Treat infections prior to initiation of COPIKTRA. Advise patients to report new or worsening signs and symptoms of infection. Cases of Pneumocystis jirovecii pneumonia (PJP) (1%) and cytomegalovirus (CMV) reactivation/infection (1%) occurred in patients taking COPIKTRA. Provide prophylaxis for PJP during treatment and following completion of treatment until the absolute CD4+ T cell count is greater than 200 cells/µL. Consider prophylactic antivirals during COPIKTRA treatment to prevent CMV infection including CMV reactivation.

Diarrhea or Colitis: Serious, including fatal (<1%), diarrhea or colitis occurred in 18% of patients receiving COPIKTRA (N=442). Median time to onset of any grade diarrhea or colitis was 4 months, with 75% of cases occurring by 8 months. The median event duration was 0.5 months. Advise patients to report any new or worsening diarrhea.

Cutaneous Reactions: Serious, including fatal (<1%), cutaneous reactions occurred in 5% of patients receiving COPIKTRA (N=442). Fatal cases included drug reaction with eosinophilia and systemic symptoms (DRESS) and toxic epidermal necrolysis (TEN). Median time to onset of any grade cutaneous reaction was 3 months with a median event duration of 1 month. Presenting features for the serious events were primarily described as pruritic, erythematous, or maculo-papular. Less common presenting features include exanthem, desquamation, erythroderma, skin exfoliation, keratinocyte necrosis, and papular rash. Advise patients to report new or worsening cutaneous reactions.

Pneumonitis: Serious, including fatal (<1%), pneumonitis without an apparent infectious cause occurred in 5% of patients receiving COPIKTRA (N=442). Median time to onset of any grade pneumonitis was 4 months with 75% of cases occurring within 9 months. The median event duration was 1 month with 75% of cases resolving by 2 months.

Hepatotoxicity: Grade 3 and 4 ALT and/or AST elevation developed in 8% and 2%, respectively, of patients receiving COPIKTRA (N=442). Two percent of patients had both an ALT or AST > 3 X ULN and total bilirubin > 2 X ULN. Median time to onset of any grade transaminase elevation was 2 months with a median event duration of 1 month. Monitor hepatic function during treatment with COPIKTRA.

Neutropenia: Grade 3 or 4 neutropenia occurred in 42% of patients receiving COPIKTRA (N=442), with Grade 4 neutropenia occurring in 24% of all patients. Median time to onset of grade ≥3 neutropenia was 2 months. Monitor neutrophil counts at least every 2 weeks for the first 2 months of COPIKTRA therapy, and at least weekly in patients with neutrophil counts < 1.0 Gi/L (Grade 3-4).

Embryo-Fetal Toxicity: COPIKTRA can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus and conduct pregnancy testing before initiating COPIKTRA treatment. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose.

ADVERSE REACTIONS

B-cell Malignancies Summary

Fatal adverse reactions within 30 days of the last dose occurred in 8% (36/442) of patients treated with COPIKTRA 25 mg BID. Serious adverse reactions were reported in 289 patients (65%). The most frequent serious adverse reactions that occurred were infection (31%), diarrhea or colitis (18%), pneumonia (17%), rash (5%), and pneumonitis (5%). The most common adverse reactions (reported in ≥20% of patients) were diarrhea or colitis, neutropenia, rash, fatigue, pyrexia, cough, nausea, upper respiratory infection, pneumonia, musculoskeletal pain and anemia.

CLL/SLL

Fatal adverse reactions within 30 days of the last dose occurred in 12% (19/158) of patients treated with COPIKTRA and in 4% (7/155) of patients treated with ofatumumab. Serious adverse reactions were reported in 73% (115/158) of patients treated with COPIKTRA and most often involved infection (38%; 60/158) and diarrhea or colitis (23%; 36/158). The most common adverse reactions with COPIKTRA (≥20% of patients) were diarrhea or colitis, neutropenia, pyrexia, upper respiratory tract infection, pneumonia, rash, fatigue, nausea, anemia and cough.

For specific information on the management of the adverse reactions above, please review Dose Modifications for Adverse Reactions within the full Prescribing Information.

DRUG INTERACTIONS

CYP3A Inducers: Coadministration with a strong CYP3A inducer may reduce COPIKTRA efficacy. Avoid coadministration with strong CYP3A4 inducers.

CYP3A Inhibitors: Coadministration with a strong CYP3A inhibitor may increase the risk of COPIKTRA toxicities. Reduce COPIKTRA dose to 15 mg BID when coadministered with a strong CYP3A4 inhibitor.

CYP3A Substrates: Coadministration of COPIKTRA with sensitive CYP3A4 substrates may increase the risk of toxicities of these drugs. Consider reducing the dose of the sensitive CYP3A4 substrate and monitor for signs of toxicities of the coadministered sensitive CYP3A substrate.

To report Adverse Reactions, contact FDA at 1-800-FDA-1088 (1-800-332-1088) or www.fda.gov/medwatch and Verastem Oncology at 1-877-7RXVSTM (1-877-779-8786).

Please see accompanying full Prescribing Information, including Boxed Warning.

About Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are cancers that affect lymphocytes and are essentially the same disease, with the only difference being the location where the cancer primarily occurs. When most of the cancer cells are located in the bloodstream and the bone marrow, the disease is referred to as CLL, although the lymph nodes and spleen are often involved. When the cancer cells are located mostly in the lymph nodes, the disease is called SLL. The symptoms of CLL/SLL include a tender, swollen abdomen and feeling full even after eating only a small amount. Other symptoms can include fatigue, shortness of breath, anemia, bruising easily, night sweats, weight loss, and frequent infections. However, many patients with CLL/SLL will live for years without symptoms. There are approximately 200,000 patients in the US affected by CLL/SLL with nearly 20,000 new diagnoses this year alone. While there are therapies currently available, real-world data reveals that a significant number of patients either relapse following treatment, become refractory to current agents, or are unable to tolerate treatment, representing a significant medical need. The potential of additional oral agents, particularly as a monotherapy that can be used in the general community physician’s armamentarium, may hold significant value in the treatment of patients with CLL/SLL.

About COPIKTRA (duvelisib)

COPIKTRA is an oral inhibitor of phosphoinositide 3-kinase (PI3K), and the first approved dual inhibitor of PI3K-delta and PI3K-gamma, two enzymes known to help support the growth and survival of malignant B-cells. PI3K signaling may lead to the proliferation of malignant B-cells and is thought to play a role in the formation and maintenance of the supportive tumor microenvironment.1,2,3 COPIKTRA is indicated for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) after at least two prior therapies and relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies. COPIKTRA is also being developed by Verastem Oncology for the treatment of peripheral T-cell lymphoma (PTCL), for which it has received Fast Track status, and is being investigated in combination with other agents through investigator-sponsored studies.4 For more information on COPIKTRA, please visit www.COPIKTRA.com. Information about duvelisib clinical trials can be found on www.clinicaltrials.gov.

On June 17, 2019 Medigene AG (FWB: MDG1, Prime Standard) reported that clinical data from the interim analysis of the ongoing Phase I / II clinical trial with Medigene’s DC vaccine for the treatment of acute myeloid leukemia was presented during the annual congress of the European Hematology Association (EHA) (Free EHA Whitepaper) taking place from 13 – 16 June in Amsterdam (Press release, MediGene, JUN 17, 2019, View Source [SID1234537117]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The poster presented was entitled "Interim Analysis of a WT-1 and PRAME ` Fast-DC´ vaccine shows safety as active immunotherapy for the prevention of AML relapse". The primary objectives of the study enrolling 20 AML patients are the safety and feasibility of this active immunotherapy with patient-derived DCs produced according to Medigene’s proprietary technology.

The data presented was generated over a period of one year of vaccination of all patients representing an interim dataset after half of the treatment period. Topline data of this interim analysis was already published on 19 December 2018, demonstrating a very good feasibility for manufacture of the vaccines as well as an excellent safety profile and encouraging data on overall survival and progression-free survival (Link to press release: View Source).

In addition, the data presented at EHA (Free EHA Whitepaper) included details about the mutational load status of patients who relapsed.

Clinical trial outline: A total of 20 subjects (median age 59, range 24 to 73) with AML (risk groups good, intermediate, poor: 13, 5, 2), in morphologic complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) after induction or consolidation therapy, not eligible for allogeneic hematopoietic stem cell transplantation, were enrolled into this safety and feasibility Phase I/II trial, vaccinated and followed up for 12 months at the interim analysis timepoint. Subjects in this trial had AML that was positive for Wilms Tumor-1 (WT-1) antigen with or without positivity for Preferentially Expressed Antigen in Melanoma (PRAME). Vaccination with dendritic cells, presenting the antigens WT-1 and PRAME, was carried out monthly, with a higher frequency within the first 6 weeks. AML diagnoses had been established with a median of 9.8 months before the first vaccination (range 4.5 to 17.5 months), and the last chemotherapy infusion had been performed at a median of 6.9 months (range 2 to 14.8 months).

Interim results: The vaccinations were well tolerated with no serious adverse events (SAEs) related to the treatment. The most common adverse events (AEs) were injection site related, accounting for 35% of all AEs and mild in nature (Grade 1). The feasibility of the manufacture of the dendritic cell vaccine in these chemotherapy-pretreated subjects was already presented at AACR (Free AACR Whitepaper) in 2018 (Link to poster: View Source).

After a 12-months treatment period, the overall survival was 89% (18 of 20 patients, 95% confi-dence interval: 61 to 97%) and the progression free survival was 60% (12 of 20 patients, 95% confidence interval: 36 to 78%). Most relapses, 5 out of 8, occurred within the first 80 days after initiation of vaccination, suggesting a possible molecular relapse upon entering the study.

The presence of common mutations was analyzed in all patients via next generation sequencing and two of the five early relapses showed mutational load upon entering the study (IDH2 and DNMT3A mutation in one patient and multiple mutations in the second (RUNX1, KRAS, ETV6, BCOR, DNMT3A). Two of the later relapses also showed mutational load before vaccination, one patient with a KRAS and TET2 mutation and one patient with multiple mutations (RUNX1, IDH2, SRSF2 and DNMT3A).

Dr. Kai Pinkernell, CMO and CDO of Medigene AG, comments: " We are pleased that the interim results after one year of treatment show an excellent safety profile, a very good manufacturability and encouraging overall and progression free survival data. In addition, the mutational load analysis may also allow patients to be stratified in future clinical trials."

The completion of the ongoing trial is scheduled for the end of 2019, following a two-year treatment period.

About acute myeloid leukaemia (AML): Acute myeloid leukaemia is a malignant disease of the hematopoietic system, affecting mainly adults above 60 years of age. In Germany, about 3,600 cases are registered annually.

AML is caused by uncontrolled growth of dysfunctional hematopoietic precursor cells in the bone marrow. These cells prevent the generation of normal blood cells, causing a decrease in erythrocytes and platelets, for example. Typical symptoms of AML include anemia, fever, increased risk of infection, and bleeding. AML progresses rapidly and may be fatal within a few weeks or months, if untreated.

AML treatment is often started with intensive chemotherapy, followed by consolidation with or without allogeneic hematopoietic stem cell transplantation. Unfortunately, a significant proportion of patients suffer a relapse of the original disease. Depending on the biologic risk profile of the disease, age and co-morbidity the long-term survival is highly variable.

About Medigene’s DC vaccines: In addition to Medigene’s development focus on T cell-receptor modified T cells (TCR-Ts), the Company has developed a new generation of antigen-tailored dendritic cell (DC) vaccines.

Dendritic cells (DC) can take up antigens, process them and present peptides on their surface in a form that can induce antigen-specific T cells to mature and proliferate. In this way, T cells recognize and eliminate tumor cells which bear the same antigen peptide on their surface. Dendritic cells can also induce natural killer cells (NK cells) to attack tumor cells. The scientific team of Medigene has developed new, fast and efficient methods for generating autologous (patient-specific) mature dendritic cells which have the relevant characteristics to generate very strong T cell and NK cell immune responses. The dendritic cells can be loaded with various tumor antigens to treat different forms of cancer. Since an immune response builds up over the total time of administration of the DC vaccine, this form of therapy is particularly designed for patients who suffer from a tumor disease which has been reduced to such an extent by chemotherapy that the prevention of the recurrence of the tumor disease is the main goal.

On June 17, 2019 Celyad (Euronext Brussels and Paris, and Nasdaq: CYAD), a clinical-stage biopharmaceutical company focused on the development of CAR-T cell therapies, reported that updated clinical data for the CYAD-01 program in r/r AML and MDS was presented in a poster presentation session on Saturday, June 15 at the 24th Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Amsterdam, Netherlands (Press release, Celyad, JUN 17, 2019, View Source [SID1234537116]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Dr. Frédéric Lehmann, VP of Clinical Development & Medical Affairs at Celyad, commented,"Our observations from the Phase 1 THINK clinical trial evaluating CYAD-01 without prior lymphodepletion in relapsed/refractory acute myeloid leukemia and myelodysplastic syndrome patients show the cell therapy is generally well tolerated. Encouragingly, this safety and tolerability profile was also demonstrated during the early stages of CYAD-01 treatment intensification where an increased systemic persistence of CAR-T cells is obtained after reduced interval dosing or in combination with preconditioning chemotherapy. As such, we continue to focus our efforts on increasing the aggressiveness of CYAD-01 to potentially deepen the breadth, frequency and duration of clinical responses in this refractory patient population."

THINK Phase 1 Trial in Hematological Malignancies Update

As of May 23 2019, preliminary anti-leukemic activity has been observed in six out of thirteen patients (46%) evaluable per protocol in the THINK Phase 1 trial with four out of thirteen patients (31%) exhibiting objective responses, including one out of the four patients experiencing a duration of response of over 90 days
Overall, multiple infusions of CYAD-01 without any prior preconditioning chemotherapy continues to show an encouraging tolerability profile with eight patients from over twenty treated experiencing grade 3/4 treatment-related adverse events (AEs). No neurotoxicity AEs have been observed in any patient receiving CYAD-01.
The denser schedule of infusions in the absence of any bridging or preconditioning chemotherapy without preconditioning chemotherapy evaluated in Cohort 10 showed that of three r/r AML or MDS patients evaluable, one patient experienced disease stabilization and two patients had disease progression following treatment with up to six doses of 1 billion cells of CYAD-01.
The denser dosing schedule was generally reported to be well-tolerated. Three patients of four patients evaluable for safety in Cohort 10 experienced grade 1/2 cytokine release syndrome (CRS), which showed rapid resolution following the appropriate treatment, including tocilizumab. One patient experienced a grade 4 infusion reaction, which was not considered to be a dose-limiting toxicity of the therapy
Overall, better time-averaged engraftment (area under the curve) was observed with a reduced interval dosing (Cohort 10) as compared to the equivalent dose of the THINK trial evaluating a cycle of three injections of CYAD-01 administered every two weeks.
Recruitment in Cohort 11 of the THINK trial evaluating the denser schedule of up to six infusions of three billion cells of CYAD-01 without preconditioning chemotherapy is ongoing and results are expected by the end of 2019.

DEPLETHINK Phase 1 Trial Update

The initial cohorts of the DEPLETHINK trial enrolled six r/r AML or MDS patients who received a single administration of a safety-precaution low-dose CYAD-01 (100 million cells per infusion) following preconditioning chemotherapy consisting of cyclophosphamide and fludarabine, or CyFlu, at two different time-intervals (three or seven days) between the preconditioning regimen and administration of CYAD-01.
As of May 23, 2019, three patients experienced grade 1/2 CRS, which showed rapid resolution following the appropriate treatment, including tocilizumab. One patient experienced a grade 4 infusion reaction, which was not considered to be a dose-limiting toxicity of the therapy, during the consolidation cycle without preconditioning.
Of the five patients evaluable per protocol, two patients experienced disease stabilization following treatment with CYAD-01.
Better time-averaged engraftment was observed after a single infusion of low-dose CYAD-01 with prior preconditioning compared to the dose-escalation segment of the THINK trial evaluating a cycle of three injections of CYAD-01.
Evaluation of higher dose-levels comparable to the Phase 1 THINK trial, including 300 million and 1 billion cells, are ongoing in the dose-escalation trial and preliminary results from these cohorts are expected by year-end 2019.
Background on THINK Phase 1 Trial

The THINK trial (NCT03018405) is an open-label, dose-escalation Phase 1 trial assessing the safety and clinical activity of multiple CYAD-01 administrations without prior preconditioning. The dose escalation segment of the trial evaluated three dose levels (300 million, 1 billion and 3 billion cells per infusion) of one cycle of three CYAD-01 administrations with two-week intervals.

In 2018, the THINK trial was amended to add two cohorts to assess a more frequent dosing schedule of CYAD-01 for the treatment of r/r AML. The cohorts will evaluate six injections of CYAD-01 without preconditioning over two months of administration. The first cycle includes three infusions of CYAD-01 separated by one-week intervals. The second cycle includes three infusions of CYAD-01 separated by two-week intervals. Patients will either receive 1 billion cells per infusion (Cohort 10) or 3 billion cells per infusion (Cohort 11). The primary endpoint of the trial is safety and secondary endpoints include clinical activity and pharmacokinetics.

Background on DEPLETHINK Phase 1 Trial

In October 2018, Celyad initiated the DEPLETHINK Phase 1 trial (NCT03466320). The open-label, dose-escalation trial will evaluate a single infusion of CYAD-01 following treatment with the standard preconditioning regimen of cyclophosphamide (300 mg/m²) and fludarabine (30 mg/m²), or CyFlu. The trial includes two different intervals between lymphodepletion and administration of CYAD-01. In addition, the trial will evaluate three dose levels of CYAD-01 including 100 million, 300 million and 1 billion cells per infusion, respectively. The primary endpoint of the trial is safety and secondary endpoints include clinical activity and pharmacokinetics.