On December 4, 2018 AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, reported its results from the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN), National Cancer Institute (NCI)-sponsored, Phase 3 study (E1912) evaluating IMBRUVICA (ibrutinib) plus rituximab versus the current National Comprehensive Cancer Network (NCCN) guidelines Category 1 treatment of fludarabine, cyclophosphamide and rituximab (FCR) in previously untreated younger patients (70 years old or younger) with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) (Press release, AbbVie, DEC 4, 2018, View Source [SID1234531879]).1,2 This interim analysis showed that IMBRUVICA plus rituximab significantly prolonged progression-free survival (PFS), the primary endpoint of the study, compared to FCR, with a 65 percent reduction in risk of progression or death. Furthermore, IMBRUVICA plus rituximab significantly improved overall survival (OS) compared to FCR. The findings were presented today during the Late-Breaker abstract oral session at the 2018 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, CA (abstract #LBA-4).

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This study evaluated 529 patients in the United States from centers spanning four cooperative groups. The study was led by ECOG-ACRIN with additional study site participation by SWOG, ALLIANCE and NRG Oncology, and was sponsored by the NCI in collaboration with Pharmacyclics LLC, an AbbVie company, through the existing Cooperative Research and Development Agreement with NCI. IMBRUVICA is a once-daily, first-in-class BTK inhibitor that is administered orally, and is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

"We have been eagerly awaiting a new treatment regimen that could help younger chronic lymphocytic leukemia patients. These findings further support IMBRUVICA-based therapy as an efficacious first-line treatment for many patients with CLL," said Danelle James, M.D., M.A.S., Head of Clinical Science, Pharmacyclics LLC, an AbbVie company. "We are proud to participate and collaborate with the National Cancer Institute and the Division of Cancer Treatment."

At a median follow-up of 33.4 months, IMBRUVICA plus rituximab showed superior PFS compared to FCR in younger and previously untreated CLL patients (HR: 0.35; 95% confidence interval [CI]: 0.22-0.56; p<0.0001). The study also demonstrated an improved OS for the IMBRUVICA plus rituximab treatment arm versus FCR (HR: 0.17; 95% CI: 0.05-0.54; p=0.0003).

CLL is one of the two most common forms of leukemia in adults and is a type of cancer that can develop from cells in the bone marrow that later mature into certain white blood cells (called lymphocytes).3 While these cancer cells start in the bone marrow, they then later spread into the blood. The prevalence of CLL is approximately 115,000 patients in the U.S. with approximately 20,000 newly diagnosed patients every year.4,5 CLL is predominately a disease of the elderly, with a median age at diagnosis ranging from 65-70 years.6

About Abstract #LBA-4: A Randomized Phase III Study of Ibrutinib (PCI-32765)-Based Therapy Vs. Standard Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in Untreated Younger Patients with Chronic Lymphocytic Leukemia (CLL): A Trial of the ECOG-ACRIN Cancer Research Group (E1912)

Late-Breaker Oral Presentation: Tuesday, December 4 at 7:30am PT

The Phase 3 study (E1912) evaluated previously untreated CLL patients age 70 or younger, who were randomly assigned to receive IMBRUVICA (420 mg/day until disease progression) and rituximab (50 mg/m2 on day 1 of cycle 2; 325 mg/m2 on day 2 of cycle 2; 500 mg/m2 on day 1 of cycles 3-7) (n=354) or six courses of intravenous fludarabine (25 mg/m2) and cyclophosphamide (250 mg/m2) days 1-3 with rituximab (50 mg/m2 on day 1 of cycle 1; 325 mg/m2 on day 2 of cycle 1; 500 mg/m2 on day 1 of cycles 2-6) every 28-days (n=175). The primary endpoint was PFS with a secondary endpoint of OS.

With a median follow-up of 33.4 months, the pre-determined, interim analysis observed 77 PFS events and 14 deaths. IMBRUVICA plus rituximab significantly improved PFS compared to FCR (HR: 0.35; 95% CI: 0.22-0.56; p<0.0001), which crossed the pre-specified boundary. The IMBRUVICA plus rituximab treatment arm also significantly improved OS compared to FCR (HR: 0.17; 95% CI: 0.05-0.54; p=0.0003, pre-specified boundary for superiority p=0.0005).

FCR was more frequently associated with Grade 3 and 4 neutropenia (FCR: 44 percent vs. IMBRUVICA plus rituximab: 23 percent; p<0.0001) and infectious complications (FCR: 18 percent vs. IMBRUVICA plus rituximab: 7 percent; p<0.0001). Grade 3 and 4 treatment-related adverse events were observed in 58 percent of IMBRUVICA plus rituximab treated patients and 72 percent of FCR treated patients (p=0.0042).

To view all IMBRUVICA company-sponsored or investigator-initiated studies being presented at ASH (Free ASH Whitepaper) 2018, please visit: View Source

About IMBRUVICA
IMBRUVICA (ibrutinib) is a first-in-class, oral, once-daily therapy that mainly works by inhibiting a protein called Bruton’s tyrosine kinase (BTK). BTK is a key signaling molecule in the B-cell receptor signaling complex that plays an important role in the survival and spread of malignant B cells.7 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.

IMBRUVICA is FDA-approved in six distinct patient populations: chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström’s macroglobulinemia (WM), along with previously-treated mantle cell lymphoma (MCL), previously-treated marginal zone lymphoma (MZL) and previously-treated chronic graft-versus-host disease (cGVHD).8

IMBRUVICA was first approved for adult patients with MCL who have received at least one prior therapy in November 2013.
Soon after, IMBRUVICA was initially approved in adult CLL patients who have received at least one prior therapy in February 2014. By July 2014, the therapy received approval for adult CLL patients with 17p deletion, and by March 2016, the therapy was approved as a frontline CLL treatment.
IMBRUVICA was approved for adult patients with WM in January 2015.
In May 2016, IMBRUVICA was approved in combination with bendamustine and rituximab (BR) for adult patients with CLL/SLL.
In January 2017, IMBRUVICA was approved for adult patients with MZL who require systemic therapy and have received at least one prior anti-CD20-based therapy.
In August 2017, IMBRUVICA was approved for adult patients with cGVHD that failed to respond to one or more lines of systemic therapy.
In August 2018, IMBRUVICA plus rituximab was approved for adult patients with WM.
Accelerated approval was granted for the MCL and MZL indications based on overall response rate. Continued approval for MCL and MZL may be contingent upon verification and description of clinical benefit in confirmatory trials.

IMBRUVICA has been granted four Breakthrough Therapy Designations from the U.S. FDA. This designation is intended to expedite the development and review of a potential new drug for serious or life-threatening diseases.9 IMBRUVICA was one of the first medicines to receive FDA approval via the new Breakthrough Therapy Designation pathway.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers and other serious illnesses. IMBRUVICA has one of the most robust clinical oncology development programs for a single molecule in the industry, with more than 130 ongoing clinical trials. There are approximately 30 ongoing company-sponsored trials, 14 of which are in Phase 3, and more than 100 investigator-sponsored trials and external collaborations that are active around the world. To date, more than 135,000 patients around the world have been treated with IMBRUVICA in clinical practice and clinical trials.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in 3% of patients, with fatalities occurring in 0.3% of 1,011 patients exposed to IMBRUVICA in clinical trials. Bleeding events of any grade, including bruising and petechiae, occurred in 44% of patients treated with IMBRUVICA.

The mechanism for the bleeding events is not well understood.

IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding.

Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections: Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 24% of 1,011 patients exposed to IMBRUVICA in clinical trials. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections.

Monitor and evaluate patients for fever and infections and treat appropriately.

Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (23%), thrombocytopenia (8%), and anemia (3%) based on laboratory measurements occurred in patients with B-cell malignancies treated with single agent IMBRUVICA.

Monitor complete blood counts monthly.

Cardiac Arrhythmias: Fatal and serious cardiac arrhythmias have occurred with IMBRUVICA therapy. Grade 3 or greater ventricular tachyarrhythmias occurred in 0.2% of patients, and Grade 3 or greater atrial fibrillation and atrial flutter occurred in 4% of 1,011 patients exposed to IMBRUVICA in clinical trials. These events have occurred particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmias.

Periodically monitor patients clinically for cardiac arrhythmias. Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias appropriately, and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.

Hypertension: Hypertension has occurred in 12% of 1,011 patients treated with IMBRUVICA in clinical trials with a median time to onset of 5 months (range, 0.03 to 22 months). Monitor patients for new onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA. Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive treatment as appropriate.

Second Primary Malignancies: Other malignancies (9%) including non-skin carcinomas (2%) have occurred in 1,011 patients treated with IMBRUVICA in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer (6%).

Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions.

Monitor patients closely and treat as appropriate.

Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA and for 1 month after cessation of therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Advise men to avoid fathering a child during the same time period.

ADVERSE REACTIONS

B-cell malignancies: The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia (58%)*, neutropenia (58%)*, diarrhea (42%), anemia (39%)*, rash (31%), musculoskeletal pain (31%), bruising (31%), nausea (28%), fatigue (27%), hemorrhage (23%), and pyrexia (20%).

The most common Grade 3 or 4 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (36%)*, thrombocytopenia (15%)*, and pneumonia (10%).

Approximately 6% (CLL/SLL), 14% (MCL), 14% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4%-10% (CLL/SLL), 9% (MCL), and 7% (WM [5%] and MZL [13%]) of patients discontinued due to adverse reactions.

cGVHD: The most common adverse reactions (≥20%) in patients with cGVHD were fatigue (57%), bruising (40%), diarrhea (36%), thrombocytopenia (33%)*, stomatitis (29%), muscle spasms (29%), nausea (26%), hemorrhage (26%), anemia (24%)*, and pneumonia (21%).

The most common Grade 3 or 4 adverse reactions (≥5%) reported in patients with cGVHD were fatigue (12%), diarrhea (10%), neutropenia (10%)*, pneumonia (10%), sepsis (10%), hypokalemia (7%), headache (5%), musculoskeletal pain (5%), and pyrexia (5%).

Twenty-four percent of patients receiving IMBRUVICA in the cGVHD trial discontinued treatment due to adverse reactions. Adverse reactions leading to dose reduction occurred in 26% of patients.

*Treatment-emergent decreases (all grades) were based on laboratory measurements and adverse reactions.

DRUG INTERACTIONS

CYP3A Inhibitors: Dose adjustments may be recommended.

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA in patients with severe baseline hepatic impairment. In patients with mild or moderate impairment, reduce IMBRUVICA dose.

On December 4, 2018 AUM Biosciences (AUM), a Singapore headquartered oncology-focused biotechnology company, reported that it has licensed its first novel, highly selective anti-cancer drug, ETC-206, from A*STAR’s Experimental Therapeutics Centre (ETC) (Press release, AUM BioSciences, DEC 4, 2018, View Source [SID1234533612]). The Agency for Science, Technology and Research (A*STAR) is Singapore’s lead public sector agency that spearheads economic oriented research to advance scientific discovery and develop innovative technology.

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AUM has licensed the global rights to develop, commercialize and manufacture ETC-206 in all indications. ETC-206 was discovered and developed through a collaboration between A*STAR’s Experimental Therapeutics Centre (ETC) and Duke-NUS Medical School (a partnership between Duke University School of Medicine and the National University of Singapore). It advanced into first-in-man trials in December 2016. Initial clinical studies suggest that ETC-206 is very well tolerated and could be used as a thera∂ßpy across a range of liquid and solid tumor types.

The drug promises a more targeted approach by inhibiting the Mnk enzyme in cancer cells, which is a key player in promoting cancer growth when activated. This could lower mortality rates for cancer and improve quality of life for cancer patients compared to traditional chemotherapy, which kills cells in a less specific fashion and affects more than just the cancer cells.

"Due to low efficacy and steep costs associated with many cancer treatments, the demand for more precise anti-cancer treatments has become imperative. AUM’s small molecule and biomarker driven approach allows us to implement innovative trial designs enabling "multiple shots on goal", in cancer treatment," AUM’s Chief Executive Officer, Mr. Vishal Doshi said.

ETC-206 is the first in AUM’s pipeline of novel targeted therapies with the potential to be developed both independently and in combination with other therapies. The drug’s ability to isolate and target only cancerous cells promises a breakthrough opportunity globally.

"ETC-206 is a prime example of how A*STAR has been able to translate R&D into positive outcomes to create economic growth and enhance lives for Singaporeans. We look forward to working closely with more Singapore based enterprises such as AUM Biosciences as we continue to leverage our drug discovery and development capabilities to support the growth of the local biotech ecosystem in Singapore." Said Dr Damian O’Connell, Chief Executive Officer of A*STAR’s Experimental Therapeutics Centre.

"Duke-NUS scientists and researchers have led many discoveries with great potential for the welfare of people in Singapore and beyond," stated Dr. David Epstein, Director of Duke-NUS’ Centre for Technology and Development (CTeD), and the School’s Vice Dean for Innovation and Entrepreneurship, who is also an associate professor of the Cancer and Stem Cell Biology Programme. "ETC-206 is an important accomplishment exemplifying Duke-NUS’s mission of facilitating the translation of basic research into commercial entities and products. We are proud to partner with A*STAR in realizing this enterprising venture that was ‘Made in Singapore’ and is being taken forward by AUM, a Singapore-based startup. We look forward to more startups creating entrepreneurship opportunities in the sector."

ETC-206’s licensing by AUM not only puts Singapore on the map, but also enables the company to be at the forefront of emerging oncology trends. This is a significant step towards its vision of "Asia to global" by accelerating the development of innovative and affordable medicines.

"We are now speaking with investors to accelerate ETC-206’s development and our broader molecule acquisition roadmap. AUM will fund further clinical development and will be responsible for regulatory filings, and for clinical studies for this and future drugs," Mr. Doshi commented.

As a future roadmap, AUM has a strategic focus of acquiring and developing promising small molecules targeted oncology assets to unlock their potential, including those that are de-prioritized or not progressed by their originators due to strategic and financial limitations in the healthcare industry. Its mandate of "No biomarker, No drug" serves to increase the probability of success.

Cancer prevalence in Asia is estimated at 17.4 million in 2018, with about 8.8 million new cases every year, accounting for about half of the new global cancer cases. The number of new cases in Asia is expected to increase from 8.8 million in 2018 to 11.8 million by 2030 creating a huge unmet medical need in Asia.

On December 4, 2018 G1 Therapeutics, Inc. (Nasdaq: GTHX), a clinical-stage oncology company, reported preliminary anti-tumor efficacy and myelopreservation data from its randomized, open-label Phase 2 trial evaluating trilaciclib in combination with chemotherapy as a treatment for metastatic triple-negative breast cancer (mTNBC) (Press release, G1 Therapeutics, DEC 4, 2018, View Source [SID1234531965]). These data will be presented on Wednesday, December 5 at a poster discussion Spotlight Session at the 2018 San Antonio Breast Cancer Symposium (SABCS), being held in San Antonio, Texas.

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The poster is now available on the Publications page of the company’s website.

"In settings such as metastatic triple-negative breast cancer where chemotherapy is dosed until disease progression, trilaciclib has the potential to deliver both multi-lineage myelopreservation and anti-tumor efficacy benefits to patients," said Raj Malik, M.D., Chief Medical Officer and Senior Vice President, R&D. "In this trial, we observed promising early progression-free survival results favoring trilaciclib, as well as myelopreservation benefits across neutrophils, red blood cells, platelets, and lymphocytes."

Trial Design

This randomized, open-label Phase 2 clinical trial enrolled 102 patients with mTNBC who had received 0-2 prior lines of therapy in the recurrent/metastatic setting. In this three-arm trial, all patients received a chemotherapy regimen of gemcitabine and carboplatin (GC). Patients were randomized to receive GC only or GC plus one of two dosing schedules of trilaciclib: trilaciclib administered on the day of chemotherapy (GC/Tx1) or trilaciclib administered the day prior to and the day of chemotherapy (GC/Tx2).

Key Trial Findings

Preliminary median progression-free survival (PFS) was 5.4 months in the GC arm, 8.8 months in the GC/Tx1 arm (hazard ratio 0.52, p=0.0669) and 7.3 months in the GC/Tx2 arm (hazard ratio 0.49; p=0.0546). A combined analysis of trilaciclib-treated patients showed PFS of 5.4 months for the GC arm and 7.9 months for trilaciclib (hazard ratio 0.50, p=0.0189).

Preliminary objective response rate (ORR) was 29.2% in the GC arm, 43.3% in the GC/Tx1 arm and 36.7% in the GC/Tx2 arm.

PFS and ORR in the control arm were consistent with historical data1.

Overall survival (OS) data is immature. OS and updated PFS and ORR will be reported when available.

J Clin Oncol 32:3840-3847

Patients in both trilaciclib groups remained on therapy for a longer duration of time compared to GC only (median weeks: GC=14.4; GC/Tx1=20.0 weeks; GC/Tx2=19.0 weeks).

On a per-patient basis, the number of patients experiencing myelosuppression events was similar across the three arms. When adjusted for the duration of chemotherapy, the trial demonstrated that patients receiving trilaciclib experienced multi-lineage myelopreservation benefits.

Consistent with previous trilaciclib Phase 2 trials, treatment was well tolerated with no trilaciclib-related serious adverse events reported.

Poster Information

Title: Trilaciclib (T), a CDK4/6 inhibitor, dosed with gemcitabine (G), carboplatin (C) in metastatic triple negative breast cancer (mTNBC) patients: Preliminary phase 2 results

Abstract Number: 1191

Presentation Number: PD1-01

Session Title: Developmental Therapeutics

Date / Time / Location: December 5, 5-7 p.m. CST/6-8 p.m. EST, Stars at Night Ballroom 1&2, Henry B. Gonzalez Convention Center

Presenter: Joyce O’Shaughnessy, M.D. (Texas Oncology-Baylor Charles A. Sammons Cancer Center)

For more information about the 2018 San Antonio Breast Cancer Symposium, please visit View Source

About Trilaciclib

Trilaciclib is a first-in-class myelopreservation therapy designed to improve outcomes of patients who receive chemotherapy by preserving hematopoietic stem and progenitor cell (HSPC) and immune system function. Trilaciclib is a short-acting intravenous CDK4/6 inhibitor administered prior to chemotherapy.

Trilaciclib is being evaluated in four randomized Phase 2 clinical trials. G1 has reported positive results from three of these trials in 2018. Two trials showed myelopreservation benefits in newly diagnosed, treatment-naive SCLC patients. In the first trial, trilaciclib was administered in combination with a chemotherapy regimen of etoposide and carboplatin (NCT02499770); topline data were released in March and additional data were reported at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) 2018 Congress. In the second trial, trilaciclib was administered in combination with the same chemotherapy regimen and the checkpoint inhibitor Tecentriq (atezolizumab) (NCT03041311); topline data were reported in November. Results from a trial in combination with chemotherapy in metastatic triple-negative breast cancer (NCT02978716) showing enhanced progression-free survival and multi-lineage myelopreservation benefits are being presented at the San Antonio Breast Cancer Symposium on December 5, 2018. The company plans to release topline data from a trial in combination with chemotherapy in previously treated SCLC (NCT02514447) by the end of 2018.

On December 4, 2018 The European Organisation for Research and Treatment of Cancer (EORTC) Brain Tumor Group and Protagen AG reported a collaboration to utilize Protagen’s Cancer Immunotherapy Array to identify autoantibody biomarkers that investigate the immunological profile and immuno-competence of long-term Glioblastoma survivors (Press release, EORTC, DEC 4, 2018, View Source [SID1234531897]).

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Glioblastoma is the most common glial brain tumor with an annual incidence above 3 per 100,000 population. The overall prognosis of glioblastoma patients remains poor. According to population-based data, median overall survival (OS) is still in the range of only one year and long-term survival is rare. However, a minority of glioblastoma patients survive for more than 60 months and these individuals are referred to as long-term survivors. The US-based Brain Tumor Funders Collaborative (BTFC) is supporting a large international research program that aims at better understanding which individuals with glioblastoma will ultimately become long-term survivors.

Through the present new collaboration, Protagen and the EORTC Brain Tumor Group will utilize Protagen’s Cancer Immunotherapy Array to understand the immunological profile of such patients to learn how to predict such long-term survival and potentially define novel pathways for therapeutic intervention.

Prof. Michael Weller, Head of the Brain Tumor Center at University Hospital Zurich and Chairman of the EORTC Brain Tumor Group, stated: "In our network we have followed and investigated this group of long-term glioblastoma survivors for many years. The focus has been to understand the molecular profile of these patients and thus over the years we have gained a much better understanding. However, we really need to understand the immunological profile and the immuno-competence of these patients better. Thus, investigating these patients by utilizing Protagen’s Cancer Immunotherapy Array may enable us to define their immune-profile, so that we can assess their immuno-competence. This will help us, together with the data already collected, to potentially understand why these patients survive for so long and how this can be extrapolated to other patients suffering from glioblastoma."

Dr. Peter Schulz-Knappe, Protagen’s Chief Scientific Officer, commented: "Our unique Cancer Immunotherapy Array has already demonstrated its potential for the prediction of therapeutic response and immune-related adverse events in Immuno-Oncology. The extension into Glioblastoma with a specific view to studying long-term survivors with one of the deadliest tumors provides a great opportunity to apply the Array for the prediction of survival but also to learn more about potential novel pathways for therapeutic intervention. Thus, we believe that applying our technology will result in a better understanding of the immunological profile of these long-term survivors which will benefit all patients suffering from Glioblastoma. We feel privileged that the EORTC Brain Tumor Group shares this vision, and are excited about the collaboration."

On December 4, 2018 Celyad (Euronext Brussels and Paris, and Nasdaq: CYAD), a clinical-stage biopharmaceutical company focused on the development of CAR-T cell-based therapies, reported updated clinical data for the CYAD-01 program in hematological malignancies presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) 60th Annual Meeting (Press release, Celyad, DEC 4, 2018, View Source [SID1234531882]).

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THINK Phase 1 Trial Update – Hematological Malignancies

Results from the dose-escalation trial were accepted as an oral presentation at ASH (Free ASH Whitepaper) and presented by Principal Investigator David A. Sallman, M.D., Department of Malignant Hematology at Moffitt Cancer Center (abstracts #902). Interim analysis was reported for ten r/r AML patients across the three dose levels of CYAD-01 without preconditioning.
Out of eight r/r AML patient evaluable per protocol (at least one cycle of treatment) in the dose escalation segment of the trial:
Five patients (62%) showed anti-leukemic activity with three out of eight patients (38%) exhibiting objective response and two patients (25%) exhibiting disease stabilization with relevant bone marrow blasts decrease.
As previously reported, one r/r AML patients achieved a complete response with partial hematological recovery (CRh). This patient was bridged to allotransplant and remains in minimal residual disease negative complete response (CRMRD-) for over 14 months. Two r/r AML patients achieved a complete response with incomplete marrow recovery (CRi) with a duration of one month.
Two r/r AML patients treated at dose level 2 experienced disease stabilization with relevant bone marrow blast decrease. One patient experienced a decrease in blast counts from 9.8% to 5.5% after an initial cycle of CYAD-01. This patient subsequently received a second cycle of CYAD-01 at dose level 2, with the first injection of the second cycle administered seven weeks after the last injection of cycle one. Treatment with a second cycle of CYAD-01 was associated with relevant reduction in bone marrow blast in the patient from 12.5% to 5.8%, which could be considered as an induction of a partial response (PR) post hematological relapse between the two cycles. Further analysis showed both patients achieved CYAD-01 engraftment in the bone marrow at day 28 of treatment.
A sixth r/r AML patient with adverse risk according the 2017 ELN stratification demonstrated a stabilization of disease at two months and is scheduled to initiate a second cycle of CYAD-01.
Only two patients evaluable per protocol progressed in the dose escalation phase of the trial.
Two additional r/r AML patients have been enrolled at dose level 3 of the trial and full results from these patients are anticipated during first half 2019.
CYAD-01 without preconditioning chemotherapy was generally reported to be well-tolerated.
Overall, 14 patients with hematological malignancies (AML, myelodysplastic syndrome and multiple myeloma) treated with CYAD-01 in the trial reached the safety follow -up.
Overall, six patients experienced grade 3/4 treatment-related AEs, which included cytokine release syndrome (CRS), lymphopenia and thrombocytopenia.
CRS occurred in six patients (three grade 1/2 AEs, two grade 3 AEs and one grade 4 AE). Patients experiencing grade 1-3 CRS showed rapid resolution following the appropriate treatment, including tocilizumab.
One r/r AML patient experienced a grade 4 CRS, which was considered a dose-limiting toxicity (DLT), following the first injection of CYAD-01 at dose level 3. The single injection resulted in a reduction of peripheral blast counts from 14% to 4%.
Dr. Christian Homsy, CEO of Celyad, commented, "Preliminary data from 14 patients with relapsed or refractory AML enrolled in the THINK trial have exceeded our expectations with five out of eight patients treated with CYAD-01 without preconditioning demonstrating a relevant anti-leukemic activity. In addition, we are encouraged by the initial safety data that shows CYAD-01 is well-tolerated. We are diligently working to enroll additional patients in our multiple ongoing clinical trials evaluating CYAD-01 in patients with acute myeloid leukemia to better assess this CAR T therapy’s ability to drive a potentially meaningful impact on the treatment of the disease."

DEPLETHINK Phase 1 Trial Update

In October 2018, Celyad enrolled the first patient in the DEPLETHINK Phase 1 trial (NCT03466320). The open-label, dose-escalation trial will evaluate a single injection 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 two dose levels of CYAD-01 including 100 million and 300 million cells per injection, respectively. Following disease assessment at day 35, patients presenting no signs of progression are eligible to receive a cycle of three CYAD-01 injections without preconditioning with two-week intervals at their initial dose levels. The primary endpoint of the trial is safety and secondary endpoints include clinical activity and pharmacokinetics.
As of November 27, 2018, three patients have received an administration of CYAD-01 following preconditioning with CyFlu. Initial data demonstrate that the regimen was well tolerated, with no DLTs nor treatment-related grade 3 or above AEs observed. All three patients were not yet evaluated for clinical response.
Preliminary data from the DEPLETHINK Phase 1 trial are expected in mid-2019.
THINK Phase 1 Trial – Schedule Optimization Cohort 10

The THINK trial was recently amended to add a cohort to assess a more frequent dosing schedule of CYAD-01 for the treatment of r/r AML. The cohort will evaluate six injections of CYAD-01 without preconditioning over two months of administration. The first cycle (induction) will include three injections of CYAD-01 separated by one-week intervals. The second cycle will include three injections of CYAD-01 separated by two-week intervals. All patients in enrolled in the cohort will received 1 billion cells per injection.
Enrollment in the cohort has begun and preliminary data are expected in first half 2019.
EPITHINK Phase 1 Trial Update

The EPITHINK trial is a dose-escalation trial designed to evaluate the administration of CYAD-01 concurrently with 5-azacytidine in treatment-naïve and/or elderly AML patients ineligible for intensive treatment.
As of November 27, 2018, no patients have been enrolled in the trial.
CYAD-01 and THINK Trial Design

CYAD-01 is an investigational CAR-T therapy in which a patient’s T cells are engineered to express the chimeric antigen receptor NKG2D, a receptor expressed on natural killer (NK) cells that binds to eight stress-induced ligands expressed on tumor cells.

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 in two parallel cohorts: i) patients with hematological malignancies, including r/r AML, and ii) patients with metastatic solid tumors. The dose escalation segment of the study evaluates three dose levels (300 million, 1 billion and 3 billion cells per injection) of one cycle of three CYAD-01 administrations with two-week intervals.