On December 4, 2018 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported new data from the Venclexta/Venclyxto (venetoclax) clinical development programme, including longer-term results from the phase III MURANO study in people with previously treated chronic lymphocytic leukaemia (CLL) and updated data from two phase Ib/II studies in people with previously untreated acute myeloid leukaemia (AML) ineligible for intensive chemotherapy due to coexisting medical conditions (Press release, Hoffmann-La Roche, DEC 4, 2018, View Source [SID1234531851]). Data from the Venclexta/Venclyxto clinical development programme that ranges across multiple blood cancers, including CLL, AML, non-Hodgkin lymphoma and multiple myeloma, will be featured in more than 30 abstracts, including 12 oral presentations, at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) 2018 Annual Meeting.

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"We’re excited by the versatility of Venclexta/Venclyxto in treating a range of distinct types of blood cancer, including difficult-to-treat forms with limited options," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "These data support our broad clinical development programme through which we hope to discover more ways Venclexta/Venclyxto can be used alone or in combination with other medicines to treat additional types of cancer."

Updated data in CLL
Two new analyses of the phase III MURANO study in relapsed or refractory (R/R) CLL demonstrated the continued clinical benefit of Venclexta/Venclyxto plus MabThera/Rituxan (rituximab) was sustained after patients completed the chemotherapy-free, two-year fixed-duration course of therapy.

An analysis showed the combination reduced the risk of disease progression or death (progression-free survival; PFS, as assessed by investigator) by 84% (HR=0.16; 95% CI: 0.12-0.23; p<0.0001) compared to standard of care bendamustine plus MabThera/Rituxan (BR) after a median three-year follow-up. At three years, 71% of patients in the Venclexta/Venclyxto plus MabThera/Rituxan arm had not experienced disease progression, compared to 15% of patients in the BR arm (median PFS: not reached vs. 17.0 months, respectively). A clinically meaningful benefit in overall survival was also observed in the Venclexta/Venclyxto arm compared to the BR arm (88% vs. 80%, HR=0.50; 95 percent CI: 0.30-0.85). Consistent benefit was observed in all patient subgroups for Venclexta/Venclyxto plus MabThera/Rituxan compared to BR, including high-risk and low-risk groups. Data were presented in an oral session on Saturday, 1 December at 14:45 PST (Abstract #184).
A separate analysis showed higher rates of minimal residual disease (MRD)-negativity observed with Venclexta/Venclyxto plus MabThera/Rituxan compared to BR were sustained after patients completed treatment (62% vs. 13%). MRD-negativity means no cancer can be detected using a specific, highly sensitive test, and was defined as less than 1 CLL cell in 10,000 leukocytes. Importantly, these results were observed in the majority of patients in the Venclexta/Venclyxto arm, including patients in high-risk subgroups and were consistent with the maintained PFS benefit seen with longer follow-up. These data support the utility of MRD in peripheral blood as a predictive marker of clinical outcome. No new safety signals were observed with the treatment combination of Venclexta/Venclyxto plus MabThera/Rituxan. These data will be presented in an oral session on Monday, 3 December at 11:30 PST (Abstract #695).
Updated data in AML
Updated data from the phase Ib M14-358 and phase I/II M14-387 studies evaluating Venclexta/Venclyxto in combination with a hypomethylating agent or low-dose cytarabine (LDAC) in people with previously untreated AML who are ineligible for intensive chemotherapy, will also be presented. These results showed that among patients who were dependent upon blood transfusions at baseline, about half were able to achieve transfusion independence (the absence of transfusions during any consecutive 56 days during the study treatment period). No unexpected safety signals were observed with Venclexta/Venclxyto in combination with hypomethylating agents or LDAC.

The M14-358 study showed high rates of complete remission (with at least partial blood count recovery, CR+CRh) of 67% for those who received Venclexta/Venclyxto plus azacitidine and 71% for those who received Venclexta/Venclyxto plus decitabine. For people taking Venclexta/Venclyxto and azacitadine or decitabine who were dependent on blood transfusions at baseline, 50% and 52% achieved red blood cell transfusion independence, respectively; and 58% or 60% achieved platelet transfusion independence, respectively.
The M14-387 study showed rates of complete remission (with or without full recovery of normal blood cell count, CR+CRi) of 54% in people who received Venclexta/Venclyxto in combination with LDAC and a median duration of remission of 8.1 months. For people taking Venclexta/Venclyxto with LDAC, 48% achieved red blood cell transfusion independence and 60% achieved platelet transfusion independence.
Results from the two studies were presented in an oral session on Sunday, December 2 at 7:45 PST and 8:00 PST, respectively (Abstract #284 and #285).

Based on earlier results from the M14-358 and M14-387 studies, Venclexta was granted accelerated approval by the US Food and Drug Administration (FDA) for the treatment of people with newly-diagnosed AML who are age 75 years or older, or for those ineligible for intensive induction chemotherapy due to coexisting medical conditions. A robust clinical development programme for Venclexta/Venclyxto in AML is ongoing, including two ongoing phase III studies evaluating Venclexta/Venclyxto in combination with azacitidine or with LDAC for people with previously untreated AML who are ineligible for intensive chemotherapy based on results from the M14-358 and M14-387 studies.

Venclexta/Venclyxto is being developed by AbbVie and Roche. It is jointly commercialised by AbbVie and Genentech, a member of the Roche Group, in the United States, and commercialised by AbbVie outside of the United States.

About the MURANO study
MURANO (NCT02005471) is a phase III open-label, international, multicentre, randomised study evaluating the efficacy and safety of Venclexta/Venclyxto in combination with MabThera/Rituxan compared to bendamustine in combination with MabThera/Rituxan (BR) in patients with relapsed or refractory chronic lymphocytic leukaemia (CLL). All treatments were of fixed duration. Following a five-week dose ramp-up schedule for Venclexta/Venclyxto, patients on the Venclexta/Venclyxto plus MabThera/Rituxan arm received six cycles of Venclexta/Venclyxto plus MabThera/Rituxan followed by Venclexta/Venclyxto monotherapy for up to two years total. Patients on the BR arm received six cycles of BR. The study included 389 patients with CLL who had been previously treated with at least one line of therapy. Patients were randomly assigned in a 1:1 ratio to receive either Venclexta/Venclyxto plus MabThera/Rituxan or BR. The primary endpoint of the study was progression-free survival (PFS). Secondary endpoints included overall survival, overall response rate and complete response rate (with or without complete blood count recovery).

About the M14-358 study
The M14-358 study (NCT02203773) is an open-label, non-randomised, phase Ib dose escalation and expansion study evaluating the safety and efficacy of Venclexta/Venclyxto in combination with hypomethylating agents, azacitidine or decitabine, in 115 newly-diagnosed people with acute myeloid leukaemia who were 60 years or older, or ineligible to receive intensive induction chemotherapy due to coexisting medical conditions. Study endpoints included complete remission rates, transfusion independence, overall survival and safety.

About the M14-387 study
The M14-387 study (NCT02287233) is an open-label, single-arm, phase I/II dose escalation and expansion study evaluating the safety and efficacy of Venclexta/Venclyxto in combination with low-dose cytarabine (LDAC) in 82 newly-diagnosed people with acute myeloid leukaemia who were 60 years or older, or ineligible to receive intensive induction chemotherapy due to coexisting medical conditions. Study endpoints included complete remission rates, transfusion independence, overall survival and safety.

About Venclexta/Venclyxto
Venclexta/Venclyxto is a first-in-class targeted medicine designed to selectively bind and inhibit the B-cell lymphoma-2 (BCL-2) protein. In some blood cancers and other tumours, BCL-2 builds up and prevents cancer cells from dying or self-destructing, a process called apoptosis. Venclexta/Venclyxto blocks the BCL-2 protein and works to restore the process of apoptosis.

Venclexta/Venclyxto is being developed by AbbVie and Roche. It is jointly commercialised by AbbVie and Genentech, a member of the Roche Group, in the United States, and commercialised by AbbVie outside of the United States. Together, the companies are committed to research with Venclexta/Venclyxto, which is currently being studied in clinical trials across several types of blood and other cancers.

In the US, Venclexta has been granted four Breakthrough Therapy Designations by the FDA: in combination with Rituxan for people with relapsed or refractory chronic lymphocytic leukaemia (CLL); as a monotherapy for people with relapsed or refractory CLL with 17p deletion; in combination with hypomethylating agents (azacitidine or decitabine) for people with untreated acute myeloid leukaemia (AML) ineligible for intensive chemotherapy; and in combination with low-dose cytarabine for people with untreated AML ineligible for intensive chemotherapy.

About Chronic Lymphocytic Leukaemia
Chronic lymphocytic leukaemia (CLL) is the most common type of leukaemia in the Western world.[1] CLL mainly affects men and the median age at diagnosis is about 70 years.[2] Worldwide, the incidence of all leukaemias is estimated to be more than 400,000[3] and CLL is estimated to affect around one-third of all people newly diagnosed with leukaemia.[1]

About Acute Myeloid Leukaemia
Acute myeloid leukaemia (AML) is an aggressive form of leukaemia that starts in immature forms of blood-forming cells, known as myeloid cells, found in the bone marrow.[4] AML is the most common type of aggressive leukaemia in adults. It has the lowest survival rates of all types of leukaemia.[5] Even with the best available therapies, older patients aged 65 and over have survival rates comparable to patients with advanced lung cancer, with a five year overall survival rate of <5%.[6;7] Approximately 20,000 people in the US and 18,000 in Europe are diagnosed with AML each year.[8;9]

On December 4, 2018 Verastem, Inc. (Nasdaq:VSTM) (Verastem Oncology or the Company), focused on developing and commercializing medicines to improve the survival and quality of life of cancer patients, reported the presentation of seven posters highlighting new and updated clinical and preclinical data from its duvelisib development program at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2018 Annual Meeting, taking place December 1-4, 2018, in San Diego (Press release, Verastem, DEC 4, 2018, View Source;p=RssLanding&cat=news&id=2379420 [SID1234531868]). Duvelisib is an oral inhibitor of phosphoinositide 3-kinase (PI3K), and the first approved dual inhibitor of PI3K-delta and PI3K-gamma.

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"The PI3K pathway is critical for the survival and proliferation of many types of cancer cells," said Robert Forrester, Verastem President and Chief Executive Officer. "At Verastem Oncology we are committed to progressing the scientific research and clinical development with our corporate, clinical and academic research partners worldwide to unlock the potential of PI3K inhibition and usher in new treatment strategies for patients in need."

"Research being presented at ASH (Free ASH Whitepaper) this year by Chen, et al used CLL patient samples to demonstrate critical points about dual PI3K-delta and PI3K-gamma inhibition," said Jonathan Pachter, PhD, Chief Scientific Officer at Verastem Oncology. "This research suggests that while PI3K-delta inhibition targets the malignant B cells directly, PI3K-gamma inhibition blocks the support of CLL growth by macrophages and T cells in the tumor microenvironment. Data presented show that when CLL cells from patients who progressed on ibrutinib were implanted in mice, dual PI3K-delta and PI3K-gamma inhibition effectively reduced the CLL burden thereby suggesting the potential value of the dual inhibition in tumors resistant to BTK inhibition. The importance of dual inhibition of PI3K-delta and PI3K-gamma, in this case in combination with BCL-2 inhibition, was also described by Ye, et al in an aggressive lymphoma model. This study highlights the synergistic activity of the combination in inhibiting ibrutinib resistance compensatory pathways and inducing apoptosis in preclinical models of Mantle Cell Lymphoma."

"We are delighted to have presented a wide range of data from our ongoing duvelisib development programs, including updated long-term follow-up data from the Phase 3 DUO study as well as the DUO crossover extension study," said Hagop Youssoufian, MSc, MD, Head of Medical Strategy at Verastem Oncology. "Other key presentations include the Zinzani and Lehmberg data, which describe compelling new biomarker research being conducted relating to predictive factors for response to duvelisib in certain hematologic malignancies."

Details for the ASH (Free ASH Whitepaper) 2018 poster presentations are as follows:

Poster Presentations

Title: Clinical and Biological Indicators of Duvelisib Efficacy in CLL from the Phase 3 DUO Study
Presenter: Jennifer Brown, Harvard Medical School and Dana-Farber Cancer Institute
Abstract Number/Publication ID: 1856
Session: 642. CLL: Therapy, excluding Transplantation: Poster I

Title: The Efficacy and Safety of Duvelisib Following Disease Progression on Ofatumumab in Patients with Relapsed/Refractory CLL or SLL: Updated Results from the DUO Crossover Extension Study
Presenter: Matthew Davids, Dana-Farber Cancer Institute
Abstract Number/Publication ID: 3140
Session: 642. CLL: Therapy, excluding Transplantation: Poster II

Title: Characterization of the Long-Term Efficacy and Safety of Duvelisib Monotherapy in Patients with Relapsed/Refractory CLL/SLL on Treatment for > 2 Years across 4 Clinical Studies
Presenter: Ian Flinn, Sarah Cannon Research Institute
Abstract Number/Publication ID: 3146
Session: 642. CLL: Therapy, excluding Transplantation: Poster II

Title: Simultaneous inhibition of BCL-2 and PI3K signaling overcomes ibrutinib resistance in mantle cell lymphoma
Presenter: Haige Ye, MD Anderson Cancer Center
Abstract Number/Publication ID: 2950
Session: 625. Lymphoma: Pre-Clinical—Chemotherapy and Biologic Agents: Poster II

Title: Prognostic and Immune-Related Factors for Response to Duvelisib in the Phase 2 DYNAMO Clinical Trial in iNHL
Presenter: Pier Luigi Zinzani, University of Bologna Institute of Hematology
Abstract Number/Publication ID: 4167
Session: 623. Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma—Clinical Studies: Poster III

Title: Dual Inhibition of PI3K-δ and PI3K-γ by Duvelisib Impairs CLL B Cells and CLL-Supporting Cells and Overcomes Ibrutinib Resistance in a Patient-Derived Xenograft Model
Presenter: Shih-Shih Chen, The Feinstein Institute for Medical Research, Northwell Health
Abstract Number/Publication ID: 4420
Session: 642. CLL: Therapy, excluding Transplantation: Poster III

Title: Dynamic BH3 Profiling Predicts Patient Response and MRD Status in Chronic Lymphocytic Leukemia (CLL) Patients Undergoing Frontline Treatment with Kinase Inhibitor Augmented (KIA) FCR
Presenter: Timothy Z. Lehmberg, Dana-Farber Cancer Institute
Abstract Number/Publication ID: 4395
Session: 641. CLL: Biology and Pathophysiology, excluding Therapy: Poster III

PDF copies of these poster presentations will be available here following the conclusion of the meeting.

On December 4, 2018 Clovis Oncology, Inc. (NASDAQ:CLVS) reported after opposition proceedings at The Hague, Netherlands, that the European Patent Office upheld claims of European Patent 2534153 in amended form covering certain crystalline forms of rucaparib camsylate, including rucaparib S-camsylate Form A, the crystalline form in Rubraca (Press release, Clovis Oncology, DEC 4, 2018, View Source [SID1234531884]).

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In its oral decision announced at the hearing, the Opposition Division upheld claims, narrowed from the originally granted patent, to certain crystalline forms of rucaparib camsylate. These forms include, but are not limited to, the commercial product. The European Opposition Division found patentability of the claimed forms based on the inventiveness of these crystalline forms and a constellation of unexpected properties. The European patent was opposed by two opponents. Clovis and/or either opponent have an opportunity to appeal the decision of the European Opposition Division within two months of the written decision, which is expected in the next few months. If appealed, all claims in the originally granted patent will remain in force until the Technical Board of Appeal issues its decision.

In addition to the rucaparib camsylate patent protection through at least 2031 confirmed today, the commercial form of Rubraca is also entitled to European regulatory exclusivity until at least 2028 (and 2029 if an indication in a second tumor type is approved). Also, Clovis has filed for supplementary protection certificate (SPC) extension on this rucaparib camsylate patent in various European countries, which if approved, would provide extension of protection until 2033 under this patent.

"We are very pleased with the outcome of the opposition proceedings today, but more importantly, we are gratified that the European Patent Office acknowledged the innovation behind this invention and upheld robust patent protection for Rubraca in Europe," said Patrick J. Mahaffy, President and CEO of Clovis Oncology. "This patent represents an important component of the intellectual property for Rubraca and we are happy that the Opposition Division upheld the relevant claims of the patent that cover the commercial form of Rubraca as well as other forms of rucaparib camsylate. We look forward to commercializing Rubraca in Europe and with this outcome, we are well-positioned to do so for a very long time."

About Rubraca (rucaparib)

Rubraca is an oral, small molecule inhibitor of PARP1, PARP2 and PARP3 being developed in multiple tumor types, including ovarian, metastatic castration-resistant prostate, and bladder cancers, as monotherapy, and in combination with other anti-cancer agents. Exploratory studies in other tumor types are also underway. Clovis holds worldwide rights for Rubraca. Rubraca is an unlicensed medical product outside of the U.S. and Europe.

On December 4, 2018 City of Hope physicians and researchers reported at the American Society of Hematology (ASH) (Free ASH Whitepaper) meeting in San Diego presented clinical trials for new leukemia and lymphoma treatments, laying the groundwork for innovative therapeutic approaches aimed at improving treatment options and quality of life for patients (Press release, City of Hope, DEC 4, 2018, View Source [SID1234531885]).

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The ASH (Free ASH Whitepaper) meeting hosted more than 25,000 hematology professionals who focus on research and treatment for blood cancers and other diseases.

"City of Hope clinical and laboratory investigators enjoyed sharing our leading-edge research findings and demonstrating our continued commitment to advancing the most promising cures against cancers, including finding new targets in CAR T cell therapy," said Stephen J. Forman, M.D., leader of City of Hope’s Hematologic Malignancies and Stem Cell Transplantation Institute and the Francis & Kathleen McNamara Distinguished Chair in Hematology and Hematopoietic Cell Transplantation.

City of Hope physician-scientists presented clinical trials that provide the foundation for new treatments for patients with T cell lymphoma, non-Hodgkin’s lymphoma and acute lymphoblastic leukemia. They also discussed mouse studies that experimented with a different and possibly more effective way of delivering chimeric antigen receptor (CAR) T cells for leukemia and lymphoma in the central nervous system (CNS). The research is discussed in more detail below.

Delivering CD19-CAR T cells directly into cerebrospinal fluid to treat a lymphoma

This study is touted as the first to demonstrate that local brain delivery of CAR T cells are capable of treating both systemic lymphoma and the CNS. Xiuli Wang, Ph.D., research professor in the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope, said immunotherapy that uses T cells genetically modified with the CD19-CAR lentivirus have been effective in treating acute lymphoblastic leukemia and diffuse large B cell lymphoma. Notably, CNS lymphoma, a disease limited to brain, cannot be treated through surgery because the tumors are widespread, and chemo-drugs cannot pass through the protective blood-brain barrier. CAR T cell therapies are usually delivered intravenously and have not been used in treatment for CNS lymphoma due to concerns of effectiveness and potential side effects such as cytokine release syndrome.

People with CNS lymphoma have limited options; City of Hope wants to expand their options. Using a mouse model, Wang and her colleagues delivered T cells modified to express a CD19-CAR directly into cerebro-spinal fluid via cerebral ventricles, a process called intracerebroventricular infusion. A single local infusion was enough to completely eradicate CNS lymphoma and systemic lymphoma throughout the mouse body after 14 days. The mice remained tumor-free for 300 days, the length of the experiment. Comparatively, the mice who received the immunotherapy treatment intravenously had delayed anti-tumor activity: Complete remission was observed about 40 days post CAR T treatment. Eventually the tumors relapsed, and all of the control mice died before day 180.

The experiment demonstrated that delivering CAR T locally into the cerebro-spinal fluid appears to be more efficacious than intravenous delivery. When researchers imaged the mice, they found that CAR T cells migrated to the tumor sites outside the brain. So, local brain delivery of this immunotherapy was able to spread throughout their body. Lastly, the CAR T cells persisted in the mice with the experimental treatment much longer than when they are delivered intravenously – helping to maintain an anti-tumor environment to ward off relapse.

Wang hypothesizes that intracerebroventricular infusion of CAR T therapy may be safer and more effective than intravenous infusion. Her team will test this hypothesis in a phase 1 clinical trial next year.

A chemotherapy-free immunotherapy that uses a special two-armed antibody

In a multisite, international phase 1/1b clinical trial, Lihua Elizabeth Budde, M.D., Ph.D., assistant professor in the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope, et al. are testing a promising two-armed antibody that could strong-arm relapsed/refractory B cell non-Hodgkin’s lymphoma into remission. (Normal antibodies have only one arm.) If proven effective, the treatment heralds a new age where chemotherapy and its painful side effects will be obsolete in the treatment of this disease.

The ongoing first-in-human study testing for safety has recruited more than 98 patients to receive varying doses of mosunetuzumab, an experimental antibody with two arms. One arm grabs specific immune cells in the body while the other grabs lymphoma cells. Now in close proximity, the immune cells are trained or forced to recognize and attack lymphoma cells.

Unlike CAR T therapy, this treatment option does not involve removing a patient’s immune cells, modifying them to attack disease and expanding the T cells outside the body. Mosunetuzumab is delivered intravenously and redirects T cells to recognize the cancer; everything happens inside the human body.

The trial’s response rate is around 70 percent, which is promising because the maximum tolerated dose has not yet been reached. So far, most patients who experienced adverse effects had minor, manageable and reversible side effects, Budde said. Most of the patients are in complete remission and have stayed in remission – the longest patient has been cancer-free for more than two years –without needing any other treatment, she added.

Novel regimen for patients with certain lymphomas undergoing a stem cell transplant

In a phase 1 clinical trial designed to test the safety and tolerability of a novel conditioning regimen for patients with peripheral T cell lymphomas undergoing autologous stem cell transplants (which use the patient’s own stem cells), Jasmine Zain, M.D., director of City of Hope’s T cell Lymphoma Program, and her colleagues found that City of Hope-manufactured 90Yttrium-radiolabeled (90Y) basiliximab appears to be safe when used in combination with BEAM. There was no increased toxicity compared to using BEAM chemotherapy alone, and side effects were minimal, the study found.

Peripheral T cell lymphomas have a poor prognosis with current treatment regimens. In spite of autologous stem cell transplants, patients often relapse within a few years. The protein CD25 is differentially expressed in T cell lymphomas. Basliximab is an antibody that targets CD25. 90Y basiliximab provides targeted radiation to tumor cells and has been shown to successfully inhibit the growth of T cell lymphomas in mouse models.

In this phase 1 study, three different dose levels of targeted radiation were explored in combination with chemotherapy with BEAM. Fourteen patients underwent the experimental treatment over a nearly three-year period with no additional toxicity. Eight patients remain in remission. A safe dose level has been established. The study was not designed to assess efficacy of the regimen, but a dose expansion phase is in progress to answer that question.

Memory-enriched CAR T cells: High response rates and low toxicity

CAR T cell therapy reportedly achieves complete remission in patients with acute lymphoblastic leukemia about 80 percent of the time; however, a large proportion of these patients have side effects such as cytokine release syndrome and neurotoxicity. Samer Khaled, M.D., associate clinical professor in the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope, said he may have found a CAR T product that is more potent and less toxic – a potential game-changer if the early results of his ongoing phase 1 clinical trial holds through future testing.

So far, the clinical trial has enrolled 16 patients with relapsed or refractory B cell acute lymphoblastic leukemia, a disease that has poor survival rates. The physician-scientists treated 13 eligible patients with T cells engineered to express CD19:28z-CAR. Investigators used a unique manufacturing platform developed at City of Hope that generates therapeutic cells from enriched memory and "naïve T cells" – immune soldiers known for their capacity for long-term persistence.

Eleven out of 11 patients evaluable for response received the treatment and are in complete remission, showing a 100 percent response rate with no significant increase in toxicity. Two patients were not eligible for response evaluation but were included in the toxicity assessment. Though the sample size was small, it is noteworthy. "Traditionally, high CAR T activity is associated with high toxicity, but our CD19 CAR T product appears to be a very powerful therapy with lower-than-normal side effects," Khaled said.

City of Hope research on a new CAR T therapy, BAFF-R

Hong Qin, Ph.D., associate research professor in City of Hope’s Department of Hematology & Hematopoietic Cell Transplantation, and Larry Kwak, M.D., Ph.D., Dr. Michael Friedman Professor in Translational Medicine and director of the Toni Stephenson Lymphoma Center, have conducted new research demonstrating that a CAR T cell therapy targeting the B-cell activating factor receptor (BAFF-R), a protein which is primarily expressed on B-cells and various subtypes of B-cell non-Hodgkin’s lymphoma (NHL) and acute lymphoblastic leukemia (ALL), can be used to help patients who are experiencing relapse after receiving other CAR T therapies.

CAR T therapies targeting CD19, another target on B-cell tumors, is becoming more common, but so are cases of CD19 antigen-loss relapse. The increase of relapse highlights an urgent need for new therapies and tumor targets.

City of Hope research has led to the development of a highly effective BAFF-R targeting CAR T cells that works against a variety of human B-cell leukemia and lymphoma models. Encouragingly, BAFF-R CAR T cells remain effective against tumor samples from ALL patients who experienced CD19 antigen-loss relapse. The new data suggest that targeting BAFF-R may add to existing alternative strategies to overcome relapse from CD19 antigen loss.

"City of Hope is planning a clinical trial in the coming year that will be the first BAFF-R CAR T trial for patients, providing new hope for patients who have no other therapeutic options," Qin said.

On December 3, 2018 ArQule, Inc. (Nasdaq: ARQL) reported its presented preliminary results from the Company’s Phase 1 dose escalation study for ARQ 531, an orally bioavailable, potent and reversible inhibitor of both wild type and C481S-mutant Bruton’s tyrosine kinase (BTK) in patients with relapsed or refractory hematologic malignancies at the 2018 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego (Press release, ArQule, DEC 3, 2018, View Source [SID1234531820]).

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Dr. Brian Schwartz, Chief Medical Officer of ArQule commented, "We are encouraged by the pace at which this trial is progressing and by the level of target engagement we are observing as we continue to dose escalate. Four out of the five heavily pretreated CLL patients enrolled in the last two cohorts with the BTK-C481S mutation have experienced tumor shrinkage."

"These data provide further evidence of ARQ 531’s potential to become a new therapeutic option for patients with B cell malignancies," commented Paolo Pucci, Chief Executive Officer of ArQule. "There is significant unmet need for patients with relapsed or refractory B-cell malignancies in particular those with the C481S-mediated resistance to irreversible BTK inhibitors such as ibrutinib."

The reported data are from the ongoing Phase 1, open label, single arm dose escalation 3+3 study and include the first six cohorts (n=20) at dose levels of 5, 10, 15, 20, 30 and 45 mg once a day in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL), Waldenstrom’s macroglobinemia and B-cell Non-Hodgkin lymphomas.

Key findings presented include the following:

ARQ 531 has demonstrated a manageable safety profile with no dose-limiting toxicities observed to date
Pharmacokinetic data are nearly dose proportional with a mean plasma half-life that supports QD dosing
Pharmacodynamic biomarkers for cohorts 4 through 6 showed profound pBTK inhibition
Anti-tumor activity, with reduction of tumor burden, was observed in 9 out of 20 patients
At the first assessment of tumor response, 80% of the ibrutinib refractory, heavily pretreated CLL patients (4 out of 5) in the highest dose cohorts (30 and 45 mg) experienced tumor shrinkages
Four out of 5 lymphoma patients derived benefit with shrinkages between 27 and 58%, including 1 PR in a Follicular Lymphoma patient who began at 5 mg, was dose escalated to 15 and then 45 mg, and remains on therapy after 70 weeks
The study is on-going and dose escalation continues
The presented poster, A Phase 1 Dose Escalation Study of ARQ 531 in Selected Patients with Relapsed or Refractory Hematologic Malignancies, is available on the company’s website at View Source

The Company will hold a conference call and webcast today at 9:00 a.m. ET to discuss these results. The live webcast can be accessed in the "Investors and Media" section of our website, www.arqule.com, under "Events & Presentations." You may also listen to the call by dialing (877) 868-1831 within the U.S. or (914) 495-8595 outside the U.S. A replay will be available two hours after the completion of the call and can be accessed in the "Investors & Media" section of our website, www.arqule.com, under "Events and Presentations."

About BTK and ARQ 531

Bruton’s tyrosine kinase, BTK, is a therapeutic target that has been clinically proven to inhibit B-cell receptor signaling in blood cancers. ARQ 531 is an orally bioavailable, potent and reversible BTK inhibitor. Biochemical and cellular studies have shown that ARQ 531 inhibits both the wild type and C481S-mutant forms of BTK. The C481S-mutation is a known resistance mechanism for first generation irreversible BTK inhibitors. In preclinical studies, ARQ 531 has demonstrated good oral bioavailability as well as favorable pharmacokinetic, pharmacodynamic and metabolic properties.