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 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 PharmaCyte Biotech, Inc. (OTCQB: PMCB), a biotechnology company focused on developing targeted cellular therapies for cancer and diabetes using its signature live-cell encapsulation technology, Cell-in-a-Box, reported that it has engaged cGMP Validation L.L.C. (cGMP Validation) to assist in the preparation of the Investigational New Drug application (IND) that must be submitted to and approved by the U.S. Food and Drug Administration (FDA) before PharmaCyte can begin its planned clinical trial in patients with locally advanced, non-metastatic, inoperable pancreatic cancer (LAPC) (Press release, PharmaCyte Biotech, DEC 4, 2018, View Source [SID1234531883]).

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cGMP Validation is playing a pivotal role for PharmaCyte and will continue to do so as it moves forward with the preparation of its IND. The role of cGMP Validation and its President and Chief Executive Officer, Jesse Gillikin, in particular, is to ensure that each and every step of the manufacturing process of PharmaCyte’s encapsulated cells completely complies with the FDA’s cGMP regulations and all other FDA requirements requested by the U.S. drug regulatory agency. In addition to ensuring that PharmaCyte’s clinical trial product meets regulatory compliance throughout the production process, cGMP Validation will also serve as a resource to Austrianova in its manufacturing process related to cGMP requirements with which it must adhere. For example, cGMP Validation will examine cGMP required documents prepared by Austrianova that concern all "production runs" of the manufacturing process and work with Austrianova to ensure compliance in every respect.

cGMP Validation will also serve, on behalf of PharmaCyte, as the agent for the "release" of the final product that will be implanted into patients before the chemotherapy prodrug ifosfamide is given during the planned clinical trial in LAPC.

PharmaCyte’s Chief Executive Officer, Kenneth L. Waggoner, commented, "We are extremely fortunate to have been able to retain cGMP Validation as our outside cGMP compliance/validation expert and to have Mr. Gillikin work directly with us and the principals at Austrianova to make certain that the very important manufacturing portion of our IND is complete and compliant with the FDA’s stringent cGMP regulations.

As I mentioned in an interview last summer, we’re almost there. Our checklist of items to be completed has been whittled down to just a few remaining items, and cGMP Validation provides us with the confidence moving forward to get across the finish line. It is imperative that our submission of the IND to the FDA is done flawlessly; therefore, cGMP Validation’s efforts will play a major role in ensuring that the IND we plan to submit to the FDA is as complete and accurate as possible."

cGMP Validation was established in 1997 as a full-service validation/compliance firm offering services for the pharmaceutical, biotechnology, biologics, medical device and medical diagnostic sectors. It has served new and repeat clients across the U.S., Puerto Rico and Canada and has international experience in Europe, Egypt, Korea, Indonesia and Vietnam. cGMP is headquartered in North Carolina, and it has an operational office in Missouri.

Mr. Gillikin is a co-founder of cGMP Validation and serves as its President and Chief Executive Officer. He has been in the pharmaceutical industry since 1978 and has experience in validation, managing QC laboratories, field auditing, and compliance, including interactions with the FDA and international regulatory agencies. His experience has included working with numerous companies in establishing validation and compliance practices. Mr. Gillikin’s experience enables him to provide clients with a wide array of validation resources, such as manufacturing equipment validation, process validation, cleaning validation and computer validation. His extensive work with other companies, as well as his long-standing relationship and experience with the FDA, also enables him to provide auditing, compliance/validation program building and the writing/execution of validation protocols.

Because of the intense efforts that PharmaCyte, cGMP Validation, and PharmaCyte’s clinical team of consultants are currently engaged in with respect to the preparation of the IND, as well as difficulty in coordinating and scheduling travel with everyone involved during the holiday season, PharmaCyte has decided to postpone its planned shareholder meeting until the first quarter of 2019.

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.

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.