On December 2, 2018 Harpoon Therapeutics, Inc. ("Harpoon"), a clinical-stage immunotherapy company developing a novel class of T cell engagers that harness the power of the body’s immune system to treat patients with cancer and other diseases, reported its preclinical data supporting the development of HPN217, a new compound targeting B cell maturation antigen (BCMA) (Press release, Harpoon Therapeutics, DEC 2, 2018, View Source [SID1234531793]). Generated from Harpoon’s Tri-specific T cell Activating Construct ("TriTAC") platform, HPN217 is engineered to re-direct a patient’s own T cells to kill BCMA-positive cancer cells. HPN217 is Harpoon’s first TriTAC designed for the treatment of hematologic cancers, such as multiple myeloma. Data were presented at the 2018 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, held December 1-4.

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"We believe the characteristics of HPN217 – including its structure as a single flexible polypeptide, low molecular weight, and in vitro and in vivo stability with half-life extension – offer advantages over conventional bispecific antibodies targeting BCMA," said Che-Leung Law, PhD, Harpoon’s Vice President, Translational Medicine. "Supported by preclinical data showing tumor growth inhibition in models of multiple myeloma and mantle cell lymphoma, HPN217 is expected to enter a Phase 1 clinical trial for multiple myeloma in 2019."

"Recent clinical data has validated the importance of BCMA as a drug target for T cells in the treatment of multiple myeloma," said Gerald McMahon, PhD, President and Chief Executive Officer of Harpoon. "The introduction of our third TriTAC compound demonstrates the ability of our technology platform to generate new product candidates."

The poster entitled "Preclinical and Nonclinical Characterization of HPN217: A Tri-specific T cell Activating Construct (TriTAC) Targeting B Cell Maturation Antigen (BCMA) for the Treatment of Multiple Myeloma" can be found on the Publications page of Harpoon’s website.

Key information presented includes:

Design of HPN217 TriTAC

The design of HPN217 is based on Harpoon’s novel TriTAC platform. It is a single polypeptide consisting of three domains that recognize human BCMA for myeloma cell targeting, serum albumin for half-life extension, and CD3ε for T cell engagement.

Proof-of-concept In Vitro and In Vivo Preclinical Studies

HPN217 demonstrated BCMA- and T cell-dependent antitumor activity in tissue culture and in xenografts modeling multiple myeloma and lymphoma. Effective preclinical antitumor activities could be observed in models with BCMA receptor copy number as low as approximately 2,200 per cell.

Pharmacokinetics Properties and In Vivo Stability in Nonclinical Studies

In animal studies, HPN217 demonstrated a circulating terminal half-life of 70-84 hours. Importantly, HPN217 remained functionally intact after one week in circulation.

About Multiple Myeloma

Multiple myeloma is the second most prevalent blood cancer after Non-Hodgkin’s lymphoma. There are approximately 229,000 people living with myeloma worldwide, with 114,000 new cases diagnosed and 87,000 deaths each year. The American Cancer Society estimates that approximately 30,700 new cases will be diagnosed and approximately 12,770 deaths are expected to occur from multiple myeloma in the United States in 2018. Despite advances in the treatment of multiple myeloma over the past decade, there remains a significant unmet need.

On December 2, 2018 Takeda Pharmaceutical Company Limited (TSE:4502) reported that data from the Phase 3 randomized, TOURMALINE-MM3 study evaluating the effect of single-agent oral NINLARO (ixazomib) as a maintenance therapy in adult patients diagnosed with multiple myeloma who previously responded to high-dose therapy (HDT) and autologous stem cell transplant (ASCT) will be presented at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting on Sunday, December 2, 2018 in San Diego, California (Press release, Takeda, DEC 2, 2018, View Source [SID1234531792]). NINLARO is currently not approved as a maintenance therapy for multiple myeloma following ASCT.

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The trial achieved its primary endpoint with NINLARO resulting in a statistically significant improvement in progression-free survival (PFS) versus placebo in adult patients diagnosed with multiple myeloma who responded to HDT and ASCT as assessed by an Independent Review Committee (IRC) (HR 0.72; p-value=0.002). This corresponds to a 28 percent reduction in risk of progression or death and a 39 percent improvement in PFS with NINLARO compared with placebo. The safety profile of NINLARO in the maintenance setting is consistent with previously reported results of single-agent NINLARO use.

"A growing body of evidence has shown that maintenance therapy in multiple myeloma may prolong the duration of disease control," said Meletios Dimopoulos, MD, Professor and Chairman of the Department of Clinical Therapeutics at the University Athens School of Medicine, Athens, Greece. "As currently approved options are limited and do not include a proteasome inhibitor, there is a need for additional maintenance treatments that can sustain response and have a tolerable safety profile. Data from the TOURMALINE-MM3 clinical trial supports single-agent NINLARO as a potential oral proteasome inhibitor maintenance therapy option post-ASCT."

"The positive results from this pivotal study – the first and only Phase 3 placebo controlled study evaluating a proteasome inhibitor in this setting – support NINLARO as a potential maintenance therapy for patients who have undergone a stem cell transplant," said Jesús Gómez Navarro, M.D., Vice President, Head of Oncology Clinical Research and Development, Takeda. "It is crucial that we continue to support patients by developing treatment options aimed to maintain or deepen response and delay disease progression. According to the findings, patients treated with NINLARO had improved progression-free survival over those in the control arm, which corresponds to a reduced risk of progression or death of nearly one-third."

"As a result of continued research, the multiple myeloma treatment landscape is constantly evolving. While this is encouraging news for the multiple myeloma community, there is still work to be done to further our goal of addressing the unmet needs of patients," said Brian GM Durie, M.D., Chairman of the Board, International Myeloma Foundation. "To that end, the development of additional safe and effective maintenance therapies is essential."

Maintenance Therapy With the Oral Proteasome Inhibitor (PI) Ixazomib Significantly Prolongs Progression-Free Survival (PFS) Following Autologous Stem Cell Transplantation (ASCT) in Patients With Newly Diagnosed Multiple Myeloma (NDMM): Phase 3 TOURMALINE-MM3 Trial Sunday, December 2, 2018, 7:30 – 9:00 a.m., Marriott Marquis San Diego Marina, Grand Ballroom 7

Key findings, which will be presented by Dr. Meletios Dimopoulos, include:

The trial achieved its primary endpoint with NINLARO resulting in a statistically significant improvement in PFS versus placebo in adult patients diagnosed with multiple myeloma who responded to HDT and ASCT as assessed by an Independent Review Committee (IRC) (HR 0.72; 95% CI: 0.582, 0.890; p-value=0.002). This corresponds to a 28 percent reduction in risk of progression or death and a 39 percent improvement in PFS with NINLARO.
Per IRC assessment, median PFS for patients in the NINLARO arm was 26.5 months compared to 21.3 months in the placebo arm.
Conversion from documented minimal residual disease (MRD) positivity at study entry to MRD negativity occurred at a higher rate among patients treated with NINLARO compared with placebo (12 percent versus 7 percent, respectively).
NINLARO maintenance led to higher rates of deepened response compared with placebo (relative risk 1.41; 95 percent CI: 1.10, 1.80; p=0.0042).
PFS benefit was seen broadly across subgroups, including ISS III (HR 0.661), PI-exposed (HR 0.750), PI-naïve (HR 0.497), and patients with high-risk cytogenetics (HR 0.625).
Secondary endpoints including median PFS2 and OS have not yet been reached in either arm. Median follow-up was 31 months.
Global Quality of Life scores (EORTC QLQ-C30) for patients on NINLARO were similar to those on placebo.
The safety profile of NINLARO in the maintenance setting is consistent with previously reported results of single-agent NINLARO use.
Discontinuation of treatment due to adverse events (AE) was low, at 7 percent in the NINLARO arm compared to 5 percent in the placebo arm.
Grade ≥3 AEs were experienced by 42 percent of patients receiving NINLARO versus 26 percent receiving placebo.
Patients in the NINLARO arm experienced serious AEs at a rate of 27 percent versus 20 percent in the placebo arm.
Common grade ≥3 AEs in both the NINLARO and placebo arms included infections (15 and 8 percent, respectively) including pneumonia (6 and 4 percent, respectively), gastrointestinal disorders (6 and 1 percent, respectively), neutropenia (5 and 3 percent, respectively) and thrombocytopenia (5 and <1 percent, respectively).
On the NINLARO arm, peripheral neuropathy events were observed in 19 percent of patients versus 15 percent on the placebo arm. In the NINLARO arm, <1 percent of peripheral neuropathy events were Grade 3 compared with 0 in the placebo arm.
The rate of second primary malignancies was 3 percent in both arms.
One patient in the NINLARO arm died on study while no patients in the placebo arm did. The single study death was considered to be treatment-related and was due to pneumonia.
About the TOURMALINE-MM3 Trial

TOURMALINE-MM3 is a randomized, placebo-controlled, double-blind Phase 3 study of 656 patients, designed to determine the effect of NINLARO (ixazomib) maintenance therapy on progression-free survival (PFS), compared to placebo, in participants with multiple myeloma who have had a response (complete response [CR], very good partial response [VGPR], or partial response [PR]) to induction therapy followed by high-dose therapy (HDT) and autologous stem cell transplant (ASCT). The primary endpoint is progression-free survival (PFS). A key secondary endpoint includes overall survival (OS). For additional information: View Source

About NINLARO (ixazomib) capsules

NINLARO (ixazomib) is an oral proteasome inhibitor which is also being studied across the continuum of multiple myeloma treatment settings as well as systemic light-chain (AL) amyloidosis. It was the first oral proteasome inhibitor to enter Phase 3 clinical trials and to receive approval. NINLARO was approved by the U.S. Food and Drug Administration (FDA) in November 2015 following a priority review and by the European Commission in November 2016. In the U.S. and Europe, NINLARO is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. NINLARO has received marketing authorization by regulatory authorities in more than 60 countries.

Ixazomib was granted orphan drug designation in multiple myeloma in both the U.S. and Europe in 2011 and for AL amyloidosis in both the U.S. and Europe in 2012. Ixazomib received Breakthrough Therapy status by the U.S. FDA for relapsed or refractory systemic light-chain (AL) amyloidosis, a related ultra orphan disease, in 2014. The Japanese Ministry of Health, Labour and Welfare granted Orphan Drug designation to ixazomib in 2016.

The comprehensive ixazomib clinical development program, TOURMALINE, includes a total of six ongoing pivotal trials – five, which together are investigating every major multiple myeloma patient population, and one in light-chain amyloidosis:

TOURMALINE-MM1, investigating ixazomib versus placebo in combination with lenalidomide and dexamethasone in relapsed and/or refractory multiple myeloma
TOURMALINE-MM2, investigating ixazomib versus placebo in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma
TOURMALINE-MM3, investigating ixazomib versus placebo as maintenance therapy in patients with newly diagnosed multiple myeloma following induction therapy and autologous stem cell transplant (ASCT)
TOURMALINE-MM4, investigating ixazomib versus placebo as maintenance therapy in patients with newly diagnosed multiple myeloma who have not undergone ASCT
TOURMALINE-AL1, investigating ixazomib plus dexamethasone versus physician choice of selected regimens in patients with relapsed or refractory AL amyloidosis; this study is currently enrolling
TOURMALINE-MM5, investigating ixazomib plus dexamethasone versus pomalidomide plus dexamethasone in patients with relapsed and/or refractory multiple myeloma who have become resistant to lenalidomide; this study is currently enrolling
For more information about actively enrolling Phase 3 studies please visit: View Source

In addition to the TOURMALINE program, ixazomib is being evaluated in multiple therapeutic combinations for various patient populations in investigator initiated studies globally.

NINLARO (ixazomib) capsules: Global Important Safety Information

SPECIAL WARNINGS AND PRECAUTIONS

Thrombocytopenia has been reported with NINLARO (28% vs. 14% in the NINLARO and placebo regimens, respectively) with platelet nadirs typically occurring between Days 14-21 of each 28-day cycle and recovery to baseline by the start of the next cycle. It did not result in an increase in hemorrhagic events or platelet transfusions. Monitor platelet counts at least monthly during treatment with NINLARO and consider more frequent monitoring during the first three cycles. Manage with dose modifications and platelet transfusions as per standard medical guidelines.

Gastrointestinal toxicities have been reported in the NINLARO and placebo regimens respectively, such as diarrhea (42% vs. 36%), constipation (34% vs. 25%), nausea (26% vs. 21%), and vomiting (22% vs. 11%), occasionally requiring use of antiemetic and anti-diarrheal medications, and supportive care.

Peripheral neuropathy was reported with NINLARO (28% vs. 21% in the NINLARO and placebo regimens, respectively). The most commonly reported reaction was peripheral sensory neuropathy (19% and 14% in the NINLARO and placebo regimens, respectively). Peripheral motor neuropathy was not commonly reported in either regimen (< 1%). Monitor patients for symptoms of peripheral neuropathy and adjust dosing as needed.

Peripheral edema was reported with NINLARO (25% vs. 18% in the NINLARO and placebo regimens, respectively). Evaluate patients for underlying causes and provide supportive care, as necessary. Adjust the dose of dexamethasone per its prescribing information or the dose of NINLARO for severe symptoms.

Cutaneous reactions occurred in 19% of patients in the NINLARO regimen compared to 11% of patients in the placebo regimen. The most common type of rash reported in both regimens was maculo-papular and macular rash. Manage rash with supportive care, dose modification or discontinuation.

Hepatotoxicity, drug-induced liver injury, hepatocellular injury, hepatic steatosis, and hepatitis cholestatic have been uncommonly reported with NINLARO. Monitor hepatic enzymes regularly and adjust dose for Grade 3 or 4 symptoms.

Pregnancy- NINLARO can cause fetal harm. Advise male and females patients of reproductive potential to use contraceptive measures during treatment and for an additional 90 days after the final dose of NINLARO. Women of childbearing potential should avoid becoming pregnant while taking NINLARO due to potential hazard to the fetus. Women using hormonal contraceptives should use an additional barrier method of contraception.

Lactation- It is not known whether NINLARO or its metabolites are excreted in human milk. There could be potential adverse events in nursing infants and therefore breastfeeding should be discontinued.

SPECIAL PATIENT POPULATIONS

Hepatic Impairment: Reduce the NINLARO starting dose to 3 mg in patients with moderate or severe hepatic impairment.

Renal Impairment: Reduce the NINLARO starting dose to 3 mg in patients with severe renal impairment or end-stage renal disease (ESRD) requiring dialysis. NINLARO is not dialyzable and, therefore, can be administered without regard to the timing of dialysis.

DRUG INTERACTIONS

Co-administration of strong CYP3A inducers with NINLARO is not recommended.

ADVERSE REACTIONS

The most frequently reported adverse reactions (≥ 20%) in the NINLARO regimen, and greater than in the placebo regimen, were diarrhea (42% vs. 36%), constipation (34% vs. 25%), thrombocytopenia (28% vs. 14%), peripheral neuropathy (28% vs. 21%), nausea (26% vs. 21%), peripheral edema (25% vs. 18%), vomiting (22% vs. 11%), and back pain (21% vs. 16%). Serious adverse reactions reported in ≥ 2% of patients included thrombocytopenia (2%) and diarrhea (2%). For each adverse reaction, one or more of the three drugs was discontinued in ≤ 1% of patients in the NINLARO regimen.

On December 2, 2018 Kite, a Gilead Company (Nasdaq: GILD), reported two-year efficacy and safety data from the pivotal ZUMA-1 trial of Yescarta (axicabtagene ciloleucel) in patients with refractory large B-cell lymphoma (Press release, Kite Pharma, DEC 2, 2018, View Source;p=irol-newsArticle&ID=2378930 [SID1234531786]). With a minimum follow-up of two years after a single infusion of Yescarta (median follow up of 27.1 months), 39 percent of patients were in an ongoing response. This updated analysis with at least 24 months of follow-up was presented at the Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) (ASH; Abstract #2967) and simultaneously published in The Lancet Oncology.

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This press release features multimedia. View the full release here: View Source

In October 2017, Yescarta became the first chimeric antigen receptor T (CAR T) cell therapy to be approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma (PMBCL), high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. Yescarta is not indicated for the treatment of patients with primary central nervous system lymphoma. The U.S. Prescribing Information for Yescarta contains a Boxed Warning regarding the risk of cytokine release syndrome (CRS) and neurologic toxicities; see below for Important Safety Information.

At two years, the best objective response via investigator assessment (n=101) showed an overall response rate of 83 percent, with 58 percent of patients having achieved a complete response. With a median follow-up of 27.1 months, 39 percent of patients remained in response. Of the patients with an ongoing response at 12 months, 93 percent remained in response at 24 months. The median duration of response was 11.1 months; the median duration of complete response was not reached. Median overall survival was not reached.

"With aggressive cancers such as refractory large B-cell lymphoma, our primary goal is to extend the lives of patients," said Sattva S. Neelapu, MD, ZUMA-1 Co-Lead Investigator and Professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center. "Outcomes with traditional standard of care for this highly refractory patient population have been extremely poor. Nearly 40 percent of patients in ZUMA-1 remain in response and half of the patients are still alive after at least two years of treatment with Yescarta."

In the two-year analysis (n=108), Grade 3 or higher CRS and neurologic events were seen in 11 percent and 32 percent of patients, respectively, and were generally reversible. Four patients developed new serious adverse events (occurring since the previous August 11, 2017 data cutoff), none of which were related to Yescarta. No new Yescarta-related CRS or neurologic events or deaths have occurred since the one-year analysis.

"The two-year point is a another major milestone for Yescarta, which has extended the lives of a significant number of patients in ZUMA-1 and has yielded important learnings that inform further research and development of CAR T therapies," said Alessandro Riva, MD, Executive Vice President, Oncology Therapeutics and Head, Cell Therapy, Gilead Sciences. "These data are not only significant for the lymphoma community, but also reinforce our leadership in cell therapy as we aim to transform the treatment of a variety of cancers with other investigational therapies in our pipeline."

Full study results are available in The Lancet Oncology:

Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial: http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30864-7/fulltext

U.S. Important Safety Information for Yescarta

BOXED WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITIES

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving Yescarta. Do not administer Yescarta to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving Yescarta, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with Yescarta. Provide supportive care and/or corticosteroids as needed.
Yescarta is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta REMS.
CYTOKINE RELEASE SYNDROME (CRS): CRS occurred in 94% of patients, including 13% with ≥ Grade 3. Among patients who died after receiving Yescarta, 4 had ongoing CRS at death. The median time to onset was 2 days (range: 1-12 days) and median duration was 7 days (range: 2-58 days). Key manifestations include fever (78%), hypotension (41%), tachycardia (28%), hypoxia (22%), and chills (20%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome. Ensure that 2 doses of tocilizumab are available prior to infusion of Yescarta. Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for 4 weeks after infusion. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab or tocilizumab and corticosteroids as indicated.

NEUROLOGIC TOXICITIES: Neurologic toxicities occurred in 87% of patients. Ninety-eight percent of all neurologic toxicities occurred within the first 8 weeks, with a median time to onset of 4 days (range: 1-43 days) and a median duration of 17 days. Grade 3 or higher occurred in 31% of patients. The most common neurologic toxicities included encephalopathy (57%), headache (44%), tremor (31%), dizziness (21%), aphasia (18%), delirium (17%), insomnia (9%) and anxiety (9%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events including leukoencephalopathy and seizures occurred with Yescarta. Fatal and serious cases of cerebral edema have occurred in patients treated with Yescarta. Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of neurologic toxicities. Monitor patients for signs or symptoms of neurologic toxicities for 4 weeks after infusion and treat promptly.

YESCARTA REMS: Because of the risk of CRS and neurologic toxicities, Yescarta is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta REMS. The required components of the Yescarta REMS are: Healthcare facilities that dispense and administer Yescarta must be enrolled and comply with the REMS requirements. Certified healthcare facilities must have on-site, immediate access to tocilizumab, and ensure that a minimum of 2 doses of tocilizumab are available for each patient for infusion within 2 hours after Yescarta infusion, if needed for treatment of CRS. Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense or administer Yescarta are trained about the management of CRS and neurologic toxicities. Further information is available at www.YESCARTAREMS.com or 1-844-454-KITE (5483).

HYPERSENSITIVITY REACTIONS: Allergic reactions may occur. Serious hypersensitivity reactions including anaphylaxis may be due to dimethyl sulfoxide (DMSO) or residual gentamicin in Yescarta.

SERIOUS INFECTIONS: Severe or life-threatening infections occurred. Infections (all grades) occurred in 38% of patients, and in 23% with ≥ Grade 3. Grade 3 or higher infections with an unspecified pathogen occurred in 16% of patients, bacterial infections in 9%, and viral infections in 4%. Yescarta should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after Yescarta infusion and treat appropriately. Administer prophylactic anti-microbials according to local guidelines. Febrile neutropenia was observed in 36% of patients and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids and other supportive care as medically indicated. Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with drugs directed against B cells. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

PROLONGED CYTOPENIAS: Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Yescarta infusion. Grade 3 or higher cytopenias not resolved by Day 30 following Yescarta infusion occurred in 28% of patients and included thrombocytopenia (18%), neutropenia (15%), and anemia (3%). Monitor blood counts after Yescarta infusion.

HYPOGAMMAGLOBULINEMIA: B-cell aplasia and hypogammaglobulinemia can occur. Hypogammaglobulinemia occurred in 15% of patients. Monitor immunoglobulin levels after treatment and manage using infection precautions, antibiotic prophylaxis and immunoglobulin replacement. The safety of immunization with live viral vaccines during or following Yescarta treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during Yescarta treatment, and until immune recovery following treatment.

SECONDARY MALIGNANCIES: Patients may develop secondary malignancies. Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES: Due to the potential for neurologic events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following Yescarta infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

ADVERSE REACTIONS: The most common adverse reactions (incidence ≥ 20%) include CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections-pathogen unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias.

On December 2, 2018 Immune Design (Nasdaq: IMDZ), an immunotherapy company focused on next-generation therapies in oncology, reported long-term follow up results from a randomized Phase 2 clinical trial of 10 ug intratumoral G100, a TLR4 agonist, with or without pembrolizumab, in follicular lymphoma patients (Press release, Immune Design, DEC 2, 2018, View Source [SID1234531785]).

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In the 26 naïve and relapsed/refractory patients in the randomized trial, the data continue to support the clinical activity of G100, with overall response rates of 46% and 23% in patients receiving a G100 regimen that includes low-dose radiation, with or without pembrolizumab, respectively. Also, disease control was shown in 92% and 85% of patients treated with the G100 regimen with or without pembrolizumab, respectively. In addition, responses appeared to be durable, with overall progression free survival at 11.1 or 7.4 months in patients treated with the G100 regimen with or without pembrolizumab, respectively. The data were presented today at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting being held in San Diego.

"Follicular lymphoma continues to be a difficult-to-treat malignancy, particularly in the relapsed setting, and to date immunotherapy has not been successful and the current standard of care is associated with a number of serious adverse events," said Carlos Paya, M.D., chief executive officer of Immune Design. "We are encouraged by the potential for lymphoma patients with G100, a first in class immuno-modulatory agent that leads to systemic anti-lymphoma benefit when injected intratumorally. The high response rates, favorable durability and excellent safety profile we’re seeing for G100 has prompted us to embark on a potentially pivotal clinical trial in the relapsed refractory setting, as well as pursue additional trials in earlier lines of therapy in follicular lymphoma and other malignancies."

Additional data presented in the poster:

Increases in immunogenicity markers of CD8+ T-cells and CD8/CD4 ratio in the tumor microenvironment correlated with clinical response (p= .0858 and .0357 respectively). Similarly, a decrease in C20-expressing tumor cells correlated with improved clinical outcomes (p=.0221).

G100 was well tolerated and the combination with pembrolizumab did not cause unexpected or worsening toxicity.
About G100

G100 is Immune Design’s lead product candidate and contains a potent synthetic small molecule toll-like receptor-4 (TLR-4) agonist called Glucopyranosyl Lipid A (GLA). G100 activates innate and adaptive immunity in the tumor microenvironment to generate an immune response against the tumor’s pre-existing diverse set of antigens. A growing set of clinical and preclinical data have demonstrated the ability of G100 to activate tumor-infiltrating lymphocytes, macrophages and dendritic cells, and promote antigen-presentation and the recruitment of T cells to the tumor. The induction of local and systemic immune responses has been shown to result in local and abscopal (shrinking of tumors outside the scope of the localized treatment) tumor control. G100 is currently in development to treat patients with relapsed follicular lymphoma (FL), a sub-type of Non-Hodgkin lymphoma. Immune Design intends to start a study in earlier-stage lymphoma patients in combination with rituximab, a standard treatment for lymphomas, and is evaluating studies in other B-cell malignancies beyond FL, as well as potential solid tumor indications.

On December 2, 2018 Celgene Corporation (NASDAQ: CELG) reported initial data from the dose-escalation part of an ongoing, open-label multicenter phase 1/2 study of investigational lisocabtagene maraleucel (liso-cel; JCAR017) in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), including patients with cytogenetic features of high-risk disease, who were previously treated with ibrutinib (Press release, Celgene, DEC 2, 2018, View Source [SID1234531784]). The data were presented by Tanya Siddiqi, M.D. in an oral presentation at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in San Diego, C.A. (Abstract #300).

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Data presented today from TRANSCEND CLL-004 include 16 patients from the ongoing phase 1 monotherapy dose-escalation part of the study. The median number of lines of prior therapy was 4.5, and 75% of patients had high-risk cytogenetic features. All patients had previously received treatment with ibrutinib, 81% had relapse/refractory disease on ibrutinib and 50% received prior treatment with ibrutinib and venetoclax. Following lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2) for three days, patients received liso-cel at dose level 1 (5×107 CAR+ T cells) or dose level 2 (1×108 CAR+ T cells).

The overall response rate (ORR), which was an exploratory objective, was 81%, with 43% of patients demonstrating a complete response (CR). As of September 2018, five patients have six-month follow-up and all have maintained a response and undetectable minimal residual disease (uMRD) in the blood as measured by flow cytometry (10-4). The median time-to-peak expansion was 16 days, and CAR+ T cells remained detectable in patients at three months.

"Ibrutinib is a standard of care for patients with CLL, but outcomes are poor for patients whose disease progresses on or after ibrutinib," said Alise Reicin, M.D., President, Global Clinical Development for Celgene. "These initial findings support further research with liso-cel in CLL and reinforce Celgene’s commitment to cellular therapy across a broad spectrum of blood cancers."

The most common treatment-emergent adverse events reported included anemia (88%), thrombocytopenia (81%), cytokine release syndrome (75%), neutropenia (63%), leukopenia (56%), hypokalemia (50%), pyrexia (38%), lymphopenia (31%), nausea (31%), diarrhea (25%), febrile neutropenia (25%), headache (25%), insomnia (25%), and tremor (25%). One patient (6.3%) experienced grade 3 cytokine release syndrome and three patients (18.8%) experienced grade 3 neurologic events. No patients experienced grade 4 cytokine release syndrome or neurologic events.

"In CLL, undetectable MRD correlates with improved outcomes for patients and is particularly difficult to achieve in patients who have progressed on ibrutinib," said lead study investigator Tanya Siddiqi, M.D., City of Hope National Medical Center. "The high response rates we observed in heavily pretreated patients in this initial data set, along with undetectable MRD status, that appears to be maintained over time, warrants further investigation of liso-cel in this area of high unmet need."

Liso-cel is not approved in any country.

About Liso-cel

Liso-cel is an investigational defined composition CD19-directed CAR T cell product candidate using a 4-1BB costimulatory domain. Celgene’s lead CAR T trial, TRANSCEND NHL-001, is studying liso-cel in adult patients with relapsed or refractory diffuse large B cell lymphoma, primary mediastinal B-cell lymphoma, follicular lymphoma Grade 3B, and mantle cell lymphoma.