On December 9, 2019 IONTAS Limited (IONTAS), a leader in the discovery and optimisation of fully human antibodies, has been informed that International Biotechnology Center (IBC) Generium, a leading Russian biopharmaceutical company, focused on developing and commercialising pharmaceutical products for the treatment of orphan diseases and cancer, reported that it has received approval from the Russian Health Authorities to initiate clinical trials with its CD3/CD19 bispecific antibody for the treatment of B-Cell Acute Lymphoblastic Leukemia (ALL) (Press release, Iontas, DEC 9, 2019, View Source [SID1234552135]). This is the first IBC Generium drug candidate developed using IONTAS technology, which was approved for clinical trials. IBC Generium and IONTAS worked together to generate the anti-CD3 component of the bispecific molecule. This approval reflects the quality of antibodies generated and expertise within IBC Generium to reach this important clinical milestone. Following on from this trial it is anticipated that further clinical trials incorporating IONTAS antibodies will be driven forward by clients of IONTAS in the coming few years.

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Dr John McCafferty, CEO and Founder of IONTAS, said: "We are very proud of our involvement in this project and delighted that IBC Generium has achieved this important landmark. We are hopeful for success in this initial trial and are excited by the prospect of our anti-CD3 antibody contributing more broadly to the armoury of new and innovative cancer treatments."

Dr Ravil Khamitov, CEO of IBC Generium, said: "IONTAS was selected because of its robust track record and technical know-how. We were confident IONTAS would deliver antibodies suitable for use in our bispecific programs and were not disappointed. This trial is vindication of that confidence. We look forward to a successful clinical trial and further success with other antibodies developed with IONTAS."

Dr Neil Butt, CBO and Dr John McCafferty, CEO and Founder of IONTAS, will attend 38th Annual J.P.Morgan Healthcare Conference (San Francisco, CA) from January 13 – 16 2020. Dr Neil Butt will be at Antibody Engineering and Therapeutics (San Diego, CA) from 9 – 13 December 2019.

On December 9, 2019 Immunocore Limited, a leading T Cell Receptor (TCR) biotechnology company, reported the start of the first-in-human clinical trial of IMC-C103C, the third bispecific developed using the company’s innovative ImmTAC technology platform (Press release, Immunocore, DEC 9, 2019, View Source [SID1234552134]). IMC-C103C is focused on targeting tumours that express the protein MAGE-A4 (Melanoma-Associated Antigen A4) and is being developed in partnership with Genentech, a member of the Roche Group.

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The trial (IMC-C103C-101) is designed to study the safety and preliminary activity of IMC-C103C as a monotherapy and in combination with atezolizumab (Tecentriq) in patients with MAGE-A4-expressing cancers.

David Berman, Head of Research and Development at Immunocore, commented: "We have now brought our third TCR- engineered bispecific ImmTAC into the clinic. IMC-C103C is designed to re-direct T cells to attack MAGE-A4 expressing tumours and we’re pleased to be moving its clinical development forward in partnership with Genentech."

On December 9, 2019 Xencor, Inc. (NASDAQ:XNCR), a clinical-stage biopharmaceutical company developing monoclonal antibodies for the treatment of cancer, autoimmune disease, asthma and allergic diseases, reported initial data from its ongoing Phase 1 dose-escalation study of XmAb13676, a CD20 x CD3 bispecific antibody, in patients with B-cell malignancies (Press release, Xencor, DEC 9, 2019, View Source [SID1234552133]). Data are being presented by Krish Patel, M.D., Director of the Lymphoma Program at Swedish Cancer Institute, in a poster session today from 6:00 p.m. to 8:00 p.m. EST at the 61stAmerican Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando, Florida.

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"XmAb13676 has been generally well tolerated and has demonstrated encouraging clinical activity in patients with advanced non-Hodgkin’s lymphoma as a monotherapy in initial dose escalation cohorts. This activity supports the potential of XmAb13676 in lymphoma treatment, and we are planning additional studies as a monotherapy and in combination with other agents," said Bassil Dahiyat, Ph.D., president and chief executive officer at Xencor. "Dose escalation and optimization of dosing schedule, using a priming dose and step-up regimen, are ongoing."

Key Highlights

At data cut off in November 2019, 45 patients with relapsed/refractory non-Hodgkin’s lymphoma (r/r NHL) had received doses of XmAb13676 ranging from 0.7 to 170 mcg/kg, and 8 patients with relapsed/refractory chronic lymphocytic leukemia (r/r CLL) had received doses ranging from 0.7 to 20 mcg/kg. The study was designed in two parts: Part A to establish an initial priming dose with flat dosing regimens and Part B to escalate dosing on subsequent administrations to the priming dose. Prophylactic treatment for cytokine release syndrome (CRS) was mandated prior to each dose of XmAb13676.

XmAb13676 was generally well tolerated, and a priming dose of 45 mcg/kg was chosen for continued dose escalation in Part B for patients with NHL.

Safety was evaluated in all 53 patients. The most common treatment-emergent adverse events (AEs) were pyrexia (55%), CRS (53%) and anemia (41%). CRS was more frequent and generally higher grade on the first dose. Three patients (6%) experienced Grade 3 or 4 CRS on the first dose, all prior to the implementation of step-up dosing. AEs consistent with the symptoms of CRS, but not reported as such, were observed in an additional 23% of patients and were mild to moderate in severity.

CRS Grades by NHL Dose Groups in Treatment Cycle 1

Nervous system disorders, which were observed in 49% of patients, were mild or moderate in severity, and the most common of these events were dizziness (17%), headache (17%), paresthesia (9%) and lethargy (6%). One patient experienced short-term encephalopathy during a CRS event (Grade 2), and one patient lost consciousness during a bowel movement. Grade 3 or 4 AEs experienced by more than 5% of patients, other than CRS, included anemia (23%), neutropenia (15%), thrombocytopenia (11%), lymphopenia (9%) and hypokalemia (6%).

Eighteen patients with diffuse large B-cell lymphoma (DLBCL) who received doses of 80 to 170 mcg/kg are included in the analysis to describe clinical activity. These patients had a median age of 63.5 years, a median of three prior systemic therapies and had been diagnosed a median of 21.5 months prior to treatment. The objective response rate was 39% (n=7), and the complete response rate was 28% (n=5). XmAb13676 demonstrated clinical activity in an apparent dose-dependent manner. At dose levels with clinical activity for patients with DLBCL, 80 to 170 mcg/kg, a complete response was observed in one patient (20%; n=1/5) with follicular lymphoma (FL). Additional complete responses have been observed in Waldenström macroglobulinemia (n=1) and Richter transformation of CLL (n=1), both at 20 mcg/kg, the highest dose administered in the ongoing Part A of the study for patients with CLL.

The poster will be made available under Archived Scientific Presentations on the Events & Presentations page in the Investors section of www.xencor.com.

Webcast Information

Xencor will provide an overview of these data in a live webcast presentation at 8:30 p.m. EST on Monday, December 9, 2019. The webcast can also be accessed on the Events & Presentations page in the Investors section of www.xencor.com, and it will remain archived for 30 days.

About XmAb13676

XmAb13676 is a tumor-targeted antibody that contains both a CD20 binding domain and a T-cell binding domain (CD3) in a Phase 1 clinical trial for the treatment of B-cell malignancies. An XmAb bispecific Fc domain serves as the scaffold for these two antigen binding domains and confers long circulating half-life, stability and ease of manufacture on XmAb13676. CD20 is highly expressed on B-cell tumors, including in chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL). Engagement of CD3 by XmAb13676 activates T cells for highly potent and targeted killing of CD20-expressing tumor cells.

About XmAb Bispecific Fc Technology

XmAb bispecific Fc domains enable the rapid design and simplified development of bispecific antibodies, and other protein structures, that bind two or more different targets simultaneously using an engineered heterodimer Fc domain. Seven XmAb bispecific antibodies are being evaluated in Phase 1 clinical studies conducted by Xencor or its pharmaceutical partners.

CD3 bispecific antibodies contain an anti-tumor associated antigen binding domain and a second binding domain targeted to CD3, an activating receptor on T cells, with the goal to recruit or activate T cells against the antigen target. Candidates in clinical development include XmAb14045 (CD123 x CD3), XmAb13676 (CD20 x CD3), XmAb18087 (SSTR2 x CD3) and Amgen’s AMG 424 (CD38 x CD3).
Tumor microenvironment (TME) activator bispecific antibodies promote tumor-selective T-cell activation by targeting multiple checkpoints or co-stimulating receptors. These candidates incorporate Xencor’s Xtend technology for longer half-life in their design. Candidates in clinical development include XmAb20717 (PD1 x CTLA4), XmAb22841 (CTLA4 x LAG3) and XmAb23104 (PD1 x ICOS).
Cytokine candidates are built on a heterodimeric Fc domain and have their potencies tuned to improve therapeutic index. These candidates incorporate Xtend technology for longer half-life.

On December 9, 2019 Trovagene, Inc. (Nasdaq: TROV), a clinical-stage, Precision Cancer Medicine oncology therapeutics company developing drugs that target cell division (mitosis), for the treatment of various cancers including leukemia, prostate and colorectal, reported the presentation of final results from the Company’s Phase 1b study of onvansertib in patients with relapsed/refractory acute myeloid leukemia (AML) in an oral session at the American Society of Hematology (ASH) (Free ASH Whitepaper) annual conference in Orlando, FL, on Saturday, December 7th (Press release, Trovagene, DEC 9, 2019, View Source [SID1234552131]). The presentation highlighted the efficacy, durability of response, favorable safety and tolerability profile, as well as correlative biomarker data from the recently completed Phase 1b trial.
The oral presentation at ASH (Free ASH Whitepaper) is available for download from the Scientific Presentations page on the Trovagene website at View Source

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"I am encouraged by the preliminary efficacy and safety/tolerability demonstrated in the dose escalation part 1b of our trial," said Dr. Amer Zeidan, lead investigator and associate professor of Medicine at the Yale School of Medicine, and Hematology expert at Yale Cancer Center. "As we continue with enrollment and assessment of efficacy in the Phase 2 portion of the trial, I look forward to seeing additional clinical benefit of onvansertib in combination with decitabine in our relapsed and refractory AML patients."

Oral Presentation Highlights
Background:

Onvansertib is an oral, highly-selective Polo-like Kinase 1 (PLK1) inhibitor with a half-life of ~24 hours
PLK1 inhibition by onvansertib, assessed via a simple blood test and shown as changes in the phosphorylation of its direct substrate, the translational controlled tumor protein, TCTP, is a biomarker for identifying patients most likely to respond to treatment

Patients eligible for enrollment in the Phase 1b trial were treatment naïve and not candidates for induction therapy or had relapsed/refractory disease to up to 3 prior regimens (Phase 1b)

Trovagene Inc. | 11055 Flintkote Avenue | San Diego | CA 92121 | Tel.: USA [+1] 888-391-7992

Treatment Summary as of October 31, 2019
Safety and Tolerability:

Treatment was well tolerated through the first 5 dose escalation cohorts (onvansertib 12 – 60 mg/m2)

9 of the 71 SAEs (13%) were considered as possibly related to onvansertib and occurred at the higher dose levels: 40 mg/m2 (1), 60 mg/m2 (1) and 90 mg/m2

The maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) was established at 60 mg/m2
Preliminary Efficacy:

6 (17%) patients had a complete response (CR, CRi); 9 (25%) had an ORR (CR, CRi, MLFS, PR) across LDAC and decitabine arms and doses

At the 4 higher dose levels (27 to 90 mg/m2), CR/CRi was observed in:
o
5 (31%) of the 16 patients in the decitabine Arm
o
1 (11%) of the 9 patients in the LDAC Arm

Median time to achieve CR/CRi was 4 cycles (range 1-7)

Median duration of response was 5 months (range 0-11.5)

4 of 6 patients remain on treatment and in remission; duration of CR/CRi is respectively 1.5, 7, 8 and 11.5 months
Biomarker Analysis:

Of the 24 evaluable patients, 8 (33%) were biomarker positive across both arms
•
Among patients with at least 1 BM biopsy (n=17), biomarker positivity was associated with higher response to treatment:
o
67% of biomarker positive patients (4/6) had a ≥20% decrease in blasts versus 18% in biomarker negative patients (1/11)
o
CR/CRi was achieved in 2 biomarker positive patients but in none of the biomarker negative patients

About the Phase 2 Clinical Trial of Onvansertib in AML
The Phase 2 AML trial (NCT03303339) of onvansertib in combination with decitabine will enroll 32 patients who are either treatment naïve and not candidates for induction therapy or who have relapsed disease after treatment with one prior regimen. Patients will receive onvansertib,

administered orally, on days 1 through 5 of each 21-28-day cycle in combination with decitabine. The primary efficacy endpoint of objective response (CR + CRi) will be assessed in patients who complete at least 1 cycle of treatment.
About Onvansertib
Onvansertib is a first-in-class, third-generation, oral and highly-selective adenosine triphosphate (ATP) competitive inhibitor of the serine/threonine polo-like-kinase 1 (PLK1) enzyme, which is over-expressed in multiple cancers including leukemias, lymphomas and solid tumors. Onvansertib targets the PLK1 isoform only (not PLK2 or PLK3), is orally administered and has a 24-hour half-life with only mild-to-moderate side effects reported. Trovagene believes that targeting only PLK1 and having a favorable safety and tolerability profile, along with an improved dose/scheduling regimen will significantly improve on the outcome observed in previous studies with a former panPLK inhibitor in AML.
Onvansertib has demonstrated synergy in preclinical studies with numerous chemotherapies and targeted therapeutics used to treat leukemias, lymphomas and solid tumor cancers, including irinotecan, FLT3 and HDAC inhibitors, taxanes and cytotoxins. Trovagene believes the combination of onvansertib with other compounds has the potential to improve clinical efficacy in acute myeloid leukemia (AML), metastatic castration-resistant prostate cancer (mCRPC), non-Hodgkin lymphoma (NHL), colorectal cancer and triple-negative breast cancer (TNBC), as well as other types of cancer.
Trovagene has three ongoing clinical trials of onvansertib: A Phase 2 trial of onvansertib in combination with Zytiga (abiraterone acetate)/prednisone in patients with mCRPC who are showing signs of early progressive disease (rise in PSA but minimally symptomatic or asymptomatic) while currently receiving Zytiga (NCT03414034); a Phase 1b/2 Study of onvansertib in combination with FOLFIRI and Avastin for second-line treatment in patients with mCRC with a KRAS mutation (NCT03829410); and a Phase 1b/2 clinical trial of onvansertib in combination with low-dose cytarabine or decitabine in patients with relapsed or refractory AML (NCT03303339). Onvansertib has been granted orphan drug designation by the FDA in the U.S. and by the EC in the European Union for the treatment of patients with AML.
Trovagene licensed onvansertib (also known as NMS-1286937 and PCM-075) from Nerviano Medical Sciences (NMS), the largest oncology-focused research and development company in Italy, and a leader in protein kinase drug development. NMS has an excellent track record of licensing innovative drugs to pharma/biotech companies, including Array (recently acquired by Pfizer), Ignyta (acquired by Roche) and Genentech.

On December 9, 2019 TG Therapeutics, Inc. (NASDAQ: TGTX), reported the first clinical data from the Company’s once daily, oral, BTK inhibitor, TG-1701, as a single agent and as a triple therapy in combination with ublituximab (TG-1101), the Company’s novel glycoengineered anti-CD20 monoclonal antibody, and umbralisib (TGR-1202), the Company’s oral, dual inhibitor of PI3K delta and CK1 epsilon, in patients with relapsed/refractory non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL) (Press release, TG Therapeutics, DEC 9, 2019, View Source [SID1234552130]). Data from this Phase I trial are being presented this evening during a poster session at the 61stAmerican Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition.

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Michael S. Weiss, Executive Chairman and Chief Executive Officer, stated, "We are highly encouraged by the first clinical data presented from our once daily, BTK inhibitor, TG-1701, which has demonstrated superior selectivity for BTK compared to ibrutinib in an in vitro whole kinome screening. The data presented today show that TG-1701 is an active BTK inhibitor as a single agent and that the combination of U2 plus TG-1701 has been generally well tolerated and active with 6 of 7 patients responding to the triple therapy at 100 mg QD, the lowest dose of TG-1701 tested. We look forward to continuing dose escalation of TG-1701 in the combination arm and identifying the optimal dose for this therapy." Mr. Weiss continued, "Our goal has always been to develop the best possible combination treatment options for patients, and we are excited to present the first data from a triple combination study in which all of the agents are being developed by TG. We believe this proprietary combination has the potential to enhance the results of BTK inhibitor therapy alone and offer patients early and deep responses with a tolerable safety profile."

Below are highlights from today’s poster presentation.

Poster Presentation: Phase 1 Study of TG-1701, a Selective Irreversible Inhibitor of Bruton’s Tyrosine Kinase (BTK), in Patients with Relapsed/Refractory B-Cell Malignancies

This presentation includes safety information from 30 patients, 21 patients treated with single agent TG-1701, and 9 patients treated with the triple combination of TG-1701 plus U2.

TG-1701, a once daily BTK inhibitor, demonstrates an encouraging safety profile to date, with clinical and pharmacodynamic activity at all dose levels evaluated
30 patients have been treated with TG-1701 at doses that ranged from 100mg to 400mg once daily for TG-1701 monotherapy; dose escalation continues in the triple combination arm
Single agent TG-1701 produced partial responses at multiple dose levels (including the lowest dose tested) across multiple B-cell diseases, including mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), Waldenström’s macroglobulinemia (WM), and small lymphocytic lymphoma (SLL)
86% (6/7) of patients treated with 100 mg TG-1701 plus U2 have achieved a response
• 4 patients with follicular lymphoma (FL): 2 Complete Responses (CR), 1 Partial Response (PR) and 1 Stable Disease (SD)
• 1 PR in marginal zone lymphoma (MZL); 1 PR in Waldenström’s macroglobulinemia (WM); and 1 PR in diffuse large B-cell lymphoma (DLBCL)
All patients treated with the triple combination of TG-1701 plus U2 remain on study
ASH Poster Presentation Details

Title: Phase 1 Study of TG-1701, a Selective Irreversible Inhibitor of Bruton’s Tyrosine Kinase (BTK), in Patients with Relapsed/Refractory B-Cell Malignancies
• Publication Number: 4001
• Session: 623. Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma—Clinical Studies: Poster III
• Date and Time: Monday, December 9, 2019; 6:00 PM – 8:00 PM ET
• Location: Orange County Convention Center, Hall B
• Presenter: Chan Cheah, MD, Sir Charles Gairdner Hospital, Hollywood Private Hospital, University of Western Australia, Blood Cancer Research Western Australia
Below recaps highlights from yesterday’s oral presentation of U2 plus venetoclax.

Title: A Phase 1/2 Study of Umbralisib, Ublituximab and Venetoclax in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

This oral presentation includes data from patients with relapsed or refractory CLL treated with the triple combination of ublituximab, umbralisib, and venetoclax. Twenty-seven patients were evaluable for safety and 23 were evaluable for efficacy. Data highlights include:

Regimen was administered with 3 cycles of U2 induction/debulking to reduce the risk of tumor lysis syndrome (TLS), followed by the combination of umbralisib and venetoclax starting in cycle 4. Patients who were bone marrow MRD negative after cycle 12 stopped all therapy.
Overall response rate (ORR) of 87% (20/23) after U2 induction period at cycle 3, prior to introduction of venetoclax, in relapsed/refractory CLL patients, including patients refractory to ibrutinib
U2 induction appeared to reduce venetoclax TLS risk, with no patients remaining as TLS high-risk following 3 cycles of U2
13 patients treated for >7 cycles and 9 patients for > 12 cycles:
• 100% ORR (13/13) after cycle 7 for the triple combination
• 100% ORR (9/9) including 44% Complete Response (CR) after cycle 12 for the combination
• 100% (9/9) of patients had undetectable minimal residual disease (MRD) (<0.01%) in peripheral blood after 12 cycles of therapy; and
• 78% (7/9) of patients who completed 12 cycles of therapy had undetectable MRD in bone marrow and have stopped therapy
No patients (n=27) have progressed to date with a median follow-up of 6.4 months
Triple combination was generally well tolerated with no events of TLS observed
An open-label, multicenter, Phase 2 study evaluating U2 plus venetoclax (ULTRA-V) in treatment naïve and previously treated CLL is now open for enrollment.

All data presented is available on the Publications page of the Company’s website at View Source