On December 9, 2019 Precision BioSciences, Inc. (Nasdaq: DTIL), a genome editing company dedicated to improving life through the application of its pioneering, proprietary ARCUS platform, reported updated interim clinical data from the ongoing Phase 1 trial of its lead investigational off-the-shelf (allogeneic) chimeric antigen receptor (CAR) T cell therapy candidate, PBCAR0191, which targets the well characterized cancer cell surface protein CD19 (Press release, Precision Biosciences, DEC 9, 2019, View Source [SID1234552126]). PBCAR0191 is being developed in collaboration with Servier, an international pharmaceutical company. Data will be presented by Bijal Shah, MD, Moffitt Cancer Center, at the 61st Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in Orlando, Florida, during a poster session from 6:00-8:00 p.m. ET today (Poster #4107, Hall B).

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"We are very encouraged by the evidence of cell-mediated anti-tumor activity and objective tumor responses that we have observed in both NHL and B-ALL patients treated with PBCAR0191, in the context of a manageable adverse event profile," said Chris Heery, MD, Chief Medical Officer of Precision BioSciences. "These data give us incremental confidence in our unique approach to allogeneic CAR T cell therapy, and we look forward to the potential of this therapy positively impacting the lives of more patients as the trial continues. At these still low dose levels, and using only mild lymphodepletion, it is remarkable to see anti-tumor activity in the majority of patients treated with PBCAR0191, including a durable response that lasted six months in one patient, and two complete responses. We have also seen preliminary evidence of dose dependent CAR T cell expansion and persistence, supporting our belief that cell persistence and clinical response is likely to increase as we increase dose level."

"New treatment options are desperately needed for patients with advanced NHL and B-ALL who often undergo multiple cycles of therapy with limited clinical benefit," commented Bijal Shah, MD, Moffitt Cancer Center. "These first-in-human data for PBCAR0191 suggest a tolerable safety profile and encouraging early evidence of clinical activity. Further study is required to determine durability of response at the current dose levels, as well as to establish safety and activity at Dose Level 3."

Patient baseline characteristics and trial overview
A total of nine patients are reported in these initial Phase 1 trial results, including six with NHL (three treated at Dose Level 1 and three treated at Dose Level 2), and three with B-ALL (all treated at Dose Level 2). Key baseline characteristics were as follows:

Dose Level 1 (3×105 cells/kg) – three NHL patients (two with diffuse large B cell lymphoma, one with mantle cell lymphoma) with a mean age of 54 years (min-max 34-64 years). Patients had received a median of four prior lines of therapy, with two patients being refractory to their last treatment, and one having previously relapsed following treatment with Yescarta, an FDA-approved autologous CD19-targeted CAR T therapy.
Dose Level 2 (1×106 cells/kg) – three NHL patients (all with mantle cell lymphoma) with a mean age of 74 years (min-max 71-77 years) who had received a median of two prior lines of therapy, with one patient refractory to their last treatment and two who had relapsed. Three B-ALL patients were also treated at DL2, with a mean age of 56 years (min-max 48-72 years); these patients had received a median of four prior lines of therapy – all three patients were refractory to their last treatment, with two patients having poor prognostic indicators at trial entry.
Patients received a single infusion of PBCAR0191 on day 0, following three days of lymphodepletion using fludarabine 30mg/m2/day and cyclophosphamide 500mg/m2/day. The primary objective of this Phase 1 portion of the ongoing Phase 1/2a trial is to evaluate safety as measured by the occurrence of dose limiting toxicities (DLTs). Secondary objectives include assessment of objective tumor responses using standard criteria, and further evaluation of adverse events (AEs) and adverse events of special interest, including graft-versus-host disease (GvHD), cytokine release syndrome (CRS), and IEC-associated neurotoxicity syndrome (ICANS). Data are presented as of a November 4, 2019 cutoff date, with additional critical data collected through December 2, 2019, including occurrence of CRS, ICANS, GvHD and evaluation of objective responses.

Safety of PBCAR0191
No serious adverse events or evidence of GvHD was observed through December 2, 2019. Three of the nine patients (33%) treated with PBCAR0191 developed CRS, including two Grade 1 cases and one Grade 2 case. One of the nine patients (11%) developed Grade 2 neurotoxicity. All events of CRS and neurotoxicity resolved, and no deaths occurred on study. In addition, one patient experienced a Grade 3 AE that was deemed related to PBCAR0191 (pain at the site of their tumor mass for one day following infusion), and one patient experienced Grade 4 lymphopenia (seven days duration) deemed related to PBCAR0191.

Clinical activity of PBCAR0191
Of the nine patients treated with PBCAR0191, seven (78%) had objective evidence of tumor shrinkage at any timepoint. Results also provide preliminary evidence of dose-dependent CAR T cell expansion and persistence.

In the NHL cohort, four of six patients (66%) achieved an objective response by Lugano 2014 criteria at day 28+, including three partial responses (two patients treated at DL1 and one patient treated at DL2) and one complete response (patient treated at DL2). As of December 2, 2019, one patient (treated at DL2) remains in complete response. One patient (treated at DL1) achieved a partial response then progressed six months after treatment with PBCAR0191. This was the most durable response observed to date and was also notable given the patient had relapsed following treatment with Yescarta. The remaining two NHL patients, one treated at DL1 and one at DL2, achieved early responses (one CR, one PR respectively) at day 14; both patients had evidence of disease progression at day 28.

In the B-ALL cohort treated at DL2, one of three patients (33%) achieved a complete response by NCCN 2017 criteria at day 28+ (with undetectable B-ALL in the bone marrow by flow cytometry, described as minimal residual disease (MRD) negative), and continues to be followed on study. The remaining two patients did not respond at day 28 – these patients had poor prognostic indicators on entry into the trial, one with prior CNS involvement and 95% blast infiltration into the bone marrow, and one with 77% blast infiltration into the bone marrow and disease refractory to two previous lines of treatment.

CAR T cell expansion and persistence in the peripheral blood was assessed at DL1 and DL2 by flow cytometry and qPCR. Evidence of a dose-dependent increase in cell expansion was observed between subjects treated at DL1 and DL2, as was a dose-dependent increase in CAR T cell persistence. B-cell aplasia and serum cytokine analysis also anecdotally correspond to observed clinical responses and CAR T cell expansion.

This trial is ongoing and treatment of patients at DL3 (3×106 cells/kg) recently commenced. Updated results, including from patients treated at DL3, are expected to be presented at a medical meeting in the first quarter of 2020.

Investigator Update & Webcast Information
Precision will host a live webcast of an investigator update event during the ASH (Free ASH Whitepaper) Annual Meeting to discuss these data, beginning at 8:15 p.m. ET on Monday, December 9, 2019. To access the webcast, please visit the "Events & Presentations" page within the Investors & Media section of the Precision BioSciences website at View Source A replay of the webcast will be available on the Precision website for 30 days following the event.

Precision’s Off-The-Shelf CAR T Platform
Precision is advancing a pipeline of cell-phenotype optimized allogeneic CAR T therapies, leveraging fully scaled, proprietary manufacturing processes. The platform is designed to maximize the number of patients who can potentially benefit from CAR T therapy by improving access to care through a well-tolerated lymphodepletion regimen, high quality cell products derived from carefully selected healthy donors, and a consistent final cell product with attributes in line with those previously observed to result in optimal safety and activity profiles. Precision carefully selects high-quality T cells derived from healthy donors as starting material, then utilizes its unique ARCUS genome editing technology to modify the cells via a single-step engineering process. By inserting the CAR gene at the T cell receptor (TCR) locus, this process knocks in the CAR while knocking out the TCR in a single step, creating a consistent product that can be reliably and rapidly manufactured and is designed to prevent graft-versus-host disease. Precision optimizes its CAR T therapy candidates for immune cell expansion in the body by maintaining a high proportion of naïve and central memory CAR T cells throughout the manufacturing process and in the final product.

On December 9, 2019 Onconova Therapeutics, Inc. (NASDAQ: ONTX) ("Onconova"), a Phase 3-stage biopharmaceutical company discovering and developing novel products to treat cancer, with an initial focus on myelodysplastic syndromes (MDS), reported data presented from INSPIRE related abstracts at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2019 Annual Meeting (Press release, Onconova, DEC 9, 2019, View Source [SID1234552125]). Preliminary genomics data from the INSPIRE Trial was presented. In addition, updated data from the Phase 2 Trial of Oral Rigosertib + Azacitidine (AZA) Versus Single Agent AZA in Treatment-Naive Patients with HR-MDS was presented in an oral presentation. The Company believes these abstracts represent important progress for the development programs of intravenous (IV) and oral rigosertib.

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Abstract #3015. "Genomic Profiling in Patients with Higher Risk Myelodysplastic Syndrome Following HMA Failure: Baseline Results From the INSPIRE Trial." At study entry, 50 different mutations were identified at baseline prior to patients receiving study treatment with either IV rigosertib or physician’s choice (PC). The average number of mutations per patient was 3. The most common mutations identified in patients were ASXL1 39%, TP53 27%, RUNX1 25%, STAG2 21%, SRSF2 19%, TET2 19%, DNM3A 15%, IDH2 13% and U2AF1 12%. In total 31 patients (19%) had mutations that are part of RAS pathway (NRAS, 4 pts; KRAS, 5 pts; CBL, 7 pts; PTPN11, 7 pts; NF1, 8 pts).

"Genomic abnormalities have revolutionized our understanding of the biology and prognosis of patients with MDS. Abnormalities involving the RAS pathway are seen in patients with MDS who have a very poor prognosis. The INSPIRE Trial has catalogued the abnormalities seen in patients with MDS who have failed the standard of care AZA. On-going studies will determine if the research drug rigosertib can target these abnormalities and prolong the lives of patients who have the spectrum of abnormalities that have been identified," said Guillermo Garcia-Manero, M.D., Department of Leukemia, The University of Texas MD Anderson Cancer Center.

Abstract #4249. "Phase II Study of Oral Rigosertib Combined with Azacitidine As First Line Therapy in Patients with HR-MDS." In HMA naïve higher risk MDS patients who require the standard of care with AZA, the combination of oral rigosertib > 840 mg and AZA produced an overall response rate of 90% and a complete response (CR) rate of 34%. CR by definition signifies the patient has a normal appearing bone marrow and the marrow produces a normal peripheral blood count. The median duration of response is 12.2 months. The Company believes these data support the design of a planned Phase 2/3 adaptive trial in HR-MDS.

"Efforts to improve the response rate with single agent AZA is an area of active research. The efficacy and safety data of the doublet of oral rigosertib and AZA warrants further investigation in a pivotal trial of this novel combination compared to AZA alone. If the preliminary efficacy of the doublet is confirmed in a pivotal controlled study and has an acceptable safety profile, patients with HMA naïve higher risk MDS may have an important new treatment option," said Lewis Silverman, M.D., Director of Translational Research Center for MDS, Division of Hematology/Oncology, at the Icahn School of Medicine at Mount Sinai.

Steven M. Fruchtman, M.D., President and Chief Executive Officer of Onconova, said, "ASH 2019 was a key milestone for Onconova. The five presentations at ASH (Free ASH Whitepaper) showcase the value of our development programs for intravenous and oral rigosertib. The genomic data from the INSPIRE Trial identifies the most common mutations in HR-MDS following AZA failure, including those of the RAS pathway that are targeted by rigosertib. We believe the oral rigosertib in combination with AZA Phase 2 data forms the foundation of a future adaptive trial in HMA naïve HR-MDS patients. We appreciate the recognition by ASH (Free ASH Whitepaper) reviewers of the value of our studies in this field."

Three additional abstracts being presented at the ASH (Free ASH Whitepaper) 2019 Annual Meeting include:

Abstract #4249. "The Inspire Study in HR MDS: A Novel Phase 3 Study Adaptive Design for Hematological Malignancies in Adults."

Abstract #4268. "Phase 3, Multi-Center, International, Randomized, Double-Blind, Placebo Controlled Study of Oral Rigosertib + Injectable Azacitidine (AZA) Versus Injectable Azacitidine in Treatment-Naïve Patients with Higher-Risk Myelodysplastic Syndrome (HR-MDS)."

Abstract #4231. "The Sequenced Combination of Rigosertib and Azacitidine Has Modulatory Effects on CXCL8, RIG-I like Receptor (RLR) and Wnt/β-Catenin Signaling and Downstream Hematopoiesis Pathways in an in Vitro Model of the Myelodysplastic Syndrome."

On December 9, 2019 Onconova Therapeutics, Inc. (NASDAQ: ONTX) ("Onconova"), a Phase 3-stage biopharmaceutical company discovering and developing novel products to treat cancer, with an initial focus on myelodysplastic syndromes (MDS), reported that it has entered into definitive agreements with healthcare focused institutional investors for the issuance and sale in a registered direct offering of 14,326,648 shares of its common stock and warrants to purchase up to 7,163,324 shares of its common stock, at a combined purchase price of $0.349 per share and associated warrant, for aggregate gross proceeds of approximately $5.0 million in a registered direct offering priced at-the-market under Nasdaq rules (Press release, Onconova, DEC 9, 2019, View Source [SID1234552124]).

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H.C. Wainwright & Co. is acting as the exclusive placement agent for the offering.

The warrants will have an exercise price of $0.287 per share and exercise period commencing immediately upon issuance and a term of five (5) years.

The offering is expected to close on or about December 10, 2019, subject to the satisfaction of customary closing conditions. Upon the closing of the offering, the Company’s stockholders’ equity is expected to exceed the minimum $2.5 million stockholders’ equity requirement for continued listing on The Nasdaq Capital Market, as set forth in Nasdaq Listing Rule 5550(b)(1), and the Company intends to provide further information to Nasdaq demonstrating its ability to sustain long-term compliance. In addition, 10,443,000 common stock warrants have been exercised since November 25, 2019, resulting in additional proceeds to the Company of approximately $2.1 million.

The Company currently intends to use the net proceeds from the offering for working capital and general corporate purposes, including advancing preparations for a planned New Drug Application (NDA) filing to the FDA for intravenous rigosertib in second-line higher-risk MDS in 2020. The Company surpassed 90% of the required enrollment of the INSPIRE Trial in November 2019 and anticipates reporting topline data in the first half of 2020, following full enrollment and reaching the number of required survival events. With the additional proceeds from the offering and the proceeds from the recent warrant exercise, the Company believes that it has the sufficient funds to extend operations and ongoing trials late into the third quarter of 2020.

The securities described above are being offered and sold by the Company pursuant to a "shelf" registration statement on Form S-3 (Registration No. 333-221684), including a base prospectus, previously filed with and declared effective by the Securities and Exchange Commission (the "SEC") on December 28, 2017. The offering of the securities will be made only by means of a prospectus supplement that forms a part of the registration statement. A final prospectus supplement and an accompanying base prospectus relating to the registered direct offering will be filed with the SEC and will be available on the SEC’s website located at View Source Electronic copies of the prospectus supplement and the accompanying base prospectus may also be obtained by contacting H.C. Wainwright & Co., LLC at 430 Park Avenue, 3rd Floor, New York, NY 10022, by phone at 646-975-6996 or e-mail at [email protected].

This press release shall not constitute an offer to sell or the solicitation of an offer to buy, nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.

On December 9, 2019 Novartis reported results from two analyses of real-world experience with Kymriah (tisagenlecleucel), the only CAR-T cell therapy approved in two distinct indications (Press release, Novartis, DEC 9, 2019, View Source [SID1234552123]). These analyses are from a readout of a 15-year post-marketing study that add to and complement the rigor of the Kymriah pivotal trials with evidence of the Kymriah real-world experience in expanded groups of patients. When Kymriah was used in the real-world setting, efficacy and safety were consistent when compared to the pivotal trials, including the 24-month analysis of JULIET in adults with r/r diffuse large B cell lymphoma (DLBCL) and ELIANA in children and young adults with r/r B-cell acute lymphoblastic leukemia (ALL)1-6. The real-world experience data were presented at the 61st American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting.

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"With increased experience supplemented by real world data, physicians like myself have a better understanding of Kymriah and its safety profile," said lead author of this real-world experience analysis, Samantha Jaglowski, MD, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James). "This along with the current practice of supportive care for CAR-T therapy provides the ability to routinely use this therapy in the hospital outpatient setting, which can reduce financial burden on patients and hospitals alike1,7."

Real-world experience with Kymriah in adults with r/r DLBCL

Efficacy
Efficacy outcomes for patients who received Kymriah in the real-world setting were similar to those demonstrated in JULIET. In this analysis of 80 patients with r/r DLBCL for whom three or more months of post-infusion outcomes were available, the overall response rate (ORR) was 58% including 40% who achieved a complete response (CR). Median follow-up was 4.5 months1. In the 24-month analysis of the JULIET trial, ORR was 52% and CR was 38% (N=115) 3.

Safety
The anticipation and management of adverse events of CAR-T cell therapy have been crucial to successful administration of this innovative and relatively new type of therapy. In this analysis of real-world experience with Kymriah (safety set, N=83), the rate of grade 3 or higher cytokine release syndrome (CRS) and neurologic events were approximately 4% and 5%, respectively, as compared to 23% and 11% in the JULIET clinical trial (safety set, N=115), suggesting safety outcomes appear more favorable. The real-world analysis used the grading scales ASTCT for CRS and ICANs for neurologic events, whereas the JULIET trial used the Penn Grading Scale for CRS and MedDRA SMQ for neurologic events1,3.

Further, for patients who had CRS, tocilizumab and corticosteroids were administered in 20% and 4% of patients, respectively, in the real-world setting, and in 27% and 19% of patients, respectively, in the JULIET trial8. Some patients in the real-world setting received tocilizumab earlier than in the clinical trial experience, indicating earlier use of supportive care may mitigate rates of high-grade CRS9. A total of 14 DLBCL patients died after treatment, all due to disease progression, however no deaths were attributed to toxicities from Kymriah1.

Patient and product characteristics
More patients in the real-word analysis had a worse performance status, and on average, these patients were older and had received more lines of therapy than those treated in the JULIET trial1-3.

Cell viability is one of many product release specifications for Kymriah. The commercial specification for the viability specification of Kymriah in the United States is set at greater than or equal to 80%. For all other markets where KYMRIAH is approved, the cell viability specification is greater than or equal to 70%. In this US real-world analysis, 29 of the 102 patients with evaluable data received product that was below 80% cell viability. Efficacy and safety for patients receiving product with cell viability below the commercial specification was the same as those receiving commercial Kymriah1.

These data on the use of Kymriah in r/r DLBCL in the real-world setting will be presented in an oral session at the ASH (Free ASH Whitepaper) annual meeting (Abstract # 766; Monday, December 9, 3:30 PM EST).

"As pioneers in bringing CAR-T cell therapy to patients, our dedication to reimagining how CAR-T cell therapy can impact patients in the future remains steadfast," said Susanne Schaffert, PhD, President, Novartis Oncology. "Our efforts include gathering and sharing real-world evidence, expanding and improving our manufacturing capacity and technology and going broader and deeper in our clinical research with Kymriah and other CAR-T cell therapies."

Real-world experience with Kymriah in children and young adults with r/r ALL

Efficacy outcomes were similar and safety outcomes appear to be more favorable in the real world setting compared to the ELIANA pivotal trial4-6. Among 146 children and young adult patients with r/r ALL treated in the real world setting for whom three or more months of post-infusion outcomes were available, CR was 85% as compared to 82% in the ELIANA trial (n=79). Median follow-up in the real-world analysis was 6 months. In this analysis (safety set, N=154), the rate of grade 3 or higher CRS and neurologic events were 14% and 8%, respectively, as compared to 48% and 13% in the ELIANA clinical trial. The real-world analysis used the grading scales ASTCT for CRS and ICANs for neurologic events, whereas the ELIANA trial used the Penn Grading Scale for CRS and MedDRA SMQ for neurologic events4-6.
"It is exciting to see how oncologists are using Kymriah and how patients are responding to it in routine clinical practice," said Stephan A. Grupp, MD, PhD, Director of the Cancer Immunotherapy Program and Section Chief of Cell Therapy and Transplant at Children’s Hospital of Philadelphia, and a Professor of Pediatrics in the Perelman School of Medicine at the University of Pennsylvania. "We are seeing broader efficacy data that replicate what we saw in the pivotal trial, and the collection of these data is ensuring that we are getting a clear view of adverse events when administering Kymriah."

These data on the use of Kymriah in r/r pediatric ALL in the real-world setting will be presented in a poster presentation at the ASH (Free ASH Whitepaper) annual meeting (Abstract #2619; Sunday, December 8, 6:00 – 8:00 PM EST).

The collection of this real-world experience data was made possible by a collaboration between the CIBMTR (Center for International Blood and Marrow Transplant Research – the research collaboration between the National Marrow Donor Program/Be The Match and the Medical College of Wisconsin) and Novartis, developed to capture long-term follow-up of recipients of Kymriah who agree to participate in the registry. For patients whose cell viability was below 80%, product is provided through an established EAP program and long-term follow-up is captured through the CIBMTR. Globally, 90% patients who have been prescribed Kymriah have received the final manufactured product, either commercially, or when out of commercial specification.

Kymriah (tisagenlecleucel, formerly CTL019) US Important Safety information
Kymriah may cause side effects that are severe or life-threatening, such as Cytokine Release Syndrome (CRS) or Neurological Toxicities. Patients with CRS may experience symptoms including difficulty breathing, fever (100.4°F/38°C or higher), chills/shaking chills, severe nausea, vomiting and diarrhea, severe muscle or joint pain, very low blood pressure, or dizziness/lightheadedness. Patients may be admitted to the hospital for CRS and treated with other medications.

Patients with neurological toxicities may experience symptoms such as altered or decreased consciousness, headaches, delirium, confusion, agitation, anxiety, seizures, difficulty speaking and understanding, or loss of balance. Patients should be advised to call their healthcare provider or get emergency help right away if they experience any of these signs and symptoms of CRS or neurological toxicities.

Because of the risk of CRS and neurological toxicities, Kymriah is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called Kymriah REMS.

Serious allergic reactions, including anaphylaxis, may occur after Kymriah infusion. Kymriah can increase the risk of life-threatening infections that may lead to death. Patients should be advised to tell their healthcare provider right away if they develop fever, chills, or any signs or symptoms of an infection.

Patients may experience prolonged low blood cell counts (cytopenia), where one or more types of blood cells (red blood cells, white blood cells, or platelets) are decreased. The patient’s healthcare provider will do blood tests to check all of their blood cell counts after treatment with Kymriah. Patients should be advised to tell their healthcare provider right away if they get a fever, are feeling tired, or have bruising or bleeding.

Patients may experience hypogammaglobulinemia, a condition in which the level of immunoglobulins (antibodies) in the blood is low and the risk of infection is increased. It is expected that patients may develop hypogammaglobulinemia with Kymriah, and may need to receive immunoglobulin replacement for an indefinite amount of time following treatment with Kymriah. Patients should tell their healthcare provider about their treatment with Kymriah before receiving a live virus vaccine.

After treatment with Kymriah, patients will be monitored lifelong by their healthcare provider, as they may develop secondary cancers or recurrence of their cancer.

Patients should not drive, operate heavy machinery, or do other dangerous activities for eight weeks after receiving Kymriah because the treatment can cause temporary memory and coordination problems, including sleepiness, confusion, weakness, dizziness, and seizures.
Some of the most common side effects of Kymriah are difficulty breathing, fever (100.4°F/38°C or higher), chills/shaking chills, confusion, severe nausea, vomiting and diarrhea, severe muscle or joint pain, very low blood pressure, dizziness/lightheadedness, and headache. However, these are not all of the possible side effects of Kymriah. Patients should talk to their healthcare provider for medical advice about side effects.

Prior to a female patient starting treatment with Kymriah, their healthcare provider may do a pregnancy test. There is no information available for Kymriah use in pregnant or breast-feeding women. Therefore, Kymriah is not recommended for women who are pregnant or breast feeding. Patients should talk to their healthcare provider about birth control and pregnancy.

Patients should tell their healthcare provider about all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
After receiving Kymriah, patients should be advised that some commercial HIV tests may cause a false-positive test result. Patients should also be advised not to donate blood, organs, or tissues and cells for transplantation after receiving Kymriah.

On December 9, 2019 Molecular Templates, Inc., (Nasdaq: MTEM) a clinical-stage biopharmaceutical company focused on the discovery and development of the Company’s proprietary engineered toxin bodies (ETBs), which are differentiated, targeted, biologic therapeutics, reported the presentations of two posters on its pipeline programs at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2019 Annual Meeting, taking place December 7-10, 2019 in Orlando, Florida (Press release, Molecular Templates, DEC 9, 2019, View Source [SID1234552122]). One of these posters includes final results from the Phase 1/1b study of MT-3724, in subjects with relapsed/refractory (R/R) diffuse large b-cell lymphoma (DLBCL).

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Poster Title: Monotherapy Activity with the First CD20-Targeted Immunotoxin, MT-3724, in Subjects with Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL)
Abstract Number: 4098
Presenter: Daniel Persky MD, University of Arizona Cancer Center
Session: 626. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Prospective Clinical Trials
Time: Monday, December 9, 2019: 6:00 PM-8:00 PM ET
This is a multi-center, open-label, dose-escalation and dose-expansion study of MT-3724, the first CD20 targeted immunotoxin to enter clinical trials. The Phase 1/1b portion of the study consists of two Parts in which a total of 27 subjects with NHL were enrolled; 21 in Part 1 (dose escalation) and 6 in Part 2 (expansion cohort), both closed to enrollment. In total, 25 subjects were evaluable for efficacy, including 19 subjects with DLBCL or mixed DLBCL/follicular lymphoma.

MT-3724 competes for binding with rituximab (RTX) and other commercially available CD20-targeting monoclonal antibodies. Consistent with this competition, initial efficacy data from the dose expansion study revealed only one of eight subjects with measurable serum rituximab (RTX) levels had any suggestion of benefit (a mixed response) to MT-3724.

The expansion cohort mandated negative serum RTX levels for enrolled subjects. Of the 13 serum rituximab negative (RTX-neg) DLBCL or mixed DLBCL/FL subjects, 5 responded (38% objective response rate) across the range of 5 to 100 μg/kg doses. Of the 5 responses, 2 were complete responses (CRs) and 3 were partial responses (PRs). Three patients had stable disease (including 2 patients with 49% and 47% tumor reductions) and 5 patients had progressive disease.

Of the 5 serum RTX-neg subjects with DLBCL who received MT-3724 at 50 μg/kg, the maximum tolerated dose (MTD), 3 responded (2 CR, 1 PRs). Of all 25 subjects evaluable for efficacy, 13 developed anti-drug antibodies (ADAs) or neutralizing antibodies (NAbs); the development of ADAs or NAbs did not preclude benefit of MT-3724, consistent with what has been seen with other immunotoxins. Safety events were mostly mild to moderate, and dose limiting toxicities (DLTs) were indicative of innate immune response, including grade 2 capillary leak syndrome and grades 1-3 arthralgias and myalgias. No life-threatening toxicities were attributed to MT-3724.

A Phase 2 dose-expansion portion of the study (Part 3) has been initiated to investigate MT-3724 in serum RTX-neg subjects with DLBCL. This is actively enrolling globally. A tolerable dose and schedule for the Phase 2 has been identified: 50 μg/kg/dose with a cap of 6000 μg/dose infused over 1 hour on Days 1, 3, 5, 8, 10 and 12 of a 21-day cycle. (ClinicalTrials.gov Identifier: NCT02361346).

Poster Title: A Phase 2a Open-Label Study to Investigate Safety and Tolerability (including the MTD), Efficacy, Pharmacokinetics, Pharmacodynamics and Immunogenicity of MT-3724 in Combination with Lenalidomide in Subjects with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma
Presenter: Jason Tache, DO, BRCR Medical Center
Abstract #: 1597
Session: 626. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Prospective Clinical Trials
Time and Location: Saturday, December 7, 2019: 5:30 PM-7:30 PM ET
MT-3724. a novel Engineered Toxin Body (ETB), possesses specific and high affinity for CD20+ cells and causes apoptosis via a unique mechanism of action, forced internalization of the ETB bound to the receptor, retrograde transport through the cytosol, and enzymatic deactivation of ribosomal function. Therefore, combining MT‑3724 with standard cytotoxic chemotherapy and/or immune modulatory agents may provide enhanced benefit in NHL treatment algorithms. This is a multi-center, open-label, multiple-dose Phase 2a study designed to evaluate MT-3724 in combination with lenalidomide in adult subjects with histologically confirmed, relapsed or refractory NHL. The primary objective is to determine safety and tolerability, including the MTD, of MT-3724 + lenalidomide. Secondary objectives include pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity and tumor response.

The study will be conducted in two parts: Part 1 will include MT-3724 dose escalation according to the modified 3+3 design to identify the MTD of MT-3724 in combination with standard doses of lenalidomide and will include up to 24 subjects with histologically confirmed NHL. Part 2 is designed to confirm the safety and tolerability of MT-3724 + lenalidomide in the MTD Expansion Cohort, where the dose declared as MTD of MT-3724 in Part 1 would be given in combination with lenalidomide in up to 40 subjects with CD20+ DLBCL. In addition, the PK, PD, immunogenicity and tumor response of MT-3724 + lenalidomide will be evaluated in Part 2.

The study is currently ongoing; eligible subjects will be identified and treated through competitive enrollment at multiple study centers (ClinicalTrials.gov Identifier: NCT03645395).

Copies of the posters presented at ASH (Free ASH Whitepaper) can be found in the Presentations section of Molecular Templates’ website at View Source