On December 9, 2019 BostonGene Corporation (BostonGene), a Boston-based biomedical software company, reported the results of its recent cancer microenvironment study during the 61st American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition held on December 7-10, 2019 (Press release, BostonGene, DEC 9, 2019, View Source [SID1234552143]). The research study examined the role of the tumor microenvironment of Diffuse Large B-Cell Lymphoma (DLBCL).

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The study, conducted as part of BostonGene’s collaboration with Weill Cornell Medicine, combined whole exome and transcriptome analyses from an integrated cohort of 3,026 DLBCL patients. The cohort includes publically available data as well as prospective patients.

The study revealed that a new classification based on the tumor microenvironment is associated with clinical outcomes independently of existing molecular subtypes.Computationally predicted results demonstrated a strong correlation with response therapy obtained in murine DLBCL models for subtypes based on stromal, immune and malignant composition.

"Improving treatment outcomes for individual DLBCL patients by integrated analysis of large-scale next-generation sequencing (NGS) data including somatic variants and gene expression changes in the tumor and the tumor microenvironment is our top priority," said Leandro Cerchietti, M.D., Associate Professor of Medicine and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. "These promising findings bring us one step closer to achieving that goal."

"We are proud to collaborate with Weill Cornell Medicine to provide advanced computational analytics for the integration of big data sets generated for each patient," said Andrew Feinberg, President and CEO of BostonGene. "We look forward to continuing our collaboration to further identify the best treatment options for cancer patients."

On December 9, 2019 CTI BioPharma Corp. (Nasdaq: CTIC) reported the presentation of data from the Company’s pacritinib development program, including results from the PAC203 Phase 2 clinical trial, at the 61st American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting being held December 7-10 in Orlando, Florida (Press release, CTI BioPharma, DEC 9, 2019, View Source [SID1234552159]).

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"The data presented at ASH (Free ASH Whitepaper) underscore the clinical and scientific rationale for our ongoing PAC203 Phase 3 PACIFICA trial evaluating pacritinib at 200 mg BID in severely thrombocytopenic myelofibrosis patients," said Adam R. Craig, M.D., Ph.D. "Pacritinib has now been demonstrated to provide clinical benefit in treating severely thrombocytopenic myelofibrosis (platelet counts less than 50,000 per microliter) in three clinical trials, including two prior randomized Phase 3 studies. Further, the PAC203 Phase 2 results from the 200 mg BID cohort demonstrate a favorable risk-benefit profile for pacritinib when treating patients with advanced disease that have high mutational risk and long durations of prior ruxolitinib exposure. The totality of the data presented at ASH (Free ASH Whitepaper) reinforces our belief that pacritinib has the potential to be an important therapy for severely thrombocytopenic myelofibrosis patients, a population for whom available therapeutic options are limited and often ineffective."

"While currently available treatments for myelofibrosis convey clinical benefit to a majority of the population, patients who are severely thrombocytopenic, and are therefore considered high-risk, continue to lack safe and efficacious therapies," said Claire N. Harrison, M.D., Consultant Haematologist and Professor of Myeloproliferative Neoplasms in London, as well as Chair of the PACIFICA steering committee and Principal Investigator of the PAC203 Phase 2 trial. "Myelofibrosis patients with platelet counts of less than 50,000 per microliter have a median survival of approximately 8 months after discontinuation of first line ruxolitinib therapy. In the PAC203 Phase 2 trial, which represents one of the most advanced and heavily pre-treated myelofibrosis patient populations studied to date as demonstrated by a median prior exposure to ruxolitinib of 1.7 years and the high risk mutational profiles, pacritinib at 200 mg BID achieved an impressive response rate in the severely thrombocytopenic patient population of 17% with a promising safety profile, demonstrating its potential to change the treatment paradigm in this area of serious unmet medical need."

All posters and presentation materials will be available at ctibiopharma.com following the presentations.

Results of PAC203: A Randomized Phase 2 Dose-Finding Study and Determination of the Recommended Dose of Pacritinib

Results from the PAC203 Phase 2 trial are being presented today, Monday, December 9, at 10:30 AM ET, in an oral presentation session.

Abstract: No. 667

Summary: PAC203 enrolled patients with myelofibrosis who were intolerant of or who had not benefitted from prior treatment with ruxolitinib. Patients were randomized in equal measure across 3 dosing arms: 200mg twice-daily (BID), 100mg BID, and 100mg daily (QD), with randomization stratified by baseline platelet count. Patients were mostly thrombocytopenic and anemic at baseline, with a median platelet count was 55,000, and 44% of patients having baseline platelet counts of less than 50,000. Patients had been heavily pre-treated with ruxolitinib, with a median 1.7 years of prior exposure. The study endpoint was broadly defined as an analysis of safety and efficacy data across dosing arms based on data after all patients either reached week 24 or stopped study treatment.

Pacritinib was shown to be generally well tolerated across dosing cohorts, with the most common treatment-emergent non-hematologic adverse events (AEs) being gastrointestinal, including diarrhea (20.5%; Grade 3: 3.1%) and nausea (20%; Grade 3: 0.6%), distributed similarly across arms. The most common hematologic AEs were thrombocytopenia and anemia, both occurring at higher frequencies at the 200 mg dose BID (32% and 22% respectively); this did not, however, lead to higher rates of Grade 3/4 hemorrhage at higher doses (200 mg BID: 5.6%; 100 mg BID: 0%; 100 mg QD: 5.8%; all Grade 3). Similarly, the highest dose saw no excess in Grade 3/4 cardiac (200 mg BID: 3.7%; 100 mg BID: 7.3%; 100 mg QD: 3.7%; all Grade 3) or infectious (200 mg BID: 15%; 100 mg BID: 11%; 100 mg QD: 12%) AEs. In this cohort of advanced MF patients, there were 7 Grade 5 (fatal) AEs: 2 at 200 mg BID (sepsis, subdural hematoma), 3 at 100 mg BID (disease progression, subdural hematoma, heart failure), and 2 at 100 mg QD (sepsis, tuberculosis).

The 200 mg BID arm had the highest observed rates of SVR ≥35% (200 mg BID: 9.3%; 100 mg BID: 1.8%; 100 mg QD: 0.0%). Of the 5 patients with SVR ≥35% at the 200 mg BID dose, 4 had platelet counts <50,000/mL, representing a 17% (4/24) response rate among patients with severe thrombocytopenia. Though a dose response relationship was not observed in total symptom score (TSS) based on the threshold of 50% reduction in symptom score, as 4 patients achieved this endpoint on all arms, the median reduction in TSS was greatest for patients treated at 200 mg BID (200 mg BID: 27%%; 100 mg BID: 16%; 100 mg QD: 3%).

The data from PAC203 support the Phase 3 PACIFICA trial, currently underway to compare the safety and efficacy of 200 mg BID of pacritinib to Physician’s Choice in 180 adult myelofibrosis patients with severe thrombocytopenia (platelet counts of less than 50,000 per microliter).

The Oral JAK2/IRAK1 Inhibitor Pacritinib Demonstrates Spleen Volume Reduction in Myelofibrosis Patients Independent of JAK2V617F Allele Burden

Results from a retrospective analysis from two Phase 3 studies, PERSIST-1 and PERSIST-2, of pacritinib in myelofibrosis patients were presented in a poster session on Saturday, December 7.

Abstract: No. 1674

Summary: A retrospective analysis of PERSIST-1 and PERSIST-2 was performed in which outcomes were stratified by JAK2 V617F mutation status and allele burden. The efficacy endpoint for this study was the percentage of patients achieving ≥35% SVR at week 24 based on an intention-to-treat analysis. Analysis was based on pooled results across the two studies for patients treated with pacritinib and those treated with best available therapy (BAT), and assessed patients with JAK2 V617F for possible relationship between allelic burden and SVR at 24 weeks. The analysis showed pacritinib was associated with a significantly higher rate of SVR response than BAT among patients with low JAK2 allele burden (<50%), while no SVR response was observed for patients treated with BAT (including ruxolitinib) who had low JAK2 allele burden or JAK2 V617F-negative disease. This data suggests that pacritinib, a JAK2/IRAK1 inhibitor, may provide benefit over a wider range of patients with myelofibrosis compared to other JAK inhibitors, specifically patients with low JAK2 allele burden who were shown to have lower baseline platelet counts, more severe anemia and smaller spleen size.

Pacritinib Demonstrates Efficacy Versus Best Available Therapy in Myelofibrosis Patients with Severe Thrombocytopenia in Two Phase 3 Studies

Results from a retrospective analysis of PERSIST-1 and PERSIST-2 will be presented in a poster session today, Monday, December 9 at 6:00 PM ET.

Abstract: No. 4195

Summary: This analysis was performed in patients treated on PERSIST-1 and PERSIST-2 with a baseline platelet count <50,000/μL. At 24 weeks, significantly more patients achieved ≥35% SVR with pacritinib compared with BAT (P-values <0.01). Although not statistically significant, TSS reductions ≥50% nearly doubled for those receiving pacritinib versus BAT. The safety profile in patients with severe thrombocytopenia was generally manageable and consistent with the overall study populations from the two Phase 3 trials. This retrospective analysis represents the largest population of patients with MF and severe thrombocytopenia to be studied in clinical trials, a population with a serious unmet medical need, and the results illustrate the clinical activity of pacritinib in the treatment of these patients.

Molecular Analysis in the Pacritinib Dose-Finding PAC203 Study in Patients with Myelofibrosis Refractory or Intolerant to Ruxolitinib

Results from a baseline mutational analysis of patients enrolled in the Phase 2 PAC203 study of pacritinib in patients with myelofibrosis will be presented in a poster session today, December 9, 2019 at 6:00 PM ET.

Abstract: No. 4214

Summary: The baseline mutational analysis was performed on 105 (out of total 164 recruited, 161 treated) myelofibrosis patients in the PAC203 study. The PAC203 cohort, characterized by ruxolitinib failure and a high burden of anemia and thrombocytopenia, was shown to be a molecularly high-risk population, characterized by high incidence of HMR, TP53 and RAS mutations, high mutational burden, and low incidence of CALR mutations.

About Myelofibrosis and Severe Thrombocytopenia

Myelofibrosis is a type of bone marrow cancer that results in formation of fibrous scar tissue and can lead to severe anemia, weakness, fatigue and an enlarged spleen and liver. Patients with severe thrombocytopenia are estimated to make up more than one-third of patients treated for myelofibrosis, or approximately 18,000 people.1 Severe thrombocytopenia, defined as blood platelet counts of less than 50,000 per microliter, has been shown to result in overall survival rates of just 15 months.2 Thrombocytopenia in patients with myelofibrosis is associated with the underlying disease but has also been shown to correlate with treatment with ruxolitinib, which can lead to dose reductions, and as a result, may potentially reduce clinical benefit. Survival in patients who have discontinued ruxolitinib therapy is further compromised, with an average overall survival of seven to 14 months.3,4 There are currently no approved therapies available to treat myelofibrosis patients with severe thrombocytopenia, or patients who have failed ruxolitinib treatment, thereby making this a significant unmet medical need.

About Pacritinib

Pacritinib is an investigational oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1 and CSF1R. The JAK family of enzymes is a central component in signal transduction pathways, which are critical to normal blood cell growth and development, as well as inflammatory cytokine expression and immune responses. Mutations in these kinases have been shown to be directly related to the development of a variety of blood-related cancers, including myeloproliferative neoplasms, leukemia and lymphoma. In addition to myelofibrosis, the kinase profile of pacritinib suggests its potential therapeutic utility in conditions such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), and chronic lymphocytic leukemia (CLL), due to its inhibition of c-fms, IRAK1, JAK2 and FLT3.

On December 9, 2019 ImmunoGen, Inc., (Nasdaq: IMGN) a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, reported that new safety and efficacy findings from the dose escalation and expansion of the first-in-human trial of IMGN632 in patients with relapsed/refractory acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN) were presented in an oral session at the 61st American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando, Florida (Press release, ImmunoGen, DEC 9, 2019, View Source [SID1234552200]). Preclinical data related to IMGN632 in combination with Vidaza (azacitidine) and Venclexta (venetoclax), and two "trial in progress" posters were also presented at the conference.

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"The data presented at ASH (Free ASH Whitepaper) demonstrate the potential of IMGN632 to offer a new treatment option for patients with AML and BPDCN," said Anna Berkenblit, MD, Senior Vice President and Chief Medical Officer of ImmunoGen. "With the benefit of a comprehensive assessment of IMGN632’s safety and efficacy across a wide range of doses and two schedules, we have selected a dose and schedule that demonstrate significant anti-tumor activity, favorable tolerability, and the convenience of a short infusion that can be administered in an outpatient setting. Together with the preclinical data on combining IMGN632 with azacitidine and venetoclax presented by our collaborators from MD Anderson, these updated clinical results provide a strong foundation for our ongoing expansion of IMGN632 monotherapy studies in BPDCN, AML, and ALL, and the recent initiation of our trial to evaluate IMGN632 combinations with azacitidine and venetoclax in relapsed and frontline AML, as well as IMGN632 as a monotherapy in minimal residual disease positive AML patients."

"We are particularly encouraged by the activity and tolerability of IMGN632 in heavily pre-treated patients, including a 40% ORR in relapsed and refractory de novo AML patients treated at the recommended phase 2 dose, and the responses in relapsed or refractory BPDCN patients previously treated with Elzonris (tagraxofusp-erzs) and intensive chemotherapy," said Naval Daver, MD, Associate Professor in the Department of Leukemia at MD Anderson Cancer Center. "We look forward to continuing to evaluate IMGN632 as a monotherapy and in combination with azacitidine and venetoclax in doublet and triplet regimens in relapsed/refractory AML and frontline older AML."

PHASE 1 DATA ON IMGN632 AS A MONOTHERAPY IN AML AND BPDCN
Oral Presentation, Abstract #734
Updated key findings from the Phase 1 study of IMGN632 include the following:

Safety

IMGN632 was administered to 95 patients over dose levels ranging from 0.015 to 0.45 mg/kg intravenously on the every 3 week schedule and 0.015 to 0.06 mg/kg on the fractionated day 1, 4, and 8 schedule every 3 weeks.
IMGN632 displays a well tolerated safety profile and activity at doses up to and including 0.09 mg/kg per cycle.
The most common treatment-related adverse event was infusion-related reactions (24% all grades, 8% grade 3); none required IMGN632 discontinuation.
Single dose-limiting toxicities were seen at the highest dose levels tested (0.18-0.45 mg/kg): three reversible cases of veno-occlusive disease and one prolonged neutropenia; no patterns of hepatotoxicity or cytopenias occurred with doses below 0.18 mg/kg.
Although no maximum tolerated dose was determined on either schedule, based on the efficacy, safety, and pharmacokinetic data generated, the dose and schedule of 0.045 mg/kg given on day 1 every 3 weeks has been selected as the monotherapy recommended Phase 2 dose.
AML Efficacy

Across all dose levels and both schedules, of the patients assessable for efficacy (n=71), 38 (54%) had a reduction in bone marrow blasts and 13 (18%) achieved an objective response, including 2 complete remissions (CR) and 10 with incomplete recovery (CRi) and one morphologic leukemia free state (MLFS) in heavily pretreated patients. The vast majority of these responders (92%) had failed prior intensive therapies, including 3 with prior transplant, 69% had failed 2-3 prior lines of therapy, and 54% had an adverse risk classification.
At the dose and schedule selected as the recommended Phase 2 dose (0.045 mg/kg Q3W), a 40% response rate was seen in relapsed and refractory patients with de novo AML, including 1 CR, 4 CRi, and 1 MLFS (with subsequent conversion to CRi).
BPDCN Efficacy

3 of 9 (33%) evaluable relapsed/refractory BPDCN patients achieved a response after a 1-2 doses of 0.045 mg/kg IMGN632 (1 CR, 1 CRi, and 1 partial remission); all three patients had received prior SL-401 (tagraxofusp-erzs), two had received intense multi-agent chemotherapy, and one had prior stem cell transplant.
PRECLINICAL DATA ON IMGN632 IN COMBINATION WITH AZACITIDINE AND VENETOCLAX
Poster Presentation, Abstract 1375
IMGN632 was evaluated in combination with azacitidine, and as a triplet with azacitidine and venetoclax in AML models, including patient derived xenografts (PDX). The addition of IMGN632 to azacitidine alone or to azacitidine plus venetoclax consistently led to reductions in tumor burden and to improved survival in these murine models. These data support clinical testing of the addition of IMGN632 to standard of care therapy including azacitidine, and azacitidine plus venetoclax in AML patients.

Additional information, including abstracts, can be found at www.hematology.org.

ABOUT IMGN632
IMGN632 is a CD123-targeting ADC in Phase I testing for hematological malignancies, including acute myeloid leukemia (AML), blastic plasmacytoid dendritic cell neoplasm (BPDCN), and acute lymphocytic leukemia (ALL). IMGN632 uses one of ImmunoGen’s novel indolino-benzodiazepine (IGN) payloads, which alkylate DNA without crosslinking. IGNs have been designed to have high potency against AML blasts, while demonstrating less toxicity to normal marrow progenitors than other DNA-targeting payloads.

ABOUT ACUTE MYELOID LEUKEMIA (AML)
AML is a cancer of the bone marrow cells that produce white blood cells. It causes the marrow to increasingly generate abnormal, immature white blood cells (blasts) that do not mature into effective infection-fighting cells. The blasts quickly fill the bone marrow, impacting the production of normal platelets and red blood cells. The resulting deficiencies in normal blood cells leave the patient vulnerable to infections, bleeding problems, and anemia. It is estimated that, in the U.S. alone, 21,380 patients will be diagnosed with AML this year and 10,590 patients will die from the disease.

ABOUT BLASTIC PLASMACYTOID DENDRITIC CELL NEOPLASM (BPDCN)
BPDCN is a rare form of blood cancer that has features of both leukemia and lymphoma, with characteristic skin lesions, lymph node involvement, and frequent spread to the bone marrow. This aggressive cancer requires intense treatment often followed by stem cell transplant. Despite the recent approval of a CD123-targeting therapy, the unmet need remains high in the relapsed/refractory setting.

ABOUT CD123
CD123, the interleukin-3 alpha chain, is expressed on multiple myeloid and lymphoid cancers including AML, BPDCN, ALL, chronic myeloid leukemia, and myeloproliferative neoplasms. With limited expression on normal hematopoietic cells, rapid internalization, and expression on AML leukemia stem cells, CD123 is a validated therapeutic target, with the recent approval of a CD123-targeting therapy for BPDCN.

On December 9, 2019 Cellectar Biosciences, Inc. (NASDAQ: CLRB), a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of drugs for the treatment of cancer, reported the presentation of fractionated dosing data in 19 patients with relapsed/refractory multiple myeloma (Press release, Cellectar Biosciences, DEC 9, 2019, View Source [SID1234552109]). Dr. Sikander Ailawadhi, M.D., Associate Professor, Division of Hematology/Oncology at Mayo Clinic Florida, presented the data in an oral presentation at the 61st Annual American Society of Hematology (ASH) (Free ASH Whitepaper) meeting.

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Dr. Ailawadhi’s presentation highlighted results from 19 patients with relapsed/refractory multiple myeloma from Cellectar’s Phase 1 and Phase 2 CLOVER-1 trial collected prior to July 30, 2019. The data from the oral presentation support prior literature and preclinical data showing that fractionated dosing provides an enhancement of efficacy and safety while reducing adverse events. The patients presented received one of 3 dose levels: a single bolus dose of 31.25 mCi/m2 or a fractionated dose of 31.25 mCi/m2 or a higher fractionated dose of 37.5 mCi/m2 of CLR 131. The fractionated 37.5 mCi/m2 dose of CLR 131 represents the greatest amount of drug administered to date in the Phase 2 CLOVER-1 trial. The overall response rate (ORR) for all multiple myeloma patients across the 3 dose cohorts was 31.3% and a 100% disease control rate. Patients receiving the higher fractionated 37.5 mCi/m2 dose demonstrated a 50% ORR with the remaining 50% having minimal responses (greater than a 25% reduction in the surrogate marker of efficacy).

The patients presented had received a median of 4 prior systemic therapies (range 2-13), had a median age of 69 (range 51-83), including 8 females and 11 males and 80% of the patients in the 37.5 mCi/m2 cohort were either quad or penta-refractory, and all were refractory to daratumumab.

"These data showing a 50% overall response rate in a cohort of heavily pretreated multiple myeloma patients and a 31.3% overall response rate in all dose levels presented is impressive," said Dr. Ailawadhi. "CLR 131 continued to demonstrate a good safety profile with limited off-target effects and the fractionated dosing of CLR 131 showed improved tolerability versus single bolus dosing. While these doses demonstrate beneficial activity, there is the potential that a second cycle or further fractionation could further enhance both efficacy and tolerability."

The primary adverse events (AEs) at all dosing levels were cytopenias and included thrombocytopenia, anemia, and neutropenia. The hematologic AEs were expected, manageable and followed a predictable timeline to nadir (average 40 days) and subsequent recovery (average 17 days post nadir). The demonstrated recovery post nadir for CLR 131 compared favorably to other similar radiotherapeutic drugs, such as Bexxar, which requires on average 90 days for recovery post nadir.

"These results showed excellent safety with limited off-target effects and improved tolerability compared to our single bolus dosing. With the overall activity observed with CLR 131 to date and efficacy signals across all doses and especially at the fractionated dosing level of 37.5 mCi/m2, we remain optimistic about the potential for continued enhancement of efficacy and safety with fractionated dosing," said Jim Caruso, president and CEO of Cellectar. "We anticipate announcing additional data in the coming weeks in patients receiving single bolus and fractionated dosing from our Phase 2 CLOVER-1 trial, in which we have enrolled approximately 50 patients."

About the Phase 2 CLOVER-1 Trial

CLOVER-1 is a Phase 2 study of CLR 131 being conducted in approximately 10 leading cancer centers in the United States in patients with relapsed or refractory B-cell hematologic cancers. The hematologic cancers being studied in the trial include multiple myeloma (MM), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), lymphoplasmacytic lymphoma (LPL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL).

The study will enroll up to 80 patients. Its primary endpoint is clinical benefit response (CBR), with additional endpoints of overall response rate (ORR), progression free survival (PFS), median overall survival (OS) and other markers of efficacy following a fractionated dose of 37.5mCi/m2 of CLR 131 administered in two 30-minute infusions of 18.75mCi/m2 of CLR 131 administered on day 1 and day 7 (± 1), with the option for a second dose cycle approximately 75-180 days later. The company expects to report topline data in 2019.

Cellectar was awarded approximately $2 million in non-dilutive grant funding from the National Cancer Institute to help fund the trial. More information about the trial, including eligibility requirements, can be found at www.clinicaltrials.gov, reference NCT02952508.

About the Phase 1 R/R MM Trial

The Phase 1 multicenter, open-label, dose-escalation study is designed to evaluate the safety and tolerability of CLR 131 administered as a 30-minute IV infusion, either as a single bolus dose or as two fractionated doses, in patients with R/R MM. All doses to date have been deemed safe and well tolerated by an independent Data Monitoring Committee (DMC). Based on the data and the recommendation of the DMC, the Company is enrolling a Cohort 7 where patients will receive 40mCi/m2 fractionated dose of CLR 131.

About CLR 131

CLR 131 is a small-molecule, targeted Phospholipid Drug Conjugate (PDC) designed to deliver cytotoxic radiation directly to cancer cells, while limiting exposure to healthy cells. CLR 131 is the company’s lead product candidate and is currently being evaluated in a Phase 2 study in B-cell lymphomas, and two Phase 1 dose-escalating clinical studies, one in multiple myeloma and one in pediatric solid tumors and lymphoma. CLR 131 was granted Orphan Drug designation for the treatment of multiple myeloma by both the U.S. and the European Commission, and was granted U.S. Orphan Drug and Rare Pediatric Disease designations for the treatment of neuroblastoma, rhabdomyosarcoma, Ewing’s sarcoma and osteosarcoma.

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.