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.

On December 9, 2019 Transgene (Paris:TNG) reported that Management will participate in the upcoming investor events set out below (Press release, Transgene, DEC 9, 2019, View Source [SID1234552144]).

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Transgene will meet institutional investors at the LifeSci Advisors Corporate Access Event from January 13 to 16, 2020, in San Francisco, USA, concurrent with the J.P. Morgan Healthcare conference.

The Company will also attend:

Oddo Forum: January 9 & 10, 2020 – Lyon, France
Biomed Event: January 28, 2020 – Paris, France

On December 9, 2019 Nektar Therapeutics (NASDAQ: NKTR) reported three presentations at the 61st American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition for its IL-15 agonist and investigational candidate, NKTR-255 (Press release, Nektar Therapeutics, DEC 9, 2019, View Source [SID1234552160]). Data were presented from a number of preclinical studies conducted in collaboration with researchers from the Dana-Farber Cancer Institute and the Fred Hutchinson Cancer Research Center.

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NKTR-255 is an interleukin-15 (IL-15) receptor agonist, which is currently being evaluated in a Phase 1 clinical study in patients with multiple myeloma (MM) and non-Hodgkin’s lymphoma (NHL). NKTR-255 is designed to work by selectively targeting the IL-15 pathway to expand both natural killer (NK) cells and memory CD8 T cell populations.

"The preclinical data being recognized at ASH (Free ASH Whitepaper) demonstrate NKTR-255’s promise in hematological malignancies through its potential to restore both NK cell and memory CD8 T cell compartments in patients," said Loui Madakamutil, Ph.D., Senior Vice President and Head of Discovery and Research at Nektar Therapeutics. "In studies presented by the laboratory of Dr. Nikhil Munshi at Dana-Farber, NKTR-255 enhanced the number and function of NK and CD8+ effector memory T cell populations in peripheral blood and bone marrow from patients with multiple myeloma and, also increased expression of activating receptors found on those NK cells. Separately, researchers from the laboratory of Dr. Cameron Turtle at Fred Hutchinson demonstrated NKTR-255 prevented tumor growth and increased survival of CAR T cells when added to a CD19-targeted CAR T cell regimen in models of B cell lymphoma. This preclinical data reinforces the basis of our ongoing clinical trial evaluating the potential of NKTR-255 in patients with multiple myeloma and non-Hodgkin’s lymphoma."

Details of the preclinical data presentations at ASH (Free ASH Whitepaper) are as follows and are available on the scientific section of Nektar’s website at View Source

Abstract 2866: "Combination of NKTR-255, a polymer conjugated human IL-15, with CD19 CAR T cell immunotherapy in a preclinical lymphoma model," Chou, C., et al. (This study was conducted in collaboration with the Turtle Laboratory in the Fred Hutchinson Cancer Research Center.)

Session: 625. Lymphoma: Pre-Clinical – Chemotherapy and Biologic Agents: Poster II
Date: Sunday, December 8, 2019, 6:00 p.m. – 8:00 p.m. Eastern Standard Time
CAR T cells treated with NKTR-255 demonstrate increased proliferation and survival both in vitro and in vivo which may in part be due to increased expression of bcl-2.
Tumor bearing mice treated with NKTR-255 and CAR T cells have decreased tumor burden and increased survival compared to mice treated with CAR T cells alone.
Tumor-bearing mice previously treated with NKTR-255 and CAR T cells are able to reject tumor re-challenge supporting persistence of functional CAR T cells.
Abstract 4398: "Restoring innate and adaptive immune repertoire in multiple myeloma for therapeutic application," Fernandez, R., et al. (This study was conducted in collaboration with Dr. Nikhil C. Munshi at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute.)
Note: Dr. Rafael Fernandez was recognized with a 2019 ASH (Free ASH Whitepaper) Abstract Achievement Award for this abstract.

Session: 652. Myeloma: Pathophysiology and Pre-Clinical Studies, Excluding Therapy: Poster III
Date: Monday, December 9, 2019, 6:00 p.m. – 8:00 pm. Eastern Standard Time
Multiple myeloma patients are known to experience impaired innate immunity and a decline in function of NK cells along with lower expression of activating receptors found on these cells.
Treatment with NKTR-255 enhanced the number and function of both NK and CD8+ effector memory T cell populations in peripheral blood from healthy donors and MM patients in a dose dependent manner.
NKTR-255 was also able to revert the inhibitory status of NK cells from MM patients and showed synergy with daratumumab and elotuzumab to significantly increase status of NK susceptibility of the MM cells.
Findings suggest NKTR-255 delivers a significant impact on the activation of effector cell function to efficiently target MM cells.
Details of the Trials in Progress poster presentation are as follows:

Abstract 4459: "A Phase 1, Open-Label, Multi-Center, Dose Escalation and Dose Expansion Study of NKTR-255 As a Single Agent in Relapsed or Refractory Hematologic Malignancies and in Combination with Daratumumab As a Salvage Regimen for Multiple Myeloma," Shah, N., et al.

Session: 704. Immunotherapies: Poster III
Date: Monday, December 9, 2019; 6:00 p.m. – 8:00 p.m. Eastern Standard Time
About the Phase 1 Study of NKTR-255 (NCT04136756)

NKTR-255 is currently being evaluated in an open-label Phase 1, dose escalation and dose expansion study in patients with select hematological malignancies (relapsed or refractory NHL or MM). The dose escalation phase of the study will evaluate the safety and tolerability of NKTR-255 as monotherapy in approximately 40 patients in order to establish a recommended Phase 2 dose (RP2D) for NKTR-255. The dose expansion phase of the study will enroll patients with MM or NHL (relapsed/refractory salvage) to evaluate the NKTR-255 RP2D in combination with targeted antibodies, including anti-CD38 monoclonal antibody, daratumumab in MM and anti-CD20 monoclonal antibody, rituximab in NHL. These studies are designed to assess pharmacokinetic and pharmacodynamic effects, anti-tumor activity and a range of biomarker assessments associated with NK and memory T cell populations.

About NKTR-255

NKTR-255 is an IL-15 receptor agonist designed to activate the IL-15 pathway and expand NK cells and promote the survival and expansion of memory CD8+ T cells without inducing suppressive regulatory T cells. Through optimal engagement of the IL-15Rα/IL-2Rβγ receptor complex, NKTR-255 enhances functional NK cell repopulation and formation of long-term immunological memory, which may lead to sustained anti-tumor immune response. NKTR-255 is uniquely designed to overcome the challenges of recombinant IL-15 and other IL-15 agonists, which are rapidly cleared from the body and have shown diminishing response to successive doses.1 Designed using Nektar’s polymer conjugation technology to extend circulating half-life, NKTR-255 can be dosed every 14 or 21 days.

On December 9, 2019 Seven and Eight BioPharmaceuticals Inc. reported that it has signed a clinical research collaboration agreement with Merck (known as MSD outside the US and Canada), through a subsidiary, to explore the combination of Seven and Eight’s BDB001, an immune modulator targeting toll-like receptors (TLR) 7 and 8, and Merck’s anti-PD-1 therapy, KEYTRUDA (pembrolizumab) in treating patients with advanced solid tumors (Press release, Seven and Eight Biopharmaceuticals, DEC 9, 2019, View Source [SID1234552201]).

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"Seven and Eight is developing a clinical pipeline that aims to address unmet medical needs. This clinical collaboration with Merck represents yet another step in our efforts to help cancer patients who fail to derive desirable clinical benefits from existing therapies."

"We are pleased to enter into a clinical collaboration with Merck," says Dr. Walter Lau, CEO of Seven and Eight. "There has been increasing evidence to show toll-like receptor agonists as a class of immune modulators to stimulate innate immune responses and enhance adaptive anti-tumor immunity. We hope through our joint efforts with Merck, we can explore how to use our lead compound BDB001 together with KEYTRUDA, especially in treating those patients with advanced and difficult-to-treat tumor types."

Dr. Lau adds, "Seven and Eight is developing a clinical pipeline that aims to address unmet medical needs. This clinical collaboration with Merck represents yet another step in our efforts to help cancer patients who fail to derive desirable clinical benefits from existing therapies."

Under the terms of the agreement, Seven and Eight will sponsor and be responsible for the conduct of the clinical study.

KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.