On December 7, 2019 Verastem, Inc. (Nasdaq:VSTM) (Verastem Oncology or the Company), a biopharmaceutical company focused on developing and commercializing medicines seeking to improve the survival and quality of life of cancer patients, reported the presentation of key abstracts highlighting COPIKTRA (duvelisib) data at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2019 Annual Meeting taking place December 7-10, 2019, in Orlando (Press release, Verastem, DEC 7, 2019, View Source [SID1234552048]).

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"Given the aggressive nature of peripheral T-cell lymphoma (PTCL) and the lack of effective therapeutic options for these patients, we are pleased to present data from the dose optimization phase of our PRIMO trial that demonstrated a 62% overall response rate (ORR), as assessed by independent central review, with a manageable safety profile consistent with previous clinical trials. The results of the trial also identified the optimal dosing regimen for future clinical study," said Brian Stuglik, Chief Executive Officer of Verastem Oncology. "The expansion phase of this registration-directed study is well underway. Upon completion, we plan to build upon our existing Fast Track Designation and Orphan Drug Designation and submit a regulatory package to the U.S. FDA with the goal of broadening the use of COPIKTRA to include treatment of PTCL."

Results from the Dose Optimization Portion of the Phase 2 PRIMO Study in Relapsed or Refractory PTCL

The PRIMO study is a multi-center, open-label, registration-directed Phase 2 study evaluating duvelisib in patients with relapsed or refractory PTCL that is expected to enroll approximately 120 patients. In the dose optimization portion of the study, patients were randomized to receive duvelisib 25mg twice daily with an option for dose escalation (cohort 1) or duvelisib 75mg twice daily continuously (cohort 2) until disease progression or unacceptable toxicity. The primary endpoint of the study was investigator-assessed overall response rate (ORR), and secondary endpoints included duration of response (DOR) and safety.

A total of 33 patients (cohort 1, n=20; cohort 2, n=13) were treated in the dose optimization phase. Investigator-assessed ORRs were 35% in cohort 1 and 54% in cohort 2, with complete response (CR) rates of 25% and 31% in cohort 1 and cohort 2, respectively. ORR, as assessed by blinded independent central review was 40% in cohort 1 and 62% in cohort 2. Thirteen of 20 patients in cohort 1 and all patients in cohort 2 were able to complete one cycle of therapy. Seven patients in cohort 1 discontinued therapy early due to disease progression and/or toxicity. Most responses were observed at the end of cycle 1 (cycle=28 days). At a median follow-up of 21.4 weeks, the majority of responders were still in response at the time of their last assessment. The most common (≥4 patients) Grade ≥3 adverse events (AEs) in all patients receiving duvelisib were neutropenia, thrombocytopenia, diarrhea, rash/maculopapular, lymphocytopenia, pneumonia and sepsis. Serious AEs occurring in ≥2 patients were colitis, diarrhea, abdominal pain, pyrexia, sepsis, pneumonia, hyponatremia, rash/maculopapular, dyspnea, and respiratory failure.

Based on these efficacy and safety data, the investigators have elected to investigate duvelisib starting at 75mg twice daily for two cycles, followed by 25mg twice daily, during the dose expansion portion of the study which is currently ongoing.

"In the dose optimization portion of the PRIMO study we observed encouraging results, including complete and durable responses at both dose levels," said Steven Horwitz, MD, Memorial Sloan Kettering Cancer Center, and principal investigator of Phase 2 PRIMO study. "We also identified a strategy for the expansion phase dosing regimen starting with 75mg twice daily for two cycles to achieve more a reliable initial tumor response, followed by 25mg twice daily to try to maintain longer-term disease control by mitigating the potential for later onset toxicity in these patients with relapsed or refractory disease."

Results from Phase 1 Study Investigating Duvelisib and Venetoclax in Patients with Relapsed or Refractory CLL/SLL

Another key presentation at the meeting highlights new data from an investigator-sponsored Phase 1 study exploring duvelisib in combination with venetoclax in relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Duvelisib plus venetoclax demonstrated promising clinical activity, a manageable tolerability profile, and a recommended Phase 2 dose (RP2D) of 400mg of venetoclax was determined for this regimen.

In the study, 12 patients were enrolled and received oral duvelisib and oral venetoclax. The primary endpoints of the study are dose limiting toxicities (DLTs), maximum tolerated dose (MTD) and identification of the RP2D. Secondary endpoints include pharmacokinetics and preliminary efficacy.

Among the 12 evaluable patients, 11 achieved a response for an ORR of 92%, including four (33%) CRs and seven (58%) partial responses. Four patients had undetectable minimum residual disease (uMRD) in the peripheral blood and bone marrow, including two patients with a CR. The most common Grade 1 and 2 AEs were fatigue (92%), hyperglycemia (83%), anemia (67%), and thrombocytopenia (67%). The most common Grade ≥3 AEs were neutropenia (84%), hypocalcemia (50%), and hypophosphatemia (25%). No DLTs were observed, and the RP2D of venetoclax was identified as 400mg once daily when given with standard dose duvelisib 25mg twice daily. This study is now in a Phase 2 portion in CLL/SLL and Richter’s Syndrome and is currently accruing new patients.

"Duvelisib plus venetoclax is a promising combination for further study, as we have found early signals of robust activity along with a manageable tolerability profile," said Matthew S. Davids, MD, Associate Director, Center for Chronic Lymphocytic Leukemia at Dana-Farber Cancer Institute, and Principal Investigator for the trial. "We are now actively accruing patients in the Phase 2 portion of the study to evaluate the efficacy of this combination in patients with CLL/SLL, with a separate cohort exploring the activity of this regimen for patients with Richter’s Syndrome, a particularly hard to treat population."

Other poster presentations at the meeting include: an analysis of cytogenetic and molecular markers associated with improved outcomes in the patients who had received 1 prior therapy in the Phase 3 DUO study and a description of the soon to be initiated TEMPO study investigating an intermittent dosing regimen of duvelisib in patients with indolent non-Hodgkin lymphoma.

The data from these studies continues to support the future potential expansion of duvelisib across multiple indications and lines of therapy.

Details for the ASH (Free ASH Whitepaper) 2019 presentations are as follows:

Poster Presentations

Title: Dose Optimization of Duvelisib in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma from the Phase 2 PRIMO Trial: Selection of Regimen for the Dose-Expansion Phase
Lead author: Steven Horwitz, Memorial Sloan Kettering Cancer Center
Poster #: 1567
Session: 624. Hodgkin Lymphoma and T/NK Cell Lymphoma – Clinical Studies: Poster I
Date and Time: Saturday, December 7, 2019; 5:30-7:30PM ET
Location: Orange County Convention Center, Hall B

Title: A Phase I Study of Duvelisib and Venetoclax in Patients with Relapsed or Refractory CLL / SLL
Lead author: Jennifer Crombie, Dana-Farber Cancer Institute
Poster #: 1763
Session: 642. CLL: Therapy, excluding Transplantation: Poster I
Date and Time: Saturday, December 7, 2019; 5:30-7:30 PM ET
Location: Orange County Convention Center, Hall B

Title: The Dual PI3K-δ/γ Inhibitor Duvelisib in Combination with the Bcl-2 Inhibitor Venetoclax Shows Promising Responses in Richter Syndrome-PDX Models
Lead author: Andrea Iannello, University of Turin
Poster #: 2862
Session: 625. Lymphoma: Pre-Clinical—Chemotherapy and Biologic Agents: Poster II
Date and Time: Sunday, December 8, 6:00-8:00 PM ET
Location: Orange County Convention Center, Hall B

Title: Cytogenetic and Molecular Marker Associations to Outcomes with Duvelisib and Ofatumumab Treatment in Patients with Relapsed or Refractory CLL/SLL in the DUO Trial
Lead author: Jennifer Brown, Dana-Farber Cancer Institute
Poster #: 4312
Session: 642. CLL: Therapy, excluding Transplantation: Poster III
Date and Time: Monday, December 9, 2019; 6:00-8:00 PM ET
Location: Orange County Convention Center, Hall B

Publication Only Presentations

Title: Trial in Progress (TiP): A Phase 2, Randomized, Open-Label, 2-Arm Study Comparing 2 Intermittent Dosing Schedules of Duvelisib in Patients with Indolent Non-Hodgkin Lymphoma (iNHL) (TEMPO)
Lead author: Reem Karmali, Lurie Cancer Center, Northwestern University
Session: 623. Mantle cell, follicular, and other indolent B Cell Lymphoma – Clinical studies

PDF copies of these poster presentations will be available here after the meeting.

COPIKTRA is indicated in the US for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least two prior therapies and in relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies. Accelerated approved in FL was based on overall response rate and continued approval may be contingent upon confirmatory trials.

SELECT IMPORTANT SAFETY INFORMATION

This does not include all information needed to use COPIKTRA (duvelisib) safely and effectively. See full Prescribing Information.

WARNING: FATAL AND SERIOUS TOXICITIES: INFECTIONS, DIARRHEA OR COLITIS, CUTANEOUS REACTIONS, and PNEUMONITIS

See full Prescribing Information for complete boxed warning

Fatal and/or serious infections occurred in 31% (4% fatal) of COPIKTRA-treated patients. Monitor for signs and symptoms of infection. Withhold COPIKTRA if infection is suspected.
Fatal and/or serious diarrhea or colitis occurred in 18% (<1% fatal) of COPIKTRA-treated patients. Monitor for the development of severe diarrhea or colitis. Withhold COPIKTRA.
Fatal and/or serious cutaneous reactions occurred in 5% (<1% fatal) of COPIKTRA-treated patients. Withhold COPIKTRA.
Fatal and/or serious pneumonitis occurred in 5% (<1% fatal) of COPIKTRA-treated patients. Monitor for pulmonary symptoms and interstitial infiltrates. Withhold COPIKTRA.
WARNINGS AND PRECAUTIONS

Hepatotoxicity: Monitor hepatic function.
Neutropenia: Monitor blood counts.
Embryo-Fetal toxicity: COPIKTRA can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception.
ADVERSE REACTIONS

The most common adverse reactions (≥20%) are diarrhea or colitis, neutropenia, rash, fatigue, pyrexia, cough, nausea, upper respiratory infection, pneumonia, musculoskeletal pain, and anemia.

To report Adverse Reactions, contact FDA at 1-800-FDA-1088 (1-800-332-1088) or www.fda.gov/medwatch and Verastem Oncology at 1-877-7RXVSTM (1-877-779-8786).

DRUG INTERACTIONS

CYP3A inducers: Avoid co-administration with strong CYP3A inducers.
CYP3A inhibitors: Monitor for COPIKTRA toxicities when co-administered with strong or moderate CYP3A inhibitors. Reduce COPIKTRA dose to 15 mg twice daily when co-administered with strong CYP3A4 inhibitors.
CYP3A substrates: Monitor for signs of toxicities when co-administering COPIKTRA with sensitive CYP3A substrates.
USE IN SPECIFIC POPULATIONS

Lactation: Advise women not to breastfeed.

Please see full Prescribing Information, including Boxed Warning.

About COPIKTRA (duvelisib)

COPIKTRA is an oral inhibitor of phosphoinositide 3-kinase (PI3K), and the first approved dual inhibitor of PI3K-delta and PI3K-gamma, two enzymes known to help support the growth and survival of malignant B-cells. PI3K signaling may lead to the proliferation of malignant B-cells and is thought to play a role in the formation and maintenance of the supportive tumor microenvironment.1,2,3 COPIKTRA is indicated for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) after at least two prior therapies and relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies. COPIKTRA is also being developed by Verastem Oncology for the treatment of peripheral T-cell lymphoma (PTCL), for which it has received Fast Track status and Orphan Drug Designation, and is being investigated in combination with other agents through investigator-sponsored studies.4 For more information on COPIKTRA, please visit www.COPIKTRA.com. Information about duvelisib clinical trials can be found on www.clinicaltrials.gov.

On December 7, 2019 Molecular Partners AG (SIX:MOLN), a clinical-stage biotech company pioneering the use of DARPin therapeutics* to treat serious diseases, reported a poster presentation at the American Society of Hematology (ASH) (Free ASH Whitepaper) 61st Annual Meeting in Orlando, FL, highlighting the activity of its tri-specific DARPin drug candidate, MP0250, in patients undergoing treatment for multiple myeloma (Press release, Molecular Partners, DEC 7, 2019, View Source [SID1234552047]).

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MP0250 is a first-in-class, tri-specific multi-DARPin drug candidate neutralizing VEGF-A and HGF and is binding to human serum albumin to increase plasma half-life. The unique mechanism of action of MP0250 represents a new approach to targeting the tumor microenvironment and increase patients’ responses to already approved therapies for multiple myeloma, potentially even after progression.

"At present, anti-angiogenic agents are not part of treatment strategies in multiple myeloma, neither alone nor in combination with approved agents," commented Nicolas Leupin, Chief Medical Officer of Molecular Partners. "MP0250 represents a unique and much-needed addition to the treatment paradigm for patients with multiple myeloma. We believe that by treating one of the underlying causes of the disease through targeting the tumor microenvironment, we can achieve durable and deep responses in patients relapsing after or refractory to treatment regimens including bortezomib, IMiDs or daratumumab. The response rate seen in this study, given the heavily pretreated patient population involved, is very encouraging. We look forward to the generation of additional combination data for MP0250 with relevant treatments to further detail the potential for this program."

The full poster, titled "The MP0250-CP201 MiRRoR Study: A Phase 2 Study Update of MP0250 Plus Bortezomib and Dexamethasone in Relapsed/Refractory Multiple Myeloma (RRMM) Patients Previously Exposed to Proteasome Inhibitors and Immunomodulatory Drugs", will be available for viewing in Exhibit Hall B from 5:30-7:30 p.m. EST on Saturday, December 7, 2019, and will be available at the company website, www.molecularpartners.com. A summary of the poster details are below:

• At the efficacy cut-off date of November 5, 2019, all 20 patients were evaluable for tumor response. One patient achieved a complete response (CR), three patients achieved very good partial responses (VGPR) and five patients achieved PRs, giving an ORR of 45%.

• All 20 patients had prior exposure to IMiDs and PIs and nine patients received PI-based regimens as their immediate prior line of therapy before the start of MP0250 + Vd. The median number of prior therapies was 4 (range 2-9).

• Importantly, six of nine patients who were either relapsed or refractory to a PI-based regimen prior to the triple combination achieved CR, VGPR or PR. Median duration of response for patients was 5 months (range 2-24 months). The patient with CR and two patients with VGPR have been on treatment for more than 9 months.

• Combining MP0250 at 8 mg/kg with standard doses of bortezomib and dexamethasone was generally well tolerated with discontinuation due to adverse events (AE) in only 15% of patients. No unexpected toxicity was observed and AEs reported were consistent with the toxicity profile of the individual agents.

Trial Design of MP0250-CP201 MiRRoR Study

The trial is recruiting adults ≥18 years of age with RRMM who have progressed after at least two prior treatment regimens, including bortezomib and an IMiD. Patients were enrolled to receive intravenous MP0250 on day 1 plus subcutaneous bortezomib 1.3 mg/m² on days 1, 4, 8, 11, oral dexamethasone 20 mg on days 1-2, 4-5, 8-9, 11-12 of each 21-day cycle. Patients will receive treatment until there is documented disease progression or unacceptable toxicity.

In addition to this poster presentation the company will highlight additional details from its MP0250 program, as well as the rest of its pipeline and discovery platform, at an R&D day to be held at the Yale Club in New York City on December 12th, 2019. To RSVP please contact Seth Lewis at [email protected]

Financial Calendar
December 12, 2019 R&D Day in New York City
February 6, 2020 Publication of Full-year Results 2019 (unaudited)
April 29, 2020 Annual General Meeting
View Source

About the DARPin Difference
DARPin therapeutics are a new class of protein therapeutics opening an extra dimension of multi-specificity and multi-functionality. DARPin candidates can engage more than five targets, offering potential benefits over those offered by conventional monoclonal antibodies or other currently available protein therapeutics. The DARPin technology is a fast and cost-effective drug discovery engine, producing drug candidates with ideal properties for development and very high production yields.

With their low immunogenicity and long half-life in the bloodstream and the eye, DARPin therapeutics have the potential to advance modern medicine and significantly improve the treatment of serious diseases, including cancer and sight-threatening disorders. Molecular Partners is partnering with Allergan to advance clinical programs in ophthalmology and is advancing a proprietary pipeline of DARPin drug candidates in oncology and immuno-oncology. The most advanced global product candidate in partnership with Allergan is abicipar, a molecule for which phase 3 data have been filed to the respective regulators in both the US and in Europe. Several DARPin molecules for various ophthalmic indications are also in preclinical development. The most advanced DARPin therapeutic candidate wholly owned by Molecular Partners, MP0250, is in phase 2 clinical development for the treatment of hematological tumors. MP0274, the second-most advanced DARPin candidate owned by Molecular Partners, binds to Her2 and inhibits downstream signaling, which leads to induction of apoptosis. MP0274 is currently in phase 1. The company’s lead immuno-oncology product candidate MP0310 is a FAP x 4-1BB multi-DARPin therapeutic candidate designed to locally activate immune cells in the tumor by binding to FAP on tumor stromal cells (localizer) and co-stimulating T cells via 4-1BB (immune modulator). Molecular Partners has closed a collaboration agreement with Amgen for the exclusive clinical development and commercialization of MP0310. The molecule has entered in phase 1 of clinical development in H2 2019. Molecular Partners is also advancing a growing preclinical and research pipeline in immuno-oncology that features its "I/O toolbox" and additional development programs such as novel therapeutic designs to target peptide-MHC complexes. DARPin is a registered trademark owned by Molecular Partners AG.

On December 7, 2019 AstraZeneca reported that it results from the interim analysis of the Phase III ELEVATE TN trial, showing that Calquence (acalabrutinib) combined with obinutuzumab or as monotherapy significantly improved progression-free survival (PFS) compared to chlorambucil plus obinutuzumab, a standard chemo-immunotherapy treatment, in patients with previously untreated chronic lymphocytic leukaemia (CLL) (Press release, AstraZeneca, DEC 7, 2019, View Source [SID1234552037]).1

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The Independent Review Committee (IRC)-assessed results were presented at the 2019 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exhibition in Orlando, US. At a median follow-up of 28.3 months, Calquence in combination with obinutuzumab or as a monotherapy significantly reduced the risk of disease progression or death by 90% and 80%, respectively, vs. chlorambucil plus obinutuzumab.1

In an exploratory analysis, Calquence in combination or alone demonstrated consistent PFS improvements across most pre-specified subgroups of patients with high-risk disease characteristics, including the unmutated immunoglobulin heavy-chain variable gene (IGHV), del(11q) and complex karyotype. Overall, the safety and tolerability profile of Calquence observed in the ELEVATE TN trial was consistent with its known profile.1

José Baselga, Executive Vice President, Oncology R&D said: "On the heels of approvals in the US, Australia and Canada, these full results provide further evidence that Calquence, as a new treatment option for patients with chronic lymphocytic leukaemia, demonstrates remarkable efficacy and a favourable tolerability profile. These results also provide, for the first time, post-hoc analysis data exploring the potential progression-free survival benefit of adding obinutuzumab to a BTK inhibitor such as Calquence versus BTK inhibitor monotherapy in a randomised trial."

Dr. Jeff Sharman, Director of Research at Willamette Valley Cancer Institute, Medical Director of Hematology Research for The US Oncology Network, and a lead author of the ELEVATE TN trial, said: "In the detailed results from the ELEVATE TN trial comparing Calquence to a commonly used chemo-immunotherapy treatment regimen, Calquence demonstrated a clinically meaningful improvement in progression-free survival, while maintaining its known tolerability and safety profile. These are encouraging results for a patient population that is known to face multiple comorbidities, and where tolerability is a critical factor in their treatment."

Summary of key efficacy results as assessed by IRC from the ELEVATE TN trial at a median follow-up of 28.3 months:1

CI, confidence interval; NR, not reached; NE, not estimable; HR, hazard ratio; ORR, overall response rate;
OS, overall survival

Adverse events (AEs) led to treatment discontinuation in 11.2% of patients treated with Calquence in combination with obinutuzumab and 8.9% of patients treated with Calquence monotherapy versus 14.1% of patients treated with chlorambucil plus obinutuzumab.1

With over two years of follow-up, 79% of patients in both the Calquence-containing arms remain on Calquence as a monotherapy. In the Calquence combination arm (n=178), the most common AEs of any grade (≥30%) included headache (39.9%), diarrhoea (38.8%) and neutropenia (31.5%). In the Calquence monotherapy arm (n=179), the most common AEs of any grade (≥30%) included headache (36.9%) and diarrhoea (34.6%). In the chlorambucil plus obinutuzumab arm (n=169), the most common AEs of any grade (≥30%) included neutropenia (45.0%), infusion-related reaction (39.6%) and nausea (31.4%).1

SPM, secondary primary malignancy; NMSC, non-melanoma skin cancer

These findings, along with previously reported data from the Phase III ASCEND trial in relapsed or refractory CLL, support the recent approvals of Calquence by the US FDA and the Australian Therapeutic Goods Administration for the treatment of adult patients with CLL or small lymphocytic lymphoma (SLL) and by Health Canada for CLL.2

About Calquence

In the US and Australia, Calquence (acalabrutinib) is approved for the treatment of adult patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) and in Canada for CLL. In the US, Canada, Australia, Brazil, Qatar, the United Arab Emirates, Mexico, Argentina, Singapore, Chile, and recently India, Calquence is also approved for adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Calquence was approved for MCL under accelerated review in the US; continued approval for previously treated MCL is contingent upon verification and confirmation of clinical benefit in confirmatory trials.

Calquence is a next-generation selective inhibitor of Bruton’s tyrosine kinase (BTK). It binds covalently to BTK, thereby inhibiting its activity.2,3,4,5 In B-cells, BTK signalling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.2

As part of an extensive clinical development programme, AstraZeneca and Acerta Pharma are currently evaluating Calquence in 23 company-sponsored clinical trials. Calquence is being developed for the treatment of multiple B-cell blood cancers including CLL, MCL, diffuse large B-cell lymphoma, Waldenström macroglobulinaemia, follicular lymphoma and other haematologic malignancies. Several Phase III clinical trials in CLL are ongoing, including ASCEND, ELEVATE TN, ELEVATE-RR (ACE-CL-006) evaluating Calquence versus ibrutinib in patients with previously treated high-risk CLL, and ACE-CL-311 evaluating Calquence in combination with venetoclax and with/without obinutuzumab versus chemoimmunotherapy in patients with previously untreated CLL without 17p deletion or TP53 mutation.

About ELEVATE TN

ELEVATE TN (ACE-CL-007) is a randomised, multicentre, open-label Phase III trial evaluating the safety and efficacy of Calquence in combination with obinutuzumab, a CD20 monoclonal antibody, or Calquence alone versus chlorambucil, a chemotherapy, in combination with obinutuzumab in previously untreated patients with CLL. Patients 65 years of age or older, or between 18 and 65 years of age with a total Cumulative Illness Rating Scale (CIRS) >6 or creatinine clearance of 30 to 69 mL/min, were enrolled. In the trial, 535 patients were randomised (1:1:1) into three arms. Patients in the first arm received chlorambucil in combination with obinutuzumab. Patients in the second arm received Calquence (100mg approximately every 12 hours until disease progression or unacceptable toxicity) in combination with obinutuzumab. Patients in the third arm received Calquence monotherapy (100mg approximately every 12 hours until disease progression or unacceptable toxicity).1,6

The primary endpoint is PFS in the Calquence and obinutuzumab arm compared to the chlorambucil and obinutuzumab arm, assessed by an independent review committee (IRC), and a key secondary endpoint is IRC-assessed PFS in the Calquence monotherapy arm compared to the chlorambucil and obinutuzumab arm. Other secondary endpoints include objective response rate, time to next treatment and overall survival.1,6

About CLL

Chronic lymphocytic leukaemia (CLL) is one of the most common types of leukaemia in adults, with an estimated 105,000 new cases globally in 2016 and 20,720 new cases in the US in 2019, and the number of people living with CLL is expected to grow with improved treatment as patients live longer with the disease.7,8,9,10 In CLL, too many blood stem cells in the bone marrow become abnormal lymphocytes and these abnormal cells have difficulty fighting infections.7 As the number of abnormal cells grows there is less room for healthy white blood cells, red blood cells and platelets.7 This could result in anaemia, infection and bleeding.7 B-cell receptor signalling through BTK is one of the essential growth pathways for CLL.

About AstraZeneca in haematology

Leveraging its strength in oncology, AstraZeneca has established haematology as one of four key oncology disease areas of focus. The Company’s haematology franchise includes two US FDA-approved medicines and a robust global development programme for a broad portfolio of potential blood cancer treatments. Acerta Pharma serves as AstraZeneca’s haematology research and development arm. AstraZeneca partners with like-minded science-led companies to advance the discovery and development of therapies to address unmet need.

About AstraZeneca in oncology

AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With at least six new medicines to be launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to AstraZeneca’s main capabilities, the Company is actively pursuing innovative partnerships and investments that accelerate the delivery of our strategy, as illustrated by the investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and, one day, eliminate cancer as a cause of death.

On December 7, 2019 AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, reported results from an extended follow-up analysis of the Phase 3 E1912 clinical study – designed and conducted by the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) and sponsored by the National Cancer Institute (NCI), which is part of the National Institutes of Health. Study results showed superior progression-free survival (PFS) and overall survival (OS) in patients with chronic lymphocytic leukemia (CLL) new to treatment (Press release, AbbVie, DEC 7, 2019, View Source [SID1234552036]).

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These results demonstrated the benefits of IMBRUVICA (ibrutinib) plus rituximab compared to a standard chemoimmunotherapy regimen of fludarabine, cyclophosphamide and rituximab (FCR) for previously untreated patients with CLL aged 70 years or younger. These results were featured today in the CLL Therapy Oral Presentation Session at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, and served as the basis of the recent supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) to expand further the IMBRUVICA prescribing label in CLL.

Additionally, a new integrated analysis of up to six years of long-term follow-up from the Phase 3 RESONATE and RESONATE-2 studies will be presented on December 8 at the ASH (Free ASH Whitepaper) Annual Meeting, evaluating the use of IMBRUVICA monotherapy in previously untreated patients. Results showed better PFS, OS and overall response rate (ORR), with good tolerability compared to use in the relapsed/refractory (R/R) setting.

"These latest findings add to the extensive clinical evidence supporting the use of IMBRUVICA, the most comprehensively studied BTK inhibitor in CLL, as both a single-agent and as a combination regimen to improve patient outcomes in early lines of treatment, which has previously been reserved for chemoimmunotherapy," said Danelle James, M.D., M.A.S., IMBRUVICA Clinical Development Lead, Pharmacyclics LLC, an AbbVie company. "We’re pleased to present extended follow-up results from the Phase 3 E1912 and RESONATE/RESONATE-2 studies at this year’s ASH (Free ASH Whitepaper) Annual Meeting – all of which are landmark clinical trials that have uniquely changed our understanding of CLL."

"Phase 3 RESONATE and RESONATE-2 trials have proven to be cornerstone studies that have significantly advanced the treatment of CLL among a variety of patients – and the latest data presented at this year’s ASH (Free ASH Whitepaper) Annual Meeting demonstrate using IMBRUVICA alone and earlier in CLL treatment results in improved patient outcomes," said Paul M. Barr, M.D., study investigator of the Phase 3 RESONATE and RESONATE-2 trials, and Associate Professor of Medicine, Hematology/Oncology at the Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York. "These results reaffirm the sustained disease control and safety profile of IMBRUVICA and further support its use as a chemotherapy-free option for previously untreated patients living with this common form of adult leukemia."

IMBRUVICA is a once-daily, first-in-class Bruton’s tyrosine kinase (BTK) inhibitor that is administered orally, and is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

Abstract #33: E1912 extended follow-up of IMBRUVICA plus rituximab compared to FCR in patients with CLL/SLL aged 70 or younger

Oral Presentation: Saturday, December 7, 2019 at 7:30 a.m. EST

Longer-term outcomes data from the Phase 3 E1912 clinical trial – designed and conducted by ECOG-ACRIN and sponsored by the NCI – were presented today in an oral session. As previously reported in earlier data readouts, the study evaluated 354 previously untreated patients with CLL aged 70 years or younger who were randomly assigned to receive IMBRUVICA and rituximab or six courses of intravenous FCR chemoimmunotherapy every 28 days. The study met the primary endpoints of PFS and OS.

At a median follow-up of 48 months, 73 percent of patients in the IMBRUVICA plus rituximab treatment arm remained on IMBRUVICA with median time on treatment of 43 months (range of 0.2 to 61 months). The median time to progression or death after discontinuing IMBRUVICA was 23 months. Superior PFS benefits were sustained for the IMBRUVICA plus rituximab arm compared to the FCR treatment arm (hazard ratio [HR]: 0.39; 95 percent confidence interval [CI], 0.26-0.57; p<0.0001). OS also continued to favor the IMBRUVICA plus rituximab arm (HR=0.34, 95 percent CI, 0.15-0.79; p=0.009). Grade 3 and above treatment-related adverse events (AEs) were observed in 70 percent of patients in the IMBRUVICA plus rituximab arm versus 80 percent in the FCR arm (odds ratio [OR]: 0.56; 95 percent CI, 0.34 – 0.90; p=0.013).

The E1912 study served as the basis of the recent sNDA to the U.S. FDA to expand the IMBRUVICA label to include the combination with rituximab for the first-line treatment of patients with CLL or SLL. The submission is being reviewed by the FDA under the Real-Time Oncology Review pilot program.

Abstract #3054: New RESONATE/RESONATE-2 long-term analysis of ibrutinib monotherapy in earlier lines of CLL treatment

Poster Presentation: Sunday, December 8, 2019 at 6:00 p.m. EST

A new integrated analysis with up to six years of follow-up from the Phase 3 RESONATE (PCYC-1112) and RESONATE-2 (PCYC-1115/1116) studies evaluating IMBRUVICA monotherapy in previously untreated patients (n=136; median age of 73 years) and R/R patients (n=135; median age of 65 years for patients with 1-2 prior lines; median age of 67 years for patients with 3 or more lines) with CLL will be presented. Results reported IMBRUVICA monotherapy demonstrated improved PFS, OS and ORR, with sustained efficacy for the first-line patient group, including patients with high-risk prognostic features, compared to the R/R group.

At up to six years of follow-up (first-line group: median of 59.8 months; 1-2 prior lines: 66.2 months; 3 or more prior lines: 65.1 months), the median PFS was not reached for the first-line or the 1-2 prior lines groups, and median PFS was 40.1 months for the 3 or more prior lines group. A greater portion of patients treated with IMBRUVICA in earlier lines remained progression-free or alive at 60 months (first-line: 70 percent; 1-2 prior lines: 60 percent; 3 or more prior lines: 33 percent), and first-line treatment resulted in a 34 percent reduction in risk of disease progression or death compared to patients who had 1-2 prior lines of therapy (HR: 0.66; 95 percent CI, 0.40 – 1.09). PFS was significantly prolonged for patients receiving first-line treatment compared to those who have received 3 or more prior therapy (HR: 0.32; 95 percent CI, 0.21 – 0.49). Furthermore, median OS for the first-line or 1-2 prior lines group was not reached and was 67.4 months for the 3 or more prior lines group. At 60 months, the ORR was 92 percent (first-line), 96 percent (1-2 prior lines) and 88 percent (3 or more prior lines).

At the time of analysis, 58 percent of patients remain on IMBRUVICA in the first-line group. Overall, 6 percent of patients in the first-line group discontinued due to progressive disease, while it was the most common reason for discontinuation for patients who received 1-2 prior lines of therapy (22 percent) and for those who received 3 or more prior lines (37 percent). Across all three groups, 19 percent of patients discontinued due to AEs (first-line: 21 percent; 1-2 prior: 19 percent; 3 or more prior: 15 percent).

About IMBRUVICA

IMBRUVICA (ibrutinib) is an oral, once-daily medicine that works differently than chemotherapy as it blocks a protein called Bruton’s tyrosine kinase (BTK). The BTK protein sends important signals that tell B cells to mature and produce antibodies. BTK signaling is needed by specific cancer cells to multiply and spread.1,2 By blocking BTK, IMBRUVICA may help move abnormal B cells out of their nourishing environments in the lymph nodes, bone marrow, and other organs.3

Since its launch in 2013, IMBRUVICA has received 10 FDA approvals across six disease areas:
chronic lymphocytic leukemia (CLL) with or without 17p deletion (del17p); small lymphocytic lymphoma (SLL) with or without del17p; Waldenström’s macroglobulinemia (WM); previously-treated patients with mantle cell lymphoma (MCL)*; previously-treated patients with marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy* – and previously-treated patients with chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic therapy.4

IMBRUVICA is now approved in 95 countries and has been used to treat more than 170,000 patients worldwide across its approved indications. IMBRUVICA is the only FDA-approved medicine in WM and cGVHD. IMBRUVICA has been granted four Breakthrough Therapy Designations from the U.S. FDA. This designation is intended to expedite the development and review of a potential new drug for serious or life-threatening diseases. IMBRUVICA was one of the first medicines to receive FDA approval via the Breakthrough Therapy Designation pathway.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CLL recommends ibrutinib (IMBRUVICA) as a preferred regimen for the initial treatment of CLL/SLL and it is the only Category 1 single-agent regimen for treatment-naïve patients without deletion 17p.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers and other serious illnesses. IMBRUVICA is the most comprehensively studied BTK inhibitor, with more than 150 ongoing clinical trials. There are approximately 30 ongoing company-sponsored trials, 14 of which are in Phase 3, and more than 100 investigator-sponsored trials and external collaborations that are active around the world. For more information, visit www.IMBRUVICA.com.

*Accelerated approval was granted for the MCL and MZL indications based on overall response rate. Continued approval for MCL and MZL may be contingent upon verification and description of clinical benefit in confirmatory trials.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA. Major hemorrhage (≥ Grade 3, serious, or any central nervous system events; e.g., intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post procedural hemorrhage) have occurred in 4% of patients, with fatalities occurring in 0.4% of 2,838 patients exposed to IMBRUVICA in 27 clinical trials. Bleeding events of any grade, including bruising and petechiae, occurred in 39% of patients treated with IMBRUVICA.

The mechanism for the bleeding events is not well understood.

Use of either anticoagulant or antiplatelet agents concomitantly with IMBRUVICA increases the risk of major hemorrhage. In IMBRUVICA clinical trials, 3.1% of patients taking IMBRUVICA without antiplatelet or anticoagulant therapy experienced major hemorrhage. The addition of antiplatelet therapy with or without anticoagulant therapy increased this percentage to 4.4%, and the addition of anticoagulant therapy with or without antiplatelet therapy increased this percentage to 6.1%. Consider the risks and benefits of anticoagulant or antiplatelet therapy when co-administered with IMBRUVICA. Monitor for signs and symptoms of bleeding.

Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections: Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 24% of 1,124 patients exposed to IMBRUVICA in clinical trials. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections.

Monitor and evaluate patients for fever and infections and treat appropriately.

Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (23%), thrombocytopenia (8%), and anemia (3%) based on laboratory measurements occurred in patients with B‑cell malignancies treated with single agent IMBRUVICA.

Monitor complete blood counts monthly.

Cardiac Arrhythmias: Fatal and serious cardiac arrhythmias have occurred with IMBRUVICA therapy. Grade 3 or greater ventricular tachyarrhythmias occurred in 0.2% of patients, and Grade 3 or greater atrial fibrillation and atrial flutter occurred in 4% of 1,124 patients exposed to IMBRUVICA in clinical trials. These events have occurred particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmias.

Periodically monitor patients clinically for cardiac arrhythmias. Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias appropriately, and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.

Hypertension: Hypertension of any grade occurred in 12% of 1,124 patients treated with IMBRUVICA in clinical trials. Grade 3 or greater hypertension occurred in 5% of patients with a median time to onset of 5.9 months (range, 0.03 to 24 months).

Monitor blood pressure in patients treated with IMBRUVICA and initiate or adjust anti-hypertensive medication throughout treatment with IMBRUVICA as appropriate.

Second Primary Malignancies: Other malignancies (10%) including non-skin carcinomas (4%) have occurred in 1,124 patients treated with IMBRUVICA in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer (6%).

Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions.

Monitor patients closely and treat as appropriate.

Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA and for 1 month after cessation of therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Advise men to avoid fathering a child during the same time period.

ADVERSE REACTIONS

B-cell malignancies: The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia (58%)*, diarrhea (41%), anemia (38%)*, neutropenia (35%)*, musculoskeletal pain (32%), rash (32%), bruising (31%), nausea (26%), fatigue (26%), hemorrhage (24%), and pyrexia (20%).

The most common Grade 3 or 4 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (18%)*, thrombocytopenia (16%)*, and pneumonia (14%).

Approximately 7% (CLL/SLL), 14% (MCL), 14% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4-10% (CLL/SLL), 9% (MCL), and 7% (WM [5%] and MZL [13%]) of patients discontinued due to adverse reactions.

cGVHD: The most common adverse reactions (≥20%) in patients with cGVHD were fatigue (57%), bruising (40%), diarrhea (36%), thrombocytopenia (33%)*, muscle spasms (29%), stomatitis (29%), nausea (26%), hemorrhage (26%), anemia (24%)*, and pneumonia (21%).

The most common Grade 3 or higher adverse reactions (≥5%) reported in patients with cGVHD were pneumonia (14%), fatigue (12%), diarrhea (10%), neutropenia (10%)*, sepsis (10%), hypokalemia (7%), headache (5%), musculoskeletal pain (5%), and pyrexia (5%).

Twenty-four percent of patients receiving IMBRUVICA in the cGVHD trial discontinued treatment due to adverse reactions. Adverse reactions leading to dose reduction occurred in 26% of patients.

*Treatment-emergent decreases (all grades) were based on laboratory measurements.

DRUG INTERACTIONS

CYP3A Inhibitors: Co-administration of IMBRUVICA with strong or moderate CYP3A inhibitors may increase ibrutinib plasma concentrations. Dose modifications of IMBRUVICA may be recommended when used concomitantly with posaconazole, voriconazole, and moderate CYP3A inhibitors. Avoid concomitant use of other strong CYP3A inhibitors. Interrupt IMBRUVICA if strong inhibitors are used short-term (e.g., for ≤ 7 days). See dose modification guidelines in USPI sections 2.4 and 7.1.

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA in patients with severe baseline hepatic impairment. In patients with mild or moderate impairment, reduce IMBRUVICA dose.

On December 7, 2019 Unum Therapeutics Inc. (NASDAQ: UMRX), a clinical-stage biopharmaceutical company focused on developing curative cell therapies for cancer, reported Phase 1 clinical updates for its Antibody-Coupled T cell Receptor (ACTR) engineered T-cell therapies, ACTR707 and ACTR087, in patients with relapsed or refractory CD20+ non-Hodgkin Lymphoma (r/r NHL) at the ASH (Free ASH Whitepaper) Annual Meeting, being held December 7-10, in Orlando, FL (Press release, Unum Therapeutics, DEC 7, 2019, View Source [SID1234552035]).

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"The clinical data presented at this year’s ASH (Free ASH Whitepaper) include updates from the ongoing Phase 1 trial of ACTR707 in combination with rituximab and the completed Phase 1 trial of ACTR087 in combination with rituximab, both conducted in patients with relapsed or refractory CD20+ NHL," said Jessica Sachs, M.D., Chief Medical Officer of Unum. "The data with ACTR707 at this year’s ASH (Free ASH Whitepaper) continue to support further dose-escalation in this Phase 1 trial and provide proof-of-mechanism for the ACTR platform that we are also applying in our lead program, a Phase 1 trial with ACTR707 in combination with trastuzumab in HER2+ solid tumor cancers. Safety data from the Phase 1 trial with ACTR087 presented at this year’s ASH (Free ASH Whitepaper) provide learnings that are being applied to ongoing clinical trials with ACTR T cell products.

Poster (#1587) Title: "Preliminary Clinical Results from a Phase 1 Study of ACTR707 in Combination With Rituximab in Subjects with Relapsed or Refractory CD20+ Non-Hodgkin Lymphoma"

ATTCK-20-03 is a Phase 1, multicenter, open-label, single-arm, dose-escalation trial evaluating ACTR707 in combination with rituximab in patients with r/r CD20+ NHL who, among other criteria, received adequate prior anti-lymphoma therapy, including anti-CD20 monoclonal antibody and chemotherapy. In this update from the first 20 patients treated, treatment with ACTR707 combined with rituximab generated clinical responses with no reports of cytokine-release syndrome (CRS) or severe neurotoxicity.
As reported today at ASH (Free ASH Whitepaper), a complete response was achieved in 40% (eight of 20) of patients in Cohorts 1 through 4. Of the eight complete responders, four remained in complete response at six months of follow-up, two remain in complete response but have not yet reached the six-month timepoint for evaluation, and two progressed before the six-month timepoint (Table 1).
Table 1: ACTR707 Preliminary Phase 1 trial clinical response results in r/r NHL (Cohorts 1-4)

Clinical Response (1) Cohort 1 (n=6) Cohort 2 (n=3) Cohort 3 (n=5) Cohort 4 (n=6) Cohorts 1-4 (n=20)
Complete Response 3 1 2 2 40% (8/20)
Partial Response 0 1 2 0 15% (3/20)
Stable Disease 0 0 0 1 5% (1/20)
Indeterminate Response 1 0 0 0 5% (1/20)
Progressive Disease 2 1 1 3 35% (7/20)
Overall Response Rate 50% (3/6) 67% (2/3) 80% (4/5) 33% (2/6) 55% (11/20)
ACTR707+T cells administered, target per patient (range) 25M (23-38M) 40M (30-50M) 55M (45-55M) 80M (65-100M)
(1) Data cutoff as of Nov 2019

In Cohorts 1 through 4, ACTR707 was reported to be well-tolerated in combination with rituximab. No dose-limiting toxicities (DLTs), no adverse events of CRS, and no severe neurological adverse events including neurotoxicity have been reported as of the November 2019 cutoff (Table 2).
Table 2: ACTR707 Preliminary Phase 1 trial safety results in r/r NHL (Cohorts 1-4)

Safety Event (1) Cohort 1 (n=6) Cohort 2 (n=3) Cohort 3 (n=5) Cohort 4 (n=6)
Dose-limiting toxicities 0 0 0 0
Severe neurologic events (> Grade 3) 0 0 0 0
CRS (any grade) 0 0 0 0
ACTR707-related SAEs 1 2 0 1
febrile neutropenia 1 1 0 1
cytopenia 0 1 0 0
(1) Data cutoff as of Nov 2019

Given favorable tolerability observed to date at relatively low doses, Unum announced in November plans to continue dose escalation in two additional cohorts (approximately four patients per cohort) in the trial, escalating the maximum dose up to 180M ACTR707+ T cells. Patient enrollment and planned dosing is underway, and Unum plans to report preliminary results from this dose escalation during 2020.
Additional details about the ATTCK-20-03 Phase 1 trial can be found here.

Oral Presentation Title (#244): "A Phase 1 Study of ACTR087 in Combination with Rituximab, in Subjects with Relapsed or Refractory CD20-Positive B-Cell Lymphoma"

Following the decision in 2018 to prioritize ACTR707 over ACTR087 for future development in r/r NHL and solid tumors, Unum completed enrollment in the ATTCK-20-2 trial, a Phase 1, multicenter, open-label, single-arm, dose-escalating trial evaluating ACTR087 in combination with rituximab in patients with r/r CD20+ NHL.

In this trial, ACTR087+ T cells, when combined with rituximab, expanded and persisted long-term (observed up to 1029 days in one patient) and generated complete responses lasting greater than six months in 20% (four of 20) of evaluable patients with aggressive CD20+ malignancies. In this trial, ACTR087 was administered across three cohorts (mean dose range of 19-67M cells).
Severe T cell-mediated toxicities (CRS and neurotoxicity) occurred in four of 26 patients who received ACTR087 in combination with rituximab, with different timing and symptomatology from those observed with currently available CD19 CAR T cell therapies. Baseline inflammation appeared to predispose patients to severe toxicity.