On December 7, 2019 Seattle Genetics, Inc. (Nasdaq:SGEN) reported updated and long-term follow-up analyses from two clinical trials evaluating ADCETRIS (brentuximab vedotin) and OPDIVO (nivolumab) in frontline Hodgkin lymphoma (HL) patients aged 60 years and older and in relapsed or refractory classical HL (Press release, Seattle Genetics, DEC 7, 2019, View Source [SID1234552050]). ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical HL. ADCETRIS and OPDIVO are not approved in combination for the treatment of HL. Results were presented today at the 61st American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition taking place December 7-10 in Orlando, Fla.

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"We continue to evaluate ADCETRIS in combination with novel therapies, such as checkpoint inhibitors, with the goal of identifying new options for CD30-expressing lymphomas where there is high unmet need," said Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics. "These data presentations at ASH (Free ASH Whitepaper) reinforce our strong commitment to the ADCETRIS clinical development program, potentially moving into new patient populations and novel combination treatment strategies."

Phase 2 Study of Frontline Brentuximab Vedotin Plus Nivolumab in Patients with Hodgkin Lymphoma Aged ≥ 60 Years (Abstract #237, oral presentation at 2:30 p.m. ET on Saturday, December 7, 2019)
Data were presented from an updated analysis from the phase 2 clinical trial evaluating ADCETRIS in combination with OPDIVO as frontline therapy for HL patients aged 60 years and older. Data were reported from 21 patients, and the median age was 72 years. The majority of patients (76 percent) had stage III/IV disease at the time of diagnosis. These results will be highlighted in an oral presentation by Christopher A. Yasenchak, M.D., Willamette Valley Cancer Institute and Research Center/US Oncology Research, Ore., and include:

Of 19 response-evaluable patients, 18 patients (95 percent) had an objective response, including 13 patients (68 percent) with a complete response and five patients (26 percent) with a partial response. All response-evaluable patients experienced tumor reduction (complete response + partial response + stable disease) following treatment with ADCETRIS in combination with OPDIVO. Median duration of response was not yet reached and the maximum duration of response was 22 months and ongoing (95% CI: 7.06, -).
The most common treatment-related adverse events of any grade occurring in at least 20 percent of patients were fatigue, diarrhea, pyrexia, infusion related reaction, peripheral motor neuropathy, peripheral sensory neuropathy and increase in lipase. One treatment-related serious adverse event was pyrexia. Fifty-seven percent of patients (12/21) had at least one treatment-related adverse event greater than or equal to Grade 3, most commonly increase in lipase (24 percent, 5/21), peripheral motor neuropathy and peripheral sensory neuropathy (each 14 percent, 3/21), and fatigue and hyponatremia (each 10 percent, 2/21).
Two-Year Follow-up Results from the Phase 1-2 Study of Brentuximab Vedotin in Combination with Nivolumab in Patients with Relapsed or Refractory Classical Hodgkin Lymphoma (Abstract #238, oral presentation at 2:45 p.m. ET on Saturday, December 7, 2019)
Data were reported from 93 patients with relapsed or refractory classical HL after failure of frontline therapy who received the combination regimen of ADCETRIS plus OPDIVO. After completion of the fourth cycle of treatment, patients were eligible to undergo an autologous stem cell transplant (ASCT). The median age of patients was 34 years. These results will be highlighted in an oral presentation by Alison J. Moskowitz, M.D., Memorial Sloan Kettering Cancer Center, NY, and include:

Of the 91 treated patients, 85 percent (77/91) had an objective response, including 67 percent (61/91) with a complete response, 16 patients with a partial response and six patients had stable disease.
Of the 91 treated patients, 67 patients received an ASCT per trial protocol with no additional salvage therapy.
For all treated patients, the two-year progression-free survival (PFS) was 79 percent (95% CI: 68%, 87%). For the 67 patients who received an ASCT per trial protocol, the two-year PFS was 92 percent (95% CI: 80%, 97%). Median follow-up for all treated patients was 24.2 months (range 1.8-41.7) and the median PFS was not reached. Estimated overall survival at two years was 94 percent (95% CI: 85%, 97%) and median overall survival was not yet reached.
Peripheral immune signatures were consistent with an activated T-cell response.
Prior to ASCT, the most common adverse events of any grade occurring in more than 20 percent of patients were nausea, infusion related reaction, fatigue, diarrhea, pruritus, headache, vomiting and pyrexia. Other adverse events included peripheral neuropathy in 16 patients (18 percent) and neutropenia in six patients (7 percent). Two patients (2 percent) discontinued treatment due to adverse events, Grade 3 peripheral neuropathy and increased gamma-glutamyltransferase. Serious adverse events occurred in 14 patients (15 percent), including pneumonia, pneumonitis and pyrexia (two patients each); and Grade 3 Guillain-Barre syndrome (one patient).
About Classical Hodgkin Lymphoma
Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Classical Hodgkin lymphoma is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell. The Reed-Sternberg cell expresses CD30.

According to the American Cancer Society, approximately 8,110 cases of Hodgkin lymphoma will be diagnosed in the United States during 2019 and 1,000 will die from the disease. Approximately half of all newly diagnosed Hodgkin lymphoma patients have Stage III/IV disease. According to the Lymphoma Coalition, over 62,000 people worldwide are diagnosed with Hodgkin lymphoma each year and approximately 25,000 people die each year from this cancer.

About ADCETRIS
ADCETRIS is being evaluated broadly in more than 70 clinical trials in CD30-expressing lymphomas. These include three completed phase 3 trials: ECHELON-2 trial in frontline peripheral T-cell lymphomas, ECHELON-1 in previously untreated Hodgkin lymphoma, and ALCANZA in cutaneous T-cell lymphoma.

ADCETRIS is an ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.

ADCETRIS injection for intravenous infusion has received FDA approval for six indications in adult patients with: (1) previously untreated systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone, (2) previously untreated Stage III or IV classical Hodgkin lymphoma (cHL), in combination with doxorubicin, vinblastine, and dacarbazine, (3) cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation, (4) cHL after failure of auto-HSCT or failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates, (5) sALCL after failure of at least one prior multi-agent chemotherapy regimen, and (6) primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy.

Health Canada granted ADCETRIS approval with conditions in 2013 for patients with (1) HL after failure of autologous stem cell transplant (ASCT) or after failure of at least two multi-agent chemotherapy regimens in patients who are not ASCT candidates and (2) sALCL after failure of at least one multi-agent chemotherapy regimen. Non-conditional approval was granted for (3) post-ASCT consolidation treatment of patients with HL at increased risk of relapse or progression in 2017, (4) adult patients with pcALCL or CD30-expressing MF who have received prior systemic therapy in 2018, (5) for previously untreated patients with Stage IV HL in combination with doxorubicin, vinblastine, and dacarbazine in 2019, and (6) for previously untreated adult patients with sALCL, peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS) or angioimmunoblastic T-cell lymphoma (AITL), whose tumors express CD30, in combination with cyclophosphamide, doxorubicin, prednisone in 2019.

ADCETRIS received conditional marketing authorization from the European Commission in October 2012. The approved indications in Europe are: (1) for the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin lymphoma following ASCT, or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, (2) for the treatment of adult patients with relapsed or refractory sALCL, (3) for the treatment of adult patients with CD30-positive Hodgkin lymphoma at increased risk of relapse or progression following ASCT, (4) for the treatment of adult patients with CD30-positive cutaneous T-cell lymphoma (CTCL) after at least one prior systemic therapy and (5) for the treatment of adult patients with previously untreated CD30-positive Stage IV Hodgkin lymphoma in combination with AVD (Adriamycin, vinblastine and dacarbazine).

ADCETRIS has received marketing authorization by regulatory authorities in 73 countries for relapsed or refractory Hodgkin lymphoma and sALCL. See select important safety information, including Boxed Warning, below.

Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

On December 7, 2019 argenx (Euronext & Nasdaq: ARGX), a clinical-stage biotechnology company developing a deep pipeline of differentiated antibody-based therapies for the treatment of severe autoimmune diseases and cancer, reported the receipt of a development milestone payment from Janssen and the presentation of updated data from the Phase 1 dose escalation trial of cusatuzumab in combination with azacytidine for the treatment of newly diagnosed acute myeloid leukemia (AML) at the 61st American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, argenx, DEC 7, 2019, View Source [SID1234552049]).

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argenx will receive the first development milestone payment of $25 million from its global collaboration and license agreement with Cilag GmbH International, an affiliate of the Janssen Pharmaceutical Companies of Johnson & Johnson. The milestone payment was triggered by the achievement of a prespecified enrollment threshold in the first trial to start under the collaboration. This dose-confirming Phase 2 pivotal CULMINATE trial of cusatuzumab is being conducted in combination with azacytidine for the treatment of newly diagnosed elderly patients with AML who are unfit for intensive chemotherapy.

"This milestone payment marks the progress made across our global collaboration with Janssen. Two trials are now underway in newly diagnosed populations with more trials expected to intiate next year in different AML settings and subpopulations. We continue to believe in the potential of the CD70/CD27 axis as a novel approach within the AML treatment landscape. The data update today further support the use of cusatuzumab in combination to treat this vulnerable patient population," commented Tim Van Hauwermeiren, Chief Executive Officer of argenx.

Key Highlights from ASH (Free ASH Whitepaper)

Adrian Ochsenbein, M.D. from the University of Bern presented translational data in support of the dual modes of action of cusatuzumab, including the blocking of CD70/CD27 signaling to stop proliferation of leukemic stem cells and cell killing via Fc-dependent, complement-dependent cytotoxicity and enhanced antibody-dependent cellular cytotoxicity (ADCC) via POTELLIGENT technology. Dr. Ochsenbein also showed updated data as of the new cut-off date of February 2019 from the Phase 1 dose escalation trial of cusatuzumab in combination with azacytidine in 12 newly diagnosed elderly patients with AML who are unfit for intensive chemotherapy.

100% of patients achieved a response including eight with a complete response (CR), two with a complete response with incomplete hematologic recovery (CRi), and two with a partial response (PR); 83% of patients achieved either a CR or CRi

Of the nine CR/CRi patients evaluable for minimal residual disease (MRD) negativity, four achieved MRD negativity using a threshold of 10-3 which is consistent with the previous data cut-off in October 2018

Four patients have remained in the study for at least 12 months

Three patients from the study have been re-classified with risk category based on new mutation information or a reassessment of existing mutation information

Cusatuzumab continued to be well-tolerated in patients with AML across the different doses

In addition to the CULMINATE trial in the newly diagnosed unfit AML population, cusatuzumab is also being evaluated in a Phase 1b platform study to explore combinations with standard AML therapies with the first trial exploring combinations of venetoclax, cusatuzumab and azacytidine.

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.