On June 16, 2018 Novartis reported 14-month results from the pivotal JULIET clinical trial showing ongoing durable responses are achievable with Kymriah (tisagenlecleucel) when administered to adult patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) (Press release, Novartis, JUN 16, 2018, View Source [SID1234527357]). The overall response rate (ORR) was 52% (95% confidence interval [CI], 41% – 62%), among 93 evaluable patients who were followed for at least 3 months or discontinued earlier[1]. A complete response (CR) was achieved in 40% of patients and 12% achieved a partial response (PR). Of the patients in CR at month 3, 83% remained in CR at month 12, and the median duration of response was not reached, indicating sustainability of response. These data will be presented in an oral presentation at the 23rd Annual Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) (Abstract # S799; Saturday, June 16, 11:30AM CEST)[1].

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"Advanced aggressive lymphoma patients who once faced a poor prognosis now have the possibility of sustained remission after a single course of therapy – a previously unimaginable and revolutionary breakthrough," said the lead author of the updated JULIET analysis Peter Borchmann, MD, Department of Internal Medicine, University Hospital of Cologne, Germany. "With 14 months of data from JULIET, we are seeing that Kymriah may continue to redefine outcomes for patients with relapsed or refractory DLBCL."

In the JULIET study, the relapse-free probability at 12 months after a patient’s first response (n=48) was 65% (95% CI, 49%-78%). In fact, 54% (13/24) of patients who had achieved a PR converted to CR, including two patients between months 9 and 12. Median overall survival (OS) was not reached for patients in CR (95% CI, 17.9-NE). The OS rate at 12 months was 49% and median OS was 11.7 months among all infused patients (n=111) (95% CI, 6.6-NE). The median time from infusion to data cutoff was 14 months with a maximum time from infusion of 23 months. At the time of data cutoff, no patients in response following treatment with Kymriah proceeded to stem cell transplant[1].

"These results from JULIET continue to show Kymriah delivers strong efficacy with durable responses, and a predictable and consistent safety profile more than a year after infused in patients with advanced DLBCL," said Samit Hirawat, MD, Head, Novartis Oncology Global Drug Development. "Novartis is committed to bringing this important and innovative treatment option to more patients around the world."

Within eight weeks of infusion with Kymriah, Grade 3/4 cytokine release syndrome (CRS), as defined by the Penn Grading Scale – a rigorous scale for grading CRS -, was reported in 22% of patients (14% grade 3; 8% grade 4). Fifteen percent of patients received tocilizumab for treatment of CRS, including only 3% of patients with Grade 2 CRS and 50% of patients with Grade 3 CRS. CRS is a known complication of CAR-T therapy that may occur when the engineered cells become activated in the patient’s body. CRS was managed globally using prior site education on implementation of the CRS treatment algorithm. No deaths due to cerebral edema were reported[1].

In this analysis, 12% of patients had grade 3/4 neurologic adverse events, which were managed with supportive care. Grade 3/4 cytopenias lasting more than 28 days, grade 3/4 infections and grade 3/4 febrile neutropenia occurred in 32%, 20% and 15% of patients, respectively[1].

"When we continued follow-up with DLBCL patients in the global JULIET study, we were extremely pleased that response rates were maintained a year or more after infusion with Kymriah, which was consistent with the durable responses seen in the pilot studies conducted at Penn," said Stephen J. Schuster, MD, the Robert and Margarita Louis-Dreyfus Professor in Chronic Lymphocytic Leukemia and Lymphoma Clinical Care and Research in Penn’s Perelman School of Medicine and director of the Lymphoma Program at the Abramson Cancer Center. "We look forward to continuing to follow these patients who we hope will remain in remission from their disease."

Analyses to better characterize and predict severe CRS and neurologic events, including relationships with baseline clinical and laboratory parameters, dose and cellular kinetics will also be presented.

Fifty patients discontinued before infusion and the majority did so due to rapid progression of their disease or deterioration in their clinical status reflecting the acute and progressive nature of r/r DLBCL. Twelve out of 165 (7.3%) enrolled patients could not be infused due to inability to manufacture an adequate dose of CAR-T cells.

In May 2018, the US Food and Drug Administration (FDA) approved Kymriah for the treatment of adult patients with r/r large B-cell lymphoma after two or more lines of systemic therapy including DLBCL, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma based on data from the JULIET study. Kymriah is not approved for the treatment of patients with primary central nervous system lymphoma. The European Medicines Agency (EMA) is evaluating the Marketing Authorization Application (MAA) for Kymriah for the treatment of children and young adults with r/r B-cell acute lymphoblastic leukemia (ALL) and for adult patients with r/r DLBCL.

About the JULIET Trial
JULIET is the first multi-center global registration study for Kymriah in adult patients with r/r DLBCL. JULIET, led by researchers at the University of Pennsylvania, is the largest and only globally conducted study examining a CAR-T cell therapy in DLBCL, enrolling patients from 27 sites in 10 countries across the US, Canada, Australia, Japan and Europe, including Austria, France, Germany, Italy, Norway and the Netherlands. In 2012, Novartis and Penn entered into a global collaboration to further research, develop and commercialize CAR-T cell therapies, including Kymriah, for the investigational treatment of cancers.

About DLBCL
DLBCL is the most common form of non-Hodgkin lymphoma, a cancer of the lymphatic system, accounting for up to 40% of all NHL cases globally[2]. An estimated 27,650 new cases of DLBCL were diagnosed in the US in 2016[3]. The crude incidence of DLBCL in Europe per year is 3.8 cases per 100,000 people, and incidence increases with age and varies considerably across Europe[4]. Roughly one-third of patients with DLBCL relapse after receiving first-line treatment[4]. Out of those patients diagnosed with DLBCL, about 10% have refractory disease and about 75% of patients who relapse or are refractory to treatment are ineligible for ASCT[2],[5]. For patients who relapse or don’t respond to initial therapy, there are limited treatment options that provide durable responses and median life expectancy is approximately six months[6].

About Kymriah Manufacturing
Kymriah is manufactured for each individual patient using their own cells at the Novartis Morris Plains, New Jersey facility. The reliable and integrated manufacturing and supply chain platform for Kymriah allows for an individualized treatment approach on a global scale. The process includes cryopreservation of a patient’s harvested (or leukapheresed) cells, giving treating physicians and centers the flexibility to initiate therapy with Kymriah based on the individual patient’s condition. Novartis has significant CAR-T manufacturing experience and has demonstrated a reproducible product. Novartis has manufactured CAR-T cells for more than 300 patients from 11 countries. Novartis continues to advance its CAR-T manufacturing expertise in Morris Plains.

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

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

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

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

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

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

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

Patients should not drive, operate heavy machinery, or do other dangerous activities for eight weeks after receiving Kymriah because the treatment can cause temporary memory and coordination problems, including sleepiness, confusion, weakness, dizziness, and seizures.

Some of the most common side effects of Kymriah are difficulty breathing, fever (100.4°F/38°C or higher), chills/shaking chills, confusion, severe nausea, vomiting and diarrhea, severe muscle or joint pain, very low blood pressure, dizziness/lightheadedness, and headache. However, these are not all of the possible side effects of Kymriah. Patients should talk to their healthcare provider for medical advice about side effects.

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

Patients should tell their healthcare provider about all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

After receiving Kymriah, patients should be advised that some commercial HIV tests may cause a false-positive test result. Patients should also be advised not to donate blood, organs, or tissues and cells for transplantation after receiving Kymriah.

Please see the full Prescribing Information for Kymriah, including Boxed WARNING, and Medication Guide at www.Kymriah.com

Disclaimer
This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as "potential," "can," "will," "plan," "expect," "anticipate," "look forward," "believe," "committed," "investigational," "pipeline," "launch," or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for Kymriah, regarding our ability to scale and sustain commercial manufacturing for Kymriah, or regarding potential future revenues from Kymriah. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that Kymriah will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Neither can there be any guarantee that Novartis will successfully scale and sustain commercial manufacturing for Kymriah, or successfully sustain a network of treatment centers to offer Kymriah. Nor can there be any guarantee that Kymriah will be commercially successful in the future. In particular, our expectations regarding Kymriah could be affected by, among other things, our ability to successfully scale and sustain commercial manufacturing and sustain a network of treatment centers; the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political and economic conditions; safety, quality or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

On June 16, 2018 Verastem, Inc. (Nasdaq: VSTM), the Company or Verastem Oncology, a biopharmaceutical company focused on developing and commercializing medicines to improve the survival and quality of life of cancer patients, reported one oral and three poster presentations at the 23rd Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) being held June 14-17, 2018 in Stockholm, Sweden (Press release, Verastem, JUN 16, 2018, View Source;p=RssLanding&cat=news&id=2354840 [SID1234527361]).

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Data were presented on the Company’s lead product candidate, duvelisib, a first-in-class oral dual inhibitor of phosphoinositide 3-kinase (PI3K)-delta and PI3K-gamma. An oral presentation by Dr. Matthew Davids, Dana-Farber Cancer Institute, highlighted the latest data from a Phase Ib/II study evaluating duvelisib in combination with FCR (dFCR) as a frontline treatment in younger patients with chronic lymphocytic leukemia (CLL). Three poster presentations highlighted additional duvelisib data, including crossover extension results from the Phase 3 DUO study in patients with relapsed or refractory CLL/small lymphocytic lymphoma (SLL), and new biomarker analyses on the tumor microenvironment modulation from the DUOTM study and the Phase 2 DYNAMOTM study in patients with refractory indolent non-Hodgkin lymphoma (iNHL), and the dual PI3K-delta and PI3K-gamma activity of duvelisib in the CONTEMPOTM study in patients with untreated follicular lymphoma (FL) who are treated with duvelisib in combination with CD20 antibody immunotherapy.

"Dr. Matthew Davids gave an oral presentation of new clinical data from the ongoing Phase Ib/II study evaluating duvelisib in combination with FCR (chemo-immunotherapy) in younger, fit CLL patients," said Diep Le, MD, PhD, Chief Medical Officer of Verastem Oncology. "The combination regimen achieved an overall response rate (ORR) of 94%, including 26% of patients experiencing a complete response or complete response with incomplete blood count recovery (CR/CRi), and 68% achieving a partial response. In addition, patients also experienced a high rate of bone marrow MRD negativity of 76%, which is significantly higher than historical data with FCR. Importantly, the results from this study demonstrated that duvelisib can be combined with a triple chemo-immunotherapy in the front-line setting with an acceptable safety profile".

Dr. Le added, "In addition, the DUO crossover extension data presented build upon the previously reported positive Phase 3 DUO study results and further support duvelisib’s potential as an oral treatment option for patients with relapsed or refractory CLL/SLL. Post-crossover, oral duvelisib monotherapy demonstrated robust clinical activity with a 73% overall response rate (ORR) and a 15-month median PFS in the 89 patients that had previously received ofatumumab on DUO and subsequently progressed. Duvelisib monotherapy also demonstrated a manageable safety profile, with results from this study consistent with the well-characterized safety profile of duvelisib monotherapy in previous studies. It is encouraging to see such a robust response to duvelisib monotherapy, similar to response observed in the parent DUO study, in patients that had failed an additional line of therapy and needed a new treatment option. Collectively, the data presented at EHA (Free EHA Whitepaper) this year continue to provide important insights to guide the future clinical development of duvelisib across a wide range of hematologic malignancies, both as a monotherapy and in combination with other agents."

Jonathan Pachter, PhD, Chief Scientific Officer of Verastem Oncology, commented, "The results presented by Drs. Casulo and Weaver continue to provide important evidence that the dual inhibition of PI3K-δ and PI3K-γ by duvelisib potentially yields added clinical benefit for CLL/SLL and FL patients by targeting both malignant B cells and the supportive tumor microenvironment. For example, these data indicate that duvelisib significantly inhibits chemokines from both cancer cells and the tumor microenvironment, and specifically, PI3K-γ inhibition impairs function of cancer-supportive macrophages and T cells."

Details for the EHA (Free EHA Whitepaper) 2018 presentation and posters are as follows:

Oral Presentation

Title: A Phase IB/II Study of duvelisib in combination with FCR (dFCR) for Frontline Therapy of Younger CLL Patients
Lead author: Dr. Matthew Davids, Dana-Farber Cancer Institute
Final Abstract Code: S807
Summary: FCR is a common initial therapy for younger CLL patients; however, only about 20% will achieve a CR/CRi with minimum residual disease (MRD) negativity in the bone marrow (BM-MRD-). Oral duvelisib had previously shown promising efficacy in CLL, and therefore, the purpose of this study was to investigate the safety and rate of CR/CRi with BM-MRD- following treatment with dFCR. This Phase Ib/II study utilized a standard 3 + 3 design and included 2 dose levels of oral duvelisib (25mg once daily or 25mg twice daily). Duvelisib was given for 1 week with FCR added on Day 8. Up to 6 cycles of dFCR were administered, followed by up to 2 years of duvelisib maintenance.

Among the 31 patients evaluable for post-dFCR response, the ORR was 94%, with 26% achieving a CR (n=4) or CRi (n=4), and 68% achieving a partial response (PR). The best rate of MRD- in the BM in patients with at least one evaluation was 81% (25 of 31). All patients who achieved CR/CRi at primary endpoint were also BM-MRD- (26%). Among survivors, the median follow-up is 24.5 months (range 6.9-46). Two-year progression-free survival and overall survival are both 97%. Eight patients have now completed two years of duvelisib maintenance therapy. The most common all grade non-hematologic adverse events were nausea (72%, all Grade 1/2), fatigue (69%, 3% Grade 3), fever (53%, all Grade 1/2), diarrhea (47%, 3% Grade 3), transaminitis (34%, 28% Grade 3/4), anorexia (34%, all Grade 1/2), vomiting (28%, all Grade 1/2), pruritus (16%, 3% Grade 3), arthritis (9%, all Grade 2) and CMV reactivation (6%, both Grade 2). The most common all grade hematologic adverse events were thrombocytopenia (65%; 34% Grade 3-4), neutropenia (59%; 50% Grade 3-4), and anemia (38%, 16% Grade 3). Serious AEs included transaminitis (n=9, including 5 Grade 3, 4 Grade 4), febrile neutropenia (n=6, all Grade 3), pneumonia (n=6, including 3 cases of PJP despite planned prophylaxis), and colitis (n=2, including 1 Grade 2 and 1 Grade 3). Based on these results the recommended Phase 2 dose of duvelisib in combination with FCR was 25mg twice daily. These results support the thesis that dFCR is an effective regimen for the initial therapy of younger, fit CLL patients and results in a high 81% rate of BM-MRD negativity, significantly higher than historical data with FCR; however infectious and immune-mediated toxicities were observed.

A copy of the oral presentation is available here.

Poster Presentations

Title: The Efficacy of Duvelisib Monotherapy Following Disease Progression on Ofatumumab Monotherapy in Patients with Relapsed/Refractory CLL or SLL in a Phase 3 Crossover Extension Study
Lead author: Dr. Peter Hillman, St. James University Hospital, Leeds, UK
Final Abstract Code: PF354
Summary: In the previously reported Phase 3 DUO study oral duvelisib monotherapy achieved a statistically significant improvement in median progression-free survival (mPFS) compared to ofatumumab in patients with relapsed or refractory CLL/ SLL (13.3 months versus 9.9 months, respectively; HR=0.52; p<0.0001), along with a manageable safety profile (Flinn, ASH (Free ASH Whitepaper) 2017). The results reported here are from the open-label, DUO crossover extension study where patients with confirmed progressive disease (PD) following treatment with ofatumumab in DUO were given the option to receive treatment with duvelisib. Duvelisib 25mg BID was administered until PD, intolerance, death, or study withdrawal and responses were determined by investigators using modified IWCLL/IWG criteria.

Among the 89 evaluable patients (median three prior therapies (range 2-8), oral duvelisib monotherapy achieved a 73% overall response rate (ORR; 95% CI: 64, 82; 5% complete response with incomplete marrow recovery (CRis), 68% partial responses [PRs]) in the extension study. While on ofatumumab in the DUO study, these 89 patients had a 28% ORR (95% CI: 19, 37; 1% complete response (CR), 27% PRs). The mPFS for duvelisib in the extension study was 15 months (95% CI: 10, 17). While on ofatumumab in the DUO study, these 89 patients had a mPFS of 9 months (95% CI: 9, 11), per investigator’s assessment. Notably, 83% of patients in the duvelisib arm post-crossover had >50% reductions in the size of their target nodal lesions. These same 89 patients had 27% reductions in the size of their target nodal lesions in the DUO ofatumumab arm. Median exposure to duvelisib in the extension study was 32 weeks. The safety profile of duvelisib monotherapy was manageable and consistent with what was observed in the Phase 3 DUO study. The most common Grade ≥3 treatment-emergent adverse events were neutropenia (22%), diarrhea (17%), colitis (9%), pneumonia (9%), rash (5%) and pyrexia (4%). These data build upon the previously reported positive DUO results and further support oral duvelisib monotherapy as an effective oral treatment option for patients with relapsed or refractory CLL/SLL.

A copy of the poster presentation will be available here.

Title: The effect of duvelisib, a dual inhibitor of PI3K-δ,γ, on components of the tumor microenvironment in previously untreated follicular lymphoma
Lead author: Dr. Carla Casulo, University of Rochester, Wilmot Cancer Center
Final Abstract Code: PF646
Summary: In previously reported data from the CONTEMPO trial, treatment-naive FL patients treated with duvelisib in combination with rituxumab had an ORR of 93% (36% CRR), and an ORR of 89% (41% CRR) was observed for patients treated with duvelisib in combination with obinutuzumab. In this study, blood samples from healthy volunteers and FL patients treated in the CONTEMPO study, both pre- and post-duvelisib treatment, were analyzed. Ex vivo and in vitro PI3K-γ assays and PI3K-δ assays, with PI3K-δ-selective (idelalisib, TGR-1202, IPI-3063) and PI3K-γ-selective (IPI-549) inhibitors were compared.

Duvelisib and idelalisib potently inhibited LPS-induced human monocytes via PI3K-δ, compared with the PI3K-γ selective IPI-549. For TGR-1202, the IC50 was below the recommended Phase 2 dose (RP2D) clinical exposure. Duvelisib and IPI-549 potently inhibited PI3K-γ dependent fMLP-stimulated human monocytes compared to idelalisib and TGR-1202. In FL patients treated with duvelisib, these PI3K-γ and PI3K-δ selective assays were inhibited 1-4 hours post treatment. Consistent with a PI3K-γ mechanism, both duvelisib and IPI-549 inhibited macrophage polarization to M2, reduced CXCL12-induced macrophage migration, and blocked CXCL12-induced T cell migration, which was not observed with PI3K-δ inhibitor IPI-3063. Collectively, these results support the thesis that duvelisib disrupts PI3K- δ,γ function in FL patients inhibiting the TME through cancer-supportive macrophages and T cells.

A copy of the poster presentation will be available here.

Title: Duvelisib inhibition of chemokines in patients with CLL (DUO study) and iNHL (DYNAMO study).
Lead author: Dr. David Weaver, Verastem Oncology
Final Abstract Code: PF649
Summary: PI3K-δ inhibition directly targets proliferation and survival of malignant leukemia and lymphoma cells, while PI3K-γ inhibition modulates the TME through key support cells, including tumor-associated macrophages, nurse-like stroma and T cells, and via soluble factors stimulating tumor growth, survival and migration. Serum samples from patients in the Phase 3 DUO study in relapsed/refractory CLL/SLL and the Phase 2 DYNAMO study in relapsed/refractory indolent NHL were collected at baseline and at C2D1 and used for correlative studies of 24 chemokines, cytokines and serum factors.

In serum samples from the DUO study, CCL1, CCL17, CXCL9, CXCL10, CXCL11, and IL-10 were reduced in patients treated with duvelisib (median 43.8%) but not in those treated with ofatumumab (p≤0.0009). Eight chemokines were reduced in both treatment arms, but the level of reduction was significantly greater for duvelisib-treated patients (median 64.6% for duvelisib versus 26.8% for ofatumumab [p≤0.001]). Many of the chemokines inhibited following duvelisib treatment are associated with the TME, including TNFα, IL-10, IL2Rα, IL12P40, CCL1, CCL17, CCL19, CXCL9, CXCL10, CXCL11, and CXCL13. In serum samples from the DYNAMO study, 13 corresponding chemokines were also inhibited (p≤0.008), including TME factors. Reductions occurred rapidly (by C2D1) in both studies. In DUO, there was a correlation between duration of response and reduction of the following chemokines: CCL17, CXCL11, IL-6, TRAIL, VEGF-D and TPO. These data support the hypothesis that treatment with duvelisib results in significant reduction of chemokines potentially derived from the tumor cells and TME and that further investigation of the effects of duvelisib on TME pharmacodynamic markers is warranted.

A copy of the poster presentation will be available here.

About Duvelisib

Duvelisib is a first-in-class investigational oral, dual inhibitor of phosphoinositide 3-kinase (PI3K)-delta and PI3K-gamma, two enzymes known to help support the growth and survival of malignant B-cells and T-cells. PI3K signaling may lead to the proliferation of malignant B- and T-cells and is thought to play a role in the formation and maintenance of the supportive tumor microenvironment.1,2,3 Duvelisib was evaluated in late- and mid-stage extension trials, including DUO, a randomized, Phase 3 monotherapy study in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL),4 and DYNAMO, a single-arm, Phase 2 monotherapy study in patients with refractory indolent non-Hodgkin lymphoma (iNHL).5 Both DUO and DYNAMO achieved their primary endpoints. Verastem Oncology’s New Drug Application (NDA) requesting the full approval of duvelisib for the treatment of patients with relapsed or refractory CLL/SLL, and accelerated approval for the treatment of patients with relapsed or refractory follicular lymphoma (FL) was accepted for filing by the U.S. Food and Drug Administration (FDA), granted Priority Review and assigned a target action date of October 5, 2018. Duvelisib is also being developed by Verastem Oncology for the treatment of peripheral T-cell lymphoma (PTCL), and is being investigated in combination with other agents through investigator-sponsored studies.6 Information about duvelisib clinical trials can be found on www.clinicaltrials.gov.

On June 15, 2018 AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, reported the presentation of investigational data from a new analysis of undetectable minimal residual disease (uMRD) rates from the pivotal Phase 3 MURANO trial of venetoclax, a first-in-class oral B-cell lymphoma-2 (BCL-2) inhibitor, in combination with rituximab (VenR) in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) (Press release, AbbVie, JUN 15, 2018, View Source [SID1234527518]). Of the 121 patients who achieved uMRD (meaning less than one CLL cell in 10,000 white blood cells were detectable using a standardized test2) at the end of combination therapy (EOCT), 83 percent (n=100) maintained uMRD and were progression-free for a median of 13.8 months (range, 5.6-23.0 months) thereafter. These results will be presented in an oral session on Saturday, June 16, at 11:45 a.m. CEST during the 23rd European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress in Stockholm.1 Venetoclax is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S.

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CLL is a slow-growing form of leukemia, or blood cancer, in which too many immature lymphocytes (type of white blood cells) are found predominantly in the blood and bone marrow.3 Undetectable minimal residual disease is an objective measure defined by the presence of less than one CLL cell in 10,000 white blood cells remaining in the blood or bone marrow following treatment.2 Prospective clinical trials have suggested that achieving undetectable minimal residual disease, also known as MRD negativity (MRD-), may have a prognostic impact on response duration and survival outcomes.4

"In this analysis of MRD data in patients with chronic lymphocytic leukemia given venetoclax in combination with rituximab, high and durable undetectable MRD rates were achieved in peripheral blood at the end of combination treatment assessment regardless of the risk features," said Peter Hillmen, Ph.D., Professor of Experimental Hematology, Leeds Teaching Hospital in the UK, and lead investigator of the MURANO study. "These undetectable MRD results, along with data regarding the nearly 14-month progression-free findings in patients who maintained undetectable MRD, are an encouraging finding from the MURANO study."

"The venetoclax data being presented at EHA (Free EHA Whitepaper) adds to the growing body of evidence that supports a correlation between undetectable minimal residual disease (MRD) and improved clinical outcomes for patients with chronic lymphocytic leukemia," said Neil Gallagher, M.D., Ph.D., Head of Global Oncology Development, AbbVie. "We continue to investigate the correlation between undetectable MRD and clinical outcomes following treatment with venetoclax alone, or in novel combinations, for the potential treatment of patients with chronic lymphocytic leukemia and other blood cancers."

Design and Results of the Phase 3 Study
The international, multicenter, open-label, randomized Phase 3 MURANO study included a total of 389 patients with R/R CLL who had received at least one prior therapy. The study was designed to evaluate the efficacy (primary endpoint of investigator-assessed progression-free survival) and safety of venetoclax in combination with rituximab (194 patients; median age 64.5 years) for up to two years compared with bendamustine in combination with rituximab (195 patients; median age 66.0 years) for six months.5

Summary of EHA (Free EHA Whitepaper) Presentation
In the analysis, MRD by peripheral blood (PB) samples were serially collected (including EOCT, month 9; and every 12 weeks thereafter for up to three years5) whereas bone marrow (BM) samples were collected at the EOCT or at best response. MRD was analyzed centrally by allele-specific oligonucleotide-PCR and/or flow cytometry.1

A high PB/BM MRD concordance was seen with VenR in patients with paired samples (84 percent). Achievement of uMRD was independent of risk factors, including del(17p), IgVH mutation and TP53 mutations. Eighty-three percent of VenR patients who attained uMRD at EOCT maintained this status and were progression-free for a median of 13.8 months (range, 5.6-23.0 months) after EOCT.1

About VENCLYXTO (venetoclax)
VENCLYXTO (venetoclax), an oral B-cell lymphoma-2 (BCL-2) inhibitor, is indicated for the treatment of chronic lymphocytic leukemia (CLL) in the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B-cell receptor pathway inhibitor; and for the treatment of CLL in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor.6 It is also being evaluated for the treatment of patients with various blood cancer types.5,7,8,9,10 The BCL-2 protein prevents apoptosis (programmed cell death) of some cells, including lymphocytes, and can be overexpressed in CLL cells.5 VENCLYXTO, which is given once-daily, is designed to selectively inhibit the function of the BCL-2 protein.5

VENCLYXTO is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S. Together, the companies are committed to BCL-2 research with venetoclax, which is currently being evaluated in Phase 3 clinical trials for the treatment of relapsed/refractory CLL, along with studies in several other cancers.

Venetoclax is currently approved in the European Union, Switzerland, Argentina, Australia, Mexico, Puerto Rico, Israel, USA, and Canada. AbbVie, in collaboration with Roche and Genentech, is currently working with regulatory agencies around the world to bring this medicine to eligible patients in need.

For more information on B-cell lymphoma-2 (BCL-2), please read "Bringing Death to Cancer Cells" on www.abbvie.com.

Important VENCLYXTO (venetoclax) EU Safety Information

Contraindications
Hypersensitivity to the active substance or to any of the excipients is contraindicated. Concomitant use of strong CYP3A inhibitors at initiation and during the dose-titration phase due to increased risk for tumor lysis syndrome (TLS). Concomitant use of preparations containing St. John’s wort as VENCLYXTO efficacy may be reduced.

Special Warnings & Precautions for Use
Tumor lysis syndrome (TLS), including fatal events, has occurred in patients with previously treated CLL with high tumor burden when treated with VENCLYXTO. VENCLYXTO poses a risk for TLS in the initial 5-week dose-titration phase. Changes in electrolytes consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of VENCLYXTO and at each dose increase. Patients should be assessed for risk and should receive appropriate prophylaxis for TLS. Blood chemistries should be monitored and abnormalities managed promptly. More intensive measures (including IV hydration, frequent monitoring and hospitalization) should be employed as overall risk increases.

Neutropenia (grade 3 or 4) has been reported and complete blood counts should be monitored throughout the treatment period.

Live vaccines should not be administered during treatment or thereafter until B-cell recovery.

Drug Interactions
CYP3A inhibitors may increase VENCLYXTO plasma concentrations. At initiation and dose-titration phase: Strong CYP3A inhibitors are contraindicated due to increased risk for TLS and moderate CYP3A inhibitors should be avoided. If moderate CYP3A inhibitors must be used, physicians should refer to the SmPC for dose adjustment recommendations. At steady daily dose: If moderate or strong CYP3A inhibitors must be used, physicians should refer to the SmPC for dose adjustment recommendations.

Avoid concomitant use of P-gp and BCRP inhibitors at initiation and during the dose titration phase.
CYP3A4 inducers may decrease VENCLYXTO plasma concentrations.

Avoid coadministration with strong or moderate CYP3A inducers. These agents may decrease venetoclax plasma concentrations.

Co-administration of bile acid sequestrants with VENCLYXTO is not recommended as this may reduce the absorption of VENCLYXTO.

Adverse Reactions
The most commonly occurring adverse reactions (>=20%) of any grade were neutropenia/neutrophil count decreased, diarrhea, nausea, anemia, upper respiratory tract infection, fatigue, hyperphosphatemia, vomiting and constipation.

The most frequently occurring adverse reactions (>=2%) were pneumonia, febrile neutropenia and TLS.

Discontinuations due to adverse reactions occurred in 9.1% of patients and dosage adjustments due to adverse reactions occurred in 11.8% of patients.

Specific Populations
Patients with reduced renal function (CrCl <80 mL/min) may require more intensive prophylaxis and monitoring to reduce the risk of TLS. Safety in patients with severe renal impairment (CrCl <30 mL/min) or on dialysis has not been established, and a recommended dose for these patients has not been determined. VENCLYXTO should be administered to patients with severe renal impairment only if the benefit outweighs the risk and patients should be monitored closely for signs of toxicity due to increased risk of TLS.

VENCLYXTO may cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential to avoid pregnancy during treatment. Advise nursing women to discontinue breastfeeding during treatment.

This is not a complete summary of all safety information. See VENCLYXTO full summary of product characteristics (SmPC) at www.ema.europa.eu. Globally, prescribing information varies; refer to the individual country product label for complete information.

On June 15, 2018 Molecular Partners AG (SIX: MOLN), a clinical-stage biopharmaceutical company developing a new class of drugs known as DARPin therapies*, reported that the company will present updated preliminary results from the ongoing Phase 2 study of its lead proprietary oncology drug MP0250 at the 23th Annual Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Stockholm (Press release, Molecular Partners, JUN 15, 2018, View Source [SID1234527337]).

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The ongoing, open label Phase 2 clinical study[1] is examining the safety and efficacy of MP0250 in combination with bortezomib (Velcade) and dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM) who have failed at least two lines of standard therapies, including bortezomib and an IMiD. The study is being performed at nine centers in Germany, Poland and Italy.

In the first of two cohorts, patients received MP0250 at 8mg/kg every 3 weeks (corresponding to 66% of the recommended dose) in combination with standard doses of bortezomib and dexamethasone.

All patients had been pretreated with at least two lines of therapy, including an IMiD and bortezomib. 50% of those patients were considered proteasome refractory. At the data cutoff on May 21, 2018, five of eight evaluable patients achieved an objective response (4 patients with PR/partial response; 1 patient with VGPR/very good partial response). Responses were durable, with median time on treatment for responding patients of 22.5 weeks and the longest response still ongoing at 41 weeks.

Main adverse events were consistent with the known side effect profile of VEGF-targeting agents and of Velcade, respectively: thrombocytopenia (4 out of 8 patients), hypertension (3 out of 8 patients) and upper respiratory infection (3 out of 8 patients).

"We are very encouraged by the initial activity and the safety profile of MP0250 in combination with bortezomib and dexamethasone, even at the low dose of MP0250. We have started the treatment of the first two patients with the higher dose of 12 mg/kg which may be even more effective," said Andreas Harstrick, Chief Medical Officer of Molecular Partners.

Patrick Amstutz, CEO of Molecular Partners added: "These results further substantiate our development plans in multiple myeloma as well as the launch of our additional phase 1b/2 study of MP0250 in combination with osimertinib in EGFR-mutated NSCLC."

The ongoing Phase study of MP0250 in multiple myeloma is currently recruiting patients at the higher dose of 12mg/kg q3weeks. Overall, a total of at least 40 patients are planned to be treated. Additional safety and efficacy data are expected by the end of 2018.

An additional phase 1b/2 study will evaluate MP0250 in combination with osimertinib in patients with EGFR-mutated NSCLC pretreated with osimertinib (Tagrisso). The study is conducted in the US and is open for patient enrollment[2].

Full details on the Molecular Partners’ poster presentation today, from 5.30 to 7.00pm CET, at EHA (Free EHA Whitepaper) Stockholm can be found on the conference website. Following its presentation at EHA (Free EHA Whitepaper), the poster will also be available one the Molecular Partners website.

[1] ClinicalTrials.gov identifier NCT03136653

[2] ClinicalTrials.gov identifier NCT03418532

*DARPin is a registered trademark owned by Molecular Partners AG.

Financial Calendar
August 30, 2018 – Publication of 2018 Half-year Results
November 01, 2018 – Q3 2018 Management Statement
View Source

About MP0250
MP0250 is a multi-DARPin candidate targeting simultaneously VEGF and HGF, two prominent escape pathways, and has the potential to reverse resistance that has built to standard of care cancer therapies. Increases in VEGF and HGF are associated with disease progression in multiple myeloma and have been linked to poor prognosis. They are known to be able to stimulate neovascularization, bone destruction, and myeloma proliferation, migration, and adhesion in the bone marrow.

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 are potent, specific, safe and very versatile. They can engage in more than 5 targets at once, 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 good safety profile, low immunogenicity and long half-life in the bloodstream and the eye, DARPin therapies 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. The most advanced global product candidate is abicipar, a molecule currently in Phase 3, in partnership with Allergan.
Several DARPin molecules for various ophthalmic indications are also in development. The most advanced systemic DARPin molecule, MP0250, is in Phase 1 clinical development for the treatment of solid tumors and in Phase 2 development for hematological tumors. In addition, Molecular Partners intends to further evaluate MP0250 for solid tumors in a phase 1b/2 trial for EGFR-mutated NSCLC. MP0274, the second-most advanced DARPin drug candidate in oncology, has broad anti-HER activity; it inhibits HER1, HER2 and HER3-mediated downstream signaling via Her2, leading to induction of apoptosis. MP0274 has moved into Phase 1. Molecular Partners is also advancing a growing preclinical pipeline that features several immuno-oncological development programs. DARPin is a registered trademark owned by Molecular Partners AG.

On June 15, 2018 MorphoSys AG (FSE: MOR; Prime Standard Segment; TecDAX; Nasdaq: MOR) reported the presentation of clinical data from the exploratory phase 2 COSMOS trial (Press release, MorphoSys, JUN 15, 2018, View Source [SID1234527338]). The trial evaluates MorphoSys’s proprietary hemato-oncological drug candidate MOR208 in combination with the cancer drug idelalisib in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), who progressed on or were intolerant to ibrutinib therapy. Data will be presented in a poster presentation on June 15, 2018, at the 23rd European Hematology Association (EHA) (Free EHA Whitepaper) Annual Meeting in Stockholm/Sweden. MOR208 is an investigational Fc-enhanced humanized monoclonal antibody directed against CD19 in clinical development for the treatment of B cell malignancies.

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"Patients with CLL after failure of ibrutinib therapy are in need of more therapeutic options. We are encouraged by the initial and, for the most part, still ongoing responses observed in this heavily pretreated patient population in our exploratory trial with MOR208 plus idelalisib," commented Dr. Malte Peters, Chief Development Officer of MorphoSys AG. "Overall, this shows the potential medical application of MOR208 in additional B cell malignancies. The data shows that MOR208 may be combined with other cancer drugs used in hematological malignancies, including PI3K inhibitors. We look forward to the upcoming results from the second cohort of MOR208 plus venetoclax of our ongoing COSMOS study which we expect later this year."

COSMOS is a phase 2, two-cohort, open-label, multicenter study evaluating the preliminary safety and efficacy of MOR208 combined with idelalisib (cohort A) or venetoclax (cohort B) in patients with r/r CLL/SLL previously treated with Bruton’s Tyrosine Kinase inhibitor (BTKi) ibrutinib.

Data presented at EHA (Free EHA Whitepaper) 2018 comprise preliminary safety and efficacy data on all 11 patients enrolled into cohort A (cut-off date: January 29, 2018). Patients enrolled had received a median of five prior treatment lines (range: 2-9 prior lines). Nine out of the eleven patients enrolled (82%) had discontinued prior ibrutinib treatment due to progressive disease and two patients (18%) due to toxicity.

The most common treatment-emerging adverse events (TEAEs) of grade 3 or higher were hematologic, with neutropenia observed for four patients (36%) and anemia for three patients (27%) being the most common reported events. Ten treatment-emergent serious adverse events (SAEs) were reported in five patients (45%) none of them being fatal. All except one of the six treatment-related SAEs reported for three patients (27%) were suspected to idelalisib.

According to the preliminary efficacy analysis conducted by the investigators, overall response rate (ORR) was 82%, including one complete response (CR, 9%) confirmed by bone marrow biopsy and eight partial responses (PR, 73%). In addition, two patients (18%) showed stable disease. The median observation time was 4.2 months. At the time of data-cut off, six patients continued treatment. One patient with a very good partial response according to response criteria was taken off the study to receive stem cell transplantation. Two previously responding patients had to discontinue the study due to progressive disease. Two patients (one PR, one stable disease SD) discontinued due to adverse events.

Details about the poster presentation on MOR208 at EHA (Free EHA Whitepaper) 2018:

Abstract Code: PF350

Two-cohort, phase II study in R/R CLL (COSMOS): First preliminary safety and efficacy results of MOR208 treatment in combination with idelalisib in patients who discontinued prior ibrutinib therapy

The poster will be presented during the session "Chronic lymphocytic leukemia and related disorders – Clinical" on Friday, June 15, 2018 5:30-7:00 pm CEST (11:30am-1:00pm EDT), in the poster area at the Stockholmsmässan in Stockholm.

In addition, the corresponding abstract will be on display on the E-poster screens at the conference from Friday, June 15, 2018, 9:30 am CEST (3:30 am EDT) to Sunday, June 17, 2018, 1:00 pm CEST (7:00 am EDT).

Additional information can be found at www.ehaweb.org, including the abstract.

About CD19 and MOR208
CD19 is broadly and homogeneously expressed across different B cell malignancies including DLBCL and CLL. CD19 has been reported to enhance B cell receptor (BCR) signaling, which is assumed important for B cell survival, making CD19 a potential target in B cell malignancies.
MOR208 (previously Xmab(R)5574) is an investigational humanized Fc-engineered monoclonal antibody directed against CD19. Fc-modification of MOR208 is intended to lead to a significant potentiation of antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), thus aiming to improve a key mechanism of tumor cell killing. MOR208 has been observed in preclinical models to induce direct apoptosis by binding to CD19, which is assumed to be a crucial component for B cell receptor (BCR) signaling.
MorphoSys is clinically investigating MOR208 as a therapeutic option in B cell malignancies in a number of ongoing combination trials. An open-label phase 2 combination trial (L-MIND study) is investigating the safety and efficacy of MOR208 in combination with lenalidomide in patients with relapsed/refractory DLBCL who are not eligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT). Based on interim data from L-MIND, in October 2017 the FDA granted Breakthrough Therapy Designation for MOR208 plus lenalidomide in this patient population. The pivotal phase 2/3 B-MIND study is designed to investigate MOR208 in combination with the chemotherapeutic agent bendamustine in patients with relapsed/refractory DLBCL who are not eligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) in comparison to the combination of the anti-CD20 antibody rituximab plus bendamustine. In addition, MOR208 is currently being investigated in patients with relapsed/refractory CLL/SLL after discontinuation of a prior Bruton tyrosine kinase (BTK) inhibitor therapy (e.g. ibrutinib) in combination with idelalisib or venetoclax.