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 16, 2018 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported that positive results from the pivotal QuANTUM-R phase 3 study of single agent quizartinib were presented today as a late-breaking oral presentation in the plenary program at the 23rd Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Stockholm, Sweden (Press release, Daiichi Sankyo, JUN 16, 2018, View Source [SID1234527368]).

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QuANTUM-R study results showed that patients with relapsed/refractory acute myeloid leukemia (AML) with FLT3-ITD mutations who received single agent quizartinib had a 24 percent reduction in the risk of death compared to patients who received salvage chemotherapy (hazard ratio [HR] = 0.76, P=0.0177, 95 percent CI 0.58-0.98). The median overall survival was 6.2 months (two-sided 95 percent CI 5.3-7.2) for patients treated with quizartinib and 4.7 months (two-sided 95 percent CI 4.0-5.5) for patients treated with salvage chemotherapy. The estimated survival probability at 1 year was 27 percent for patients who received quizartinib and 20 percent for patients who received salvage chemotherapy.

"FLT3-ITD mutated AML represents a high unmet need entity as patients with this aggressive form of the disease have an overall dismal prognosis as evidenced by low response rates to current available therapies, high risk of relapse and a shorter overall survival than those without this mutation," said Jorge E. Cortes, MD, Deputy Chair of the Department of Leukemia in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center. "In relapsed/refractory AML with FLT3-ITD mutations, these findings represent the first reported clinical data demonstrating that a single agent can significantly improve overall survival, suggesting that quizartinib could potentially help these patients live longer. Additionally, in the study, a higher proportion of patients received a stem cell transplant in the quizartinib arm compared to the chemotherapy arm."

Secondary and key exploratory analyses including composite complete remission (CRc) are consistent and supportive of the primary analysis.

"Results of this study are consistent with previous phase 2 studies of quizartinib and demonstrate the value of targeting the FLT3-ITD driver mutation. We are encouraged by these data, which will form the basis of regulatory submissions to health authorities. If approved, quizartinib has the potential to redefine the treatment of patients with relapsed/refractory AML with FLT3-ITD mutations," said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo. "These results also build on our understanding of this difficult-to-treat type of AML as we continue to explore the potential role of quizartinib in combination with chemotherapy and other novel mechanisms to further advance the treatment of patients with relapsed/refractory and newly-diagnosed AML with FLT3-ITD mutations."

The safety profile observed in QuANTUM-R appears consistent with that observed at similar doses in the quizartinib clinical development program. The median treatment duration with quizartinib was 4 cycles of 28 days (97 days; range: 1-1,182 days) versus 1 cycle (range: 1-2) in the salvage chemotherapy arm. The median relative dose intensity for quizartinib was 89 percent. Incidence of treatment-emergent adverse events were comparable between patients who received single agent quizartinib (n=241) and those who received salvage chemotherapy (n=94). The most common adverse events (>30 percent, any Grade) in patients treated with quizartinib versus chemotherapy, respectively, included nausea (48 vs 42 percent), thrombocytopenia (39 vs 34 percent), fatigue (39 vs 29 percent), musculoskeletal pain (37 vs 28 percent), pyrexia (38 vs 45 percent), anemia (37 vs 32 percent), neutropenia (34 vs 26 percent), febrile neutropenia (34 vs 28 percent), vomiting (33 vs 21 percent) and hypokalemia (32 vs 28 percent). The most common adverse events Grade ≥3 (>10 percent of patients) were thrombocytopenia (35 vs 34 percent), anemia (30 vs 29 percent), neutropenia (32 vs 25 percent), febrile neutropenia (31 vs 21 percent), leukopenia (17 vs 16 percent), sepsis/septic shock (16 vs 18 percent), hypokalemia (12 vs 9 percent) and pneumonia (12 vs 9 percent). QTcF >500 msec occurred in 8 patients (3.3 percent) and 2 out of 241 patients discontinued quizartinib due to QTcF prolongation. There were no reported events of Grade 4 QTcF prolongation (Torsade de Pointe, sudden death or cardiac arrest) in the quizartinib arm.

About the QuANTUM-R Study

QuANTUM-R is a pivotal, global, phase 3, open-label randomized study that enrolled 367 patients with FLT3-ITD-mutated AML who were refractory to or in relapse following (with duration of remission of six months or less) standard first-line AML therapy with or without hematopoietic stem cell transplantation (HSCT). Patients were randomized in a 2:1 ratio to receive either single agent oral quizartinib (60 mg, with 30 mg lead-in) or salvage chemotherapy. The primary objective of the study was to determine whether single agent quizartinib prolonged overall survival compared to salvage chemotherapy.

About Quizartinib

Quizartinib, the lead investigational agent in the AML Franchise of the Daiichi Sankyo Cancer Enterprise, is an oral selective FLT3 inhibitor currently in global phase 3 development for relapsed/refractory (QuANTUM-R) and newly-diagnosed (QuANTUM-First) AML with FLT3-ITD mutations, and phase 2 development for relapsed/refractory AML with FLT3-ITD mutations in Japan.

Quizartinib has been granted Fast Track designation by the U.S. Food and Drug Administration (FDA) for the treatment of relapsed/refractory AML. Quizartinib also has been granted Orphan Drug designation by the FDA and European Medicines Agency (EMA) for the treatment of AML. Quizartinib is an investigational agent that has not been approved for any indication in any country. Safety and efficacy have not been established.

About Acute Myeloid Leukemia with FLT3-ITD Mutations

AML is an aggressive blood and bone marrow cancer that causes uncontrolled growth and accumulation of malignant white blood cells that fail to function normally and interfere with the production of normal blood cells.1 The five-year survival rate of AML reported from 2005 to 2011 was approximately 26 percent, which was the lowest of all leukemias.1

FLT3 gene mutations are one of the most common genetic abnormalities in AML.2 The FLT3-ITD mutation is the most common FLT3 mutation, affecting approximately one in four patients with AML.3,4,5,6 Patients with FLT3-ITD-mutated AML have a worse overall prognosis, including an increased incidence of relapse, an increased risk of death following relapseand a higher likelihood of relapse following HSCT as compared to those without this mutation.7,8

On June 15, 2018 MEI Pharma, Inc. (NASDAQ: MEIP) a pharmaceutical company focused on leveraging its extensive development and oncology expertise to identify and advance new therapies for cancer, reported that results from a Phase 1b study of ME-401 in patients with relapsed or refractory follicular lymphoma (FL), chronic lymphocytic lymphoma (CLL) and small lymphocytic lymphoma (SLL) are being presented during a poster presentation today, Friday, June 15, 2018 at the 23rd Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Stockholm, Sweden (Press release, MEI Pharma, JUN 15, 2018, View Source [SID1234527351]). Complete data results on the Phase 1b study were previously announced at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago in June 2018.

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"The data demonstrates that ME-401 achieved a 90% response rate across all patient groups treated and was generally well tolerated with no dose-limiting toxicities identified at any dose level," said Daniel P. Gold, Ph.D., president and chief executive officer of MEI Pharma. "The full data from our ME-401 study is very encouraging and we expect to initiate a registration study for ME-401 this year for the treatment of adults with relapsed or refractory FL."

ME-401 is being evaluated in a Phase 1b dose escalation study in patients with relapsed or refractory FL, CLL and SLL. As of May 14, 2018, 46 patients were enrolled: 31 patients received monotherapy and 30 were evaluable for efficacy (12 patients at 60 mg, 12 patients at 120 mg and six patients at 180 mg). Based on the data, the Company determined that no further dose escalation was required. An expansion cohort of up to 30 patients with FL, CLL and SLL was added to further evaluate the safety and efficacy of ME-401 as a single agent at the 60 mg dose. An additional 15 patients are enrolled in the study arm evaluating ME-401 (60 mg) in combination with rituximab (marketed as Rituxan) in patients with various B cell malignancies.

The ME-401 EHA (Free EHA Whitepaper) 2018 poster can be accessed on the MEI Pharma website.

On June 15, 2018 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported data from the final analysis of the CLL11 study evaluating Gazyva/Gazyvaro (obinutuzumab)-based treatment in previously untreated chronic lymphocytic leukaemia (CLL) which will be presented during the Presidential Symposium at the 23rd European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress, 14 – 17 June, in Stockholm (Press release, Hoffmann-La Roche, JUN 15, 2018, View Source [SID1234527335]). After a follow-up of nearly five years, final results showed clinically meaningful improvements with Gazyva/Gazyvaro plus chlorambucil across multiple endpoints, including progression-free survival (PFS) and overall survival (OS), when compared head-to-head with MabThera/Rituxan (rituximab) plus chlorambucil. Gazyva/Gazyvaro-based treatment reduced the risk of death by 24% compared to MabThera/Rituxan-based treatment (median OS not reached vs. 73.1 months, HR= 0.76; 95% CI 0.60-0.97; p<0.0245). These new data add to the growing body of evidence for the OS benefit with Gazyva/Gazyvaro in first-line CLL after the previously reported OS benefit with Gazyva/Gazyvaro combined with chlorambucil versus chlorambucil alone.

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"We are very pleased that the majority of patients treated with Gazyva/Gazyvaro are still alive after nearly five years of follow-up in the CLL11 study," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "This meaningful survival benefit compared to MabThera/Rituxan-based therapy reinforces that Gazyva/Gazyvaro-based therapy is an important option for people with previously untreated CLL."

After a median observation time of nearly five years (59.4 months) this final analysis of the CLL11 study demonstrated:

A reduction in the risk of disease progression or death of 51% for patients treated with Gazyva/Gazyvaro plus chlorambucil versus those treated with MabThera/Rituxan plus chlorambucil (median PFS 28.9 vs. 15.7 months, HR= 0.49; 95% CI 0.41-0.58; p<0.0001).
A clinically meaningful improvement in OS for patients receiving Gazyva/Gazyvaro plus chlorambucil compared to MabThera/Rituxan plus chlorambucil. At the time of final analysis the median OS in the Gazyva/Gazyvaro plus chlorambucil arm was not yet reached which means that more than half of these patients were still alive after nearly five years. A 24% reduction in the risk of death was observed with Gazyva/Gazyvaro plus chlorambucil treatment (median OS not reached vs. 73.1 months, HR= 0.76; 95% CI 0.60-0.97; p<0.0245).
A prolonged time to initiation of the next therapy (time to new treatment; TTNT) with Gazyva/Gazyvaro plus chlorambucil (median 56.4 vs. 34.9 months, Gazyva/Gazyvaro plus chlorambucil vs. MabThera/Rituxan plus chlorambucil, HR= 0.58; 95% CI 0.46-0.73; p<0.0001).
Patients treated with Gazyva/Gazyvaro plus chlorambucil achieved a higher rate of minimal residual disease (MRD) negativity versus those treated with MabThera/Rituxan plus chlorambucil (24% vs. 2% of patients MRD-negative, Gazyva/Gazyvaro plus chlorambucil vs. MabThera/Rituxan plus chlorambucil). Being MRD negative means no cancer can be detected in the blood and or bone marrow using a sensitive test.
No new or unexpected safety concerns for the combination of Gazyva/Gazyvaro plus chlorambucil.

Gazyva/Gazyvaro is currently approved in more than 90 countries in combination with chlorambucil, for people with previously untreated CLL, based on previously reported data from the CLL11 study.1

About the CLL11 study
CLL11 is a phase III, multicenter, open-label, randomised three-arm study to investigate the safety and efficacy profile of Gazyva/Gazyvaro plus chlorambucil compared to MabThera/Rituxan plus chlorambucil or chlorambucil alone in nearly 800 people with previously untreated CLL and comorbidities. The primary endpoint of the study is PFS with secondary endpoints including response rate, molecular remission rate, OS, TTNT and safety profile. In terms of analysis, the study was divided into three stages:

Stage 1a compared the addition of Gazyva/Gazyvaro to chlorambucil vs. chlorambucil alone
Stage 1b compared the addition of MabThera/Rituxan to chlorambucil vs. chlorambucil alone
Stage 2 compared Gazyva/Gazyvaro plus chlorambucil to MabThera/Rituxan plus chlorambucil
About Gazyva/Gazyvaro (obinutuzumab)
Gazyva/Gazyvaro is an engineered monoclonal antibody designed to attach to CD20, a protein expressed on certain B cells, but not on stem cells or plasma cells. Gazyva/Gazyvaro is designed to attack and destroy targeted B-cells both directly and together with the body’s immune system. Gazyva is marketed as Gazyvaro in the EU and Switzerland.

Gazyva/Gazyvaro is currently approved in more than 90 countries in combination with chlorambucil for people with previously untreated chronic lymphocytic leukaemia (CLL), in more than 80 countries in combination with bendamustine for people with certain types of previously treated follicular lymphoma and in more than 60 countries in combination with chemotherapy for previously untreated, follicular lymphoma.

Additional combination studies investigating Gazyva/Gazyvaro with other approved or investigational medicines, including cancer immunotherapies and small molecule inhibitors, are underway across a range of blood cancers.

About Chronic Lymphocytic Leukaemia
Chronic lymphocytic leukaemia (CLL) is the most common type of leukaemia in the Western world. 2 CLL mainly affects men and the median age at diagnosis is about 70 years.3 Worldwide, the incidence of all leukaemias is estimated to be over 350,000 and CLL is estimated to affect around one-third of all people newly diagnosed with leukaemia.4

About Roche in haematology