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Novartis pivotal CTL019 6-month follow-up data show durable remission rates in children, young adults with r/r B-cell ALL

On June 23, 2017 Novartis reported updated results from the ELIANA clinical trial demonstrating CTL019 (tisagenlecleucel) remission rates are maintained at six months in relapsed/refractory (r/r) pediatric and young adult patients with B-cell acute lymphoblastic leukemia (ALL) (Press release, Novartis, JUN 23, 2017, View Source [SID1234519672]). These data from this pivotal trial of CTL019 show that 83% (52 of 63; 95% confidence interval [CI]: 71%-91%) of patients achieved complete remission (CR) or CR with incomplete blood count recovery within three months of infusion. No minimal residual disease (MRD) was detected among responding patients[1]. MRD, which measures the elimination of residual disease in the blood and bone marrow at the molecular level following treatment, is important because it may be an indicator of potential relapse[2]. Results from this study of CTL019 – an investigational chimeric antigen receptor T cell (CAR-T) therapy – will be presented at the European Hematology Association (EHA) (Free EHA Whitepaper) Annual Meeting (Abstract #S476; Saturday, June 24, 4:00 PM CEST).

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The ELIANA study also showed that the relapse-free probability was 75% (95% CI, 57%-87%; median duration of response not reached) at six months and 64% (95% CI, 42%-79%) at 12 months among responders. In addition, the probability of survival was 89% (95% CI, 77%-94%) at six months and 79% (95% CI, 63%-89%) at 12 months. The median time from infusion to data cutoff was 8.8 months[1].

"The updated CTL019 ELIANA data illustrating early observed response rates that have held steady over six months’ time are exciting findings. Durability is an important measure for children and young adults with relapsed or refractory B-cell ALL, and we are truly encouraged by the results of this study," said lead investigator Stephan Grupp, MD, PhD, the Yetta Deitch Novotny Professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania (Penn), and Director of the Cancer Immunotherapy Frontier Program at the Children’s Hospital of Philadelphia (CHOP).

Forty-seven percent of patients in ELIANA experienced grade 3 or 4 cytokine release syndrome (CRS), a known complication of the investigational 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. There were no deaths due to refractory CRS and no incidents of cerebral edema were reported. Fifteen percent of patients experienced grade 3 neurologic events, with no grade 4 events seen[1].

The ELIANA trial enrolled 88 patients. Of the 88, 16 patients discontinued before infusion and the majority (nine patients) did so due to rapid progression of their disease or deterioration in their clinical status. This reflects the acute and progressive nature of this disease. Of the 16 patients who weren’t infused, seven were a result of insufficiently formulated CAR-T cell product. Additionally, five infused patients had not reached three-month follow-up and four patients were pending infusion at the time of data cutoff.

"These positive, updated ELIANA data help us better understand the ability for CTL019 to maintain durable responses in r/r ALL," said Vas Narasimhan, MD, Global Head of Drug Development and Chief Medical Officer, Novartis. "The results, including relapse-free survival findings at six and 12 months, reaffirm our confidence in CTL019 to potentially become an effective treatment for pediatric and young adult patients with r/r ALL in need of more options."

ELIANA (NCT02435849) is the first pediatric global CAR-T cell therapy registration trial, with study enrollment having occurred across 25 centers in the US, Canada, EU, Australia and Japan. The single-arm, open-label, multicenter Phase II study included patients aged three to 23 years who were primary refractory, refractory to chemotherapy after their first relapse, relapsed after second line therapy or ineligible for an allogeneic stem cell transplant (SCT). Patients in the trial received a median of three prior lines of therapy and 59% of patients had a prior SCT.

CTL019 was first developed by Penn and uses the 4-1BB costimulatory domain to enhance cellular responses. In 2012, Novartis and Penn entered into a global collaboration to further research, develop and then commercialize CAR-T cell therapies, including CTL019, for the investigational treatment of cancers.

Additional CTL019 data at EHA (Free EHA Whitepaper)
A pooled data analysis from two multicenter trials of CTL019 in pediatric and young adult patients with r/r B-cell ALL, including ELIANA and ENSIGN (NCT02228096), will also be highlighted in a presentation at the meeting. This research is aimed to identify any new safety issues with CTL019 as a result of its use in multicenter trials, which included 25 sites across 11 countries. Study authors concluded that there were no new safety issues and that CRS and neurologic events were effectively managed. Prolonged follow-up will be required to determine the long-term safety of B-cell aplasia (Abstract #P517; Saturday, June 24, 5:30 PM CEST).

An oral presentation will feature pooled analyses from two multicenter trials of CTL019 in pediatric and young adult patients with r/r B-cell ALL, including ELIANA and ENSIGN, observing response analysis and impact of intrinsic/extrinsic and manufacturing factors on CTL019 expansion and persistence (Abstract #S477; Saturday, June 24, 4:15 PM CEST).

Novartis will also present an encore of results from its global, pivotal multi-center Phase II JULIET study (NCT02445248; Abstract #LB2604, June 25, 12:00 PM CEST), evaluating CTL019 in adults with r/r diffuse large-b-cell lymphoma (DLBCL).

CTL019 was granted Priority Review from the FDA earlier this year in the treatment of r/r pediatric and young adult patients with B-cell ALL, and Novartis plans to file with the European Medicines Agency (EMA) later in 2017. The investigational therapy received PRIME (PRIority MEdicines) designation from the EMA in 2016. The FDA also granted Breakthrough Therapy designation to CTL019 for the treatment of adult patients with r/r DLBCL, whose disease has progressed on or after two or more prior therapies.

About CTL019 Manufacturing
Novartis leukapheresis process using cryopreservation allowed for manufacturing and treatment of patients from around the world. Cryopreserved leukapheresis gives physicians the flexibility to schedule apheresis at a time that is in the best interest of their patients. Novartis commercial manufacturing for CTL019 continues to build on its experience in its Morris Plains, New Jersey facility, which has already manufactured CTL019 for hundreds of patients in global clinical trials. Novartis believes that experience is important in cell therapy manufacturing, and the experience gained at the Morris Plains, New Jersey facility will be a foundation for commercial manufacturing of CAR-T therapies. Novartis has made and continues to make investments in manufacturing.

About CAR-T and CTL019
CAR-T is different from typical small molecule or biologic therapies because it is manufactured for each individual patient using their own cells. During the treatment process, T cells are drawn from a patient’s blood and reprogrammed in the laboratory to create T cells that are genetically coded to hunt the patient’s cancer cells and other B-cells expressing a particular antigen. In March 2017, Novartis announced that the FDA granted Priority Review for the company’s Biologics License Application for CTL019 in the treatment of r/r pediatric and young adult patients with B-cell ALL.

Because CTL019 is an investigational therapy, the safety and efficacy profile has not yet been established. Access to investigational therapies is available only through carefully controlled and monitored clinical trials. These trials are designed to better understand the potential benefits and risks of the therapy. Because of the uncertainty of clinical trials, there is no guarantee that CTL019 will ever be commercially available anywhere in the world.

About ALL
Acute lymphoblastic leukemia makes up approximately 25% of cancer diagnoses among children under 15 years old and is the most common childhood cancer in the US[3]. Patients with r/r ALL have limited treatment options, and the chance of survival for children with the disease who relapse or fail to attain remission is between 16% to 30.1%[4]

Novartis Kisqali® (ribociclib) receives positive CHMP opinion as first-line treatment for HR+/HER2- locally advanced or metastatic breast cancer in combination with any aromatase inhibitor

On June 23, 2017 Novartis reported the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending approval of Kisqali (ribociclib) in combination with an aromatase inhibitor for treatment of postmenopausal women with hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) locally advanced or metastatic breast cancer as initial endocrine-based therapy (Press release, Novartis, JUN 23, 2017, View Source [SID1234519671]). The CHMP recommendation of combining Kisqali with any aromatase inhibitor means that, if approved, oncologists could prescribe Kisqali with letrozole, anastrozole or exemestane, giving them the discretion to select the therapy they believe is most appropriate for each individual patient.

"This positive CHMP opinion brings us one step closer to improving the lives of women diagnosed with advanced or metastatic breast cancer throughout Europe," said Bruno Strigini, CEO, Novartis Oncology. "There is currently no cure for advanced breast cancer, and approximately 30 percent of those affected by early-stage breast cancer will go on to develop advanced disease. We look forward to working with European health authorities to make Kisqali available to those who may benefit from it as quickly as possible."

The positive CHMP opinion is based on superior efficacy and demonstrated safety of Kisqali plus letrozole versus letrozole alone in the pivotal Phase III MONALEESA-2 trial. The trial, which globally enrolled 668 postmenopausal women with HR+/HER2- advanced or metastatic breast cancer who received no prior systemic therapy for their advanced breast cancer, showed that Kisqali plus the aromatase inhibitor letrozole reduced the risk of progression or death by 44% over letrozole alone at interim analysis[1]. Most adverse events in the MONALEESA-2 trial were mild to moderate in severity, identified early through routine monitoring, and generally managed through dose interruption and/or reduction[1].

A subsequent, pre-planned analysis of overall survival with an additional 11 months of follow-up demonstrated a median PFS of 25.3 months for Kisqali plus letrozole and 16.0 months for letrozole alone (HR=0.568 (95% CI: 0.457-0.704; p<0.0001))[2]. More than half of women with measurable disease taking Kisqali plus letrozole saw their tumor size shrink by at least 30% (overall response rate (ORR) in patients with measurable disease = 55% vs 39%, p=0.00025)[2],[4]. Follow-up to measure overall survival is ongoing as data remain immature[4].

The European Commission will review the CHMP recommendation and usually delivers its final decision within two months. The decision will be applicable to all 28 European Union member states plus Iceland, Norway and Liechtenstein. Additional regulatory filings are underway with other health authorities worldwide.

In March 2017, Kisqali was approved by the US Food and Drug Administration (FDA) in combination with an aromatase inhibitor as initial endocrine-based therapy for treatment of postmenopausal women with HR+/HER2- advanced or metastatic breast cancer. Kisqali can be taken with or without food as a once-daily oral dose of 600 mg (three 200 mg film-coated tablets) for three weeks, followed by one week off treatment. Kisqali is taken in combination with four weeks of any aromatase inhibitor.

Globally, an estimated 250,000 women will be diagnosed with advanced breast cancer each year[3]. Up to one-third of patients with early-stage breast cancer will subsequently develop metastatic disease, for which there is currently no cure[5],[6].

About Kisqali (ribociclib)
Kisqali (ribociclib) is a selective cyclin-dependent kinase inhibitor, a class of drugs that help slow the progression of cancer by inhibiting two proteins called cyclin-dependent kinase 4 and 6 (CDK4/6). These proteins, when over-activated, can enable cancer cells to grow and divide too quickly. Targeting CDK4/6 with enhanced precision may play a role in ensuring that cancer cells do not continue to replicate uncontrollably.

Kisqali was developed by the Novartis Institutes for BioMedical Research (NIBR) under a research collaboration with Astex Pharmaceuticals. In the European Union, Kisqali is an investigational agent and has not been approved.

About the Kisqali Clinical Trial Program
Novartis is continuing to assess Kisqali through the robust MONALEESA clinical trial program, which includes two additional Phase III trials, MONALEESA-3 and MONALEESA-7 that are evaluating Kisqali in combination with multiple endocrine therapy partners across a broad range of patients, including premenopausal women. MONALEESA-3 is evaluating Kisqali in combination with fulvestrant compared to fulvestrant alone in postmenopausal women with HR+/HER2- advanced breast cancer who have received no or a maximum of one prior endocrine therapy. MONALEESA-7 is investigating Kisqali in combination with endocrine therapy and goserelin compared to endocrine therapy and goserelin alone in premenopausal women with HR+/HER2- advanced breast cancer who have not previously received endocrine therapy. These trials are fully enrolled.

Novartis is initiating two multi-center, randomized, double-blind Phase III clinical trials, EarLEE-1 and EarLEE-2, to evaluate the safety and efficacy of Kisqali with endocrine therapy as adjuvant therapy in pre- and postmenopausal women who have not previously received treatment with CDK4/6 or aromatase inhibitors. EarLEE-1 will assess Kisqali with adjuvant endocrine therapy compared to adjuvant endocrine therapy alone in women with HR+/HER2- high-risk early breast cancer. EarLEE-2 will investigate Kisqali with adjuvant endocrine therapy compared to adjuvant endocrine therapy alone in women with HR+/HER2- intermediate-risk early breast cancer.

The CompLEEment study is evaluating the safety and efficacy of Kisqali plus letrozole in men and pre- or postmenopausal women with HR+/HER2- advanced breast cancer with no prior hormonal therapy for advanced disease. The open-label, multicenter, Phase IIIb CompLEEment-1 trial is currently enrolling participants.

About Novartis in Advanced Breast Cancer
For more than 25 years, Novartis has been at the forefront of driving scientific advancements for breast cancer patients and improving clinical practice in collaboration with the global community. With one of the most diverse breast cancer pipelines and the largest number of breast cancer compounds in development, Novartis leads the industry in discovery of new therapies and combinations, especially in HR+ advanced breast cancer, the most common form of the disease.

Kisqali (ribociclib) Important Safety Information FROM THE US PRESCRIBING INFORMATION
KISQALI (ribociclib) is a prescription medicine used in combination with an aromatase inhibitor as the first hormonal-based therapy to treat women who have gone through menopause with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. It is not known if KISQALI is safe and effective in children. KISQALI can cause a heart problem known as QT prolongation. This condition can cause an abnormal heartbeat and may lead to death. Patients should tell their health care provider right away if they have a change in their heartbeat (a fast or irregular heartbeat), or if they feel dizzy or faint. KISQALI can cause serious liver problems. Patients should tell their health care provider right away if they get any of the following signs and symptoms of liver problems: yellowing of the skin or the whites of the eyes (jaundice), dark or brown (tea-colored) urine, feeling very tired, loss of appetite, pain on the upper right side of the stomach area (abdomen), and bleeding or bruising more easily than normal. Low white blood cell counts are very common when taking KISQALI and may result in infections that may be severe. Patients should tell their health care provider right away if they have signs and symptoms of low white blood cell counts or infections such as fever and chills. Before taking KISQALI, patients should tell their health care provider if they are pregnant, or plan to become pregnant as KISQALI can harm an unborn baby. Females who are able to become pregnant and who take KISQALI should use effective birth control during treatment and for at least 3 weeks after the last dose of KISQALI. Do not breastfeed during treatment with KISQALI and for at least 3 weeks after the last dose of KISQALI. Patients should tell their health care provider about all of the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements since they may interact with KISQALI. Patients should avoid pomegranate or pomegranate juice, and grapefruit or grapefruit juice while taking KISQALI. The most common side effects (incidence >=20%) of KISQALI when used with letrozole include white blood cell count decreases, nausea, tiredness, diarrhea, hair thinning or hair loss, vomiting, constipation, headache, and back pain. The most common grade 3/4 side effects in the KISQALI + letrozole arm (incidence >2%) were low neutrophils, low leukocytes, abnormal liver function tests, low lymphocytes, and vomiting. Abnormalities were observed in hematology and clinical chemistry laboratory tests.

Please see full Prescribing Information for KISQALI, available at www.kisqali.com (link is external).

Presentation confirms Venclexta/Venclyxto monotherapy benefit in certain patients with high-risk chronic lymphocytic leukaemia and its potential in other hard-to-treat blood cancers

On June 23, 2017 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported new data from multiple studies of Venclexta/Venclyxto (venetoclax), presented at the 22nd European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress, 22-25 June, in Madrid (Press release, Hoffmann-La Roche, JUN 23, 2017, View Source [SID1234519670]). Data presented in relapsed or refractory chronic lymphocytic leukaemia (CLL) confirmed the efficacy of Venclexta/Venclyxto with high and durable response rates and a well-tolerated safety profile in this high-risk population, including people with 17p chromosomal deletion who had previously received treatment. Additionally, phase Ib data demonstrated the anti-cancer activity of Venclexta/Venclyxto in acute myeloid leukaemia (AML) and relapsed or refractory multiple myeloma (MM), further supporting the potential of this treatment in a broader range of blood cancers. Venclexta/Venclyxto is being developed by AbbVie and Roche. It is jointly commercialised by AbbVie and Genentech, a member of the Roche Group, in the United States and commercialised by AbbVie outside of the United States.

"Confirmation that Venclexta/Venclyxto achieves a high response rate in relapsed or refractory chronic lymphocytic leukaemia in people with 17p deletion is very promising, as these patients have a particularly poor prognosis," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "We are also pleased to see early data highlighting the potential central role of BCL-2 in other difficult-to-treat blood cancers and look forward to validating these results in further studies."

The safety and efficacy of Venclexta/Venclyxto is being evaluated in a number of clinical studies in patients with CLL, some of which have led to European Medicines Agency (EMA) conditional marketing authorisation (M13-982 and M14-032) of Venclyxto and Food and Drug Administration (FDA) accelerated approval (M13-982) for Venclexta monotherapy in CLL. Data being presented at EHA (Free EHA Whitepaper) include:

Oral presentation of phase II monotherapy data in high-risk patients with relapsed/refractory CLL with 17p deletion showed an acceptable safety profile and a high response rate of 79%. Minimal residual disease (MRD)-negativity, an exploratory endpoint that is a measure of absence of residual blood cancer in patients’ blood or bone marrow, correlated with a progression-free survival (PFS) rate of 100% at 24 months. [Study M13-982 – Abstract S771, oral presentation Sunday, 25 June, 8:30 CET]. In addition, Venclexta/Venclyxto monotherapy demonstrated improved quality of life (QoL), with sustained and clinically meaningful improvement of several key aspects of functioning and health-related QoL. [Study M13-982 – Abstract S771, oral presentation Sunday 25 June, 8:30 CET and Study M14-032 – Abstract P728, poster presentation Saturday, 24 June, 17:30 CET].

Phase Ib data with Venclexta/Venclyxto in combination with MabThera/Rituxan (rituximab) in patients with relapsed/refractory CLL/small lymphocytic leukaemia (SLL) showed an acceptable safety profile and deep and durable responses, with 51% patients achieving a complete response (CR/CRi), 59% achieving marrow MRD-negativity and an overall response rate (ORR) of 86%. Data in patients achieving MRD-negativity suggested a prolonged treatment-free remission period even after Venclexta/Venclyxto treatment was stopped. [M13-365 study – Abstract P247, poster presentation Friday, 23 June, 17:15 CET].

The safety and efficacy of Venclexta/Venclyxto is also being evaluated in other blood cancers, including AML, an aggressive form of leukaemia that starts in myeloid cells, and MM, a cancer formed from malignant plasma cells.
In AML, Venclexta/Venclyxto has shown an acceptable safety profile in combination with decitabine or azacitidine and a high ORR of 68% in elderly patients with previously untreated AML. [Study M14-358 – Abstract S472, oral presentation Saturday, 24 June, 16:15 CET]. A further open-label phase I/II study in previously untreated elderly patients with AML showed durable efficacy with an acceptable safety profile for Venclexta/Venclyxto in combination with low-dose cytarabine. [Study M14-387 – Abstract E911 to be presented as an Eposter].

In MM, data from a phase Ib study of Venclexta/Venclyxto in combination with bortezomib and dexamethasone demonstrated an acceptable safety profile and anti-myeloma activity. When treated with Venclexta/Venclyxto, an overall response rate of 67% was achieved in patients with relapsed or refractory MM. [Study M12-901- Abstract S460, oral presentation Saturday, 24 June, 17:00 CET].

About Venclexta/Venclyxto
Venclexta/Venclyxto is a small molecule designed to selectively bind and inhibit the BCL-2 protein, which plays an important role in a process called apoptosis (programmed cell death). Overexpression of the BCL-2 protein in CLL has been associated with resistance to certain therapies. It is believed that blocking BCL-2 may restore the signalling system that tells cells, including cancer cells, to self-destruct.

Venclexta/Venclyxto is being co-developed by AbbVie and Roche. Together, the companies are committed to research with Venclexta/Venclyxto , which is currently being evaluated in phase III clinical trials for the treatment of relapsed, refractory and previously untreated CLL, along with studies in several other cancers. Venclexta/Venclyxto is commercialised jointly by AbbVie and Genentech, a member of the Roche Group, in the United States and commercialised by AbbVie outside of the United States.

About Roche in haematology
For more than 20 years, Roche has been developing medicines that redefine treatment in haematology. Today, we are investing more than ever in our effort to bring innovative treatment options to people with diseases of the blood. In addition to approved medicines MabThera/Rituxan (rituximab), Gazyva/Gazyvaro (obinutuzumab), and Venclexta/Venclyxto (venetoclax) in collaboration with AbbVie, Roche’s pipeline of investigational haematology medicines includes Tecentriq (atezolizumab), an anti-CD79b antibody drug conjugate (polatuzumab vedotin/RG7596) and a small molecule antagonist of MDM2 (idasanutlin/RG7388). Roche’s dedication to developing novel molecules in haematology expands beyond malignancy, with the development of the investigational haemophilia A treatment emicizumab.

Roche presents new data from GALLIUM study reinforcing clinical benefit of Gazyva/Gazyvaro in people with previously untreated follicular lymphoma

On June 23, 2017 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that new data from additional analyses of the pivotal phase III GALLIUM study in people with previously untreated follicular lymphoma will be presented at the 22nd European Hematology Association (EHA) (Free EHA Whitepaper) annual congress, 22-25 June, in Madrid, Spain (Press release, Hoffmann-La Roche, JUN 23, 2017, View Source [SID1234519668]). The data confirmed that the improvement in progression-free survival (PFS) with Gazyva/Gazyvaro (obinutuzumab)-based treatment over MabThera/Rituxan(rituximab)-based treatment was sustained in an updated analysis with a further six months of follow-up, irrespective of chemotherapy regimen. In addition, health-related quality of life (HRQoL) as reported by people in the Gazyva/Gazyvaro treatment group improved from the baseline assessment, suggesting that lymphoma-related symptoms were reduced by treatment and that this improvement was not diminished by treatment-related side effects. Additional preliminary analyses support the potential use of positron emission tomography (PET) as an early predictor of progression-free survival and overall survival in untreated follicular lymphoma.

"These data add to the growing body of evidence that Gazyva/Gazyvaro plays an important role in advancing the treatment of follicular lymphoma," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "Gazyva/Gazyvaro helped people with follicular lymphoma live longer without their disease worsening compared to MabThera/Rituxan, regardless of chemotherapy regimen. Importantly, this benefit did not come at the expense of health-related quality of life, an important measure of the patient’s treatment experience."
The following new data from the GALLIUM study will be presented:

A subanalysis by chemotherapy regimen showed that improvement in investigator-assessed PFS was superior for Gazyva/Gazyvaro-based treatment vs MabThera/Rituxan-based treatment across CHOP, CVP and bendamustine chemotherapy regimens. The benefit in PFS with Gazyva/Gazyvaro-based treatment was sustained over time. After a further six months of follow-up, for a total follow-up period of 41.1 months, the reduction in the risk of disease progression or death in the Gazyva/Gazyvaro-treated group remained consistent with the previous analysis (HR= 0.68; 95% CI 0.54-0.87; p=0.0016). [Abstract S775, to be presented in an oral presentation on Sunday, 25 June at 08:15 CET].

An additional subanalysis demonstrated that around 50% of people in both the Gazyva/Gazyvaro-based treatment group
and the MabThera/Rituxan-based treatment group reported clinically meaningful improvements in HRQoL from their baseline. This effect underscores the importance of treatment in effect in alleviating symptoms of follicular lymphoma that impact patients’ HRQoL. Importantly, the improvement seen was not diminished by treatment-related side effects. When viewed in the context of longer PFS, these results further support the relative benefit of Gazyva/Gazyvaro-based treatment over MabThera/Rituxan-based treatment in this setting. [Abstract S502 to be presented in an oral presentation on Saturday, 24 June at 16:15 CET].

Data from GALLIUM provides the first large-scale prospective comparison of standard contrast-enhanced CT versus PET scanning. After a median follow-up of 34.5 months, PET status at end of induction, as determined by independent review committee, was highly predictive of PFS (PET-complete remission (CR) vs PET non-CR: HR 0.39; 95% CI 0.25-0.60; p<0.0001) and overall survival (OS) (HR 0.41; 95% CI 0.19-0.86; p=0.018). [Abstract S774, to be presented in an oral presentation on Sunday, 25 June at 08:00 CET].

About the GALLIUM study
GALLIUM (NCT01332968) is a global phase III open-label, multicentre, randomised two-arm study examining the efficacy and safety of Gazyva/Gazyvaro plus chemotherapy followed by Gazyva/Gazyvaro alone for up to two years, as compared head-to-head against MabThera/Rituxan plus chemotherapy followed by MabThera/Rituxan alone for up to two years or until disease progression (whichever occurs first). Chemotherapies (CHOP, CVP or bendamustine) were selected by each participating study site prior to beginning enrolment. GALLIUM included 1401 patients with previously untreated indolent non-Hodgkin lymphoma (iNHL), of which 1202 patients had follicular lymphoma. The primary endpoint of the study was investigator-assessed PFS in patients with follicular lymphoma, with secondary endpoints including PFS 3/5
assessed by independent review committee (IRC), PFS in the overall study population (iNHL), response rate (overall response, ORR; and complete response, CR), overall survival (OS), and safety. The GALLIUM study is being conducted in cooperation with the NCRI (United Kingdom), GLSG (Germany), the East German Study Group Hematology and Oncology (OSHO; Germany).

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/Gazyvaro is currently approved in more than 80 countries in combination with chlorambucil, for people with previously untreated chronic lymphocytic leukaemia (CLL), and in combination with bendamustine for people with certain types of previously treated follicular lymphoma. The approvals in CLL were based on the CLL11 study, showing significant improvements with Gazyva/Gazyvaro plus chlorambucil across multiple clinical endpoints, including PFS, overall response rate (ORR), complete response rate (CR), and minimal residual disease (MRD) when compared head-to-head with MabThera/Rituxan plus chlorambucil.

The approvals in certain types of previously treated follicular lymphoma were based on the phase III GADOLIN study, in people with follicular lymphoma who did not respond to or who progressed during or within six months of prior MabThera/Rituxan-based therapy, showing a significant improvement in PFS and overall survival (OS) with Gazyva/Gazyvaro-based therapy compared to bendamustine alone.

Gazyva is marketed as Gazyvaro in the EU and Switzerland. 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 Follicular Lymphoma
Follicular lymphoma is the most common indolent (slow-growing) form of non-Hodgkin lymphoma (NHL), accounting for about one in five cases of NHL.1 It is considered incurable and relapse is common. Every day, more than 50 people in Europe are diagnosed with this type of NHL.2 It is estimated that more than 75,000 people are diagnosed with follicular lymphoma each year worldwide.2

Acceleron Provides Updated Results from Ongoing Phase 2 Study of Luspatercept in Myelodysplastic Syndromes at the 22nd Congress of the European Hematology Association

On June 23, 2017 Acceleron Pharma Inc. (NASDAQ:XLRN), a clinical stage biopharmaceutical company focused on the discovery, development, and commercialization of innovative therapeutics to treat serious and rare diseases, reported preliminary results from the ongoing Phase 2 studies of luspatercept in patients with lower-risk myelodysplastic syndromes (MDS) at the 22nd Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Madrid, Spain (Press release, Acceleron Pharma, JUN 23, 2017, View Source [SID1234519667]). Luspatercept is being developed to treat a range of hematologic diseases including MDS, beta-thalassemia, and myelofibrosis as part of a global collaboration between Acceleron and Celgene.

"This Phase 2 update further supports our confidence that luspatercept could become a potential first-in-class treatment for lower-risk MDS patients. With some patients continuing on study for more than 26 months, we are very encouraged by both the durability of response and safety profile of luspatercept," said Habib Dable, President and Chief Executive Officer of Acceleron. "With Phase 3 trials across two indications ongoing and new studies planned, we and Celgene remain committed to exploring the full opportunity for luspatercept to transform patients’ lives."

Phase 2 Results

A total of 88 lower-risk MDS patients have been treated with therapeutic dose levels of luspatercept in the ongoing Phase 2 study.

50% (44 of 88) achieved a clinically meaningful erythroid response of an increase in hemoglobin or reduction in red blood cell (RBC) transfusion burden as per the International Working Group’s Hematologic Improvement Erythroid (IWG HI-E) response criteria.
38% (23 of 60 patients with ≥ 2 units RBC / 8 weeks transfusion burden at baseline) achieved RBC transfusion independence (RBC-TI) for ≥ 8 weeks.
Patients with a low transfusion burden ( < 4 units / 8 weeks and hemoglobin < 10 g/dL) demonstrated a clinically meaningful increase in hemoglobin for up to 26 months, with several remaining on treatment.
The results presented at EHA (Free EHA Whitepaper) confirm and extend previously reported results across the lower-risk MDS patient subpopulations, showing erythroid responses regardless of prior use of erythropoiesis-stimulating agents (ESA), baseline erythropoietin (EPO) levels, and ring sideroblast (RS) status.

Phase 2 Safety Summary

A total of 95 lower-risk MDS patients have been treated with luspatercept in the ongoing Phase 2 studies (all dose levels).

The majority of adverse events (AEs) were Grade 1 or 2. AEs possibly related to study drug that occurred in at least three patients during the studies were headache, fatigue, hypertension, bone pain, diarrhea, arthralgia, injection site erythema, myalgia, and edema peripheral.
Grade 3 non-serious AEs possibly related to study drug were ascites, blast cell count increase, blood bilirubin increase, bone pain, hypertension, platelet count increase, and pleural effusion. These Grade 3 non-serious AEs occurred in six individual patients with one patient accounting for both the ascites and pleural effusion AEs.
Grade 3 serious AEs (SAEs) possibly related to study drug were ataxia, general physical health deterioration, and myalgia; a Grade 2 SAE possibly related to study drug of muscle weakness was reported.
"The longer term results of these Phase 2 studies reinforce the potential of inhibiting ligands in the TGF-beta superfamily for patients with lower-risk MDS," said Michael Pehl, President, Hematology/Oncology for Celgene. "With the Phase 3 study now fully enrolled, we look forward to advancing luspatercept as part of our ongoing commitment to individuals with MDS around the world."

Luspatercept is an investigational product that is not approved for use in any country.

The MEDALIST trial, a global Phase 3 study of luspatercept in patients with lower-risk MDS who require red blood cell transfusions, is fully enrolled and top-line results are expected in mid-2018.

The MDS poster presentation is available under the Science page of the Company’s website at www.acceleronpharma.com/.

About the MDS Phase 2 Studies

Data from two Phase 2 studies were presented at the conference: the base study in which patients received treatment with luspatercept for three months and the long-term extension study in which patients who completed the base study may receive treatment with luspatercept for up to an additional five years. In both the three-month base study and the long-term extension study, lower-risk MDS patients were enrolled and treated with open-label luspatercept, dosed subcutaneously once every three weeks.

The outcome measures for the studies included the proportion of patients who had an erythroid response (IWG HI-E) or achieved RBC transfusion independence (RBC-TI). IWG HI-E was defined as hemoglobin increase ≥ 1.5 g/dL sustained for ≥ 8 weeks in patients with < 4 units RBC / 8 weeks transfusion burden at baseline and hemoglobin levels below 10 g/dL. For patients with a ≥ 4 units RBC / 8 weeks transfusion burden at baseline, erythroid response was defined as a reduction of ≥ 4 units RBC sustained for ≥ 8 weeks. RBC-TI was defined as no RBC transfusions for ≥ 8 weeks in patients with a ≥ 2 units RBC / 8 weeks baseline transfusion burden.

About Luspatercept

Luspatercept is a modified activin receptor type IIB fusion protein that acts as a ligand trap for members in the transforming growth factor-beta superfamily involved in the late stages of erythropoiesis (red blood cell production). Luspatercept regulates late-stage erythrocyte (red blood cell) precursor cell differentiation and maturation. This mechanism of action is distinct from that of erythropoiesis stimulating agents (ESAs), which stimulate the proliferation of early-stage erythrocyte precursor cells. Acceleron and Celgene are jointly developing luspatercept as part of a global collaboration. Phase 3 clinical trials are underway to evaluate the safety and efficacy of luspatercept in patients with myelodysplastic syndromes (the "MEDALIST" study) and in patients with beta-thalassemia (the "BELIEVE" study). For more information, please visit www.clinicaltrials.gov.