On June 29, 2016 Novartis reported that The New England Journal of Medicine (NEJM) published data for PKC412 (midostaurin) demonstrating an overall response rate, defined as a major or partial response, of 60% (95% confidence interval [CI], 49-70%; P<0.001) in patients with advanced systemic mastocytosis (SM) (Press release, Novartis, JUN 29, 2016, View Source [SID:1234513631]). The median duration of response for all responders in the primary efficacy population was 24.1 months (95% CI, 10.8-not estimated [NE])[1]. Advanced SM is a rare disease characterized by the accumulation of abnormal mast cells, a type of white blood cell, in the bone marrow, liver, spleen and other organs, leading to organ damage. It is also characterized by frequent activating mutations of the KIT gene[5]. Patients with advanced SM have a poor prognosis, with overall survival varying between less than 6 months to 3.5 years, depending on subtype[2],[3], and currently there is no approved treatment for the majority of patients[4],[5]. The pivotal Phase II study, CPKC412D2201, was the largest and longest-running prospective trial ever conducted in this rare disorder. Jason Gotlib, MD, of Stanford University School of Medicine and Stanford Cancer Institute, served as lead author of the study, which enrolled 116 people with advanced SM. Eligibility and responses were reviewed by a Study Steering Committee and 89 patients were eligible for inclusion in the primary efficacy population. Patients received single-agent, oral PKC412 (midostaurin) until disease progression or unacceptable toxicity. Results demonstrated a median overall survival (OS) of 28.7 months (95% CI, 18.1-NE). Improvements in both bone marrow mast cell burden and serum tryptase levels - a marker for mast cell burden - were seen in 78% of patients, and were associated with disease regression[1]. "These data show clear disease and symptom improvement with oral midostaurin treatment across a range of study participants who were reflective of the heterogeneity of this disease," said Professor Andreas Reiter, Department of Hematology and Oncology, University Hospital Mannheim of the University of Heidelberg, Germany and senior author of the study. "If approved, midostaurin will offer patients a much needed treatment option." The most frequent side effects were gastrointestinal. With the exception of nausea and vomiting, all 32 symptoms self-reported with the Memorial Symptom Assessment Scale significantly decreased with treatment (P<0.001). Quality of life, assessed by the 12-item Short Form Health Survey (SF-12), was also significantly increased with PKC412 (midostaurin) treatment, compared to baseline values: improvement was shown by a 26% (P<0.001) increase in mental health scores and a 29% (P<0.001) increase in physical health scores[1]. "Patients with advanced SM are part of a very small, highly underserved community that has suffered from a lack of medical innovation for many years," said Alessandro Riva, MD, Global Head, Novartis Oncology Development and Medical Affairs. "Novartis is proud to have developed a treatment that shows benefit for these patients, and is now working with regulatory authorities to make midostaurin available as quickly as possible." The Phase II study results are also reinforced in a letter published in the same issue of NEJM by the French Reference Centre of Mastocytosis (CEREMAST) regarding a compassionate use program for PKC412 (midostaurin) in advanced SM[6]. After a median follow-up time of 18.5 (3-36) months, the overall response rate to treatment was 71%. After a similar follow-up time, the overall survival (OS) rate was 42.7%, compared with 14.9% in a matched historic control group (P=0.03). A more than twofold higher risk of death was also observed in the control group (HR 2.2; P=0.02)[6]. The most frequent side effects were nausea/vomiting in 89% of patients (leading to failure/discontinuation in 18%), lymphocytopenia in 61% without opportunistic infection and photosensitivity in 25%. The authors concluded that PKC412 (midostaurin) is effective in advanced SM[6]. PKC412 (midostaurin) is an investigational, oral, multi-targeted kinase inhibitor that was recently granted Breakthrough Therapy Designation for adults with newly-diagnosed FLT3-mutated acute myeloid leukemia (AML) by the US Food and Drug Administration (FDA). PKC412 (midostaurin) additionally has orphan drug status in the EU and US for both AML and mastocytosis. Since PKC412 (midostaurin) is investigational at this time, Novartis opened a Global Individual Patient Program (compassionate use program) to enable PKC412 (midostaurin) access to pediatric and adult patients presenting with aggressive systemic mastocytosis (ASM), mast cell leukemia (MCL) or mast cell sarcoma (MCS). Physicians who wish to request PKC412 (midostaurin) for eligible patients should contact a Novartis medical representative in their respective countries. In the US, patients can call 1-888-NOW-NOVA (1-888-669-6682) for more information. Additional information about the Phase II study The Phase II, single arm, open-label study of adults (18 years and older) included the following subtypes of advanced SM in the primary efficacy population: aggressive systemic mastocytosis (ASM, N=16), mast cell leukemia (MCL, N=16) and SM with an associated hematologic neoplasm (SM-AHN, N=57)[1]. A key secondary endpoint of the study was OS, which varied between subtypes: 20.7 months (95% CI, 16.0-44.4) in patients with SM-AHN and 9.4 months (95% CI, 7.5-NE) in patients with MCL. Median overall survival in patients with ASM was not reached at the time of analysis (95% CI, 28.7 months-NE). Median progression-free survival (PFS) was longer in those with ASM (28.7 months, 95% CI, 24.8-NE) than in those with SM-AHN (11.0 months, 95% CI, 7.4-17.0) and MCL (11.3 months, 95% CI, 2.8-NE)[1]. The most frequent non-hematologic adverse events (>=50%) were nausea (79%), vomiting (66%) and diarrhea (54%). The most frequent Grade 3/4 non-hematologic adverse events (>=8%) were fatigue (9%) and diarrhea (8%). Dose reduction for toxicity occurred in 56% of patients[1].

For more information on the trial, visit clinicaltrials.gov (NCT00782067).

About systemic mastocytosis
Systemic mastocytosis (SM) comprises a group of rare diseases, affecting between 1 in 20,000 to 40,000 people worldwide[7], whereby uncontrolled growth and accumulation of mast cells occurs in one or more organs[5]. The uncontrolled proliferation of mast cells is caused in many people by a KIT gene mutation – the most common mutation, encoding the D816V substitution, occurs in approximately 90% of patients[8]. The KIT gene mutation results in activation of the KIT enzyme, which triggers the abnormal proliferation and survival of mast cells[7],[9].

In advanced SM, the uncontrolled growth of neoplastic mast cells causes organ damage (e.g. liver dysfunction), low blood counts and weight loss. Patients also suffer from debilitating systemic symptoms such as pruritus (severe itching of the skin) caused by mast cells releasing inflammatory mediators such as histamine into the blood[5].

Advanced SM includes the subtypes aggressive systemic mastocytosis (ASM), mast cell leukemia (MCL) and SM with an associated hematologic neoplasm (SM-AHN)[4]. Median overall survival is 3.5 years, less than 6 months and 2 years, for ASM, MCL and SM-AHN, respectively[2],[3].

About PKC412 (midostaurin)
PKC412 (midostaurin) is an investigational, oral, multi-targeted kinase inhibitor (targeting both wild type KIT and the KIT D816V mutation, among others), in development for the treatment of patients with AML with a FLT3 mutation, as well as patients with advanced SM. The safety and efficacy profile has not been fully established. There is no guarantee that PKC412 (midostaurin) will become commercially available.

On June 29, 2016 Novartis reported that The New England Journal of Medicine (NEJM) published data for PKC412 (midostaurin) demonstrating an overall response rate, defined as a major or partial response, of 60% (95% confidence interval [CI], 49-70%; P<0.001) in patients with advanced systemic mastocytosis (SM) (Press release, Novartis, JUN 29, 2016, View Source [SID:1234513631]). The median duration of response for all responders in the primary efficacy population was 24.1 months (95% CI, 10.8-not estimated [NE])[1].

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Advanced SM is a rare disease characterized by the accumulation of abnormal mast cells, a type of white blood cell, in the bone marrow, liver, spleen and other organs, leading to organ damage. It is also characterized by frequent activating mutations of the KIT gene[5]. Patients with advanced SM have a poor prognosis, with overall survival varying between less than 6 months to 3.5 years, depending on subtype[2],[3], and currently there is no approved treatment for the majority of patients[4],[5].

The pivotal Phase II study, CPKC412D2201, was the largest and longest-running prospective trial ever conducted in this rare disorder. Jason Gotlib, MD, of Stanford University School of Medicine and Stanford Cancer Institute, served as lead author of the study, which enrolled 116 people with advanced SM. Eligibility and responses were reviewed by a Study Steering Committee and 89 patients were eligible for inclusion in the primary efficacy population. Patients received single-agent, oral PKC412 (midostaurin) until disease progression or unacceptable toxicity. Results demonstrated a median overall survival (OS) of 28.7 months (95% CI, 18.1-NE). Improvements in both bone marrow mast cell burden and serum tryptase levels – a marker for mast cell burden – were seen in 78% of patients, and were associated with disease regression[1].

"These data show clear disease and symptom improvement with oral midostaurin treatment across a range of study participants who were reflective of the heterogeneity of this disease," said Professor Andreas Reiter, Department of Hematology and Oncology, University Hospital Mannheim of the University of Heidelberg, Germany and senior author of the study. "If approved, midostaurin will offer patients a much needed treatment option."

The most frequent side effects were gastrointestinal. With the exception of nausea and vomiting, all 32 symptoms self-reported with the Memorial Symptom Assessment Scale significantly decreased with treatment (P<0.001). Quality of life, assessed by the 12-item Short Form Health Survey (SF-12), was also significantly increased with PKC412 (midostaurin) treatment, compared to baseline values: improvement was shown by a 26% (P<0.001) increase in mental health scores and a 29% (P<0.001) increase in physical health scores[1].

"Patients with advanced SM are part of a very small, highly underserved community that has suffered from a lack of medical innovation for many years," said Alessandro Riva, MD, Global Head, Novartis Oncology Development and Medical Affairs. "Novartis is proud to have developed a treatment that shows benefit for these patients, and is now working with regulatory authorities to make midostaurin available as quickly as possible."

The Phase II study results are also reinforced in a letter published in the same issue of NEJM by the French Reference Centre of Mastocytosis (CEREMAST) regarding a compassionate use program for PKC412 (midostaurin) in advanced SM[6]. After a median follow-up time of 18.5 (3-36) months, the overall response rate to treatment was 71%. After a similar follow-up time, the overall survival (OS) rate was 42.7%, compared with 14.9% in a matched historic control group (P=0.03). A more than twofold higher risk of death was also observed in the control group (HR 2.2; P=0.02)[6]. The most frequent side effects were nausea/vomiting in 89% of patients (leading to failure/discontinuation in 18%), lymphocytopenia in 61% without opportunistic infection and photosensitivity in 25%. The authors concluded that PKC412 (midostaurin) is effective in advanced SM[6].

PKC412 (midostaurin) is an investigational, oral, multi-targeted kinase inhibitor that was recently granted Breakthrough Therapy Designation for adults with newly-diagnosed FLT3-mutated acute myeloid leukemia (AML) by the US Food and Drug Administration (FDA). PKC412 (midostaurin) additionally has orphan drug status in the EU and US for both AML and mastocytosis.

Since PKC412 (midostaurin) is investigational at this time, Novartis opened a Global Individual Patient Program (compassionate use program) to enable PKC412 (midostaurin) access to pediatric and adult patients presenting with aggressive systemic mastocytosis (ASM), mast cell leukemia (MCL) or mast cell sarcoma (MCS). Physicians who wish to request PKC412 (midostaurin) for eligible patients should contact a Novartis medical representative in their respective countries. In the US, patients can call 1-888-NOW-NOVA (1-888-669-6682) for more information.

Additional information about the Phase II study
The Phase II, single arm, open-label study of adults (18 years and older) included the following subtypes of advanced SM in the primary efficacy population: aggressive systemic mastocytosis (ASM, N=16), mast cell leukemia (MCL, N=16) and SM with an associated hematologic neoplasm (SM-AHN, N=57)[1].

A key secondary endpoint of the study was OS, which varied between subtypes: 20.7 months (95% CI, 16.0-44.4) in patients with SM-AHN and 9.4 months (95% CI, 7.5-NE) in patients with MCL. Median overall survival in patients with ASM was not reached at the time of analysis (95% CI, 28.7 months-NE). Median progression-free survival (PFS) was longer in those with ASM (28.7 months, 95% CI, 24.8-NE) than in those with SM-AHN (11.0 months, 95% CI, 7.4-17.0) and MCL (11.3 months, 95% CI, 2.8-NE)[1].

The most frequent non-hematologic adverse events (>=50%) were nausea (79%), vomiting (66%) and diarrhea (54%). The most frequent Grade 3/4 non-hematologic adverse events (>=8%) were fatigue (9%) and diarrhea (8%). Dose reduction for toxicity occurred in 56% of patients[1].

For more information on the trial, visit clinicaltrials.gov (NCT00782067).

About systemic mastocytosis
Systemic mastocytosis (SM) comprises a group of rare diseases, affecting between 1 in 20,000 to 40,000 people worldwide[7], whereby uncontrolled growth and accumulation of mast cells occurs in one or more organs[5]. The uncontrolled proliferation of mast cells is caused in many people by a KIT gene mutation – the most common mutation, encoding the D816V substitution, occurs in approximately 90% of patients[8]. The KIT gene mutation results in activation of the KIT enzyme, which triggers the abnormal proliferation and survival of mast cells[7],[9].

In advanced SM, the uncontrolled growth of neoplastic mast cells causes organ damage (e.g. liver dysfunction), low blood counts and weight loss. Patients also suffer from debilitating systemic symptoms such as pruritus (severe itching of the skin) caused by mast cells releasing inflammatory mediators such as histamine into the blood[5].

Advanced SM includes the subtypes aggressive systemic mastocytosis (ASM), mast cell leukemia (MCL) and SM with an associated hematologic neoplasm (SM-AHN)[4]. Median overall survival is 3.5 years, less than 6 months and 2 years, for ASM, MCL and SM-AHN, respectively[2],[3].

About PKC412 (midostaurin)
PKC412 (midostaurin) is an investigational, oral, multi-targeted kinase inhibitor (targeting both wild type KIT and the KIT D816V mutation, among others), in development for the treatment of patients with AML with a FLT3 mutation, as well as patients with advanced SM. The safety and efficacy profile has not been fully established. There is no guarantee that PKC412 (midostaurin) will become commercially available.

On June 29, 2016 Xcovery, a developer of targeted therapeutics for cancer, reported the initiation of its Phase 3 trial of X-396 in patients with anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) (Press release, Xcovery, JUN 29, 2016, View Source [SID:1234513622]). The eXalt3 trial is an open-label, randomized study designed to evaluate the efficacy and safety of X-396, the Company’s lead ALK inhibitor drug candidate, versus crizotinib in over 400 patients with ALK+ NSCLC.

“The initiation of our Phase 3 eXalt3 trial represents an important step forward in Xcovery’s advancement of our lead candidate, X-396,” said Michael Webb, Chief Executive Officer and President of Xcovery. “The recently released data from our ongoing Phase 1/2 study of X-396 showed promising activity with durable responses noted in both treatment-naïve patients as well in patients resistant to current standard-of-care. These results, coupled with a favorable tolerability profile, support the continued development of X-396 as a potential new treatment option for patients with ALK+ NSCLC. Xcovery will now focus on actively recruiting additional patients and new clinical sites across the globe.”

About the Phase 3 eXalt3 Study

The Phase 3 eXalt3 study is an open-label, randomized study that will evaluate the efficacy and safety of the ALK inhibitor X-396 compared to crizotinib in patients with ALK+ NSCLC. The primary efficacy endpoint being measured is progression-free survival (PFS) as assessed by an independent radiology review based on RECIST v. 1.1 criteria. The study will also allow the Company to obtain additional pharmacokinetic data on X-396 in select patients and samples for exploratory biomarkers research to be compared against the clinical outcomes. The company expects to enroll approximately 400 patients who have received up to one prior chemotherapy regimen and no prior ALK tyrosine kinase inhibitor (TKI) treatments. The trial is designed so patients either receive a 225 mg daily dose of X-396 or a 250 mg dose twice a day of standard-of-care crizotinib over a 28-day schedule.

About X‐396 (Ensartinib)

Xcovery’s lead asset is X‐396, a small molecule, anaplastic lymphoma kinase (ALK) inhibitor. It is being studied in the eXalt2 and eXalt3 studies, Phase 2 and Phase 3 trials for the treatment of ALK‐positive non‐small cell lung cancer (NSCLC). Both studies are currently enrolling patients. To learn more, visit: www.xalt2study.com or ClinicalTrials.gov.

About NSCLC and ALK

Lung cancer is the second most common type of cancer identified in the United States with an estimated 221,000 new diagnoses expected in 2015. Non‐small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for an estimated 85‐90% of the lung cancer cases. The anaplastic lymphoma kinase (ALK) gene is located on chromosome 2 and rearrangement of the ALK gene can lead to its activation or expression, therefore increasing a person’s chance of developing certain types of cancer, including NSCLC. Between three and seven percent of patients with NSCLC have the ALK rearrangement, making this a molecular target warranting investigation for NSCLC patients.

On June 29, 2016 Xcovery, a developer of targeted therapeutics for cancer, reported the initiation of its Phase 3 trial of X-396 in patients with anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) (Press release, Xcovery, JUN 29, 2016, View Source [SID:1234513622]). The eXalt3 trial is an open-label, randomized study designed to evaluate the efficacy and safety of X-396, the Company’s lead ALK inhibitor drug candidate, versus crizotinib in over 400 patients with ALK+ NSCLC.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"The initiation of our Phase 3 eXalt3 trial represents an important step forward in Xcovery’s advancement of our lead candidate, X-396," said Michael Webb, Chief Executive Officer and President of Xcovery. "The recently released data from our ongoing Phase 1/2 study of X-396 showed promising activity with durable responses noted in both treatment-naïve patients as well in patients resistant to current standard-of-care. These results, coupled with a favorable tolerability profile, support the continued development of X-396 as a potential new treatment option for patients with ALK+ NSCLC. Xcovery will now focus on actively recruiting additional patients and new clinical sites across the globe."

About the Phase 3 eXalt3 Study

The Phase 3 eXalt3 study is an open-label, randomized study that will evaluate the efficacy and safety of the ALK inhibitor X-396 compared to crizotinib in patients with ALK+ NSCLC. The primary efficacy endpoint being measured is progression-free survival (PFS) as assessed by an independent radiology review based on RECIST v. 1.1 criteria. The study will also allow the Company to obtain additional pharmacokinetic data on X-396 in select patients and samples for exploratory biomarkers research to be compared against the clinical outcomes. The company expects to enroll approximately 400 patients who have received up to one prior chemotherapy regimen and no prior ALK tyrosine kinase inhibitor (TKI) treatments. The trial is designed so patients either receive a 225 mg daily dose of X-396 or a 250 mg dose twice a day of standard-of-care crizotinib over a 28-day schedule.

About X‐396 (Ensartinib)

Xcovery’s lead asset is X‐396, a small molecule, anaplastic lymphoma kinase (ALK) inhibitor. It is being studied in the eXalt2 and eXalt3 studies, Phase 2 and Phase 3 trials for the treatment of ALK‐positive non‐small cell lung cancer (NSCLC). Both studies are currently enrolling patients. To learn more, visit: www.xalt2study.com or ClinicalTrials.gov.

About NSCLC and ALK

Lung cancer is the second most common type of cancer identified in the United States with an estimated 221,000 new diagnoses expected in 2015. Non‐small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for an estimated 85‐90% of the lung cancer cases. The anaplastic lymphoma kinase (ALK) gene is located on chromosome 2 and rearrangement of the ALK gene can lead to its activation or expression, therefore increasing a person’s chance of developing certain types of cancer, including NSCLC. Between three and seven percent of patients with NSCLC have the ALK rearrangement, making this a molecular target warranting investigation for NSCLC patients.

On June 29, 2016 Selexis SA, a pioneering life sciences company and a global leader in mammalian (suspension-adapted CHO-K1) cell line generation, reported that Symphogen A/S, a private biopharmaceutical company developing recombinant antibody mixtures, has progressed its Sym015 clinical candidate into a Phase 1 dose escalation trial in patients with solid tumors (Press release, Selexis, JUN 29, 2016, View Source!2016jun29-symphogen-cla/c1d4o [SID:1234513619]). Symphogen relied upon Selexis SGE (Selexis Genetic Elements) to facilitate the rapid, stable, and cost-effective expression of Sym015, which is a multi-targeting monoclonal antibody (MAb) mixture that targets the MET receptor.

The proto-oncogene c-MET, also called MET, has been recognized as an important mediator of uncontrolled growth of solid tumors. Research has shown that driver mutations that result in activation of the MET receptor tyrosine kinase (RTK) are associated with a wide range of human malignancies including cancers of the kidney, liver, stomach, breast, and brain.

Selexis SGEs are the foundation of the SUREtechnology Platform. SGEs are unique epigenetic DNA-based elements that control the dynamic organization of chromatin in all mammalian cells and allow for higher and more stable expression of recombinant proteins.

“We are pleased that the power of our Selexis Genetic Elements helped Symphogen efficiently produce their next-generation antibody candidate, Sym015, and move it rapidly into clinical development,” said Igor Fisch, PhD, chief executive officer and chairman of Selexis. “The goal of our proprietary technology is to help our biopharmaceutical partners advance their discovery development programs into clinical trials and, ultimately, biologics manufacturing, offering patients new and improved treatment options.”

In December 2014, Selexis and Symphogen A/S entered into a commercial license agreement and signed the continuation of their R&D license agreement. Symphogen has licensed the rights to the Selexis SUREtechnology Platform and SURE CHO-M Cell Line for the development of recombinant MAb mixtures for the treatment of various cancers and infectious diseases. Symphogen has developed unique technologies for the controlled, reproducible production of highly characterized MAb mixtures manufactured as single drug products.