On July 24, 2017 Novocure (NASDAQ:NVCR) reported a new arm for a phase 1b study to evaluate the safety of marizomib and temozolomide in combination with Optune, Novocure’s Tumor Treating Fields (TTFields) delivery system, as adjuvant treatment for patients with newly diagnosed glioblastoma (GBM) following radiation therapy with concurrent temozolomide (Press release, NovoCure, JUL 24, 2017, View Source [SID1234519860]). The trial is the first to study Optune in combination with an investigational drug.

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Marizomib is a novel, brain-penetrant proteasome inhibitor developed by Triphase Accelerator Corporation and acquired by Celgene Corporation. Celgene is responsible for marizomib’s development.

"This collaboration marks an important first step toward testing Optune with a promising new investigational compound for the treatment of GBM," said Principal Investigator Dr. Roger Stupp, Associate Director for Strategic Initiatives at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. "Optune is the first treatment in over a decade to improve survival in GBM. I believe that combining Optune with new pharmacologic treatments in clinical trials, like this phase 1b study, will help advance our understanding of how to treat this devastating disease."

Celgene and Triphase modified their current phase 1b multicenter, open-label study of marizomib in combination with temozolomide and radiotherapy in patients with grade IV malignant gliomas to include Optune. A cohort of 12 GBM patients will be treated with Optune in combination with marizomib and temozolomide after initial treatment with radiation and temozolomide has been completed.

The primary objective for the Optune portion of the study is to determine the safety of the combination of marizomib and temozolomide with the addition of Optune in patients entering the adjuvant treatment phase. Secondary objectives for the Optune portion of the study include assessing preliminary clinical activity of the combination of Optune, marizomib and temozolomide in patients entering adjuvant therapy, progression-free survival and overall survival. The protocol has been submitted to an institutional review board, and this arm of the trial is expected to open in the third quarter of 2017.

"We believe TTFields has the potential to be an excellent development candidate in combination with other solid tumor cancer treatments," said Dr. Eilon Kirson, Novocure’s Chief Science Officer and Head of Research and Development. "As innovators in cancer treatment, we know collaboration is essential to improve patient outcomes. We hope this is the first collaboration of many."
Tumor Treating Fields in combination with temozolomide and marizomib is experimental for the treatment of glioblastoma. Limited by law to investigational use only.

On July 21, 2017 Bayer reported that a Phase II clinical trial evaluating its investigational oncology compound anetumab ravtansine (BAY 949343) as a monotherapy in patients with recurrent malignant pleural mesothelioma (MPM), who were previously treated, did not meet its primary endpoint of progression-free survival (Press release, Bayer, JUL 21, 2017, View Source [SID1234519851]). The safety and tolerability of anetumab ravtansine were consistent with earlier clinical findings. Detailed study results are expected to be presented at an upcoming medical meeting.

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"Malignant pleural mesothelioma is a very difficult-to-treat tumor, and we had hoped for a better outcome for patients," said Robert LaCaze, Executive Vice President and Head of the Oncology Strategic Business Unit at Bayer. "We would like to thank the patients and their caregivers, as well as the study investigators for their participation and contributions in this study. Based on the available data, we remain committed to further evaluating the utility and safety of anetumab ravtansine across multiple tumor types with significant unmet medical need."

Anetumab ravtansine is currently being investigated, as monotherapy and in combination, in additional studies, including a Phase Ib multi-indication study in six different types of advanced solid tumors, as well as a Phase Ib combination-study in patients with recurrent platinum-resistant ovarian cancer.

About the Phase II Study
The phase II clinical trial (NCT02610140) is a randomized, open-label, active-controlled, multicenter superiority study investigating anetumab ravtansine as second line treatment in patients with advanced or metastatic mesothelin-positive malignant pleural mesothelioma (MPM), whose disease had progressed after treatment with first-line platinum/pemetrexed-based chemotherapy. The trial randomized 248 patients in a 2:1 ratio to receive either anetumab ravtansine (6.5 mg/kg intravenously every three weeks) or vinorelbine (30 mg/m2 intravenously every week).

The primary endpoint of the study was progression-free survival. Secondary endpoints included overall survival, as well as other indicators of efficacy, such as patient-reported outcomes, objective tumor response rate, duration of response, disease control rate, and durable response rate. Safety and tolerability of patients were also continuously monitored.

About Mesothelioma
Malignant pleural mesothelioma (MPM) is a rare and deadly cancer affecting more than 25,000 people globally, with about 3,000 new cases being diagnosed in the US and more than 12,000 in Europe each year. It is commonly caused by occupational or environmental exposure to asbestos. The majority of patients with MPM are not diagnosed until the disease has progressed to an advanced stage, with the onset of the disease in many cases occurring 20 to 40 years after exposure. Due to its aggressive nature, the estimated median overall survival is approximately one year from diagnosis. Rapid deterioration and poor survival are hallmarks of MPM. In first line therapy, cisplatin/pemetrexed has become the standard of care but nearly all MPM-patients progress during or after first-line treatment. In the second-line setting, the lack of an accepted standard of care treatment underscores the substantial unmet need in the treatment of MPM.

About Anetumab Ravtansine (BAY 949343)
Anetumab ravtansine is an antibody-drug conjugate (ADC) that specifically targets mesothelin, a surface marker protein overexpressed in many cancers. After binding to mesothelin, anetumab ravtansine is taken up inside the tumor cells, where degrading enzymes release cytotoxic DM4, a maytansinoid tubulin inhibitor, which induces cell cycle arrest and apoptosis in dividing cells.

In a Phase I clinical trial in patients with advanced solid tumors, anetumab ravtansine demonstrated promising efficacy with durable responses in patients with malignant pleural mesothelioma (MPM), and a manageable safety profile. In addition to the Phase II clinical trial in MPM, anetumab ravtansine is currently being investigated in a variety of other mesothelin-positive tumors, including a Phase Ib multi-indication study in six different types of advanced solid tumors (NCT03102320), as well as a Phase Ib combination-study in patients with recurrent platinum-resistent ovarian cancer (NCT02751918).

Anetumab ravtansine is a compound developed by Bayer. In the development, the following collaborators were involved: The antibody was derived from the HuCAL technology platform of MorphoSys AG. In a 2008 license agreement with ImmunoGen, Inc., Bayer was granted exclusive rights for using their maytansinoid ADC technology to develop anti-tumor therapies targeting mesothelin. Both partners are entitled to milestone payments and royalties on commercial sales, if any.

On July 21, 2017 Syros Pharmaceuticals (NASDAQ: SYRS) reported that data providing the foundation of its clinical development strategy for SY-1425, its first-in-class selective retinoic acid receptor alpha (RARα) agonist currently in a Phase 2 clinical trial in genomically defined subsets of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), were published online in Cancer Discovery, a peer-reviewed journal of the American Association of Cancer Research. Syros is on track to present initial data from the Phase 2 clinical trial this fall (Press release, Syros Pharmaceuticals, JUL 21, 2017, View Source [SID1234519876]).

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The publication highlights Syros’ discovery of a subset of AML patients with a super-enhancer associated with the RARA gene, which was shown in preclinical studies to be predictive of response to SY-1425. Syros also found a subset of MDS patients with high expression of the RARA gene and demonstrated in ex vivo studies that RARA-high MDS had a similar response to SY-1425 as that seen in AML driven by the RARA super-enhancer.

"The publication of our work in Cancer Discovery is a demonstration of our pioneering approach for analyzing non-coding regulatory regions of the genome to identify disease-driving genes with the goal of developing new medicines that make a meaningful difference for patients," said Eric Olson, Ph.D., Chief Scientific Officer of Syros. "Although genetic mutations associated with AML and MDS in protein-coding regions of the genome are well known, there are limited targeted therapy options in these diseases and there remains a high unmet need. Our investigation of the regulatory genome adds a new dimension to the understanding of AML and MDS disease biology that offers the potential to address these underserved patient populations and improve their prognosis and treatment."

In collaboration with the Majeti lab at Stanford University School of Medicine, Syros used its gene control platform to analyze 66 AML patients’ tumor samples and identified six distinct patient subsets based on super-enhancer profiles, including one enriched for a super-enhancer associated with the RARA gene. The data show that:

· Super-enhancer profiles were strongly associated with survival outcomes, often independent of known genetic mutations in AML.

· The RARA super-enhancer was associated with high expression of the RARA gene, which codes for a transcription factor targeted by SY-1425.

· The RARA super-enhancer was predictive of response to SY-1425. In AML cells with high RARA expression, SY-1425 reduced proliferation and promoted differentiation. Moreover, SY-1425 decreased tumor burden and prolonged survival in patient-derived xenograft (PDX) models of AML with high RARA expression, while no effect was found on AML cells or PDX models with low RARA expression. Notably, ATRA, a less potent and non-selective retinoid, produced no survival benefit in PDX models with high RARA expression.

· SY-1425 induced profound transcriptional changes promoting cell differentiation in AML cells with high RARA expression but little to no transcriptional changes in AML cells with low RARA expression.

· DHRS3 was the most strongly and rapidly induced gene in response to treatment with SY-1425, leading to the identification of DHRS3 induction as a pharmacodynamic marker for use in the ongoing Phase 2 clinical trial as an early indicator of whether SY-1425 is affecting the targeted biology in defined subsets of AML and MDS patients.

· SY-1425 induced transcriptional and epigenomic changes in AML cells with high RARA expression similar to those seen in acute promyelocytic leukemia (APL) cells treated with SY-1425. SY-1425 is approved in Japan as Amnolake (tamibarotene) to treat relapsed or refractory APL, a form of AML that is driven by fusions of the RARA gene, and has a well-established safety and efficacy profile in those patients.

The Phase 2 clinical trial of SY-1425 is assessing the safety and efficacy of SY-1425 as a single agent in four AML and MDS patient populations, as well as in combination with azacitidine, a standard-of-care therapy, in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy. All patients in the trial are prospectively selected using biomarkers for high expression of RARA or IRF8, which are genes associated with the RARA pathway. Additional details about the trial can be found using the identifier NCT02807558 at www.clinicaltrials.gov

LIDDS has entered into a research agreement with Ferring Pharmaceuticals which has an exclusive option right to leverage the NanoZolid technology for the development of an injectable, controlled-release formulation for cancer treatment (Press release, Lidds, JUL 21, 2017, View Source [SID1234555959]).

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Under the terms of the agreement, LIDDS will conduct feasibility studies fully funded by the other party. Upon completion of the development work, the right to exercise its option and enter into an exclusive agreement with LIDDS to further develop the novel formulation based on NanoZolid.

– LIDDS is committed to provide the NanoZolid technology to enhance the performance of drugs by either reducing its side effects or facilitate longer acting pharmaceuticals to improve compliance and quality of life for patients. We are very pleased with the new agreement which adds another exciting project that does not compete with LIDDS own development portfolio, says Monica Wallter, CEO of LIDDS.

LIDDS has several ongoing development projects in oncology. The prostate cancer project is currently in Phase IIb and there are several promising preclinical projects where NanoZolid is combined with cytotoxic drugs and with immuno active substances such as antibodies.

On July 21, 2017 MorphoSys AG (FSE: MOR; Prime Standard Segment, TecDAX; OTC: MPSYY) reported that its partner Bayer AG has reported that a phase 2 clinical study examining anetumab ravtansine as monotherapy in patients with recurrent malignant pleural mesothelioma did not meet the primary endpoint of progression-free survival (Press release, MorphoSys, JUL 21, 2017, View Source [SID1234556342]). Anetumab ravtansine is an antibody-drug conjugate (ADC) directed against mesothelin, comprising an antibody made using MorphoSys’s HuCAL technology. Malignant pleural mesothelioma is a rare cancer and is commonly caused by occupational or environmental exposure to asbestos.

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"The outcome of this phase 2 study with anetumab ravtansine in recurrent malignant pleural mesothelioma is disappointing, in particular for the patients suffering from this serious and extremely difficult to treat disease", said Dr. Markus Enzelberger, Interim Chief Scientific Officer of MorphoSys AG. "Nevertheless, Bayer remains committed to further evaluating the potential of this compound across multiple tumor types with significant unmet medical need. We are proud of our long-standing relationship with Bayer, and we look forward to further updates about the development program with anetumab ravtansine going forward."

The phase 2 clinical trial is a randomized, open-label, active-controlled, multicenter superiority study evaluating the safety and efficacy of anetumab ravtansine as second-line treatment in 248 patients with advanced or metastatic mesothelin-positive malignant pleural mesothelioma whose disease had progressed after treatment with first-line platinum/pemetrexed-based chemotherapy.

Bayer reported further that anetumab ravtansine is currently being investigated, as monotherapy and in combination, in additional studies, including a Phase Ib multi-indication study in six different types of advanced solid tumors, as well as a Phase Ib combination-study in patients with recurrent platinum-resistant ovarian cancer. According to Bayer, based on the available data, Bayer remains committed to further evaluating the utility and safety of anetumab ravtansine across multiple tumor types with significant unmet medical need. Bayer further announced that, in the trial reported, the safety and tolerability of anetumab ravtansine were consistent with earlier clinical findings and that detailed study results are expected to be presented at an upcoming medical meeting.

Further detailed information about mesothelioma and the clinical study can be found in a press release issued by Bayer or at clinicaltrials.gov.

There is no change to MorphoSys’s financial guidance for Fiscal Year 2017.

About anetumab ravtansine
Anetumab ravtansine is an antibody-drug conjugate (ADC) that specifically targets mesothelin, a surface marker protein overexpressed in many cancers. After binding to mesothelin, anetumab ravtansine is taken up inside the tumor cells, where degrading enzymes release cytotoxic DM4, a maytansinoid tubulin inhibitor, which induces cell cycle arrest and apoptosis in dividing cells. Anetumab ravtansine comprises an antibody made using MorphoSys’s HuCAL technology.