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MorphoSys Starts Phase 2 Trial of MOR208 in Combination with Idelalisib in Patients with Relapsed or Refractory CLL or SLL Previously Treated with a BTK Inhibitor

On December 13, 2016 MorphoSys AG (FSE: MOR; Prime Standard Segment, TecDAX; OTC: MPSYY) reported that the first patient was dosed in a Phase 2 combination trial of MOR208 with idelalisib (Zydelig) (Press release, MorphoSys, DEC 12, 2016, View Source [SID1234517058]). The trial, which has been named COSMOS (CLL patients assessed for ORR & Safety in MOR208 Study), is designed to evaluate the safety and efficacy of MOR208 in combination with the PI3K delta inhibitor idelalisib in adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Patient enrolled must have been refractory or shown relapse or intolerance to a prior, most recent, therapy with a Bruton’s Tyrosine Kinase (BTK) inhibitor (e.g. ibrutinib). MOR208 is an investigational Fc-engineered monoclonal antibody targeting CD19 that is being developed for the treatment of patients with B cell malignancies. CLL is the most common type of leukemia in Western populations.

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"We are pleased to kick off the COSMOS trial. This is the third in a series of clinical studies we have initated this year investigating combination therapies with our CD19 antibody MOR208 in hemato-oncological indications", commented Dr. Arndt Schottelius, Chief Development Officer of MorphoSys AG. "There is a particularly high medical need for chronic lymphocytic leukemia (CLL) patients, especially following discontinuation of a BTK inhibitor therapy. We look forward to exploring the potential of MOR208 in this indication in combination with idelalisib. In addition, we are also planning to investigate MOR208 with a second combination partner in this patient population and will provide more details soon."

The single-arm, open-label, multicenter COSMOS study will enroll patients in Europe and in the USA. Patients will receive intravenous infusions of MOR208 for up to 24 cycles of 28 days each. Idelalisib is taken orally, 150 mg twice-daily for the study duration. The study will include a safety run-in phase consisting of a safety evaluation by an independent data monitoring committee (IDMC).

The study’s primary endpoint is overall response rate (ORR), comprising complete responses (CR) and partial responses (PR). Secondary outcome measures include progression-free survival (PFS), overall survival (OS) and duration of response (DoR), as well as an evaluation of the drug combination’s safety and pharmacokinetic parameters of MOR208.

Detailed information on the trial can be found on clinicaltrials.gov.

About CD19
CD19 is broadly and homogeneously expressed across different B cell malignancies including DLBCL and CLL. CD19 enhances B cell receptor (BCR) signaling, which is important for B cell survival, making CD19 a potential target in B cell malignancies.

About MOR208
MOR208 (previously Xmab5574) is an Fc-engineered ("Fc-enhanced") monoclonal antibody targeting CD19. Fc-modification of MOR208 is intended to lead to a significant potentiation of antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), thus possibly improving a key mechanism of tumor cell killing. Furthermore, MOR208 induces direct apoptosis by binding to CD19, which is a crucial component for B cell receptor (BCR) signaling.
MorphoSys is currently investigating MOR208 as an immunotherapeutic treatment option in several phase 2 combination studies in patients with B cell malignancies. A phase 2 study namend L-MIND (Lenalidomide-MOR208 IN DLBCL) is investigating the safety and efficacy of MOR208 in combination with lenalidomide in patients with relapsed or refractory DLBCL. A phase 2/3 study named B-MIND (Bendamustine-MOR208 IN DLBCL) is evaluating the safety and efficacy of MOR208 in combination with the chemotherapeutic agent bendamustine in comparison to rituximab plus bendamustine in patients with relapsed or refractory DLBCL. The B-MIND trial, which is currently in the safety part, is planned to be transitioned into a pivotal phase 3 part in 2017. A third trial namend COSMOS (CLL patients assessed for ORR & Safety in MOR208 Study) is investigating safety and efficacy of MOR208 together with idelalisib in patients with relapsed or refractory CLL or SLL after discontinuation of BTK inhibitor therapy.

Daiichi Sankyo and DarwinHealth Announce Strategic Partnership to Deploy a Quantitative Systems Biology Discovery Platform to Prioritize Daiichi Sankyo Cancer Enterprise Compounds for Development

On December 12, 2016 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) and DarwinHealth reported a strategic partnership to use quantitative systems biology-based algorithms and novel, validated approaches focused on tumor checkpoints — a new class of cancer targets — to help prioritize investigational compounds in the Daiichi Sankyo Cancer Enterprise pipeline for clinical development (Press release, Daiichi Sankyo, DEC 12, 2016, View Source [SID1234517057]).

Utilizing DarwinHealth’s proprietary, oncotecture-based technology, the vast majority of investigational compounds in the Daiichi Sankyo Cancer Enterprise portfolio will be evaluated and compared against an extensive repository of patient-derived tumor samples to measure their efficacy in disrupting the master regulator proteins that represent the most critical vulnerabilities of each specific tumor. These studies will provide a comprehensive readout of each compound’s potential clinical value, including its genome-wide mechanism of action, its tumor-specific biomarkers of sensitivity and resistance, and its ability to synergize with other drugs for combination therapy applications. Through quantitative modeling, the developmental trajectory of each potential treatment will be predicted to help Daiichi Sankyo design more effective, successful and focused clinical studies to leverage key opportunities that are currently being missed or may not be identified using traditional methodologies.

"As we begin to see quantitative science revolutionize the approach to clinical development, we are very excited about entering into this partnership with DarwinHealth," said Igor Matushansky, MD, PhD, Global Head Oncology Translational Development, Daiichi Sankyo. "These insights will help us to focus on compounds with a higher likelihood of success to ultimately ensure the best treatment options are reaching patients with cancer sooner."

"Genetics has been the basis of the development of precision medicine, but even more targeted and integrative approaches are now needed to deal with the complexity of cancer," explained Dr. Andrea Califano, Clyde and Helen Wu Professor and Chair of Systems Biology at Columbia University and co-founder of DarwinHealth. "The evolution of cancer research has expanded our universe from gene mutations to the ultimate effects these genomic alterations have on protein activity. Virtual, computation-based methods have finally achieved the accuracy necessary to systematically detect aberrantly activated proteins representing the master regulators of a cancer cell. We have created sophisticated tools, such as the VIPER algorithm, to identify tightly-knit modules of master regulator proteins – which we call tumor checkpoints – that represent a new class of actionable therapeutic targets in cancer."

Cellectar Biosciences Announces USPTO Grants Patent for Paclitaxel PDC; Provides Additional Patent Protection for Select Solid Tumors Through 2035

On December 12, 2016 Cellectar Biosciences, Inc. (Nasdaq: CLRB) (the "company"), an oncology-focused clinical stage biotechnology company, reported that the United States Patent and Trademark Office ("USPTO") has granted patent number 9,480,754 covering the method of use for CLR 1603 to treat breast, lung, colorectal and prostate cancers as well as their associated cancer stem cells (Filing, 8-K, Cellectar Biosciences, DEC 12, 2016, View Source [SID1234517049]). CLR 1603 consists of Cellectar’s proprietary phospholipid drug conjugate ("PDC") delivery platform technology using a unique chemical linker, conjugated to the chemotherapeutic agent paclitaxel.

This patent and the previously granted composition of matter patent provide intellectual property protection for CLR 1603 to the end of 2035. Earlier this year, the company announced that CLR 1603 showed an increased delivery of between 20 – 30 times that of paclitaxel alone to a tumor in a preclinical xenograft cancer model. Additionally, CLR 1603 did not require the use of Cremophor in its formulation, a desired feature as Cremophor has been linked to a number of serious adverse events. As a result, CLR 1603 improved formulation, combined with its targeted delivery, has the potential to significantly reduce adverse events typically associated with other paclitaxel-based therapies.

"This patent provides intellectual property protection for one of our most interesting paclitaxel PDCs," said Jim Caruso, president and CEO of Cellectar. "The chemotherapeutic conjugate program is an exciting addition to CLR 131, our lead radiotherapeutic PDC currently in a Phase I clinical study for relapsed or refractory multiple myeloma. We plan to initiate a Phase II trial for CLR 131 in patients with relapsed or refractory multiple myeloma and select hematologic malignancies in early 2017. We are enthusiastic about the potential of each of these programs and look forward to reporting continued progress."

About Phospholipid Drug Conjugates (PDCs)
Cellectar’s product candidates are built upon its patented cancer cell-targeting delivery and retention platform of optimized phospholipid ether-drug conjugates (PDCs). The company deliberately designed its phospholipid ether (PLE) carrier platform to be coupled with a variety of payloads to facilitate both therapeutic and diagnostic applications. The basis for selective tumor targeting of our PDC compounds lies in the differences between the plasma membranes of cancer cells compared to those of normal cells. Cancer cell membranes are highly enriched in lipid rafts, which are glycolipoprotein microdomains of the plasma membrane of cells that contain high concentrations of cholesterol and sphingolipids, and serve to organize cell surface and intracellular signaling molecules. PDCs have been tested in over 70 different xenograft models of cancer.

European Commission Grants Marketing Authorization for Arzerra® (ofatumumab) in combination with Fludarabine and Cyclophosphamide in Relapsed CLL

On December 12, 2016 Genmab A/S (Nasdaq Copenhagen: GEN) reported that the European Commission (EC) has granted a marketing authorization for the use of ofatumumab (Arzerra) in combination with fludarabine and cyclophosphamide (FC) for the treatment of adult patients with relapsed chronic lymphocytic leukemia (CLL) in the European Union (Press release, Genmab, DEC 12, 2016, View Source [SID1234517045]). The variation to the Marketing Authorization for this indication was submitted to the European Medicines Agency (EMA) in March 2016 by Novartis under the ofatumumab collaboration between Novartis and Genmab. Subsequently, on November 10, the Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion recommending that Arzerra be approved in this indication.

"We welcome this decision by the European Commission to expand the use of Arzerra, as this further broadens the treatment options for CLL patients in Europe," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

The EC’s approval was based on results from the Phase III COMPLEMENT 2 study that evaluated ofatumumab in combination with FC versus FC alone in patients with relapsed CLL. Top-line results from COMPLEMENT 2 were reported in April 2015.

About CLL
CLL is the most commonly diagnosed adult leukemia in Western countries, and accounts for approximately 1 in 4 cases of leukemia.1 Most CLL patients experience disease progression despite initial response to therapy and may require additional treatment.2

About COMPLEMENT 2
COMPLEMENT 2 (NCT00824265) is an open-label, two-arm, randomized, Phase III study, which included 365 patients in 18 countries with relapsed CLL. Patients in the study were randomized 1:1 to treatment with up to six cycles of ofatumumab in combination with fludarabine and cyclophosphamide (FC) or up to six cycles with fludarabine and cyclophosphamide alone.

The primary endpoint of the study was progression free survival (PFS), which was assessed by an Independent Review Committee (IRC) according to the International Workshop for Chronic Lymphocytic Leukaemia (iwCLL) updated 2008 National Cancer Institute-sponsored Working Group (NCIWG) guidelines.3 The study met the primary endpoint with a median progression free survival in patients receiving ofatumumab in combination with FC of 28.9 months, compared to 18.8 months in patients receiving FC alone (HR =0.67, p=0.0032). Secondary endpoints included overall response rate, overall survival, patient reported outcomes, time to response, duration of response, time to progression, time to next therapy, safety assessments and quality of life. The safety profile observed in this study was consistent with other trials of ofatumumab and no new safety signals were observed.

About Ofatumumab (Arzerra)
Ofatumumab is a human monoclonal antibody that is designed to target the CD20 molecule found on the surface of chronic lymphocytic leukemia (CLL) cells and normal B lymphocytes.
In the United States, Arzerra is approved for use in combination with chlorambucil for the treatment of previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate, for use in combination with fludarabine and cyclophosphamide for the treatment of patients with relapsed CLL, and for extended treatment of patients who are in complete or partial response after at least two lines of therapy for recurrent or progressive CLL. In the European Union, Arzerra is approved for use in combination with chlorambucil or bendamustine for the treatment of patients with CLL who have not received prior therapy and who are not eligible for fludarabine-based therapy. In more than 50 countries worldwide, Arzerra is also indicated as monotherapy for the treatment of patients with CLL who are refractory after prior treatment with fludarabine and alemtuzumab.

Under the collaboration with Novartis, a subcutaneous formulation of ofatumumab is in Phase III development for relapsing multiple sclerosis.

Please see full Prescribing Information, including Boxed WARNING for Arzerra (ofatumumab).

Arzerra is marketed under a collaboration agreement between Genmab and Novartis. Novartis has rights to develop ofatumumab in autoimmune indications, including multiple sclerosis.

SYROS PHARMACEUTICALS PRESENTS NEW PRECLINICAL DATA DEMONSTRATING SIGNIFICANT ANTI-PROLIFERATIVE EFFECTS OF ITS FIRST-IN-CLASS SELECTIVE RARΑ AGONIST IN GENOMICALLY DEFINED SUBSETS OF BREAST CANCER

On December 10, 2016 Syros Pharmaceuticals (NASDAQ: SYRS) reported the presentation of new data on SY-1425, its first-in-class selective retinoic acid receptor alpha (RARα) agonist, showing that SY-1425 inhibited tumor growth in multiple preclinical models of breast cancer driven by high levels of RARA gene expression (Press release, Syros Pharmaceuticals, DEC 10, 2016, View Source;p=irol-newsArticle&ID=2228847 [SID1234517024]). In these studies, SY-1425 showed significant anti-proliferative activity both as a single agent and in combination with standard-of-care breast cancer therapies in in vitro and in vivo models of breast cancer, including those resistant to existing treatments. These data were presented at the 39th Annual San Antonio Breast Cancer Symposium (SABCS).

"Despite tremendous progress in treating certain types of breast cancer, two of the greatest remaining challenges are our ability to identify the right treatment for the right patient and cancer’s ability to become resistant to treatment," said Nancy Simonian, M.D., Chief Executive Officer of Syros. "The new data on SY-1425 show that we have the potential to address both these challenges for subsets of breast cancer patients whose disease is driven by abnormally high expression of the RARA gene."

The data presented at SABCS show that subsets of breast cancer patients’ tumors have a highly specialized region of regulatory DNA, known as a super-enhancer, that is associated with the RARA gene and drives high levels of RARA gene expression. In preclinical models of breast cancer, high RARA gene expression was shown to be predictive of response to treatment with SY-1425. The data highlight that SY-1425:

Inhibited tumor growth in breast cancer cell lines as well as cell line-derived xenograft and patient-derived xenograft models of breast cancer with high RARA gene expression, including models of HER2-positive breast cancer resistant to treatment with trastuzumab and ER-positive breast cancer resistant to hormonal therapies. By contrast, SY-1425 did not inhibit tumor growth in models of breast cancer with low RARA gene expression.
Reduced the expression of genes responsible for tumor growth in HER2-positive and ER-positive breast cancer cells with high RARA expression.
Increased the anti-tumor effects of standard-of-care therapies, including tamoxifen and palbociclib in ER-positive breast cancer cells with high RARA expression and lapatinib in HER2-positive breast cancer cells with high RARA expression.
These data support the potential clinical development of SY-1425 in genomically defined subsets of breast cancer patients.

SY-1425 is currently in a Phase 2 clinical trial in genomically defined subsets of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients. Using its gene control platform, Syros discovered subsets of AML, MDS and breast cancer patients whose tumors have the super-enhancer associated with the RARA gene, which codes for the RARα transcription factor. The resulting over-expression of RARα locks the cells in an immature, undifferentiated and proliferative state. Treatment with SY-1425 in cancer cells with this super-enhancer promotes differentiation of these cells. Upon achieving clinical proof-of concept in AML and MDS, Syros plans to expand development of SY-1425 into genomically defined subsets of breast cancer patients.

SY-1425 is approved in Japan as Amnolake (tamibarotene) to treat relapsed or refractory APL, a form of AML that is driven by a fusion of the RARA gene with other genes. Syros in-licensed SY-1425 for development and commercialization in North America and Europe in cancer. Additional details about the ongoing Phase 2 trial in AML and MDS can be found using the identifier NCT02807558 at www.clinicaltrials.gov.