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. Schedule your 30 min Free 1stOncology Demo! 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.
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"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.
Author: [email protected]
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. Schedule your 30 min Free 1stOncology Demo! "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.
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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).
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"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.
Seattle Genetics Highlights Phase 1 Data for Novel Antibody-Drug Conjugate SGN-LIV1A in Patients with Metastatic Breast Cancer at San Antonio Breast Cancer Symposium
On December 10, 2016 Seattle Genetics, Inc. (NASDAQ: SGEN), a global biotechnology company, reported data from an ongoing phase 1 clinical trial evaluating SGN-LIV1A for patients with metastatic breast cancer (MBC), with particular focus on triple-negative MBC (TN MBC), at the 39th San Antonio Breast Cancer Symposium (SABCS) taking place in San Antonio, Texas, December 6-10, 2016 (Press release, Seattle Genetics, DEC 10, 2016, View Source;p=RssLanding&cat=news&id=2228848 [SID1234517023]). SGN-LIV1A is an investigational antibody-drug conjugate (ADC) which consists of a LIV-1-targeted monoclonal antibody linked to the cell-killing agent monomethyl auristatin E (MMAE) by a protease-cleavable linker. LIV-1 is a protein expressed by most metastatic breast cancers. SGN-LIV1A is one of four clinical-stage empowered antibody therapies under development by Seattle Genetics for solid tumors.
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"Breast cancer is the most common cancer among women, with an estimated 1.67 million new cases per year worldwide. About 15 to 20 percent of breast cancers are triple negative, which means they lack expression of three breast cancer-associated proteins that serve as key therapeutic targets. Triple-negative breast cancers are more aggressive and generally have poor prognoses," said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. "The data presented at SABCS on SGN-LIV1A demonstrate promising early antitumor activity with a 37 percent partial response rate in patients with triple negative metastatic breast cancer, for which there are no available targeted treatments. We are enrolling additional patients with triple negative metastatic breast cancer in our phase 1 study to optimize the dose and inform the next steps for development of SGN-LIV1A in this population with high unmet need."
Interim data from the ongoing phase 1 study of SGN-LIV1A in patients with MBC were previously presented at the 2015 SABCS. The following updated results from this trial describe safety data for all patients and antitumor activity data for patients with TN MBC.
Interim Analysis of a Phase 1 Study of the Antibody-Drug Conjugate SGN-LIV1A in Patients with Metastatic Breast Cancer (Poster# P6-12-04, Poster Session 6 – Treatment: New Drugs and Treatment Strategies at 7:30 – 9:00 a.m. CT on Saturday, December 10, 2016)
Data were reported from 53 patients with LIV-1-expressing MBC who were treated with SGN-LIV1A monotherapy administered every three weeks. Of these patients, 35 had TN MBC. The median age of all patients was 56 years. Patients had received a median of four prior systemic therapies for metastatic disease. Key findings presented by Dr. Andres Forero-Torres, University of Alabama at Birmingham included:
Thirty of 47 efficacy-evaluable patients had TN MBC. Among these patients, 11 (37 percent) achieved a partial response (PR). The disease control rate (DCR) was 67 percent and the clinical benefit rate (CBR) was 47 percent. DCR is defined as patients achieving a complete response (CR), PR or stable disease (SD). CBR is defined as patients achieving CR or PR of any duration plus patients achieving SD lasting at least 24 weeks.
At the time of this interim data analysis, the estimated median progression-free survival for TN MBC patients was 12 weeks with seven patients remaining on treatment.
The maximum tolerated dose was not reached among doses ranging from 0.5 to 2.8 milligrams per kilogram (mg/kg). Dose escalation is complete and a disease-specific expansion cohort of TN MBC patients is currently enrolling.
For all patients in the study, the most common adverse events of any grade occurring in 20 percent or more of patients included fatigue (57 percent), nausea (53 percent), alopecia (42 percent), decreased appetite (34 percent) and constipation (32 percent).
The incidence of grade 3/4 neutropenia at the 2.5 mg/kg dose was 50 percent. Two patients (seven percent) experienced febrile neutropenia, and there was one treatment-related death due to sepsis. Based on these safety data, a separate expansion cohort at 2.0 mg/kg is currently being evaluated.
Peripheral neuropathy events occurred in 38 percent of patients and were generally low grade and manageable.
Enrollment continues for patients with TN MBC in the SGN-LIV1A monotherapy part of the study. In addition, enrollment is ongoing for patients with HER2+ breast cancer to evaluate SGN-LIV1A in combination with trastuzumab.
More information about the SGN-LIV1A phase 1 clinical trial, including enrolling centers, is available by visiting www.clinicaltrials.gov.
About SGN-LIV1A
SGN-LIV1A is a novel investigational ADC targeted to LIV-1 protein utilizing Seattle Genetics’ proprietary ADC technology. LIV-1 is expressed by most metastatic breast cancers. It has also been detected in a number of other cancers, including melanoma, prostate, ovarian, and cervical cancer. SGN-LIV1A consists of a LIV-1-targeted monoclonal antibody linked to a potent microtubule-disrupting agent, monomethyl auristatin E (MMAE) by a protease-cleavable linker, using the same technology as ADCETRIS (brentuximab vedotin). It is designed to bind to LIV-1 on cancer cells and release the cell-killing agent into target cells upon internalization. SGN-LIV1A may also cause antitumor activity through other mechanisms, including activation of an immune response.
About Breast Cancer
Breast cancer is a cancer which forms in breast tissue. Metastatic breast cancer occurs when the cancer has spread to other parts of the body. While most new diagnoses of breast cancer are made at an early stage, approximately one-third of these patients will eventually develop recurrent or metastatic disease. Breast cancers are commonly categorized by the expression (or lack thereof) of three key proteins, which serve are targets for therapeutics. These include the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Triple-negative breast cancer (TNBC) lacks all three proteins and HR+/HER2- breast cancer expresses one or both hormone receptors (HR) but not HER2. According to the World Health Organization, breast cancer is the second most common cancer in the world and the most frequent cancer among women with an estimated 1.67 million new cancer cases diagnosed in 2012. Furthermore, breast cancer ranks as the fifth cause of death from cancer overall. New treatment approaches are needed to improve outcomes for breast cancer patients, particularly for those with TNBC where there are currently no available targeted therapies.
Corcept Therapeutics Announces Encouraging Results of Phase 1/2 Trial of Mifepristone Plus Eribulin in Triple-Negative Breast Cancer
On December 10, 2016 Corcept Therapeutics Incorporated (NASDAQ: CORT pharmaceutical company engaged in the discovery, development and commercialization of drugs that treat severe metabolic, psychiatric and oncologic disorders by modulating the effects of the stress hormone cortisol, reported efficacy data today from its Phase 1/2 trial of mifepristone to treat patients with metastatic (TNB). The data were presented at the 2016 San Antonio Breast Cancer Symposium (Press release, Corcept Therapeutics, DEC 10, 2016, http://www.corcept.com/news_events/view/pr_1481381366 [SID1234517022]).
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"The results of this trial support our hypothesis that cortisol modulation augments the benefits of chemotherapy in solid-tumor cancers that express the glucocorticoid receptor (GR)," said Joseph K. Belanoff, MD, Corcept’s Chief Executive Officer. "As we have mentioned before, we are excited to report that investigators at the University of Chicago are leading a multi-center, placebo-controlled, Phase 2 trial of mifepristone in combination with nab-paclitaxel (Abraxane) to treat patients with advanced TNBC."
"Our oncology program continues to gain in depth and breadth," said Robert S. Fishman, MD, Corcept’s hief Medical Officer. "The Phase 1/2 trial of our proprietary cortisol modulator, CORT125134, continues to progress. Next year we plan to study this compound’s efficacy, in combination with Abraxane, as a treatment for patients with TNBC and ovarian cancer. Early next year, we will also advance to the clinic the selective cortisol modulator, CORT125281, which has shown great promise in animal models of castration-resistant prostate cancer (CRPC). Our study of selective cortisol modulators fits well with the important work with mifepristone being performed by University of Chicago investigators, who are leading a multi-center, double-blind, controlled Phase 2 trial of mifepristone plus enzalutamide (Xandie) in CRPC and are leading, as Dr. Belanoff said, a multi-center, placebo-controlled Phase 2 trial of mifepristone in combination with Abraxane to treat patients with TNBC."
Efficacy Results in Corcept’s Phase 1/2 Trial of Mifepristone to Treat TNBC
This open-label trial was designed to investigate whether the addition of mifepristone enhances the effect of denibulin (Halaven) in patients with TNBC whose tumors express GR, one of the receptors to which mifepristone binds.
The trial studied 21 patients with GR positive tumors, one with a GR negative tumor and one whose GR status is not known. As determined using the Response Evaluation Criteria in Solid Tumors (RECIST), efficacy results in this group were as follows: Four patients exhibited a partial response, defined as a 30 percent or greater reduction in tumor size, eight had stable disease and 11 had progressive disease. patient (who has exhibited a partial response) continues therapy (see Figure 1).
Figure 1
"These data are encouraging," said Dr. Fishman. "Six patients achieved progression-free survival (PFS) longer than the upper bound for PFS (15 weeks) in patients receiving Halaven monotherapy in a comparable population (Aegis et al., Annals of Oncology 23: 1441-1448, 2012). Median PFS in our trial was 11.1 weeks – compared to 7.2 weeks in the Halaven monotherapy study reported by Aegis. We continue to collect overall survival data. Eight study patients are known to be alive."
About TNBC
TNBC is a form of breast cancer in which the three receptors that fuel most breast cancer growth – estrogen, progesterone and HER-2 – are not present. Because the tumor cells lack these receptors, treatments that target estrogen, progesterone and HER-2 are ineffective. Approximately 40,000 women are diagnosed with triple-negative breast cancer each year. It is estimated that more than 75 percent of these women’s tumor cells express GR. There is no FDA-approved treatment and neither a targeted treatment nor an app oved standard chemotherapy regimen for relapsed triple-negative breast cancer patients exists. Corcept has licensed patents from the University of Chicago covering the use of GR antagonists in combination with chemotherapy to treat TNBC and castration-resistant prostate cancer.
About CRPC
Castration-resistant prostate cancer (CRPC) is a form of the disease that progresses despite androgen receptor blockade. There are approximately 130,000 patients with metastatic CRPC in the United States. The prognosis for patients with metastatic disease is poor.
About Mifepristone
Mifepristone is the active ingredient in Corcept’s product, Korlym 300mg tablets, which the FDA has approved for the once-daily oral treatment of hyperglycemia secondary to endogenous Cushing’s syndrome in adult patients with glucose intolerance or diabetes mellitus type 2 who have failed surgery or are not candidates for surgery. Korlym (mifepristone) ameliorates the symptoms of Cushing’s syndrome by modulating the activity of cortisol at GR, one of the two receptors to which cortisol binds. Korlym was the first FDA-approved treatment for that illness and the FDA has designated it as an Orphan Drug for that indication.