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Preliminary data suggest promising anti-tumor activity of the combination of monalizumab and cetuximab in patients with platinum pretreated SCCHN

On April 17, 2018 Euronext Paris: FR0010331421 – IPH) reported preliminary data from an ongoing Phase I/II trial evaluating the safety and efficacy of the combination of monalizumab, a first-in-class monoclonal antibody targeting NK checkpoint receptor NKG2A, with cetuximab (anti-EGFR) in previously treated patients with recurrent and/or metastatic squamous cell carcinoma of the head & neck (R/M SCCHN) (Press release, Innate Pharma, APR 17, 2018, View Source [SID1234525441]). These data are highlighted in a poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, April 14-18, in Chicago.

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Roger B. Cohen, Prof. of Medicine at the Hospital of the University of Pennsylvania, Associate Director of Clinical Research, Abramson Cancer Center Philadelphia and the lead investigator of the study, commented: "The data so far show that this therapy is active in patients with advanced head and neck cancer. The activity of cetuximab in patients previously treated with platinum salts is limited, with a response rate of around 13%. The addition of monalizumab appears to increase the response rate without potentiating the side effects of cetuximab. Since monalizumab targets a checkpoint that is different from other currently targeted immune checkpoints, it’s an interesting option as a combination partner for a variety of novel immunotherapeutic approaches".

Pierre Dodion, Chief Medical Officer of Innate Pharma, added: "While PD-1/L1 therapy is quickly changing the treatment paradigm of SCCHN, there remains a high unmet medical need for the majority of patients who don’t benefit from checkpoint inhibitor therapy. These preliminary data support further investigation of this novel combination in third line recurrent and metastatic SCCHN. We look forward to sharing updated data from the ongoing trial at medical conferences during 2018."

The highest dose tested for monalizumab in the dose-escalation portion of the study (10 mg/kg every 2 weeks) was given in combination with the approved dose and schedule of cetuximab (400 mg/m² load, then 250 mg/m² weekly) in the Phase II cohort expansion. Patients could be either HPV (-) or HPV (+) and had progressed after platinum-based therapy with a maximum of 2 prior systemic treatment regimens for R/M disease. Prior cetuximab treatment (when used for the definitive treatment of locally advanced disease in combination with radiation) and prior immuno-oncology (IO) therapy were allowed.

Among the 31 patients enrolled in the expansion part, the combination was well tolerated, consistent with previously presented data at AACR (Free AACR Whitepaper) 2017, with no additional safety concerns compared to monalizumab or cetuximab given alone. The majority of adverse events (AE) were of Grade 1-2 severity, rapidly reversible and easily manageable. No infusion-related reactions or treatment-related deaths occurred. The most frequent AEs (skin disorders) described with cetuximab were not potentiated by the combination with monalizumab.
Among the patients enrolled, as per study design, all had been previously treated with platin-containing regimens. In addition, 14 patients had been previously treated with PD-1 antibodies and 3 with prior cetuximab.
Twenty-six patients were evaluable for efficacy; the other 5 patients are too early on study to have had a post-baseline assessment. At the cut-off date of March 9, 2018, there were 8 confirmed RECIST partial responses (31%) with median time to follow-up of 129 days, achieving the predefined number of 8 responses needed to declare the trial positive. 14 patients (54%) had stable disease. Median duration of response has not yet been reached; six responders are still on treatment. The trial has now enrolled all planned patients (n=40). Further follow-up is needed to evaluate the duration of response, progression-free survival (PFS) and overall survival (OS).

H3 Biomedicine Reports Discovery of Recurrent RNA Splicing Factor Mutations in Non-Hodgkin’s Lymphoma and Multiple Myeloma

On April 17, 2018 H3 Biomedicine Inc., a clinical stage biopharmaceutical company specializing in the discovery and development of next-generation cancer medicines using its data science and precision chemistry product engine, reported novel findings from a comprehensive genomic analysis of 6,235 patients across 15 hematologic malignancies (Press release, H3 Biomedicine, APR 17, 2018, View Source [SID1234525440]). The results include the first-ever observance of recurrent RNA splicing factor mutations in non-Hodgkin’s lymphoma (NHL) and multiple myeloma (MM). While splicing factor mutations have been observed in other hematologic malignancies, including myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML) and chronic lymphocytic leukemia (CLL), the presence of these mutations in NHL and MM has not been reported previously.

Presented today at the 2018 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Chicago, these new findings demonstrate the continued emergence of splicing factor mutations as a hallmark of dozens of hematologic and solid tumor cancers, their potential role in tumor formation and growth, and, thus, the opportunity to advance a new class of therapies.
At the AACR (Free AACR Whitepaper) meeting, Dominic Reynolds, Ph.D., Vice President of Chemistry at H3 Biomedicine, also gave an oral presentation discussing the discovery of H3B-8800, the Company’s first-in-class potent, selective and orally bioavailable small molecule modulator of the SF3b complex currently in Phase I clinical trials in patients with AML, CMML and MDS with splicing factor mutations.
"We continue to uncover new insights into the prevalence of splicing factor mutations across a broad spectrum of hematologic and solid tumor cancers and are leveraging this knowledge for our existing development programs and to inform the discovery of new targets and drugs," said Peter Smith, Ph.D., chief scientific officer at H3 Biomedicine. "For example, our work presented at AACR (Free AACR Whitepaper) describes mutations that are addressed by our lead splicing modulator, H3B-8800, which we’re already evaluating in AML, MDS and CMML patients in an ongoing Phase 1 clinical study. These new findings of mutations in non-Hodgkin’s lymphoma and multiple myeloma could expand the addressable patient population for H3B-8800."

Dr. Smith continued, "Beyond our own development efforts, we hope the novel insights from this research will help advance the oncology community’s understanding of the pathogenesis of multiple myeloma and non-Hodgkin’s lymphoma and stimulate new drug discovery programs to help patients whose cancer cannot be effectively treated or cured with existing therapies."

The findings presented today were the result of an ongoing collaboration between H3 Biomedicine and Foundation Medicine Inc. (NASDAQ:FMI) to help advance the discovery and development of precision medicines in oncology. H3 Biomedicine scientists and scientists from Foundation Medicine jointly uncovered the mutations through computational biology based on the genomics data from FoundationOneHeme, Foundation Medicine’s comprehensive genomic profiling (CGP) assay for hematologic malignancies and sarcomas. H3 Biomedicine is now performing additional translational research to validate the findings.
"Comprehensive genomic profiling (CGP) is a critical tool to drive the discovery and development of precision medicines in both hematologic and solid tumor cancers," said Vincent Miller, M.D., chief medical officer at Foundation Medicine. "The inherent complexity of all cancers mandates the use of an unbiased comprehensive approach in genomic profiling to speed target identification and therapeutic options. These results obtained using FoundationOneHeme and our FoundationCore database further underscore that premise. We look forward to understanding how these findings may translate to potential new therapeutic strategies for patients."

About the Findings
H3 Biomedicine and Foundation Medicine scientists surveyed somatic mutations of several splicing factors (SF3B1, SRSF2, U2AF1, ZRSR2, DDX3X, ZMYM3, PCBP1 and U2AF2) in 6,235 patients across 15 hematological malignancies. While these mutations have been observed in MDS, AML, CMML and CLL, the frequency of these mutations in other hematological malignancies was unknown. In the analysis, 405 genes were analyzed by DNA sequencing using FoundationOneHeme,

The researchers, for the first time, identified splicing factor mutations in NHL (13.8%) and MM (9%), including hotspot somatic mutations of SF3B1, U2AF1 and SRSF2, and loss of function or missense mutations in DDX3X.
NHL-Specific Highlights
Among NHL patients, diffuse large B-cell lymphoma (DLBCL) demonstrated the highest frequency of splicing factor mutations, and these patients exhibited increased tumor mutation burden.
The RNA helicase DDX3X (an enzyme implicated in several types of cancer) was the most frequently mutated in NHL.
The majority of mutations were loss of function or missense mutations, suggesting a pathological relevance of DDX3X in lymphoid malignancies

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MM-Specific Highlights
Among MM patients, SF3B1 and SRSF2 were the two most frequently mutated genes, and patients with these mutations also exhibited increased tumor mutation burden.
Although the most common SF3B1 mutation in hematopoietic malignancies is p.K700E, the findings revealed the most frequent SF3B1 mutation in MM is p.K666.

Findings Across All 15 Hematologic Malignancies
Consistent with prior reports, the hematopoietic malignancies that demonstrated the most frequent splicing factor mutations were CMML, MDS, AML and CLL.

In addition to mutations found across the different hematopoietic malignancies in the genes SRSF2, SF3B1, U2AF1 and ZRSR2, the researchers found DDX3X to be the fifth most frequently mutated gene, followed by ZMYM3, PCBP1 and U2AF2, indicating the importance of splicing dysregulation in hematological malignancies.
For additional details, please clink here to review the abstract.
The novel discovery of splicing factor mutations in NHL and MM underscores the potential of H3’s product engine to identify previously unknown cancer drivers for the discovery and development of next-generation targeted cancer therapies. Splicing modulation is one of several research focus areas for H3.

About RNA Splicing Factor Mutations
RNA splicing is the biological process by which pre-cursor messenger RNA (pre-mRNA) is edited into a mature messenger RNA (mRNA) and, ultimately, translated into a protein. Splicing factors carry out the editing process. They are responsible for removing introns, which are a part of a pre-mRNA molecule that do not code for proteins. When RNA splicing factors are mutated, normal RNA splicing becomes aberrant, leading to gene and protein expression changes that likely play a role in tumorigenesis
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About H3B-8800 – H3 Biomedicine’s First-in-Class Splicing Modulator
H3 Biomedicine is advancing novel cancer therapies that target core splicing factor mutations. A Phase 1 study is underway in patients with hematologic malignancies for H3B-8800, H3 Biomedicine’s first spliceosome pathway-targeting cancer therapeutic. H3B-8800 is a potent, selective and orally bioavailable small molecule modulator of wild-type and mutant SF3b complex, a splicing factor gene. The Phase 1 study is evaluating the safety and preliminary efficacy of H3B-8800 in patients with myelodysplastic syndromes, acute myeloid leukemia, and chronic myelomonocytic leukemia who carry mutations in splicing factor genes. In February 2018, H3 Biomedicine published preclinical data in Nature Medicine demonstrating that H3B-8800 modulates RNA splicing and shows preferential antitumor activity in a range of spliceosome-mutant cancer models.

Genmab Announces Net Sales of DARZALEX® (daratumumab) for First Quarter of 2018

On April 17, 2018 Genmab A/S (Nasdaq Copenhagen: GEN) reported that worldwide net sales of DARZALEX (daratumumab) as reported by Johnson & Johnson were USD 432 million in the first quarter of 2018 (Press release, Genmab, APR 17, 2018, View Source [SID1234525439]). Net sales were USD 264 million in the U.S. and USD 168 million in the rest of the world. Genmab will receive royalties on the worldwide net sales of DARZALEX under the exclusive worldwide license to Janssen Biotech, Inc. to develop, manufacture and commercialize DARZALEX.

About DARZALEX (daratumumab)
DARZALEX (daratumumab) injection for intravenous infusion is indicated in the United States in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy; in combination with pomalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor (PI); and as a monotherapy for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a PI and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.1 DARZALEX is the first monoclonal antibody (mAb) to receive U.S. Food and Drug Administration (FDA) approval to treat multiple myeloma. DARZALEX is indicated in Europe for use in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy and as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a PI and an immunomodulatory agent and who have demonstrated disease progression on the last therapy. In Japan, DARZALEX is approved in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for treatment of adults with relapsed or refractory multiple myeloma. DARZALEX is the first human CD38 monoclonal antibody to reach the market. For more information, visit www.DARZALEX.com.
Daratumumab is a human IgG1k monoclonal antibody (mAb) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. Daratumumab triggers a person’s own immune system to attack the cancer cells, resulting in rapid tumor cell death through multiple immune-mediated mechanisms of action and through immunomodulatory effects, in addition to direct tumor cell death, via apoptosis (programmed cell death).1,2,3,4,5

Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license to develop, manufacture and commercialize daratumumab from Genmab. A comprehensive clinical development program for daratumumab is ongoing, including multiple Phase III studies in smoldering, relapsed and frontline multiple myeloma settings and in amyloidosis. Additional studies are ongoing or planned to assess the potential of daratumumab in other malignant and pre-malignant diseases, such as NKT-cell lymphoma, myelodysplastic syndromes, B and T-ALL and selected solid tumors. Daratumumab has received two Breakthrough Therapy Designations from the U.S. FDA, for multiple myeloma, as both a monotherapy and in combination with other therapies.. Net sales were USD 264 million in the U.S. and USD 168 million in the rest of the world. Genmab will receive royalties on the worldwide net sales of DARZALEX under the exclusive worldwide license to Janssen Biotech, Inc. to develop, manufacture and commercialize DARZALEX.

DelMar Pharmaceuticals Presents Positive Updates on Two Ongoing Clinical Trials with VAL-083 for Treatment of MGMT-unmethylated GBM

On April 17, 2018 DelMar Pharmaceuticals, Inc. (NASDAQ: DMPI) ("DelMar" or the "Company"), a biopharmaceutical company focused on the development and commercialization of new cancer therapies, reported that the Company presented a positive update on its two ongoing clinical trials of VAL-083, a first-in-class small molecule chemotherapeutic, for the treatment of MGMT-unmethylated Glioblastoma Multiforme ("GBM") at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) ("AACR") Annual Meeting (Press release, DelMar Pharmaceuticals, APR 17, 2018, View Source [SID1234525438]).

"We are pleased with the continued progress of our ongoing clinical trials with VAL-083 as a potential treatment for MGMT-unmethylated GBM," said Saiid Zarrabian, interim president and chief executive officer. "These trials are important elements of our clinical development strategy to advance VAL-083 as a potential treatment for GBM patients who have little or no viable alternatives."
DelMar presented the following updates in two poster presentations at the AACR (Free AACR Whitepaper) Annual Meeting.
1. A biomarker-driven, Phase 2 clinical trial of VAL-083 in patients with MGMT-unmethylated bevacizumab (Avastin)-naïve recurrent glioblastoma, currently being conducted in collaboration with the University of Texas MD Anderson Cancer Center.

Up to 48 patients with MGMT-unmethylated, bevacizumab-naïve, recurrent GBM, will be enrolled to determine if treatment with VAL-083 improves overall survival compared to historical reference control.
22 of a planned 48 patients have been enrolled as of March 31, 2018, compared to 15 patients enrolled as of October 31, 2017.

7 of the 22 enrolled patients (32%) have exhibited stable disease as best response.
Similar to prior clinical experience, myelosuppression has been the most common adverse event observed.
2. A Phase 1-2 clinical trial of VAL-083 in combination with radiotherapy in patients with newly diagnosed MGMT-unmethylated GBM, currently being conducted in collaboration with Sun Yat-sen University Cancer Center.
Up to 30 patients with newly diagnosed MGMT-unmethylated GBM will be treated with VAL-083 combined with radiotherapy by 24 weeks of VAL-083 maintenance therapy. The study is being conducted in two parts: (1) Dose-confirmation: VAL-083 in cohorts (20, 30 and 40 mg/m2/day IV) to assess safety and activity when administered concurrently with x-ray telescope ("XRT") to confirm the maximum tolerated dose ("MTD"), and (2) Expansion: VAL-083 will be studied in up to 20 additional patients at the target dose of 40mg/m2 VAL-083 administered concurrently with XRT.

Dose-confirmation studying 20 and 30 mg/m2/day cycles has been completed (4 patients enrolled).
No dose-limiting toxicities have been reported following treatment with multiple cycles of VAL-083.
The next patient enrolled will receive the study target dose of 40 mg/m2/day VAL-083 combined with radiation.
DelMar’s poster presentations can be viewed on the company’s website at:
View Source

About VAL-083
VAL-083 (dianhydrogalactitol) is a "first-in-class," DNA-targeting agent that introduces interstrand DNA cross-links at the N7-position of guanine leading to DNA double-strand breaks and cancer cell death. VAL-083 has demonstrated clinical activity against a range of cancers including GBM and ovarian cancer in historical clinical trials sponsored by the U.S. National Cancer Institute ("NCI"). DelMar has demonstrated that VAL-083’s anti-tumor activity is unaffected by common mechanisms of chemoresistance in vitro. Further details regarding these studies can be found at:
View Source.
VAL-083 has been granted an orphan drug designation by the U.S. FDA Office of Orphan Products for the treatment of glioma, medulloblastoma and ovarian cancer, and in Europe for the treatment of malignant gliomas. VAL-083 has been granted fast-track status for the treatment of recurrent GBM by the US FDA.

Preclinical Data Demonstrate That Deciphera Pharmaceuticals’ DCC-2618 Exhibits Broader Inhibition Profile Against Primary and Secondary Drug-Resistant Mutations in Gastrointestinal Stromal Tumors (GIST) Compared to Approved and Investigational Agents

On April 17, 2018 Deciphera Pharmaceuticals, Inc. (NASDAQ:DCPH), a clinical-stage biopharmaceutical company focused on addressing key mechanisms of tumor drug resistance, reported pre-clinical data for DCC-2618 confirming a broad spectrum of potent inhibition across primary and secondary KIT mutations and primary PDGFRα mutations (Press release, Deciphera Pharmaceuticals, APR 17, 2018, View Source [SID1234525437]). Compared to the FDA approved and investigational compounds tested in this pre-clinical study, DCC-2618 demonstrated the broadest profile of inhibition of primary and secondary KIT mutations and primary PDGFRα mutations. The data will be presented today at the 2018 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Chicago, IL in a poster titled "Inhibition of oncogenic and drug-resistant PDGFRA and KIT alterations by DCC-2618".

Deciphera is currently evaluating DCC-2618 in multiple clinical studies including INVICTUS, a Phase 3 pivotal study in 4th line and 4th line plus GIST patients, and in a Phase 1 study in other KIT and/or PDGFRα-driven diseases, including 2nd line to 4th line plus GIST, SM, glioblastoma multiforme and other cancers. Deciphera expects to initiate a Phase 3 registration study in 2nd line GIST patients in the second half of 2018 and to report top-line data from the ongoing INVICTUS study in 2019.

"In GIST patients receiving FDA approved therapies, secondary drug resistance KIT mutations frequently result in disease progression. Our pre-clinical results confirm that among the kinase inhibitors tested, both approved and investigational, DCC-2618 exhibits the broadest profile of inhibition against these heterogenous, difficult to treat mutations," said Michael D. Taylor, Ph.D., Deciphera’s President and Chief Executive Officer. "A significant need exists for therapies with the potential to address both activating mutations and other genetic alterations in KIT and PDGFRα, which have been identified in >85% of patients with GIST and >90% of patients with systemic mastocytosis."

These data describe the breadth of inhibition achieved with DCC-2618 and its active metabolite, DP-5439, across both primary and secondary KIT mutations and primary PDGFRα mutations compared to the in vitro profiles of the FDA-approved kinase inhibitors, imatinib, sunitinib, regorafenib, midostaurin and the investigational agent, avapritinib (BLU-285). Highlights from the poster include:

DCC-2618, a Type II switch control kinase inhibitor of KIT and PDGFRα, broadly inhibits KIT mutants in exons 9, 11, 13, 14 17, and 18 and PDGFRα mutants in exons 12, 14, and 18, forcing even aggressively activated kinase mutants into a Type II inactive conformation.

Compared to the approved and investigational compounds tested, DCC-2618 and its active metabolite, DP-5439, exhibit the broadest profile of inhibition across primary and secondary drug-resistant KIT mutations, and primary PDGFRα mutations.

Other Type II inhibitors, such as imatinib, sunitinib and regorafenib, do not broadly inhibit KIT exon-17 mutations or mutations in PDGRFα while Type I inhibitors, such as avapritinib (BLU-285), have weaker activity against KIT mutations in exons 13 and 14.

DCC-2618 also exhibited a superior exon 9 KIT mutation profile compared to imatinib, sunitinib, and avapritinib (BLU-285), including complex KIT mutations involving exon 9 coupled with secondary KIT mutations in exons 13, 14, and 17.

In enzyme assays at relevant cellular levels of adenosine triphosphate (ATP), DCC-2618 broadly inhibited primary and drug-resistant KIT mutants and primary PDGFRα mutants. DCC-2618 also broadly inhibited KIT and PDGFRα mutations in a panel of GIST, mastocytosis, leukemia, lung cancer, and transfected cell assays, as well as in various in vivo xenograft models.

As previously reported, translational liquid biopsy data from the Phase 1 clinical trial has shown that in heavily pre-treated GIST patients, many of whom had received all three of the FDA approved drugs for GIST, DCC-2618 decreased mutant KIT circulating tumor DNA (ctDNA) across the spectrum of KIT exons 9, 11, 13, 14, 17, and 18.

About DCC-2618
DCC-2618 is a KIT and PDGFRα kinase switch control inhibitor in clinical development for the treatment of KIT and/or PDGFRα-driven cancers, including gastrointestinal stromal tumors, systemic mastocytosis and glioblastoma multiforme. DCC-2618 was specifically designed to improve the treatment of GIST patients by inhibiting a broad spectrum of mutations in KIT and PDGFRα. DCC-2618 is a KIT and PDGFRα inhibitor that blocks initiating KIT mutations in exons 9, 11, 13, 14, 17, and 18, involved in GIST as well as the primary D816V exon 17 mutation involved in SM. DCC-2618 also inhibits primary PDGFRα mutations in exons 12, 14,and 18, including the exon 18 D842V mutation, involved in a subset of GIST.