On June 3, 2019 Dynavax Technologies Corporation (NASDAQ: DVAX), reported increasingly favorable results from the Phase 1b/2 (SYNERGY-001), open-label, multicenter study of the combination of SD-101 and KEYTRUDA (pembrolizumab) in advanced melanoma patients who are naïve to anti-PD-1/PD-L1 treatment (Press release, Dynavax Technologies, JUN 3, 2019, View Source [SID1234536807]). The results were presented today in a poster session at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.

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"To consistently see an overall response rate above 70% among advanced melanoma patients, which has historically been a difficult population to treat, is very encouraging and exciting," said Robert Janssen, M.D., chief medical officer of Dynavax. "Additionally, in response to treatment, we have seen immunologically cold tumors reach similarly high levels of immune cell activation as immunologically hot tumors."

The Phase 1b/2 clinical study (NCT02521870) in patients with advanced melanoma is ongoing. In the study, SD-101 is administered intratumorally with 8 mg in 1 lesion or 2 mg in 1–4 lesions combined with intravenous administration of 200 mg of pembrolizumab.

Key highlights from the clinical data presentation include:

Efficacy:
º The overall response rate (ORR) in the SD-101 2 mg/lesion group (76%) was higher than in the SD-101 8 mg/lesion group (49%)
º The median duration of response (DOR) in both groups has not been reached, with the lower bound of the 95% confidence interval of at least 14 months
º The 18-month progression free survival (PFS) rate in the SD-101 2 mg/lesion group (72%) was higher than in the SD-101 8 mg/lesion group (36%)
º Similar rates of responses occurred in patients with PD-L1 negative tumors and PD-L1 positive tumors
º Tumor shrinkage has been observed in both injected and non-injected lesions, including visceral lesions such as the liver and lung

Immunologically cold tumors are a therapeutic challenge for anti-PD-1 therapy; the ability of SD-101 with pembrolizumab to convert cold tumors (PD-L1 negative, low IFNγ and T cell signature at baseline) into T cell rich tumors is demonstrated by biomarker data in the samples tested
º This ability to convert cold into inflamed tumors is consistent with similar effects in head and neck squamous cell carcinoma (HNSCC) (ASCO 2019, Abstract 6039)

The superior induction of infiltrating effector immune cells in lesions treated with the 2 mg/lesion dose compared with 8 mg/lesion is consistent with the increased response observed

The combination of SD-101 and pembrolizumab was well tolerated, consistent with previous report
º AEs associated with SD-101 were transient, mild to moderate injection-site reactions and flu-like symptoms that were manageable with over-the-counter medications
º No increase in immune-related AEs over pembrolizumab monotherapy were observed
A table accompanying this announcement is available at View Source

The ORR in patients with BRAF mutant tumors who received 2 mg/lesion (n=18) was 61%
The ORR in patients with PD-L1 negative tumors who received 2 mg/lesion (n=14) was 79%
In addition, the company presented data from the Phase 1b/2, open label, multicenter, study of the combination of SD-101 and pembrolizumab in patients with advanced/metastatic melanoma resistant to anti-PD-1/PD-L1 therapy.

Key highlights from the clinical data presentation include:

Efficacy results from the combination of SD-101 and pembrolizumab in confirmed PD-1 resistant or refractory patients demonstrated an 19.4% ORR in the SD-101 2 mg/lesion group and a 13.3% ORR in the SD-101 8 mg/lesion group
Responses were observed in SD-101 injected and non-injected lesions (including liver and lung metastases)
Responses and disease control were observed in BRAF mutant or wild type tumors
Biomarker data demonstrate that SD-101 added to pembrolizumab significantly changes the tumor microenvironment of patients that previously failed PD-1 blockade including the infiltration of activated T cells, NK cells, and B cells
The combination of SD-101 and pembrolizumab was well tolerated, consistent with previous reports
º No evidence of an increased incidence or severity of AEs over pembrolizumab monotherapy
º No increase in immune-related AEs over pembrolizumab monotherapy
º AEs associated with SD-101 were mainly mild to moderate injection-site reactions and flu-like symptoms that were manageable with over-the-counter medications
In addition, a poster titled: "Overcoming genetically based resistance mechanisms to PD-1 blockade" (Abstract No: 2584) was presented. The goal of the preclinical study was to assess mechanism-based strategies to overcome resistance to anti-PD1 therapy. Results demonstrated that even in the extreme setting of genetic resistance to PD-1 blockade by JAK1/2 LoF, resistance can be overcome by SD-101, a TLR9 agonist.

About SYNERGY-001 (KEYNOTE-184)
SYNERGY-001, previously referred to as MEL-01, is a Phase 1b/2 SYNERGY-001/KEYNOTE-184 trial in combination with KEYTRUDA which includes patients with histologically or cytologically confirmed unresectable Stage IIIC/IV melanoma. The primary endpoint of the trial is objective response rate assessed by RECIST v1.1. The secondary endpoints are safety and tolerability, progression-free survival and duration of response, with an exploratory endpoint of immunophenotype of the tumor microenvironment.

About SD-101
SD-101 is a proprietary, second-generation, Toll-like receptor 9 (TLR9) agonist CpG-C class oligodeoxynucleotide. Dynavax is evaluating SD-101 in several clinical studies to assess its safety and activity, including a Phase 2 study in combination with KEYTRUDA (pembrolizumab) in advanced melanoma and metastatic or recurrent head and neck squamous cell cancer in collaboration with Merck, and in high risk breast cancer in collaboration with I-SPY 2. Dynavax maintains all commercial rights to SD-101.

On June 3, 2019 DelMar Pharmaceuticals, Inc. (NASDAQ: DMPI) ("DelMar" or the "Company"), a biopharmaceutical company focused on the development of novel cancer therapies reported clinical updates from the Company’s ongoing first- and second-line trials in patients with MGMT-unmethylated glioblastoma multiforme (GBM) at a key opinion leader (KOL) forum focused on brain tumors and the role of VAL-083 to address the unmet medical need in GBM during the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting in Chicago, IL (Press release, DelMar Pharmaceuticals, JUN 3, 2019, View Source;and-second-line-trials-in-patients-with-mgmt-unmethylated-glioblastoma-at-a-key-opinion-leader-forum-during-the-american-society-of-clinical-oncology-asco-annual-meeting [SID1234536806]).

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At the KOL forum, the Company provided an update on the ongoing Phase 1/2 clinical study investigating the front line treatment of VAL-083 with radiation therapy in newly diagnosed MGMT-unmethylated GBM. This trial is being conducted at the Sun Yat-sen University Cancer Center (SYSUCC) in Guangzhou, China in collaboration with Guangxi Wuzhou Pharmaceutical Company. The trial is designed to enroll up to 30 patients to determine if first-line therapy with VAL-083 treatment, in lieu of first-line temozolomide, improves progression free survival (PFS).

As of May 17, 2019, eighteen patients have been enrolled in the trial. Of these patients, fifteen have received their post-cycle 3 MRI and investigator assessment, and ten have received their post-cycle 7 MRI and investigator assessment. Two patients have not been on the study long enough to reach their first assessment, and one patient died before their first assessment. Assessments are based on the trial investigator’s clinical and radiologic assessment, according to the Response Assessment in NeuroOncology (RANO) criteria. For the fifteen patients who have received at least one assessment, eight patients were assessed with a best response of "Complete Response" (8/15, 53.3% CR) and seven patients were assessed with a best response of "Stable Disease" (7/15, 46.7% SD). Fourteen of the eighteen patients were still alive at the data cut-off date.

The Company also provided an update on the ongoing second-line Phase 2 clinical study of VAL-083 in patients with MGMT-unmethylated, Bevacizumab-naïve recurrent GBM. This study is being conducted in collaboration with The University of Texas MD Anderson Cancer Center (MDACC). This biomarker-driven trial (testing for MGMT methylation status) has been amended to enroll up to 83 patients (35 with a starting dose of 40 mg/m2; 48 with a starting dose of 30 mg/m2) to determine the potential of VAL-083 treatment to improve overall survival compared to historical reference control of 7.2 months with lomustine.

As of May 5, 2019, 51 patients have been enrolled, 35 patients at a starting dose of 40 mg/m2, and 16 patients at a starting dose of 30 mg/m2.
For the 47 patients who have been on study long enough to be assessed at the post-cycle 2 MRI:
9/35 (25.7%) patients initially receiving 40 mg/m2 exhibited "Stable Disease" per investigator assessment at the end of cycle 2
4/12 (33.3%) patients initially receiving 30 mg/m2 exhibited "Stable Disease" per investigator assessment at the end of cycle 2
Additionally, the study protocol has been amended to include enrollment of up to 24 newly-diagnosed GBM patients who have completed chemoradiation treatment with TMZ and received no subsequent TMZ maintenance therapy but will receive VAL-083 instead (Group 2). This Group has been included to explore whether earlier intervention with VAL-083 instead of TMZ maintenance therapy offers clinical benefit and extends the time to recurrence as compared to TMZ maintenance therapy.

Consistent with prior studies, myelosuppression (primarily thrombocytopenia and neutropenia) is the most common adverse event in both ongoing clinical trials.

"We are pleased with the progress to date with our two Phase 2 programs for VAL-083. In our view, these results support the preclinical and prior clinical efficacy that was observed in the MGMT-unmethylated GBM population. Additionally, we continue to view the 2017 revised NCCN guidelines for MGMT-unmethylated GBM patients quite favorably for VAL-083, which cautions against the use of temozolomide (TMZ) for this particular patient population. The MGMT-unmethylated patients represent over 60% of the GBM cases and the revised NCCN guidelines expand the therapeutic opportunity for VAL-083 to all major lines of GBM treatment from front-line and maintenance as well as second line (recurrent) GBM," commented Saiid Zarrabian, DelMar’s Chief Executive Officer.

About VAL-083

VAL-083 (dianhydrogalactitol) is a "first-in-class", bifunctional DNA-targeting agent that introduces inter-strand 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, including MGMT, in cancer cell models and animal studies. Further details regarding these studies can be found at:

View Source

VAL-083 has been granted orphan drug designations 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

On June 3, 2019 DelMar Pharmaceuticals, Inc. (NASDAQ: DMPI) ("DelMar" or the "Company"), a biopharmaceutical company focused on the development and commercialization of new cancer therapies, reported that it entered into securities purchase agreements with certain institutional investors in connection with a registered direct offering of an aggregate of 1,170,000 shares of common stock and, in a concurrent private placement, warrants to purchase 760,500 shares of common stock (Press release, DelMar Pharmaceuticals, JUN 3, 2019, View Source [SID1234536805]). The combined purchase price for one share of common stock and each warrant will be $3.10, for aggregate gross proceeds of $3.6 million. The warrants have an exercise price of $3.10 per share, are immediately exercisable and have a term of exercise of five years. The offering and concurrent private placement are expected to close on or about June 5, 2019, subject to the satisfaction of customary closing conditions.

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Maxim Group LLC is acting as the lead placement agent and Dawson James Securities, Inc. is acting as co-placement agent in connection with the offering and concurrent private placement.

DelMar currently intends to use the net proceeds of the offering and concurrent private placement for its clinical trials and for general corporate purposes, which may include working capital, capital expenditures, research and development and other commercial expenditures. In addition, DelMar may use the net proceeds for investments in businesses, products or technologies that are complementary to its business.

The shares are being offered pursuant to an effective shelf registration statement on Form S-3, as amended (File No. 333-213601), that was previously filed with the Securities and Exchange Commission ("SEC") and declared effective on September 27, 2016. A prospectus supplement relating to and describing the terms of the offering will be filed with the SEC and will be available on the SEC’s website at www.sec.gov. The offering is being made only by means of a prospectus and related prospectus supplement, copies of which may be obtained, when available, from Maxim Group LLC, 405 Lexington Avenue, New York, NY 10174, Attention: Syndicate Department, or via email at [email protected] or telephone at (212) 895-3745.

This press release shall not constitute an offer to sell, or the solicitation of an offer to buy, nor may there be any sale of these securities in any state or jurisdiction in which such an offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.

On June 3, 2019 Constellation Pharmaceuticals, Inc. (Nasdaq: CNST), a clinical-stage biopharmaceutical company using its expertise in epigenetics to discover and develop novel therapeutics, reported the presentation of updated interim data from MANIFEST, the Company’s Phase 2 clinical trial of CPI-0610 in MF (Press release, Constellation Pharmaceuticals, JUN 3, 2019, View Source [SID1234536803]). The interim data, which highlight the tolerability and potentially disease-modifying activity of CPI-0610, were presented in a poster at the annual meeting of the American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago.

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"We are excited by these interim data from the MANIFEST trial, which indicate that CPI-0610 is generally well-tolerated and showed signs that it is an active therapeutic agent for the treatment of myelofibrosis, both as a monotherapy and in combination with a standard-of-care JAK inhibitor," said Adrian Senderowicz, M.D., Chief Medical Officer at Constellation Pharmaceuticals. "Moreover, as these data highlight improvements across key hallmarks of myelofibrosis, we believe that CPI-0610 has the potential to address a broad range of unmet needs in patients with this difficult-to-treat cancer. We look forward to the continued evaluation of CPI-0610 in this ongoing Phase 2 trial and to providing additional data from MANIFEST later this year."

The data were gathered from 44 patients enrolled as of April 17, 2019. Twelve patients received 24-week assessments and 16 patients received 12-week assessments. Below is a summary of results from the interim update across primary and secondary endpoints from the trial:

14 of 16 evaluable patients demonstrated spleen volume reductions. Overall, the median best on-trial spleen volume change from baseline was -19.2%.

Of these 16 evaluable patients, 11 were evaluable for improvement in Total Symptom Score (TSS) according to the Myelofibrosis Symptom Assessment Form, Version 4.0. Six of the 11 (55%) evaluable patients achieved greater than 50% TSS improvement from baseline as a best response.

All of these 16 patients were evaluable for Patient Global Impression of Change (PGIC). Fifteen of 16 (94%) evaluable patients reported improvements in PGIC, of which 10 reported feeling either "much improved" or "very much improved" and no patients reported feeling worse following treatment.

Of 12 evaluable patients who received at least 24 weeks of treatment, three were severely anemic and dependent on red-blood-cell transfusions at baseline. Of these three patients, two converted to transfusion independence. These two patients have remained transfusion independent for more than 69 and 24 weeks, respectively, as of April 17, 2019, and remain on trial.

Ten patients were evaluable for bone marrow fibrosis, of which six (60%) experienced improvement in bone marrow morphology of at least one point on a scale of 0-3. Four of these six patients exhibited improvements within six months of starting CPI-0610 therapy.
Based on the interim data, CPI-0610 was generally well-tolerated, both as a monotherapy and in combination with ruxolitinib. Overall, the most commonly reported side effects (≥10%) were diarrhea, vomiting, upper respiratory tract infection, headache, epistaxis, fatigue, dysgeusia, cough and pruritis. Grade 3 or greater treatment-emergent adverse events were only reported in the combination arm, and those reported in more than one patient included thrombocytopenia, anemia, and decreased platelet counts, each of which was reported in two patients. There was one patient death, which the Company assessed as unlikely to have been related to CPI-0610. The combination therapy of CPI-0610 and ruxolitinib showed a non-cumulative, manageable, and mostly reversible asymptomatic thrombocytopenia.

Each of the first four patients enrolled in MANIFEST, of which two received CPI-0610 as a monotherapy and two received CPI-0610 in combination with ruxolitinib, remained on therapy and had been treated for approximately 16 and 20 months, respectively, as of April 17, 2019.

Please see the poster in the Investors & Media section of Constellation’s website for additional details.

As previously announced in November 2018, Constellation expanded the MANIFEST trial to include a third cohort, designed to evaluate CPI-0610 in combination with ruxolitinib as a first-line therapy in JAK-inhibitor-naïve patients with advanced MF. The Company has begun treating patients in this arm of the trial and expects to provide initial results from this cohort, as well as additional data from the ruxolitinib-resistant and -refractory (second-line) cohorts, in the fourth quarter of 2019.

Investor Event

Constellation will host an analyst/investor meeting, with an accompanying conference call and webcast, to discuss this interim update in the Jackson Park D room at Hyatt Regency McCormick Place in Chicago at 8:00 AM EDT/7:00 AM CDT on June 4, 2019. The agenda of the meeting will include:

An overview of myelofibrosis (MF) and the potential impact of Constellation’s BET inhibitor CPI-0610 in treating MF
A review of the interim data from the MANIFEST clinical trial presented in a poster at ASCO (Free ASCO Whitepaper) on June 3
A panel discussion with two key opinion leaders in MF:
Dr. Srdan Verstovsek, a medical oncologist at the University of Texas MD Anderson Cancer Center and an investigator in the MANIFEST trial; and
Dr. Raajit Rampal, a hematologic oncologist at Memorial Sloan Kettering Cancer Center
The event will be webcast live and can be accessed on the Investor Relations section of Constellation’s website at View Source Participants may also access the event and participate in the live question-and-answer session by dialing (877) 473-2077 (domestic) or (661) 378-9662 (international) and referring to conference ID 1295319.

Medical Presentation at EHA (Free EHA Whitepaper)

Dr. Ronald Hoffman of Mt. Sinai Health System, an investigator in the MANIFEST trial, will make an oral presentation on this interim update of MANIFEST at the European Hematology Association (EHA) (Free EHA Whitepaper) annual meeting at 12:15 PM CEST/6:15 AM EDT on June 15, 2019. Slides from the presentation will be posted to Constellation’s website.

About MANIFEST

MANIFEST is an open-label Phase 2 clinical trial of CPI-0610 in patients with myelofibrosis (MF), a rare cancer of the bone marrow that disrupts the body’s normal production of blood cells. Constellation is evaluating CPI-0610, either as a monotherapy or in combination with ruxolitinib, in a second-line setting in patients with MF who are refractory to or intolerant of or have relapsed or lost response to ruxolitinib. Patients in the two second-line arms are being stratified based on transfusion-dependent status. The primary endpoint for the cohorts with transfusion-dependent patients is conversion to transfusion independence for 12 consecutive weeks. The primary endpoint for the patients who were not transfusion-dependent at baseline is spleen volume reduction. In addition, the Company added a third arm designed to evaluate treatment with CPI-0610 in combination with ruxolitinib as a first-line therapy in JAK-1/2-inhibitor-naïve MF patients.

On June 3, 2019 Celgene Corporation (NASDAQ: CELG) reported an updated analysis of data from the Phase 2 JAKARTA2 clinical study demonstrating clinically meaningful response rates with investigational fedratinib in patients with myelofibrosis previously treated with ruxolitinib (Press release, Celgene, JUN 3, 2019, View Source [SID1234536802]). This updated analysis of fedratinib employed intent-to-treat (ITT) principles and utilized a narrower definition of ruxolitinib relapsed, refractory, or intolerant patients. Results were shared in a poster presentation today at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago.

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In the ITT population (n=97), the proportion of patients who exhibited a 35% or greater reduction in spleen volume at end of cycle 6 was 31% (95% CI 22, 41). Of these 97 patients, 79 (81%) met the narrower criteria for ruxolitinib resistance or intolerance. In this cohort, the proportion of patients who exhibited a 35% or greater reduction in spleen volume at end of cycle 6 was 30% (95% CI 21, 42), consistent with the response rate observed in the ITT population. In addition, the proportion of patients who exhibited a 50% or greater symptom response rate was 27% in both the ITT population (95% CI, 18, 37) and the patients in the analysis of the narrower criteria (95% CI, 17, 39).

The most common grade 3–4 hematologic abnormalities were anemia (46%) and thrombocytopenia (24%). Most common non-hematologic treatment-emergent adverse events (TEAEs) in all treated patients were diarrhea (62%), nausea (56%), vomiting (41%), and constipation (21%).

"Myelofibrosis is a serious and rare bone marrow disorder for which there is only one currently approved treatment option," said Claire N. Harrison, M.D., Deputy Clinical Director of Cancer and Haematology at a NHS Foundation Trust Hospital in London. "Patients may become intolerant or resistant to the therapy. These updated results show meaningful reductions in spleen volume and symptoms and reinforce the potential of fedratinib in these difficult-to-treat patients who no longer receive benefit from ruxolitinib."

"Fedratinib has the potential to be the first new treatment option since 2011 for patients with myelofibrosis," said Dr. Alise Reicin, President, Global Clinical Development, for Celgene. "Patients with myelofibrosis who are relapsed, refractory or intolerant to ruxolitinib represent a population of particularly high unmet medical need and we are committed to bringing this important treatment option forward."

About JAKARTA2
JAKARTA2 is a Phase 2, multicenter, open label, single-arm trial that evaluated the efficacy of a once daily dose of fedratinib (400 mg starting dose) in patients previously treated with ruxolitinib and with a diagnosis of intermediate-1 with symptoms, intermediate-2 or high-risk primary myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis. The study included 97 subjects across 40 sites in 10 countries.

The primary endpoint was spleen volume response rate, defined as the proportion of patients who had a reduction in spleen volume of at least 35% as measured by MRI or CT scan after six one-month treatment cycles. Secondary endpoints included symptom response rate, defined as the proportion of patients with a 50% or greater reduction in Total Symptom Score after six one-month treatment cycles as measured by the modified Myelofibrosis Symptoms Assessment Form (MFSAF) v2.0 diary.

In August 2017, the FDA removed the clinical hold on the fedratinib development program that it had placed in 2013, following potential cases of Wernicke’s encephalopathy (WE) being reported in eight out of 877 patients receiving one or more doses (less than 1% of treated patients). WE is a neurological condition induced by vitamin B1 deficiency that manifests itself in the form of paralysis of one or more extraocular muscles, lack of muscle coordination and confusion. Rates of WE range from 0.8% to 2.8% of the general population, as determined by autopsy studies, however the incidence in MPN patients is reportedly three times greater.1

About Fedratinib
Fedratinib is an oral kinase inhibitor with activity against wild type and mutationally activated Janus Associated Kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3). Fedratinib is a JAK2-selective inhibitor with higher potency for JAK2 over family members JAK1, JAK3 and TYK2. Abnormal activation of JAK2 is associated with myeloproliferative neoplasms (MPNs), including myelofibrosis and polycythemia vera. In cell models expressing mutationally active JAK2, fedratinib reduced phosphorylation of signal transducer and activator of transcription (STAT3/5) proteins, inhibited cell proliferation, and induced apoptotic cell death. In mouse models of JAK2V617F-driven myeloproliferative disease, fedratinib blocked phosphorylation of STAT3/5, improved survival and disease-associated signs (including white blood cell counts, hematocrit, splenomegaly, and fibrosis).

Fedratinib is an investigational compound that is not approved for any use in any country.

About Myelofibrosis
Myelofibrosis is a serious and rare bone marrow disorder that disrupts the body’s normal production of blood cells. Bone marrow is gradually replaced with fibrous scar tissue, which limits the ability of the bone marrow to make red blood cells.2 The disorder can lead to anemia, weakness, fatigue and swelling of the spleen and liver, among other symptoms.2 Myelofibrosis is classified as a myeloproliferative neoplasm, a group of rare blood cancers that derive from blood-forming stem cells.3am In the U.S. myelofibrosis occurs in 1.5 of every 100,000 people each year,4 and between 16,000 and 18,500 people are living with the disease.5 Both men and women are affected and, while the disease can affect people of all ages, the median age at diagnosis ranges from 60 to 67 years.6,7