On June 14, 2017 Helsinn, a Swiss pharmaceutical group focused on building quality cancer care products, and MEI Pharma, Inc. (Nasdaq: MEIP), an oncology company focused on the clinical development of novel therapies for cancer, reported that the first patient has been dosed in a Phase 2 dose-optimization study of pracinostat in combination with azacitidine in patients with higher risk myelodysplastic syndromes (MDS) who are previously untreated with hypomethylating agents (HMAs) (Press release, MEI Pharma, JUN 14, 2017, View Source [SID1234519540]).

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The two-stage study will be conducted at approximately 25 sites and is expected to enroll up to 120 patients with high and very high risk MDS per the Revised International Prognostic Scoring System (IPSS-R). The high and very high risk groups represent the highest unmet need in MDS, with median survival estimates of only 1.6 years and 0.8 years, respectively1. The cost of this study will be shared by Helsinn and MEI Pharma. Data from the first stage is expected in the first quarter of 2018.

"Based on our clinical experience with the combination, we believe that a reduced dose of pracinostat has the potential to improve tolerability in patients with higher risk MDS, thereby improving efficacy of the combination compared to azacitidine alone," said Robert D. Mass, MD, Chief Medical Officer of MEI Pharma. "We look forward to working with the study’s investigators and Helsinn to evaluate this hypothesis in the clinic while we await the outcome of our pivotal Phase 3 study of the combination in acute myeloid leukemia (AML)."

Sergio Cantoreggi, PhD., Helsinn Group Chief Scientific Officer said, "We are pleased to announce that the first patient with higher risk myelodysplastic syndromes has been dosed in this Phase 2 dose-optimization study of pracinostat in combination with azacitidine. Pracinostat is a promising late-stage asset and a key part of Helsinn’s broadened focus into therapeutic clinical development and we look forward to seeing the results in early 2018."

In a recently published, placebo-controlled Phase 2 study (MEI-003) conducted in 102 patients with intermediate-2 and high risk MDS, pracinostat (60mg) and azacitidine failed to increase the complete response rate, the study’s primary endpoint, compared to azacitidine and placebo2. Drug discontinuation within the first two months of treatment, due to poor tolerability (primarily fatigue and myelosuppression), occurred twice as frequently in the pracinostat group compared to placebo. A sensitivity analysis, including 54 patients who received at least four cycles of study therapy (pracinostat or placebo) and azacitidine showed a trend for better progression-free survival and overall survival (hazard ratio = 0.37 and 0.59, respectively) compared to the control group. These data suggest that insufficient exposure to treatment may have limited the overall efficacy of the combination and are consistent with recently presented findings from an analysis of patients in a Phase 2 study of pracinostat and azacitidine in AML which showed that continued treatment increases the rate of minimal residual disease clearance3.

This two-stage, Phase 2 study will investigate a pracinostat dose of 45 mg, 25% lower than the dose used in study MEI-003, in combination with the standard dose of azacitidine to determine whether lowering the pracinostat dose in a higher risk patient population can improve the tolerance of the combination while achieving a clinically meaningful improvement in efficacy.

The first stage of the study will be open-label, single arm in up to 40 patients to assess if the lower pracinostat dose will result in a discontinuation rate that approximates the rate that was observed with azacitidine alone in study MEI-003 (10%). If results from the first stage support expansion of enrollment, the second stage will be randomized and placebo-controlled to confirm the discontinuation rate in a blinded setting and to provide data on safety and efficacy.

The primary endpoints of the study are 1) safety and tolerability and 2) overall response rate, defined as complete remission (CR), partial remission (PR) and marrow CR. Secondary endpoints include CR rate, overall hematologic improvement (HI) response rate, clinical benefit rate (defined as rate of CR + PR + HI + Marrow CR), rate of cytogenetic complete response/remission, duration of response, rate of leukemic transformation, event-free survival, progression-free survival and overall survival.

About Higher Risk MDS
Higher risk MDS (high and very high risk in the IPSS-R classification) is a serious medical condition, with median survival of less than 18 months. The only curative therapy is allogeneic stem cell transplantation (SCT), however most patients with MDS are not candidates for SCT given their typically advanced age, comorbidities and lack of a suitable donor. Standard therapy with HMAs in higher risk MDS provides modest responses, though azacitidine has been shown to improve survival when compared to conventional care regimens4. Patients who do not respond to HMAs or progress after therapy with HMAs have a very poor outcome, with a median survival of less than one year5.

About Pracinostat
Pracinostat is an oral histone deacetylase (HDAC) inhibitor that is in late stage clinical development. The U.S. Food and Drug Administration has granted Breakthrough Therapy Designation for pracinostat in combination with azacitidine for the treatment of patients with newly diagnosed AML who are ≥75 years of age or unfit for intensive chemotherapy. In August 2016, Helsinn and MEI Pharma entered into an exclusive license, development and commercialization agreement for pracinostat in AML and other potential indications. The deal provides the complementary resources from both organizations to advance pracinostat into Phase III clinical development in AML and expand into additional areas of clinical development, including MDS. Pracinostat is an investigational agent and is not approved for commercial use in the U.S.

On June 14, 2017 Kura Oncology, Inc. (NASDAQ:KURA), a clinical stage biopharmaceutical company focused on the development of precision medicines for oncology, reported that clinical and preclinical data for tipifarnib in the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL) was presented at the International Conference on Malignant Lymphoma (ICML) being held June 14-17, 2017 in Lugano, Switzerland (Press release, Kura Oncology, JUN 14, 2017, View Source [SID1234519539]).

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Kura Oncology is conducting preclinical and clinical development studies in clinical indications where tipifarnib has previously shown signs of activity with the goal to identify and validate biomarkers associated with the observed clinical activity of tipifarnib. The preliminary Phase 2 clinical data presented at ICML indicate that tipifarnib has antitumor activity in PTCL, particularly in patients with angioimmunoblastic T-cell lymphoma (AITL) histology and PTCL-NOS (Not Otherwise Specified) histology with high levels of CXCL12 gene expression and absence of single nucleotide gene variations in the 3′-untranslated region of the CXCL12 gene.

"Patients with PTCL have a poor overall survival of about 40%. Effective options for relapsed patients are limited and new drugs with novel mechanisms of action are needed," said Thomas Witzig, M.D., Professor of Medicine at the Mayo Clinic and a lead investigator on the study. "The preliminary results of this study are exciting because they may define a molecular mechanism of action and characterize a subgroup of patients that derive significantly greater clinical benefit from a targeted therapy such as tipifarnib."

"These results identify the CXCL12/CXCR4 pathway as a potential target of tipifarnib. CXCL12 is secreted in large amounts by lymph nodes, bone marrow stroma, liver, and lung, and plays key roles in tumor invasion, bone marrow homing and site of metastasis. Its receptor, CXCR4, signals in part through HRAS, a protein that is uniquely farnesylated, and it is one of the most frequently over-expressed chemokine receptors in malignant cells," said Antonio Gualberto, M.D., Ph.D., Chief Medical Officer at Kura Oncology. "Based on our preliminary data, we believe CXCL12/CXCR4 may have the potential to unlock the therapeutic value of farnesyl transferase inhibition in a number of tumor indications."

Patients in the Phase 2 study received tipifarnib 600 mg orally twice daily on days 1-7 and 15-21 in 28-day cycles. Among the 18 patients in stages 1 and 2 of this trial, 3 achieved a partial response (PR), and two of the PRs occurred in the two patients on study with AITL. An additional 4 patients had meaningful tumor size reductions and prolonged disease stabilization. In addition, tipifarnib was generally well-tolerated with adverse events consistent with its known safety profile and no patient discontinued due to adverse events. The Phase 2 study has been extended to enroll an additional 12 patients with AITL histology aimed at confirming the preliminary observations and validating CXCL12 as a biomarker of tipifarnib activity.

The preliminary results from the Phase 2 study in PTCL were also selected for a poster presentation at the 22nd Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) taking place June 22-25, 2017 in Madrid, Spain.

On June 14, 2017 Epizyme, Inc. (NASDAQ:EPZM), a clinical-stage biopharmaceutical company creating novel epigenetic therapies, reported positive interim efficacy data from the company’s ongoing Phase 2 clinical trial of tazemetostat, a first-in-class, oral EZH2 inhibitor, as a single-agent treatment for relapsed or refractory patients with follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL) grouped by EZH2 mutational status (Press release, Epizyme, JUN 14, 2017, View Source [SID1234519538]). The data were presented today during a plenary session at the International Conference on Malignant Lymphoma (ICML), which is being held June 14-17, 2017 in Lugano, Switzerland. In addition, data from a 62-gene panel biomarker study of tazemetostat in patients with various subtypes of non-Hodgkin lymphoma will be presented during a poster session at the conference.

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Interim data as of June 1, 2017 show that tazemetostat treatment resulted in a clinically meaningful benefit in patients with FL. The subset of FL patients with EZH2 activating mutations have a 92 percent objective response rate (ORR). Patients with FL with EZH2 wild-type have an ORR of 26 percent and 22 percent of patients with stable disease are still on study. Promising activity was also observed in DLBCL patients with EZH2 mutations, which includes recently enrolled patients, with an ORR of 29 percent. As the size of the mutation study groups increase and patients remain on study, Epizyme expects the data will continue to evolve. In addition, tazemetostat continues to demonstrate a favorable safety profile across all patient populations in this study.

"I believe that tazemetostat may play a significant role in disease management for my patients, and am particularly excited by the impact observed in patients with follicular lymphoma," said Franck Morschhauser, M.D., Ph.D., Centre Hospitalier Régional Universitaire de Lille, France, and lead investigator of the Phase 2 study. "I am also encouraged by the level of activity in DLBCL patients with EZH2 mutations, especially in light of the bleak prognosis associated with advanced disease. Tazemetostat has demonstrated a uniquely tolerable safety profile, and I look forward to further exploring its full benefit in patients with relapsed or refractory FL and DLBCL as the data mature."

"These interim data findings represent an important step forward for our tazemetostat program, with anti-tumor activity observed across all groups of the study," said Rob Bazemore, chief executive officer of Epizyme. "The activity we have observed in patients with an EZH2 mutation exceeds what we have seen so far with wild-type EZH2, consistent with our scientific hypothesis, and we are encouraged by both the objective responses and durability of responses in FL and DLBCL. Our focus is on continuing to increase enrollment of patients with an EZH2 mutation, and engaging with FDA in the second half of the year to determine potential registration paths to bring tazemetostat to patients as quickly as we can."

Follicular Lymphoma Efficacy Data
FL, an indolent form of non-Hodgkin lymphoma (NHL), is considered to be incurable with existing treatments and is characterized by cycles of relapse that become increasingly difficult to treat with each disease progression. Approximately 25,000 patients in the U.S. and major European countries are diagnosed with FL every year1, of which an estimated 15 to 20 percent have an EZH2 mutation. There are no approved treatments indicated for patients with FL with an EZH2 mutation. In April 2017, Epizyme was granted Fast Track designation for FL regardless of EZH2 mutational status.

As of June 1, 2017, Epizyme enrolled 19 FL patients with EZH2 activating mutations in the Phase 2 trial, of which 13 are evaluable for efficacy. Enrollment of FL patients with EZH2 wild-type was completed in late 2016 with a total of 54 patients, all of which are evaluable for efficacy. More than 75 percent of evaluable FL patients had three or more prior treatments, and approximately 50 percent of patients in each group were refractory to their last prior therapy.

Key interim efficacy findings are as follows:

FL with EZH2 MT FL with EZH2 WT
Evaluable for efficacy on June 1, 2017 n =13 n =54
Objective Response Rate (CR + PR) 12 (92%) 14 (26%)
Complete Response (CR) 1 (8%) 3 (6%)
Partial Response (PR) 11 (85%) 11 (20%)
Stable Disease (SD) 1 (8%) 23 (43%)
SD study drug ongoing 1 (8%) 12 (22%)
Progressive Disease 0 13 (24%)
No Data, Unknown (UNK) 0 4 (7%)
Time to first Response (weeks)
median (range) 11.9
(6.9 – 35.9) 15.2
(8.1 – 32.1)
The activity of tazemetostat across FL patients is encouraging, and when combined with the well-tolerated safety profile, supports its potential utility as both as monotherapy and a combination agent. Combination treatment has become the evolving standard-of-care for FL, and Epizyme plans to begin investigating tazemetostat as a combination agent in FL this year.

Diffuse Large B-Cell Lymphoma Efficacy Data
DLBCL is an aggressive form of NHL that once diagnosed, typically requires immediate treatment. Approximately 45,000 patients are diagnosed with DLBCL in the U.S. and major European countries every year2. Among patients with germinal center DLBCL, an estimated 15 to 20 percent have an EZH2 mutation. Forty to 50 percent of patients will relapse on their first-line treatment, which is most commonly the chemotherapy regimen R-CHOP, and there are few treatment options for patients who relapse or become refractory to chemotherapy. In November 2016, Epizyme was granted Fast Track designation for DLBCL with EZH2 mutations.

As of June 1, 2017, Epizyme had enrolled 22 DLBCL patients with EZH2 mutations, and efficacy was assessed on 17 patients. Enrollment of DLBCL patients with EZH2 wild-type (germinal center and non-germinal center) was completed in early 2017 with 120 patients, of which 119 were evaluable for efficacy. Patients with DLBCL with EZH2 activating mutations represent the most advanced and severely ill patients in the study, with 82 percent having been previously treated with at least three therapeutic regimens and refractory to their last treatment.

Key interim efficacy findings are as follows:

DLBCL EZH2 MT DLBCL EZH2 WT
Evaluable for efficacy on June 1, 2017 n = 17 n = 119
Objective Response Rate (CR + PR) 5 (29%) 18 (15%)
Complete Response (CR) 0 10 (8%)
Partial Response (PR) 5 (29%) 8 (7%)
Stable Disease (SD) 6 (35%) 22 (18%)
SD study drug ongoing 1 (6%) 4 (3%)
Progressive Disease 6 (35%) 60 (50%)
No Data, Unknown (UNK) 0 19 (16%)
Time to first Response (weeks)
median (range) 8.3
(4.6 – 48.1) 8.5
(5.3 – 24.7)
Epizyme believes that activity is likely to be enhanced for wild-type disease through combination treatment. The company has a robust combination program underway in DLBCL evaluating tazemetostat in an immuno-oncology combination with atezolizumab and a steroid combination with prednisolone. In addition, tazemetostat is being evaluated in the front-line setting in combination with R-CHOP in newly diagnosed, high-risk DLBCL patients.

Tazemetostat Safety Profile
Safety data from patients in this Phase 2 trial (n=210), as of the data cutoff, demonstrate a favorable tolerability profile, consistent with the experience observed in a nearly 400-patient safety database from tazemetostat clinical trials to date. Across all cohorts of this trial, dose reductions and discontinuations due to treatment-related adverse events are low, at only three and two percent, respectively.

The majority of treatment-emergent adverse events are grade 1 or 2, with only 18 percent of grade 3 or higher being considered treatment-related. Treatment-emergent adverse events, regardless of attribution and affecting more than five percent of patients, are nausea (20%); thrombocytopenia (19%); anemia (16%); cough (14%); fatigue (12%); diarrhea (11%); asthenia, neutropenia, pyrexia and vomiting (10% each); bronchitis (7%); and constipation, decreased appetite, upper respiratory infection, abdominal pain, headache and urinary tract infection (6% each).

Poster Presentation Information
Data from a 62-gene panel biomarker study of tazemetostat in patients with various subtypes of NHL will also be presented in a poster by Stephen Blakemore Ph.D., titled "Preliminary evidence of a molecular predictor of tazemetostat response, beyond EZH2 mutation, in NHL patients via characterization of archive tumor and circulating tumor DNA" on June 14, 2017 (Poster Board No.: 154).

The data in the poster detail both potential positive and negative predictors of response to tazemetostat. In the case of positive predictors, both EZH2 and MYD88 are mutations that appear to enhance patients’ sensitivity to tazemetostat. The company has also detected EZH2 mutations by circulating tumor DNA in patient serum, indicating the potential future use of a tube of blood for patient identification of EZH2 mutations rather than testing patient’s archival tumor samples.

Conference Call Information
Epizyme will host a conference call and audio webcast today at 10:30 a.m. ET. To participate in the conference call, please dial (877) 844-6886 (domestic) or (970) 315-0315 (international) and refer to conference ID 15855261. The webcast, and accompanying slides for the call, will be accessible under "Events and Presentations" in the Investor Relations section of the Company’s website at View Source

About the Tazemetostat Clinical Trial Program
Tazemetostat, a first-in-class EZH2 inhibitor, is currently being studied in ongoing Phase 2 programs in both follicular lymphoma and diffuse large B-cell lymphoma (DLBCL) forms of non-Hodgkin lymphoma; certain molecularly defined solid tumors, including epithelioid sarcoma and other INI1-negative tumors; and mesothelioma, as well as in combination studies in DLBCL. Tazemetostat has been granted Fast Track designation by the U.S. Food and Drug Administration for both relapsed/refractory follicular lymphoma and DLBCL with EZH2 activating mutations, as well as Orphan Drug designation for malignant rhabdoid tumors.

On June 13, 2017 Threshold Pharmaceuticals, Inc. (NASDAQ:THLD) a clinical-stage biopharmaceutical company developing novel therapies for cancer, reported that the University of Texas MD Anderson Cancer Center has dosed the first patient in a Phase 1 immunotherapy clinical trial investigating ipilimumab and evofosfamide for the treatment of patients with metastatic or locally advanced prostate cancer, metastatic pancreatic cancer, melanoma or human papillomavirus (HPV) negative squamous cell carcinoma of head and neck for which standard therapy does not offer the potential for increased survival (Press release, Threshold Pharmaceuticals, JUN 13, 2017, View Source [SID1234519545]).

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“We believe that adding evofosfamide to certain immunotherapies has the potential to render some of the most therapeutically resistant cancers more sensitive to the immunotherapy and we are excited to have dosed the first patient in this study,” said Tillman Pearce, M.D., Chief Medical Officer at Threshold Pharmaceuticals. “Thanks to preclinical research conducted by Dr. Curran at MD Anderson Cancer Center, it is well-understood that certain tumors have hypoxic zones that resist infiltration by T cells, which are capable of attacking and killing tumor cells, and that combination therapy with evofosfamide and anti-CTLA-4/anti-PD-1 treatment opens up the hypoxic zones to T cell infiltration.”

Evofosfamide (also known as TH-302) is Threshold’s proprietary, hypoxia-activated prodrug of a bis-alkylating agent that is preferentially activated under severe hypoxic tumor conditions, a feature of many solid tumors. In preclinical research conducted by Michael Curran, Ph.D., Assistant Professor at the University of Texas MD Anderson Cancer Center, evofosfamide has sensitized highly resistant solid tumor models to treatment with certain immune checkpoint inhibitors through evofosfamide-driven disruption of hypoxic zones. Specifically, hypoxia in the tumor microenvironment forms a barrier to T cell infiltration and fosters immunotherapy resistance in prostate cancer and other solid tumors.

The Phase 1 clinical trial is a single-arm, open label study that will enroll up to 69 patients with metastatic or locally advanced prostate cancer, metastatic pancreatic cancer, melanoma or HPV-negative squamous cell carcinoma of head and neck. Eligible patients will receive evofosfamide on Days one and eight of the first two cycles and ipilimumab on Day eight of a 28-day cycle. Immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) response rate is the primary endpoint. Secondary endpoints include duration of response, progression-free survival, overall survival, safety, tolerability and pharmacokinetics. The study is open at MD Anderson Cancer Center in Houston, Texas. More details can be found here.

About Evofosfamide
Evofosfamide (previously known as TH-302) is an investigational hypoxia-activated prodrug of a bis-alkylating agent that is preferentially activated under severe hypoxic tumor conditions, a feature of many solid tumors. Areas of low oxygen levels (hypoxia) in solid tumors are due to insufficient blood vessel supply. Similarly, the bone marrow of patients with hematological malignancies has also been shown, in some cases, to be severely hypoxic. Discussions remain ongoing with the Japanese PMDA regulatory agency on what additional clinical trials may be required to support submission of evofosfamide for the treatment of pancreatic cancer patients in Japan.