On June 4, 2018 Clovis Oncology, Inc. (NASDAQ: CLVS) reported the submission of a regulatory application to the European Medicines Agency (EMA), as part of a type II variation seeking to expand the marketing authorization for Rubraca (rucaparib) to include maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum based chemotherapy (Press release, Clovis Oncology, JUN 4, 2018, View Source [SID1234527248]).

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On May 29, 2018, Rubraca became the first PARP inhibitor licensed in the EU as a monotherapy treatment for women with recurrent ovarian cancer. It is currently indicated for adult patients with platinum sensitive, relapsed or progressive, BRCA mutated (germline and/or somatic), high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have been treated with two or more prior lines of platinum based chemotherapy, and who are unable to tolerate further platinum based chemotherapy. The Rubraca Summary of Product Characteristics is available on the European Medicines Agency website.

This submission is based on the positive results from the phase 3 ARIEL3 study, which evaluated rucaparib in the ovarian cancer maintenance treatment setting among three populations: 1) BRCA mutant (BRCAmut+) 2) HRD positive inclusive of BRCAmut+ and, 3) all patients treated in ARIEL3. ARIEL3 successfully achieved its primary endpoints, extending investigator assessed progression-free survival (PFS) versus placebo in all patients treated, regardless of BRCA status. Safety findings from the ARIEL3 trial were consistent with previous clinical trials.

Based on the timing of this submission, the company anticipates an opinion from the Committee for Medicinal Products for Human Use (CHMP) by end of 2018.

About the ARIEL3 Clinical Trial
The ARIEL3 pivotal study of rucaparib is a confirmatory randomized, double-blind study comparing the effects of rucaparib against placebo to evaluate whether rucaparib given as a maintenance treatment to platinum-sensitive ovarian cancer patients can extend the period of time for which the disease is controlled after a complete or partial response to platinum-based chemotherapy. The study enrolled 564 patients with high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer. To be eligible for the study, participants had to have received at least two prior platinum-based treatment regimens, been sensitive to the penultimate platinum regimen, and achieved a complete or partial response to their most recent platinum-based regimen. There were no genomic selection criteria for this study. Trial participants were randomized 2:1 to receive 600 milligrams of rucaparib twice daily (BID) or placebo.

About Rubraca (rucaparib)
Rucaparib is an oral, small molecule inhibitor of PARP1, PARP2 and PARP3 being developed in multiple tumor types, including ovarian, metastatic castration-resistant prostate, and bladder cancers, as monotherapy, and in combination with other anti-cancer agents. Exploratory studies in other tumor types are also underway. Clovis holds worldwide rights for rucaparib. Rucaparib is an unlicensed medical product outside of the U.S. and Europe.

Rubraca EU Authorized Use
Rucaparib is licensed for adult patients with platinum sensitive, relapsed or progressive, BRCA mutated (germline and/or somatic), high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have been treated with two or more prior lines of platinum based chemotherapy, and who are unable to tolerate further platinum based chemotherapy.
Click here to access the current Summary of Product Characteristics. Healthcare professionals should report any suspected adverse reactions via their national reporting systems.

Rubraca U.S. FDA Approved Indications and Important Safety Information
Rubraca is indicated as monotherapy for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.
Rubraca is indicated as monotherapy for the treatment of adult patients with deleterious BRCA mutation (germline and/or somatic) associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or more chemotherapies and selected for therapy based on an FDA-approved companion diagnostic for Rubraca.

Select Important Safety Information
Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) occur uncommonly in patients treated with Rubraca, and are potentially fatal adverse reactions. In approximately 1100 treated patients, MDS/AML occurred in 12 patients (1.1%), including those in long term follow-up. Of these, 5 occurred during treatment or during the 28-day safety follow-up (0.5%). The duration of Rubraca treatment prior to the diagnosis of MDS/AML ranged from 1 month to approximately 28 months. The cases were typical of secondary MDS/cancer therapy-related AML; in all cases, patients had received previous platinum-containing regimens and/or other DNA damaging agents.
Do not start Rubraca until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1).

Monitor complete blood counts for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities (> 4 weeks), interrupt Rubraca or reduce dose (see Dosage and Administration (2.2) in full Prescribing Information) and monitor blood counts weekly until recovery. If the levels have not recovered to Grade 1 or less after 4 weeks or if MDS/AML is suspected, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Rubraca.

Based on its mechanism of action and findings from animal studies, Rubraca can cause fetal harm when administered to a pregnant woman. Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Rubraca.

Most common adverse reactions in ARIEL3 (≥ 20%; Grade 1-4) were nausea (76%), fatigue/asthenia (73%), abdominal pain/distention (46%), rash (43%), dysgeusia (40%), anemia (39%), AST/ALT elevation (38%), constipation (37%), vomiting (37%), diarrhea (32%), thrombocytopenia (29%), nasopharyngitis/upper respiratory tract infection (29%), stomatitis (28%), decreased appetite (23%), and neutropenia (20%).

Most common laboratory abnormalities in ARIEL3 (≥ 25%; Grade 1-4) were increase in creatinine (98%), decrease in hemoglobin (88%), increase in cholesterol (84%), increase in alanine aminotransferase (ALT) (73%), increase in aspartate aminotransferase (AST) (61%), decrease in platelets (44%), decrease in leukocytes (44%), decrease in neutrophils (38%), increase in alkaline phosphatase (37%), and decrease in lymphocytes (29%).

Most common adverse reactions in Study 10 and ARIEL2 (≥ 20%; Grade 1-4) were nausea (77%), asthenia/fatigue (77%), vomiting (46%), anemia (44%), constipation (40%), dysgeusia (39%), decreased appetite (39%), diarrhea (34%), abdominal pain (32%), dyspnea (21%), and thrombocytopenia (21%).

Most common laboratory abnormalities in Study 10 and ARIEL2 (≥ 35%; Grade 1-4) were increase in creatinine (92%), increase in alanine aminotransferase (ALT) (74%), increase in aspartate aminotransferase (AST) (73%), decrease in hemoglobin (67%), decrease in lymphocytes (45%), increase in cholesterol (40%), decrease in platelets (39%), and decrease in absolute neutrophil count (35%).

Co-administration of rucaparib can increase the systemic exposure of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, which may increase the risk of toxicities of these drugs. Adjust dosage of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, if clinically indicated. If co-administration with warfarin (a CYP2C9 substrate) cannot be avoided, consider increasing frequency of international normalized ratio (INR) monitoring.
Because of the potential for serious adverse reactions in breast-fed children from Rubraca, advise lactating women not to breastfeed during treatment with Rubraca and for 2 weeks after the last dose.
You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Clovis Oncology, Inc. at 1-844-258-7662.
Click here for full Prescribing Information and additional Important Safety Information.

On June 4, 2018 At the American Society Clinical Oncology’s 2018 annual meeting, scientists from National Institute of Cancer Research Taiwan reported results from a phase 1 clinical study, showing that Polaris lead therapeutic candidate ADI‑PEG 20 in combination with pembrolizumab has activity for advanced solid tumors (Press release, Polaris Pharmaceuticals, JUN 4, 2018, View Source [SID1234527208]).

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The study results showed that ADI‑PEG 20 could be safely combined with pembrolizumab at its full dose (200 mg) for the treatment of advanced solid tumors. In the dose escalation cohort, two patients, one with thymus cancer and one with nasopharyngeal carcinoma, both in the fourth-line systemic treatment, had a partial response (PR). The main toxicity has been transient and manageable neutropenia. The study is currently enrolling patients in two recommended phase 2 dose cohorts: one for advanced cancers with low PD-L1 expression and one for head and neck cancer. Overall, the study has an objective response rate (ORR) of 27.8% (5/18) in evaluable patients at this time.

In the advanced cancers with low PD-L1 expression cohort, only patients with less than 50% PD-L1 expression are eligible for entry. Of the first 8 evaluable patients in this group, the current ORR is 37.5% as 3 PRs have been observed in heavily pre-treated patients: a third-line mucosal melanoma, a fifth-line cholangiocarcinoma and a fourth-line esophageal carcinoma. These preliminary results suggest that ADI-PEG 20 could potentially be synergistic with program death compounds, and various combinations that include ADI‑PEG 20 and other immunotherapies should be further explored in multiple cancer types.

"Preclinical data indicated that ADI‑PEG 20 could up-regulate PD-L1 expression, turning immune ‘cold’ tumors to express PD-L1 and thus more receptive to programmed death inhibition with agents such as pembrolizumab. We are gratified to see this same scenario occur in patients," said John Bomalaski, M.D., Executive Vice President, Medical Affairs, of Polaris. "Based on this encouraging data, we now have multiple trials planned with ADI‑PEG 20 and various checkpoint inhibitors, including combinations with both programmed death and CTLA-4 inhibitors. The enhancement of sensitivity to programmed death inhibition, combined with ADI-PEG 20’s efficacy, tolerability, and different mechanism of action make it an ideal agent for incorporation into checkpoint agent therapy," he added.

About ADI-PEG 20

ADI‑PEG 20 is a biologic being developed by Polaris Group to treat cancers carrying a major metabolic defect that renders them unable to internally synthesize arginine. Because arginine is essential for protein synthesis and survival of cells, these cancer cells become dependent upon the external supply of arginine to survive and grow. ADI‑PEG 20 is designed to deplete the external supply of arginine, causing arginine-dependent cancer cells to die while leaving the patient’s normal cells unharmed. Multiple cancers have been reported to have a high degree of arginine-dependency and can potentially be treated with ADI‑PEG 20.

On June 4, 2018 HUYA Bioscience International (HUYA), the leader in accelerating global development of China’s pharmaceutical innovations, reported it is at a key stage in the company’s development of HBI-8000, HUYA’s lead novel epigenetic drug with important immunomodulatory properties (Press release, HUYA Bioscience, JUN 4, 2018, View Source [SID1234527194]). HUYA is conducting a Phase 2 trial of HBI-8000 in the US, investigating efficacy and safety in combination with nivolumab for the treatment of solid tumors. The ongoing Phase 2 study is an open label study of patients with advanced renal cell cancer, non-small cell lung cancer and melanoma.

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"We are at an important milestone in the development of HBI-8000 as we test the compound’s ability to improve the clinical benefit of checkpoint inhibitors for the treatment of solid tumors" said Dr Mireille Gillings, HUYA’s CEO and Executive Chair. "The emerging data for the combination are encouraging, leading to our ultimate goal which is to harness the demonstrated immunomodulatory properties of HBI-8000 to improve the outcome for patients treated with immunological therapies."

HBI-8000 is a member of the benzamide class of histone deacetylase (HDAC) inhibitors designed to block the catalytic pocket of Class I HDACs. Recent data show greatly expanded immunomodulatory properties which explain in greater depth the strong results now being seen in the clinic. HBI-8000 is an orally bioavailable, low-nanomolar inhibitor of cancer-associated HDAC enzymes with favorable pharmacology and safety profiles. Studies with human-derived tumor cell lines and animal tumor models have demonstrated that HBI-8000 inhibits the growth of many tumors via multiple mechanisms of action, including epigenetic regulation of tumor cell growth and apoptosis, immunomodulatory effects regulating antitumor activity, as well as repression of genes associated with drug resistance. HBI-8000 is approved in China for the treatment of peripheral T-cell lymphoma.

Dr Bob Goodenow, President, HUYA, said "We’ve targeted a significant improvement for the combination relative to nivolumab’s overall response rate, disease control rate and other clinical parameters to proceed to registration studies. Our results to date exceed expectations and clearly demonstrate the combination should be tested in a pivotal setting for the clinical benefit observed in our Phase 2 trial."

On June 4, 2018 Selecta Biosciences, Inc. (the "Company") presents and/or distributes to the investment community at various industry and other conferences slide presentations to provide updates and summaries of its business (Presentation, Selecta Biosciences, JUN 4, 2018, View Source [SID1234527193]).

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On June 4, 2018 Progenics Pharmaceuticals, Inc. (Nasdaq:PGNX), an oncology company developing innovative medicines and other products for targeting and treating cancer, reported updated overall survival data from the Company’s pivotal Phase 2 trial of its targeted, high-specific-activity radiotherapeutic candidate, AZEDRA (iobenguane I 131), in patients with malignant, recurrent, or unresectable pheochromocytoma and paraganglioma (pheo/para), which is the subject of an oral presentation at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, Illinois (Press release, Progenics Pharmaceuticals, JUN 4, 2018, View Source [SID1234527185]).

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"This pivotal study, the largest prospective clinical trial in pheochromocytoma and paraganglioma to date, has demonstrated multiple clinical benefits of AZEDRA treatment, which has translated into impressive overall survival data in this highly pre-treated and advanced patient population," said Dr. Daniel Pryma, Associate Professor of Radiology & Radiation Oncology and Chief, Division of Nuclear Medicine & Clinical Molecular Imaging at the Perelman School of Medicine at the University of Pennsylvania, the trial’s lead investigator. "The primary cause of death in pheo/para patients is tumor progression. In this study, 98% of patients who received two doses experienced stable disease or better as measured by Response Evaluation Criteria In Solid Tumors (RECIST). In addition, 30% of pheo/para patients die from complications due to catecholamine-associated hypertension, while patients treated with AZEDRA were able to achieve control of catecholamine-associated hypertension and a sustained reduction of antihypertensive medications. These benefits were correlated with a robust tumor biomarker response. With no approved therapies in the U.S. for pheo and para, AZEDRA has the potential to offer a meaningful treatment option for patients with these life-threatening tumors."

Dr. Pryma will review the data today in an oral presentation entitled, "AZEDRA (iobenguane I 131) in patients with malignant, recurrent and/or unresectable pheochromocytoma or paraganglioma (PPGL): Updated efficacy and safety results from a multi-center, open-label, pivotal phase 2 study."

The pivotal phase 2 open-label, multi-center trial was conducted under a Special Protocol Assessment (SPA) with the U.S. Food and Drug Administration (FDA). The trial met the primary endpoint evaluating the proportion of pheochromocytoma and paraganglioma patients who achieved a 50% or greater reduction of all antihypertensive medication for at least six months, and showed favorable results from a key secondary endpoint evaluating the proportion of patients with overall tumor response as measured by RECIST. 92.2% of patients treated with at least one therapeutic dose of AZEDRA achieved a confirmed partial response or stable disease by 12 months. AZEDRA was also shown to be safe and generally well tolerated.

Median overall survival time as of December 4, 2017 was 37 months from first AZEDRA therapeutic dosing in the overall study population, and 44 months among patients who received two therapeutic doses, compared to 18 months among patients who received only one therapeutic dose. The study data also suggest the potential for AZEDRA to extend survival in patients with liver or lung metastasis, which is generally considered in the literature to be less than 24 months. In this study, median survival time was similar in patients with lung or liver metastasis compared to those without (43 vs. 41 months). Long term follow-up continues.

"These data, which are the basis of our New Drug Application, show that AZEDRA has the potential to address the dual goals of therapy in pheo and para – to reduce the cardiovascular symptoms associated with the excess hormone production, and to produce favorable tumor responses," said Mark Baker, Chief Executive Officer of Progenics. "We are eagerly anticipating the FDA’s decision on AZEDRA, as we believe it has the potential to be a breakthrough treatment option for patients with these deadly, ultra-rare neuroendocrine cancers."

About AZEDRA

AZEDRA (iobenguane I 131) is a high-specific-activity radiotherapeutic product candidate in development as a treatment for malignant, recurrent, or unresectable pheochromocytoma and paraganglioma, which are rare neuroendocrine tumors of neural crest origin. AZEDRA is a substrate for norepinephrine reuptake transporter, which is highly expressed on the cell surface of neuroendocrine tumors. AZEDRA has been granted Orphan Drug designation, Fast Track status, and Breakthrough Therapy designation in the U.S. Under a SPA agreement with the FDA, a Phase 2 pivotal study has been completed in patients with malignant, recurrent, or unresectable pheochromocytoma and paraganglioma. The FDA granted Priority Review of Progenics’ New Drug Application and has set an action date of July 30, 2018 under the Prescription Drug User Fee Act. There are currently no FDA-approved therapies for the treatment of these ultra-rare diseases.

About Pheochromocytoma and Paraganglioma

Pheochromocytoma and paraganglioma are rare neuroendocrine tumors that arise from cells of the autonomic nervous system. Pheochromocytoma forms in the adrenal medulla, whereas paragangliomas form outside the adrenal gland. Standard treatment options for these tumors include surgery, palliative therapy and symptom management. Pheochromocytoma and paraganglioma tumors frequently secrete high levels of hormones that can lead to life-threatening hypertension, heart failure, and stroke in these patients. Malignant and recurrent pheochromocytoma and paraganglioma may result in unresectable disease with a poor prognosis, representing a significant management challenge with very limited treatment options and no approved anti-tumor therapies.