On September 20, 2017 Nektar Therapeutics (Nasdaq: NKTR) reported that new data across its wholly-owned immuno-oncology (I-O) portfolio will be presented at the upcoming Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting, which is being held from November 10 to November 12, 2017, at the Gaylord National Hotel & Convention Center in National Harbor, Maryland (Press release, Nektar Therapeutics, SEP 20, 2017, View Source [SID1234520574]). Seven abstracts were selected for presentation for three Nektar I-O pipeline programs: NKTR-214, a CD122-biased agonist; NKTR-255, an IL-15 memory T cell stimulating cytokine; and NKTR-262, a novel toll-like receptor (TLR) agonist.

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Clinical data from the PIVOT program evaluating NKTR-214 in combination with the checkpoint inhibitor nivolumab were accepted for an oral presentation in the Clinical Trials: Novel Combinations Session on November 11, 2017. The PIVOT trial is comprised of two stages, the dose-escalation stage (PIVOT-02, n=38) and the expansion cohort stage (PIVOT-04, n=250). The dose-escalation stage, which has completed enrollment, is evaluating NKTR-214 in combination with nivolumab in I-O therapy-naïve patients with melanoma, renal cell carcinoma and non-small cell lung cancer. The expansion cohort stage, which is actively enrolling patients, is evaluating NKTR-214 in combination with nivolumab in five tumor types and eight different indications. PIVOT is being conducted in a collaboration with Bristol-Myers Squibb with each company equally sharing costs of the combination therapy trials and Nektar maintaining its global commercial rights to NKTR-214.

NKTR-214 is an investigational immuno-stimulatory therapy designed to expand specific cancer-fighting CD8+ effector T cells and natural killer (NK) cells directly in the tumor micro-environment and increase expression of PD-1 on these immune cells. NKTR-214 targets CD122 specific receptors found on the surface of cancer-fighting immune cells in order to stimulate their proliferation and activation. In clinical and preclinical studies, treatment with NKTR-214 resulted in expansion of these cells and mobilization into the tumor.1,2 NKTR-214 has an antibody-like dosing regimen similar to the existing checkpoint inhibitor class of approved medicines.

Nektar is also enrolling a separate clinical trial (the PROPEL study) to evaluate NKTR-214 in combination with two additional checkpoint inhibitors (atezolizumab and pembrolizumab).

Details of the oral presentation of clinical data from the PIVOT-02 study are as follows:

Abstract Title: PIVOT-02: Preliminary safety, efficacy and biomarker results from the Phase 1/2 study of CD-122-biased agonist NKTR-214 plus nivolumab in patients with locally advanced/metastatic solid tumors
Presenter: Dr. Adi Diab, MD Anderson Cancer Center
Session Title, Date and Time: Clinical Trials: Novel Combinations, Saturday, November 11, 2017, 3:30 – 6:00 p.m. Eastern Time

Six abstracts were accepted for presentation in the following categories:

Biomarkers and Immune Monitoring

Data presentation for the clinical trial of single-agent NKTR-214 in patients with advanced solid tumors:

Bentebibel, S., et al., "The novel IL-2 cytokine immune agonist NKTR-214 harnesses the adaptive and innate immune system for the treatment of solid cancers."
Cancer Vaccines

Data presentation for preclinical studies of NKTR-214 in combination with checkpoint blockade therapy or peptide-based vaccination:

Sharma, M., et al., "NKTR-214 enhances anti-tumor T cell immune responses induced by checkpoint blockade or vaccination."
Combination Therapy

Data presentation for preclinical studies of NKTR-214 in combination with NKTR-262, a novel small molecule agonist that targets toll-like receptors (TLRs) found on innate immune cells in the body:

Kivimae, S., et al., "Harnessing the innate and adaptive immune system to eradicate treated and distant untreated solid tumors."
Data presentation for preclinical studies of NKTR-214 with high-dose radiotherapy:

Walker, J, et al., "Combination of NKTR-214 and radiotherapy (RT) to reverse anergy and expand tumor-specific CD8 T Cells."
Immune Modulation, Cytokines, and Antibodies

Data presentation for preclinical studies of NKTR-255, a memory T cell stimulating cytokine designed to engage the IL-15 pathway to induce long-term T cell activation and improve the quality of T cell memory response to treat cancer:

Kirk, P, et al., "Preclinical efficacy and tolerability of NKTR-255, a polymer-conjugated IL-15 for immuno-oncology."
Personalized Vaccines and Technologies/Personalized Medicines

Data presentation for preclinical studies of NKTR-214 with novel neoantigens vaccine:

D’Alise, A.M., et al., "Great apes adenoviral vaccine encoding neoantigens synergizes with immunomodulators to cure established tumors in mice"

On September 20, 2017 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a clinical-stage pharmaceutical company, reported a successful outcome from the Phase 2 portion of the SEAL study evaluating the activity of selinexor (KPT-330), the Company’s lead, novel, oral Selective Inhibitor of Nuclear Export / SINE compound, in 57 patients with previously treated, advanced unresectable dedifferentiated liposarcoma (Press release, Karyopharm, SEP 20, 2017, View Source [SID1234520573]). For the SEAL study’s primary endpoint of progression-free survival (PFS), oral selinexor showed superiority over placebo, achieving a hazard ratio (HR) of 0.60, representing a 40% reduction in the risk of progression or death. PFS was assessed by Independent Central Radiological Review (ICRR) based on RECIST v1.1.

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In this randomized, blinded Phase 2 portion of the study, oral selinexor demonstrated an expected and manageable safety profile, primarily with nausea, anorexia and fatigue, low levels of Grade 3/4 cytopenias, and no new or unexpected safety signals identified. The majority of treatment-related adverse events (AEs) were low grade and reversible with dose modifications and/or standard supportive care. Importantly, the incidence of infections in the selinexor arm (overall 29%; Grades ³3, 0%) was less than that reported in the placebo arm (overall 39%; Grade ³3, 19%).

Additional efficacy assessments included PFS by World Health Organization (WHO) response criteria, effects on metabolic parameters via PET Scans, and PFS according to Choi Criteria. PFS per WHO criteria achieved a HR of 0.84; the WHO response criteria will not be included as part of the Phase 3 study objectives. Karyopharm intends to submit detailed results from the Phase 2 portion of the SEAL study for presentation at a future medical meeting.

"There are few effective treatment options for previously treated patients with recurrent dedifferentiated liposarcoma and extending PFS is an important clinical goal because the rapid progression of disease frequently results in early mortality," said Mrinal M. Gounder, MD, Attending Physician, Sarcoma Service and Developmental Therapeutics Service, Memorial Sloan Kettering Cancer Center, and Lead Investigator of the SEAL trial. "These data are promising because they show that oral selinexor is active and has the potential to prolong PFS in this patient population, with an expected and manageable safety profile. As an orally administered agent, selinexor could be a welcome addition to the liposarcoma treatment landscape and we look forward to further elucidating selinexor’s efficacy and safety in the already ongoing Phase 3 portion of the SEAL study."

The Phase 3 portion of the SEAL study, which was originally initiated in North America, is ongoing and has been expanded to include Europe. In this blinded, placebo-controlled Phase 3 study, up to 222 patients are expected

Targeting Disease at the Nuclear Pore

to be enrolled and randomized 2:1 to receive either oral selinexor, (60mg fixed dose twice weekly) until disease progression or intolerability, or placebo. Patients whose disease progresses on placebo will be permitted to cross over to the selinexor arm. The primary endpoint of the Phase 3 portion of the study is PFS (RECIST v1.1) as assessed by the ICRR. The Phase 3 study design and primary endpoint of PFS were agreed to by the U.S. Food and Drug Administration (FDA). Top-line data from the Phase 3 portion of the SEAL study are anticipated by the end of 2019. Assuming a positive outcome, these data are expected to support a New Drug Application for oral selinexor as a potential new treatment for patients with advanced dedifferentiated liposarcoma.

"Liposarcomas are difficult to treat solid tumors that arise from the body’s fat tissue cells or their precursors," said Sharon Shacham, PhD, MBA, President and Chief Scientific Officer of Karyopharm. "Dedifferentiated liposarcoma is an aggressive form of the disease that is resistant to both standard chemotherapy and radiation and has a particularly high rate of recurrence following surgery. Most patients who progress following surgery will ultimately succumb to their disease, highlighting the significant unmet need that exists for novel therapies. The FDA has confirmed their acceptance of the proposed Phase 3 SEAL study design, including the PFS primary endpoint, and agreed that positive results from this study could support regulatory approval in this patient population."

About Selinexor
Selinexor (KPT-330) is a first-in-class, oral Selective Inhibitor of Nuclear Export / SINE compound. Selinexor functions by binding with and inhibiting the nuclear export protein XPO1 (also called CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells. To date, over 2,100 patients have been treated with selinexor and it is currently being evaluated in several mid- and later-phase clinical trials across multiple cancer indications, including in multiple myeloma in a pivotal, randomized Phase 3 study in combination with Velcade (bortezomib) and low-dose dexamethasone (BOSTON), in combination with low-dose dexamethasone (STORM) and backbone therapies (STOMP), and in diffuse large B-cell lymphoma (SADAL), and liposarcoma (SEAL), among others. Additional Phase 1, Phase 2 and Phase 3 studies are ongoing or currently planned, including multiple studies in combination with one or more approved therapies in a variety of tumor types to further inform the Company’s clinical development priorities for selinexor. Additional clinical trial information for selinexor is available at www.clinicaltrials.gov.

On September 20, 2017 DelMar Pharmaceuticals, Inc. (Nasdaq: DMPI) ("DelMar" and "the Company"), a biopharmaceutical company focused on the development of new cancer therapies, reported that the U.S. Patent and Trademark Office (USPTO) has issued to DelMar, United States Patent No. 9,759,698 covering improved analytical methods for analyzing and determining impurities in dianhydrogalactitol (VAL-083) (Press release, DelMar Pharmaceuticals, SEP 20, 2017, View Source [SID1234520572]).

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DelMar’s new patent strengthens the Company’s control over the VAL-083 manufacturing process and related controls. DelMar is establishing broad new intellectual property protection around VAL-083, a first-in-class DNA targeting agent that demonstrated clinical activity against a range of tumor-types in prior clinical trials sponsored by the U. S. National Cancer Institute (NCI).

VAL-083 is currently protected by eight US patents and eight patents outside of the US, with issued claims providing patent protection into 2033 in the United States. DelMar has made patent filings under 14 separate patent families encompassing more than 100 individual patent applications.

On September 20, 2017 AVEO Oncology (NASDAQ:AVEO) and EUSA Pharma reported that EUSA Pharma, under its multi-territory licensing agreement with AVEO for FOTIVDA (tivozanib), has opted into the Phase 1/2 TiNivo study. Under terms of the agreement, EUSA may utilize data from the study for regulatory or commercial purposes in exchange for a research and development funding payment totaling $2.0 million (Press release, AVEO, SEP 20, 2017, View Source [SID1234520570]). EUSA’s decision follows approval in August of tivozanib by the European Commission for the treatment of adult patients with advanced renal cell carcinoma (RCC) in the European Union plus Norway and Iceland.

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The TiNivo trial is a Phase 1/2 trial of tivozanib in combination with Bristol-Myers Squibb’s OPDIVO (nivolumab), an immune checkpoint, or PD-1, inhibitor, for the treatment of RCC. The TiNivo trial is being led by the Institut Gustave Roussy in Paris under the direction of Bernard Escudier, MD, Chairman of the Genitourinary Oncology Committee. In June, AVEO announced the advancement of the trial into the Phase 2 expansion portion following successful completion of the Phase 1 dose escalation portion. The combination was well tolerated to the full dose and schedule of single agent tivozanib, with no dose limiting toxicities. The expansion portion of the trial is expected to enroll an additional 20 subjects. Phase 1 results from the ongoing study have been submitted for presentation at a scientific meeting taking place in the fourth quarter.

"We look forward to working with EUSA in helping shape the future direction of FOTIVDA in an evolving treatment landscape for advanced RCC," said Michael Bailey, president and chief executive officer of AVEO. "Immunotherapy is defining an important role as an early treatment option for this disease, creating an opportunity to investigate the role of TKIs following immunotherapy or in combination with immunotherapy. Having already demonstrated superior PFS and an improved side effect profile compared to sorafenib in the pivotal TIVO-1 study, FOTIVDA is currently being evaluated in an ongoing third line pivotal trial stratifying for prior immunotherapy, and is well positioned to play a role in this evolving treatment landscape."

Lee Morley, EUSA Pharma’s Chief Executive Officer said, "Following the recent European approval of FOTIVDA for the first-line treatment of patients with advanced RCC, emerging data from the TiNivo study indicates the potential for FOTIVDA in this setting. With our partner AVEO and the RCC community, we are committed to the ongoing development of FOTIVDA and look forward to investigating new and innovative treatment options for patients with advanced RCC."

Under the terms of their December 2015 agreement, EUSA Pharma has agreed to pay AVEO up to $388 million in future milestone payments and research and development funding, assuming successful achievement of specified development, regulatory and commercialization objectives. In addition, a tiered royalty will be due to AVEO ranging from a low double-digit up to mid-twenty percent on net sales of tivozanib in the agreement’s territories. With European approval, AVEO will be eligible for up to $12 million in milestones from EUSA based on reimbursement and regulatory approvals. In the territories licensed to EUSA, thirty percent of milestone and royalty payments received by AVEO, excluding research and development payments such as the one announced today, are due to Kyowa Hakko Kirin (KHK) as a sublicensing fee. In the territories retained by AVEO, the royalty obligation to KHK ranges from the low- to mid-teens on net sales.

About Tivozanib (FOTIVDA)

An over-expression of VEGF protein, and a resulting increase in tumour blood supply (angiogenesis), is a common feature of RCC.1 VEGFR-TKIs reduce the supply of blood to the tumour and are the recommended first-line treatment for advanced RCC in Europe, however, patients often experience significant side effects, including fatigue, diarrhoea, and hand-foot syndrome.

In the global Phase III trial (TIVO-1)1 of over 500 patients with advanced RCC, tivozanib demonstrated a significant PFS benefit versus sorafenib (11.9 vs. 9.1 months in the overall patient population [HR, 0.797; 95% CI, 0.639 to 0.993; P =.042], and 12.7 vs. 9.1 months in treatment-naïve patients [HR, 0.756; 95% CI, 0.580 to 0.985; P =.037]).1 There was also an improved side-effect profile versus sorafenib, with significantly fewer patients on tivozanib (14% versus 43%) requiring a dose reduction due to AEs; and less than 5% of patients experiencing severe side effects (grade 3&4, such as diarrhoea, asthenia (physical weakness) and hand-foot syndrome. Hypertension (44%) and dysphonia (21%) were the most commonly reported AEs on tivozanib.1

Under EUSA Pharma’s license agreement with AVEO, announced in December 2015, the company holds exclusive commercialization rights to tivozanib in RCC in Europe and in a number of other territories outside North America, including South America and South Africa. Under the terms of the agreement, EUSA Pharma will undertake and fund the commercialization of the product in its territories, assuming licensing. AVEO retains the rights to commercialize the product in North America. Tivozanib was discovered by Kyowa Hakko Kirin.