On June 8, 2017 Sophiris Bio Inc. (NASDAQ: SPHS) (the "Company" or "Sophiris") reported that the first patient has been dosed in its Phase 2b study to evaluate the safety and tolerability of topsalysin in focally treating men with clinically significant localized prostate cancer (Press release, Sophiris Bio, JUN 8, 2017, View Source [SID1234519475]). Topsalysin (PRX302) is an innovative, first-in-class pore-forming protein engineered to be activated only in the presence of enzymatically-active PSA, which is only found within the prostate.

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This Phase 2b study will build on the successful Phase 2a proof-of-concept study for the treatment of localized prostate cancer which demonstrated that a targeted intraprostatic administration of topsalysin has the potential to safely ablate prostate tumor cells.

"Topsalysin has the potential to provide a much-needed opportunity to treat the patients who have clinically significant localized prostate cancer in a targeted focal manner, ablate pre-identified lesions and downgrade the patient to non-significant cancer," said Dr. Hashim Ahmed, professor and chair of urology, Imperial College London. "This would be extremely exciting and clinically meaningful for men, as it could help them either avoid or delay the need for radical therapies and significant side effects associated with radical therapy."

"We have the potential to provide an efficacious, less invasive treatment option for patients with clinically significant localized prostate cancer," said Randall E. Woods, president and CEO of Sophiris Bio. "Our goal with this international Phase 2b clinical study is to confirm the dose and optimize the delivery of topsalysin and to evaluate the safety and efficacy of a second dose of topsalysin in a clinical setting."

About the Phase 2b Study

The study is a multi-center, open-label, Phase 2b study evaluating the safety and efficacy of targeted intraprostatic administration of topsalysin for the treatment of histologically proven, clinically significant, localized prostate cancer. Approximately 40 patients will be enrolled in the study at multiple sites in the United States and the United Kingdom. The study will utilize previously obtained MRI images of each patient’s prostate mapped to real time 3D ultrasound to target the delivery of topsalysin directly into and around a pre-identified clinically significant tumor. Safety and tolerability will be assessed post-treatment over 26 weeks. Efficacy will be assessed by biopsy and imaging (mpMRI) at 24 weeks. The Company expects to receive six month biopsy data for all patients in the first quarter of 2018 assuming enrollment is completed as expected.

Importantly, the Phase 2b study includes an option to re-treat patients with a second dose of topsalysin, with a targeted biopsy to occur six months following the second dose. In order to be eligible for a second dose, the patient cannot have experienced a significant adverse event attributable to topsalysin or the dosing procedure from the first dose and the patient will need to have had a clinical response from the first dose but still have the presence of a clinically significant lesion area. The Company expects to have final biopsy data on all patients who receive a second dose in the fourth quarter of 2018.

About Localized Prostate Cancer

Prostate cancer is the second most common form of cancer in men in the US with an estimated 161,000 new cases in 2017. Approximately 80 percent of patients in the US are diagnosed with localized disease. Research has shown that patients with early, localized disease have a low likelihood of the cancer spreading beyond the confines of the prostate; however, many men with clinically significant localized disease choose to undergo radical treatment. Radical therapies include surgery to remove the entire prostate and/or radiation. Potential toxicities from radical treatments can be significant and permanent and include erectile dysfunction, urinary incontinence, and rectal toxicity.

About Topsalysin

Topsalysin (PRX302), an innovative, "First-in-Class" pore-forming protein, was engineered to be activated only by enzymatically-active PSA, which is produced in large quantities exclusively within the prostate of men with prostate cancer. The targeted focal treatment of prostate cancer is in line with current treatment trends for solid tumors such as breast and liver, where the goal is to remove the tumor and preserve as much of the organ and organ function as possible.

Topsalysin has the potential to provide a focal targeted therapy for the ablation of localized prostate cancer while potentially avoiding many of the complications and side effects associated with whole gland radical treatments. The increasing use of multiparametric magnetic resonance imaging (mpMRI) and advances in mapping previously obtained mpMRI images with real-time three-dimensional ultrasound images enables urologists to more accurately locate tumors within the prostate when taking biopsies. This increases the accuracy with which men with clinically significant lesions are identified. It also enables the injection of an ablative agent, such as topsalysin, directly into previously identified clinically significant tumors located within the prostate.

On June 8, 2017 CytRx Corporation (NASDAQ: CYTR) a biopharmaceutical research and development company specializing in oncology, reported an update on the regulatory pathway for a New Drug Application (NDA) submission for aldoxorubicin in soft tissue sarcomas (STS) (Press release, CytRx, JUN 8, 2017, View Source [SID1234519474]).

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The Company plans to submit a rolling NDA under section 505(b)(2) to the FDA for aldoxorubicin as a treatment for STS. The 505(b)(2) pathway is designed for a new drug that contains the same active ingredient as a previously approved drug, also known as a reference drug. For aldoxorubicin, doxorubicin is the reference drug. The NDA submission is not reliant solely on the recently completed Phase 3 clinical trial in STS or overall survival results. Rather, CytRx’s completed pharmacokinetic clinical trial, Phase 2b and Phase 3 trials in STS, along with preclinical safety and efficacy studies, will serve as "scientific bridges" between aldoxorubicin and doxorubicin. These studies, along with the published literature of doxorubicin’s effectiveness and safety, will form the basis of the NDA filing for aldoxorubicin under the 505(b)(2) regulations.

"Having worked on aldoxorubicin’s regulatory strategy and as a participant in the March FDA meeting, the 505(b)(2) regulatory pathway is the most appropriate for aldoxorubicin in STS," said Scott Wieland, PhD, CytRx’s Senior Vice President of Drug Development. "As noted in the FDA meeting, the aldoxorubicin preclinical and clinical studies will support a 505(b)(2) NDA submission, and no new clinical trials were requested by the FDA at the meeting. Additionally, CytRx’s previously approved special protocol assessment is no longer applicable."

Aldoxorubicin has received Orphan Drug Designation by the FDA for the treatment of STS. Orphan designation provides several benefits including seven years of market exclusivity after approval, certain R&D related tax credits and protocol assistance by the FDA. European regulators granted aldoxorubicin Orphan Medicinal Product Designation for STS which confers ten years of market exclusivity among other benefits. CytRx plans to discuss with the European Medicines Agency (EMA) a path to filing a Marketing Authorization Application (MAA).

The proposed product label would allow the treatment of soft tissue sarcomas. New data could support future use of aldoxorubicin in neoadjuvant (pre-surgery) settings, as well as a replacement for doxorubicin in chemotherapy combinations. CytRx is also working on a market expansion strategy which would include other indications for aldoxorubicin including combinations with other chemotherapeutics and immunotherapies.

About a 505(b)(2) New Drug Application

A new drug application (NDA) under the Food and Drug Administration’s (FDA) section 505(b)(2) is for a new drug containing the same active ingredient as a previously approved drug. According to the publication Regulatory Focus (Reg Focus, Apr. 2010, 8-13.), a drug reviewed under 505(b)(2) represents a modified version of a previously approved product that requires additional clinical and nonclinical studies, other than bioavailability/bioequivalence studies, to demonstrate its safety and efficacy. Such an application differs from a typical NDA in that the sponsor can rely on, at least in part, the FDA’s findings of safety and effectiveness for the previously approved reference drug.

About the Phase 2b and Phase 3 Clinical Trials

The global Phase 2b trial involved 123 patients at 31 sites. Patients with advanced soft tissue sarcomas were randomized 2:1 to receive either 350 mg/m2 of aldoxorubicin (83 patients) or 75 mg/m2 of doxorubicin (40 patients) every 3 weeks for up to 6 cycles. The trial was designed to compare aldoxorubicin directly with doxorubicin.

The randomized, controlled Phase 3 trial enrolled a total of 433 patients at 79 clinical sites. Patients with metastatic, locally advanced or unresectable soft tissue sarcomas who had either not responded to, or who had progressed following treatment with one or more systemic regimens of non-adjuvant chemotherapy were randomized 1:1 to be treated with 350 mg/m2 of aldoxorubicin until disease progression or the investigator’s choice of an approved chemotherapeutic regimen, including doxorubicin, ifosfamide, dacarbazine, pazopanib (Votrient), or gemcitabine plus docetaxel.

About Soft Tissue Sarcoma

Soft tissue sarcoma is a cancer occurring in muscle, fat, blood vessels, tendons, fibrous tissues and connective tissue. It can arise anywhere in the body at any age. STS remains a high unmet medical need because of the difficulty in treating the more than 50 types of this aggressive cancer. According to the American Cancer Society, in 2017 more than 12,300 new cases were diagnosed in the U.S. and approximately 5,000 Americans died from this disease. In addition, approximately 40,000 new cases and 13,000 deaths in the U.S. and Europe are part of a growing underserved market.

About Aldoxorubicin

Aldoxorubicin is a rationally engineered cytotoxic which combines doxorubicin, a widely used chemotherapeutic agent, with a novel linker molecule that binds directly and specifically to circulating albumin, the most abundant protein in the bloodstream. Protein-hungry tumors concentrate albumin, which facilitates the delivery of the linker molecule with the attached doxorubicin to tumor sites. In the acidic environment of the tumor, but not the neutral environment of healthy tissues, doxorubicin is released. Typically, doxorubicin is delivered systemically and is highly toxic, which limits its dose to a level below its maximum therapeutic benefit. Doxorubicin also is associated with many side effects, especially the potential for damage to heart muscle at cumulative doses greater than 450 mg/m2. Using this acid-sensitive linker technology, aldoxorubicin delivers greater doses of doxorubicin (3 ½ to 4 times). To date, there has been no evidence of clinically significant effects of aldoxorubicin on heart muscle, even at cumulative doses of the drug well in excess of 5,000 mg/m2. Aldoxorubicin is the first-ever single agent to show superiority over doxorubicin in a randomized clinical trial in first-line STS.

On June 8, 2017 Cascadian Therapeutics, Inc. (NASDAQ:CASC), a clinical-stage biopharmaceutical company, reported that tucatinib, an investigational oral, small molecule kinase inhibitor that is highly selective for HER2 and the Company’s lead product in development, has been granted orphan drug designation by the U.S. Food and Drug Administration ("FDA") for the treatment of breast cancer patients with brain metastases (Press release, Cascadian Therapeutics, JUN 8, 2017, View Source [SID1234519473]).

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"Brain metastases arise in up to 50 percent of women with HER2-positive metastatic breast cancer and these metastases can compromise quality of life and survival," explained Eric P. Winer, MD, of Boston’s Dana-Farber Cancer Institute.

Winer’s colleague, Nancy U. Lin, MD, added, "Treatments for patients with brain metastases have been limited, and we urgently need new and more effective approaches."

"There remains an unmet medical need for patients with HER2-positive metastatic breast cancer, including patients whose disease has metastasized to the brain," said Scott Myers, President and CEO of Cascadian Therapeutics. "New treatment options are clearly needed and tucatinib is being developed to fit within the current and emerging treatment paradigm. Our ongoing registrational trial of tucatinib known as HER2CLIMB is enrolling patients with all types of brain metastases, including untreated, previously treated stable or progressing brain metastases. Approximately half of patients enrolled in HER2CLIMB to date have had brain metastases at study entry, which will allow us to assess activity in that subpopulation in a statistically meaningful way. We are encouraged by results from our ongoing Phase 1b combination study of tucatinib plus capecitabine and/or trastuzumab, which showed a 42 percent response rate in patients with HER2-positive brain metastases."

The FDA’s Orphan Drug Designation program provides orphan status to drugs defined as those intended for the safe and effective treatment, diagnosis or prevention of rare diseases that affect fewer than 200,000 people in the U.S. Orphan designation qualifies the sponsor of the drug for certain development incentives, including tax credits for qualified clinical testing, prescription drug user fee exemption and 7-year marketing exclusivity upon FDA approval.

About Tucatinib

Tucatinib is an investigational, orally bioavailable, potent tyrosine kinase inhibitor that is highly selective for HER2 without significant inhibition of EGFR. Inhibition of EGFR has been associated with significant toxicities, including skin rash and diarrhea. Tucatinib has shown activity as a single agent and in combination with both chemotherapy and other HER2 directed agents such as trastuzumab.1,2 Studies of tucatinib in these combinations have shown activity both systemically and in brain metastases. HER2 is a growth factor receptor that is overexpressed in multiple cancers, including breast, ovarian and gastric cancers. HER2 mediates cell growth, differentiation and survival. Tumors that overexpress HER2 are more aggressive and historically have been associated with poor overall survival, compared with HER2-negative cancers.

About HER2CLIMB Pivotal Trial

HER2CLIMB is a randomized (2:1), double-blind, placebo-controlled pivotal clinical trial comparing tucatinib vs. placebo in combination with capecitabine and trastuzumab in patients with locally advanced or metastatic HER2-positive breast cancer who have had prior treatment with a taxane, trastuzumab, pertuzumab and ado-trastuzumab emtansine, also known as T-DM1. The primary endpoint is progression-free survival (PFS) based upon independent radiologic review. Key objectives related to assessing activity in brain metastases include a key secondary endpoint of PFS in a subset of patients with brain metastases. All patients will be followed for overall survival. HER2CLIMB is currently enrolling patients in the United States and Canada. Clinical sites in Western Europe, Australia and Israel are expected to open in the first half of 2017.

About HER2-Positive Metastatic Breast Cancer

Patients with HER2-positive breast cancer have tumors with high levels of a protein called human epidermal growth factor receptor 2 (HER2), which promotes the aggressive spread of cancer cells. The American Cancer Society estimates that 20-25 percent of the approximately 246,660 annual new cases of breast cancer diagnoses in the U.S. are HER2-positive. Historically, HER2 disease has been associated with shorter survival times as well as a higher risk of recurrence and CNS disease (brain metastases). Approximately 30 to 50 percent of HER2-positive breast cancer patients develop brain metastases over time.3,4 Over the past two decades, the approvals of four targeted treatments (trastuzumab, pertuzumab, lapatinib, and T-DM1) have led to improved time to progression and survival rates of patients with HER2-positive breast cancer. Despite these advances, there is still a significant need for new therapies that can impact metastatic disease, including brain metastases, and be tolerated for longer periods of time.

On June 8, 2017 AVEO Oncology (NASDAQ:AVEO) reported that its Phase 1/2 AVEO-sponsored TiNivo trial evaluating tivozanib in combination with Bristol-Myers Squibb’s anti-PD-1 therapy, Opdivo (nivolumab), in subjects with advanced renal cell carcinoma (RCC) has progressed to the Phase 2 portion of the trial (Press release, AVEO, JUN 8, 2017, View Source [SID1234519472]).

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Advancement of the study into the Phase 2 expansion follows the successful completion of the Phase 1 dose escalation portion of the trial, where tivozanib was administered in two escalating dose cohorts in combination with nivolumab at a constant 240 mg every 2 weeks (n=6). The combination was well tolerated to the full dose and schedule of single agent tivozanib, with no dose limiting toxicities. The full dose tivozanib regimen of 1.5 mg daily for 21 days, followed by a 7 day rest period, is the recommended Phase 2 dose (RP2D) for the expansion portion of the trial, which is expected to enroll up to an additional 20 subjects. The TiNivo study is being led by the Institut Gustave Roussy in Paris under the direction of Bernard Escudier, MD, Chairman of the Genitourinary Oncology Committee. Phase 1 results from the ongoing study will be submitted for presentation at an upcoming scientific meeting.

"The promise of delivering synergistic activity by combining VEGF TKIs and PD-1s in renal cell carcinoma hinges on the tolerability of the combination," said Dr. Escudier. "Tivozanib has a uniquely favorable tolerability profile as demonstrated in past single agent and combination studies. These initial results are very promising in that we see both evidence of a uniquely tolerable combination as well as early and meaningful activity. I look forward to enrolling the expansion cohort and to establishing a broader understanding for the potential of this compelling combination."

"Together with the longest progression free survival from a Phase 3 first line RCC study, tivozanib’s tolerability is distinct from other VEGF TKIs, which we believe better position it for use in combination with immunotherapy and other agents," said Michael Bailey, president and chief executive officer of AVEO. "As our registration strategy for single agent tivozanib reaches key inflection points, with a European regulatory decision expected in the near-term and readout of our US registration-directed TIVO-3 study expected in the first quarter of 2018, our attention is increasing on tivozanib immuno-oncology combinations that have the potential to deliver significantly improved outcomes and tolerability to patients. The TiNivo trial is an important first step in this effort, and we share Dr. Escudier’s enthusiasm for the completion of this trial."

About Tivozanib

Tivozanib is an oral, once-daily, vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI). It is a potent, selective and long half-life inhibitor of all three VEGF receptors and is designed to optimize VEGF blockade while minimizing off-target toxicities, potentially resulting in improved efficacy and minimal dose modifications. Tivozanib has been investigated in several tumors types, including renal cell, colorectal and breast cancers.a