On June 26, 2018 Arcus Biosciences, Inc. (NYSE:RCUS), a clinical-stage biopharmaceutical company focused on creating innovative cancer immunotherapies, and Infinity Pharmaceuticals, Inc. (NASDAQ:INFI), a clinical-stage biopharmaceutical company developing IPI-549, a first-in-class immuno-oncology product candidate that selectively inhibits phosphoinositide-3-kinase gamma (PI3K-gamma), reported that they have entered into a clinical collaboration to evaluate two triple combination therapies in selected tumor types which typically show minimal response to checkpoint inhibition monotherapy (Press release, Arcus Biosciences, JUN 26, 2018, View Source [SID1234527474]).

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The collaboration will evaluate IPI-549 in combination with AB928, Arcus’s dual adenosine receptor antagonist, and AB122, Arcus’s anti-PD-1 antibody, as well as IPI-549 in combination with AB928 and chemotherapy in patients with triple negative breast cancer (TNBC) or ovarian cancer in four separate cohorts. These four cohorts will be incorporated into Arcus’s recently initiated Phase 1/1b trial to evaluate AB928 combinations in TNBC and ovarian cancer. As both macrophages and high adenosine levels are believed to play critical roles in creating a highly immune-suppressive tumor microenvironment in TNBC and ovarian cancer, the triple combinations being evaluated could represent a promising approach to treating these tumor types. By intervening in multiple mechanisms that mediate immuno-suppression, the companies hope to address two tumor types that lack effective therapies, particularly in later lines of treatment.

"This partnership with Infinity is important as, for the first time, we will be investigating the potential for the triple combination of a selective PI3K-gamma inhibitor, a dual adenosine receptor antagonist, and either a PD-1 inhibitor or chemotherapy to effectively treat patients with triple negative breast cancer or ovarian cancer," said Terry Rosen, Ph.D., Chief Executive Officer of Arcus Biosciences. "This collaboration also allows us to expand the number of promising combinations with strong biological rationale that we plan to evaluate in our recently initiated Phase 1/1b trial for AB928. Arcus has carefully considered which immuno-oncology therapies can best target immune suppressive macrophages and has concluded that selective inhibition of PI3K-gamma is a fundamental mechanism for reprogramming macrophages from a pro-tumor to an anti-tumor function."

"This collaboration with Arcus Biosciences enables an important expansion of our clinical development of IPI-549, investigating IPI-549 in triple-combination therapy with other important immuno-oncology agents as well as with chemotherapy," said Adelene Perkins, Chief Executive Officer and Chair of Infinity Pharmaceuticals. "Combining these agents may result in enhanced reduction of pro-tumor immune suppression and increased anti-tumor immune activation. We look forward to working with the terrific team at Arcus in investigating these triple-combination therapies as potentially new treatment options for patients with cancers that are not adequately addressed by existing therapies."

Under the terms of the agreement, Infinity and Arcus will share equally expenses related to the four triple-combination cohorts to evaluate the safety and activity of IPI-549 + AB928 + AB122 and IPI-549 + AB928 + chemotherapy. Each of the four triple-combination cohorts will enroll approximately 15 patients. Topline data from these studies are expected in 2019.

About AB928

AB928 is an orally bioavailable, highly potent antagonist of the adenosine 2a and 2b receptors. The activation of these receptors by adenosine interferes with the activity of key populations of immune cells and inhibits an optimal anti-tumor immune response. By blocking these receptors, AB928 has the potential to reverse adenosine-induced immune suppression within the tumor microenvironment. AB928 was designed specifically for the oncology setting, with a profile that includes potent activity in the presence of high concentrations of adenosine and a minimal shift in potency due to non-specific protein binding, both essential properties to be efficacious in the tumor microenvironment. AB928 has other attractive features, including high penetration of tumor tissue and low penetration through the healthy blood-brain barrier. In a Phase 1 trial in healthy volunteers, AB928 has been shown to be safe and well tolerated and to have pharmacokinetic and pharmacodynamic profiles consistent with a once-daily dosing regimen.

About IPI-549 and the Ongoing Phase 1/1b Study

IPI-549 is an investigational first-in-class, oral, immuno-oncology product candidate targeting tumor-associated myeloid cells through selective phosphoinositide-3-kinase-gamma (PI3K-gamma) inhibition, thereby reducing pro-tumor macrophage function and increasing anti-tumor macrophage function. In preclinical studies, IPI-549 demonstrated the ability to reprogram macrophages from a pro-tumor (M2), immune-suppressive function, to an anti-tumor (M1) immune-activating function and enhance the activity of, and overcome resistance to, checkpoint inhibitors.i ii As such, IPI-549 may have the potential to treat a broad range of solid tumors and represents a potentially additive or synergistic approach to restoring anti-tumor immunity in combination with other immunotherapies such as checkpoint inhibitors.

The ongoing Phase 1/1b study being conducted by Infinity is designed to evaluate the safety, tolerability, activity, pharmacokinetics and pharmacodynamics of IPI-549 as a monotherapy and in combination with Opdivo in approximately 200 patients with advanced solid tumors.iii The study includes monotherapy and combination dose-escalation components, in addition to monotherapy expansion and combination expansion components. The monotherapy dose-escalation and expansion components are complete. The combination dose-escalation component is also complete, and combination expansion cohorts are enrolling.

The combination expansion component of the study includes multiple cohorts designed to evaluate IPI-549 in patients with specific types of cancer, including patients with non-small cell lung cancer (NSCLC), melanoma and head and neck cancer whose tumors show initial resistance or initially respond to but subsequently develop resistance to immune checkpoint blockade therapy. The combination expansion component also includes a cohort of patients with triple negative breast cancer (TNBC) who have not been previously treated with immune checkpoint blockade therapy, a cohort of patients with mesothelioma, a cohort of patients with adrenocortical carcinoma and a cohort of patients with high baseline blood levels of MDSCs.

On June 26, 2018 Merrimack Pharmaceuticals, Inc. (Nasdaq: MACK), a clinical-stage oncology company focused on biomarker-defined cancers, reported top-line results from the CARRIE study, a randomized Phase 2 trial evaluating the addition of MM-141 (istiratumab) to standard-of-care treatment in patients with previously untreated metastatic pancreatic cancer and high serum levels of free Insulin-like Growth Factor-1 (IGF-1) (Press release, Merrimack, JUN 26, 2018, View Source [SID1234527475]). The study did not meet its primary or secondary efficacy endpoints in patients who received MM-141 in combination with nab-paclitaxel and gemcitabine, compared to nab-paclitaxel and gemcitabine alone. These results were consistent in all subgroups analyzed. Based on these results, Merrimack will not devote additional resources to the development of MM-141.

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Merrimack plans to present the complete data from this Phase 2 study at an upcoming medical oncology meeting.

"Pancreatic cancer is the third leading cause of cancer-related death in the Unites States and a very difficult cancer to treat," said Sergio Santillana, M.D., MSc., Chief Medical Officer of Merrimack. "Although we were unsuccessful in our effort to improve the standard of care for these patients, we want to express our gratitude to our investigators and our team, and, of course, to the patients and their families for their support and participation in the CARRIE study."

"While these results are disappointing, looking forward our focus remains on the continued development of our deep, wholly-owned pipeline, including two clinical programs, MM-121 and MM-310, with data readouts expected in 2018," said Richard Peters, M.D., Ph.D., President and CEO of Merrimack.

MM-121 (seribantumab), a monoclonal antibody targeting the HER3 (ErbB3) receptor, is being tested in combination with standard-of-care treatment in two randomized Phase 2 studies: SHERLOC, in patients with non-small cell lung cancer, and SHERBOC in patients with metastatic breast cancer. Both studies are enrolling patients with high tumor expression of heregulin, the signal for the HER3 receptor. Top-line results from the SHERLOC study are expected in 2H 2018.

MM-310, an antibody-directed nanotherapeutic targeting the EphA2 receptor, is currently being tested in a Phase 1 study in solid tumors, with safety data and the maximum tolerated dose expected in 2H 2018.

On June 26, 2018 Puma Biotechnology, Inc. (Nasdaq: PBYI) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive trend vote recommending the approval of the Marketing Authorisation Application (MAA) for neratinib for the extended adjuvant treatment of early stage HER2-positive hormone receptor positive breast cancer (Press release, Puma Biotechnology, JUN 26, 2018, View Source [SID1234527476]). Today’s decision follows a reexamination of the negative opinion announced by the CHMP at its formal meeting with the Company to discuss the MAA on February 23, 2018. The CHMP communicated its intention to hold a final vote at its next meeting.

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About HER2-Positive Breast Cancer

Approximately 20% to 25% of breast cancer tumors over-express the HER2 protein. HER2-positive breast cancer is often more aggressive than other types of breast cancer, increasing the risk of disease progression and death. Although research has shown that trastuzumab can reduce the risk of early stage HER2-positive breast cancer returning after surgery, up to 25% of patients treated with trastuzumab experience recurrence.

On June 26, 2018 Oncology Venture US Inc., Oncology Venture AB (OV:ST) ("OV") and Medical Prognosis Institute A/S (MPI:ST) reported dosing of the first patient in a Phase 2, open-label clinical trial to investigate the anti-tumor effect and tolerability of 2X-121 in patients with metastatic breast cancer selected by a novel drug response predictor (DRP) mRNA-driven multiple biomarker, the 2X-121 DRP (Press release, 2X Oncology, JUN 26, 2018, View Source [SID1234527477]). The drug is being developed by Oncology Venture US Inc. (formerly 2X Oncology Inc.).

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"This targeted Phase 2 study will enable us to rapidly evaluate the efficacy of our Tankyrase and PARP inhibitor in heavily pre-treated metastatic breast cancer patients, using the 2X-121 DRP to prospectively select likely responders to this differentiated therapy," said George Elston, CEO of Oncology Venture US Inc.

2X-121 is an orally-available small molecule PARP and tankyrase inhibitor. This clinical trial is designed to enroll 30 metastatic breast cancer patients regardless of hormone receptor, HER2 status and BRCA1 or 2 status, who have relapsed on two or more different prior therapies and who are identified by the 2X-121 DRP as highly likely to respond to treatment with 2X-121.

The 2X-121 DRP is a novel, tumor-agnostic (i.e. independent of tumor site) molecular biomarker based on expression of 414 genes predictive of response to 2X-121. In a study presented at ASCO (Free ASCO Whitepaper), the 2X-121 DRP correctly identified responders and non-responders to treatment irrespective of BRCA mutation status. Although a patient’s BRCA status is used to identify potential responders for treatment with approved PARP inhibitors, other likely responders are excluded. The 2X-121 DRP biomarker is expected to identify those patients who are likely responders while excluding the likely non-responders.

In this clinical trial, patients will receive oral treatment with 600 mg of 2X-121, as a single agent, in a 21-day cycle. The primary endpoint of this study is clinical benefit rate, defined as complete response, partial response, or stable disease at greater than 24 weeks post-treatment using the RECIST criteria. Secondary endpoints include progression free survival, duration of response (from first response to progression), and overall survival.

2X-121 Phase 2 study in metastatic Breast Cancer (mBC)
2X-121 is an investigational, orally-available small molecule targeted inhibitor of Poly ADP ribose polymerase (PARP), a key enzyme involved in DNA damage repair in cancer cells. The drug candidate has a novel dual-inhibitory action against both PARP 1/2 and Tankyrase 1/2. The molecule is also active in P-glycoprotein expressing cells, suggesting it may overcome PARP inhibitor resistance. Patients will receive oral treatment with 600 mg 2X-121, as a single agent, in a 21-day cycle. The primary endpoint of this study is clinical benefit rate defined as complete response, partial response, or stable disease at greater than 24 weeks post-treatment using the RECIST criteria. Secondary endpoints include progression free survival, duration of response (from first response to progression), and overall survival.

Separate, targeted Phase 2 studies of 2X-121 are planned using the validated DRP biomarker in recurrent ovarian cancer, castration resistant prostate cancer, and pancreatic cancer to identify patients likely to respond to and benefit from treatment with the drug.

About the Drug Response Predictor – DRP Companion Diagnostic
Oncology Venture uses the Medical Prognosis Institute (MPI) multi gene DRP to select those patients who by the genetic signature of their cancer are found to have a high likelihood of responding to the drug. The goal is developing the drug for the right patients, and by screening patients before treatment the response rate can be significantly increased. The DRP method builds on the comparison of sensitive vs. resistant human cancer cell lines, including genomic information from cell lines combined with clinical tumor biology and clinical correlates in a systems biology network. DRP is based on messenger RNA from the patient’s biopsies.

The DRP platform, i.e. the DRP and the PRP tools, can be used in all cancer types and is patented for more than 70 anti-cancer drugs in the US. The PRP is used by MPI for Personalized Medicine. The DRP is used by Oncology Venture for drug development.

DRP is a registered trademark of Medical Prognosis Institute A/S.

On June 25, 2018 Sophiris Bio Inc. (NASDAQ: SPHS) (the "Company" or "Sophiris"), a biopharmaceutical company studying topsalysin (PRX302), a first-in-class, pore-forming protein, in late stage clinical trials for the treatment of patients with urological diseases, reported top-line interim safety and biopsy data following a single administration of topsalysin from its ongoing open-label, Phase 2b clinical trial (Press release, Sophiris Bio, JUN 25, 2018, View Source [SID1234527461]). A single administration of topsalysin continues to demonstrate an ability to ablate targeted prostate cancer cells with 10 of 35 patients (29%) demonstrating a clinical response of which 6 patients had a complete ablation with no detectable cancer on targeted biopsy of the treated area. Separately, Sophiris was recently notified that a patient death occurred on the same day as their second administration. The company is currently investigating the cause and as a precaution no additional patients will receive a second administration of topsalysin.

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"We are extremely saddened by the death of a patient after receiving a second administration of topsalysin," said Randall E. Woods, president and CEO of Sophiris. "Understanding the cause of the patient’s death is our first priority and essential to determining the potential for re-administration of topsalysin in future clinical trials."

To date, over 450 patients have received a single administration of topsalysin at various doses. The drug continues to appear to be well-tolerated in patients who received a single administration, with no new safety signals reported. In addition, biopsy data from the Phase 2b trial demonstrated that 29% (10/35) of patients sustained a clinical response at six-month follow-up – defined as no detectable tumor following targeted biopsy of the treated lesion or a reduction in the tumor to clinically insignificant.

"We are very encouraged by the safety and biopsy results from a single administration of topsalysin in the Phase 2b study. Biopsy results improved from what we saw in the Phase 2a proof of concept trial and safety and tolerability remains in-line with what we have seen historically," stated Mr. Woods. "We believe that the safety and biopsy data from the first administration of topsalysin supports moving forward into potential registration studies. We will continue to evaluate whether future clinical development will include an option to administer a second dose as we receive more information about the patient death and additional information from the 10 patients who received a second dose. We will be able to evaluate this towards the end of this year."

Top-Line Interim Safety Results from a Single Administration of Topsalysin:

The primary objective of this trial is to evaluate the safety and tolerability of a single, and if applicable, a second administration of topsalysin, when used to focally ablate a histologically-proven, clinically-significant lesion in patients with localized prostate cancer.

To date, a single administration of topsalysin continues to appear safe and well tolerated by patients. No hypersensitivity reactions or other serious systemic reactions to study medication were observed after a single administration. Adverse events considered related to topsalysin and occurring in more than one patient were: dysuria (n=3 patients), urinary retention (n=3 patients), nocturia (n=2 patients), micturition urgency (n=2 patients) and strangury (n=2 patients). All adverse events were considered mild and typically resolved within the same day. One event of micturition urgency was considered severe and resolved the same day and one event of urinary retention was considered moderate and the event was considered resolved after the patient underwent a transuretheral resection of the prostate.

In May 2018, an independent data monitoring committee (IDMC) met to review the safety data from all 38 patients administered a single dose of topsalysin as well the safety data available on the first seven patients who received a second administration of topsalysin. At that time, the IDMC unanimously recommended the clinical trial continue without changes to the protocol.

Top-Line Interim Biopsy Results From a Single Administration of Topsalysin:

A secondary objective of the study is to evaluate the efficacy of a single administration of topsalysin and, if applicable, a second administration of topsalysin to selectively target and focally ablate a pre-identified lesion.

In the Phase 2b clinical trial, 38 patients with pre-identified, clinically-significant low-to-intermediate risk localized prostate cancer received a single administration of topsalysin. Six months after administration, patients received a follow-up targeted biopsy of the treated lesion. At the time of this release, targeted follow-up biopsies have been undertaken and evaluated from 35 of 38 patients treated with a single dose of topsalysin. Two of the remaining patients are expected to receive follow-up biopsies in the coming weeks.

Based on the six-month follow-up biopsy results, 29% of patients (10/35) demonstrated a clinical response, defined in this study as no detectable tumor on targeted biopsy of the treated lesion or a sufficient reduction to deem the lesion clinically-insignificant (cancer lesion of Gleason Score 6 (3+3) and a Maximum Cancer Core Length (MCCL) of less than 6 millimeters). This compares favorably to 17% of patients (3/18) moving to clinically-insignificant disease in the previously completed Phase 2a localized prostate cancer study. Of the 10 clinical responders in the Phase 2b trial, six experienced a complete ablation with no histological evidence of the tumor remaining.

Additionally, the Phase 2b single administration follow-up biopsy data show that:

37% of patients (13/35) experienced a partial response, defined as a reduction in MCCL and/or Gleason pattern, but the targeted lesion was still deemed clinically-significant.
34% (12/35) of patients did not respond to treatment defined as no change in the targeted lesion or an increase in MCCL and/or Gleason pattern
"The initial biopsy results released today, following a single intraprostatic administration of topsalysin are highly encouraging and definitely improve upon the Proof of Concept study results with a greater proportion of patients experiencing successful treatment of their treated lesion," stated Dr. Hashim Ahmed, the study’s chief investigator and chair of urology & consultant urological surgeon, Imperial College Healthcare NHS Trust & professor urology Imperial College. "Importantly, we have shown that the targeted intraprostatic injection of a single administration of topsalysin continues to appear safe and well tolerated. Furthermore, targeted focal therapy with topsalysin in this patient population is transferable to other clinicians with at least half of the clinical sites observing patients with no detectable lesion on re-biopsy of the targeted tumor and all eight sites observing patients in which lesions were at least partially ablated."

"Advances in the imaging of the prostate – by virtue of MRI – and the precise risk-stratification that this now permits has opened up new therapeutic opportunities for men with low-intermediate risk prostate cancer," stated Professor Mark Emberton, Dean University College London Faculty of Medical Sciences. "Men truly welcome the opportunity to undergo a targeted treatment of their prostate cancer (often in an ambulatory setting) without exposure to the commonly occurring side-effects of urinary incontinence, sexual dysfunction and rectal symptoms that have tended to accompany the more traditional approaches of surgery and radiotherapy. Topsalysin is beginning to show the spectrum of attributes we would want to see in a prostate cancer treatment of the future."

Administration of a Second Topsalysin Dose:

The Phase 2b prostate cancer study represents the first trial designed to allow qualified patients to receive a second administration of topsalysin six months after initial treatment. To be eligible to receive a second administration, patients could not have experienced a clinically-significant adverse event attributable to either topsalysin or the dosing procedure. Additionally, patients must have demonstrated evidence of a response to treatment with topsalysin, either through a reduction in lesion size, Gleason pattern, or MCCL. The objective of re-administering topsalysin is to determine if additional clinical benefit is observed.

Eleven patients elected to receive a second dose of topsalysin. The patients will continue to be monitored per the trial’s protocol and data are expected to be available in the fourth quarter of 2018.

Webcast scheduled for today at 11:00 a.m. Eastern Time

The Sophiris management team will host a conference call and webcast today, June 25, at 11:00 a.m. Eastern Time to review the topsalysin prostate cancer data. Dr. Hashim Ahmed, Chair of Urology, Imperial College of London & Imperial College Healthcare NHS Trust and investigator for the Phase 2b clinical trial will also participate in the call.

A live audio webcast will be accessible on the "Investor Relations" page of the Sophiris corporate website at www.Sophirisbio.com. A replay will be available at the same location.

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" transmembrane pore-forming protein, was genetically modified to be activated only by enzymatically-active PSA, which is produced in large quantities 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 targeted focal therapy for the ablation of localized prostate cancer lesions 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 software to co-register 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.