On December 08, 2015 Oncothyreon Inc. (Nasdaq:ONTY), a clinical-stage biopharmaceutical company dedicated to the development of therapeutic products that can improve the lives and outcomes of patients with cancer, reported updated data from the company’s ongoing trials of ONT-380, an orally active, reversible and selective small-molecule HER2 inhibitor being developed for the treatment of HER2-positive metastatic breast cancer (Press release, Oncothyreon, DEC 8, 2015, View Source [SID:1234508502]). The data will be the subject of two presentations at the San Antonio Breast Cancer Symposium (SABCS) being held December 8-12, 2015 in San Antonio, TX.

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The first presentation (Abstract P4-14-20) highlights data from a Phase 1b trial of ONT-380 in combination with Kadcyla (ado-trastuzumab emtansine or T-DM1) in patients who have previously failed treatment with Herceptin (trastuzumab) and a taxane for HER2-positive breast cancer ( ClinicalTrials.gov Identifier NCT01983501). The data demonstrate an overall response rate of 41% and a clinical benefit rate (CBR) of 59% in an advanced stage patient population, 60% of whom have a history of central nervous system (CNS) metastases. The CNS CBR for patients with response assessable CNS metastases was 64%. The second presentation (Abstract P4-14-19) combines data for patients with response assessable brain metastases from two trials, the Phase 1b trial in combination with Kadcyla and a Phase 1b trial of ONT-380 in combination with Herceptin and/or Xeloda (capecitabine) (ClinicalTrials.gov Identifier NCT02025192). The analysis includes patients with previously untreated CNS metastases as well as patients with progressive or new CNS metastases after prior treatment with radiation or surgery. Responses and clinical benefit in the CNS were seen for both groups and in all combinations tested.

"We are pleased by the response rate and clinical benefit rate we have seen in the combination trial of ONT-380 and Kadcyla, including in patients with brain metastases," said Robert L. Kirkman, M.D., President and CEO of Oncothyreon. "In addition, the analysis of patients with response assessable brain metastases from both our trials reinforce and expand upon our previously reported results, increasing our commitment to exploring ONT-380 in this indication. Our planned Phase 2 trial of ONT-380 in combination with Xeloda and Herceptin includes significant CNS-focused endpoints. We also plan to explore additional options to develop ONT-380 in combination with Kadcyla in patients with CNS metastases."

"CNS metastases occur in up to 50 percent of women with HER2-positive metastatic breast cancer, and these patients have limited options for systemic treatment," said Stacy Moulder, M.D., Associate Professor, Section Chief of Clinical Research, Breast Medical Oncology, University of Texas MD Anderson Cancer Center. "The level of clinical activity seen in the expanded data set for ONT-380 in these advanced stage patients is encouraging and worthy of urgent further development."

About the Clinical Results

The Phase 1b trial of ONT-380 in combination with Kadcyla is a dose escalation trial in patients with HER2-positive metastatic breast cancer who have been previously treated with Herceptin and a taxane. Patients with a history of CNS metastases, including patients with untreated asymptomatic metastases and patients with progression following prior local therapy, were eligible for enrollment in the trial. The trial enrolled a total of 57 patients. The maximally-tolerated dose (MTD) of ONT-380 in this trial was determined to be 300 mg given twice per day, and the detailed safety and efficacy results included here are for 50 patients treated at this dose. For this patient population, the median number of prior non-hormonal systemic treatments was two (range 0-6). Twenty-three (46%) of the patients had received prior Perjeta (pertuzumab) therapy and 10 (20%) had received prior Tykerb (lapatinib) therapy. Thirty (60%) of the patients had CNS metastases, of whom 19 had prior therapy for those metastases.

Best responses were measured using RECIST 1.1 criteria in 48 evaluable patients. In 34 patients with measurable disease, a best response of a confirmed partial response (cPR) was seen in 14 (41%), stable disease (SD) in 15 (44%) and progressive disease (PD) in 5 (15%). Fourteen patients had non-target lesions, primarily bone metastases, none of whom had a best response of PD (all were non-CR/non-PD by RECIST 1.1). The CBR, defined as patients with a complete response (CR), a cPR, or either SD or non-CR/non-PD for at least 6 months, was 59% (23/39). Patients active on study at the time of the analysis with SD for less than six months were excluded from the calculation of CBR. Twenty patients had response assessable CNS metastases. Of these patients twelve had measurable lesions and a follow-up scan, with a best CNS response of one CR, three PRs and eight SDs, for an overall response rate of 33%. One patient did not have a follow-up CNS scan as a result of progressive systemic disease. All seven patients with assessable non-target lesions had non-CR/non-PD as a best response. The CNS CBR was 64%. A calculation of progression free survival is not yet possible in this trial, as 25 of the 50 patients enrolled at the MTD remained active on the study at the time of the analysis.

Combination therapy with ONT-380 and Kadcyla was well-tolerated in this trial. The most common clinical adverse events were nausea, vomiting, diarrhea, vomiting and constipation, the majority of which were Grade 1 in severity. The most common laboratory abnormality was elevation in liver function tests (ALT/AST), the majority of which were Grade 1 or 2. All elevations in ALT/AST which were Grade 3 or greater were reversible with dose interruption, except in the setting of progressive metastatic liver disease, and most patients with Grade 3 or greater elevations were able to resume treatment with reduced dose ONT-380 and/or Kadcyla.

The role of ONT-380 in the treatment of CNS metastases from HER2-positive breast cancer was further evaluated in a combined analysis of 34 patients with response-assessable CNS metastases from both the Phase 1b trial of ONT-380 in combination with Kadcyla and the Phase 1b trial of ONT-380 in combination with Herceptin and/or Xeloda. CNS metastases were considered response assessable if they were either untreated with radiation or surgery, or were new or progressive lesions following prior radiation or surgery. Of 14 patients with previously untreated lesions, eight had measurable disease, with a best CNS response of one CR, two cPRs and four SDs. One patient did not have a follow up CNS scan secondary to progressive systemic disease. Six patients with previously untreated lesions had non-target lesions only, of whom five were non-CR/non-PD and one was not evaluable. The CNS CBR for the previously untreated CNS metastases was 44%. Of 20 patients with new or progressive lesions following prior therapy, 17 had measurable disease, with a best CNS response of five cPRs, nine SDs, and one PD. Two patients remain too early to evaluate. Three patients with non-target lesions only had non-CR/non-PD. The CNS CBR for patients with new or progressive lesions following prior therapy was 59%. Of note, responses and clinical benefit were seen when ONT-380 was combined with each of Kadcyla, or Herceptin and/or Xeloda.

About the Planned ONT-380 Clinical Development Program

Oncothyreon plans to initiate a Phase 2 randomized, double-blind, controlled study of ONT-380 versus placebo in combination with capecitabine and trastuzumab in patients with unresectable locally advanced or metastatic HER2-positive breast cancer (ClinicalTrials.gov Identifier: NCT02614794). The trial is expected to enroll approximately 180 patients in multiple centers located in the United States, Canada and Western Europe. Eligible patients must have centrally confirmed HER2-positive breast cancer and must have been previously treated with a taxane, trastuzumab, pertuzumab and TDM-1. The primary endpoint of the trial is bi-compartmental progression free survival, both CNS and non-CNS, as assessed by independent review using both RECIST 1.1 and Response Assessment in Neuro-Oncology – Brain Metastases (RANO-BM) criteria. Secondary endpoints include time to CNS progression, objective response rate, CBR rates for both CNS and non-CNS metastatic disease and overall survival. Oncothyreon currently expects to initiate the first clinical sites for the Phase 2 trial before the end of 2015 and to treat the first patient in early 2016.

Based on the results of the Phase 1b trial of ONT-380 in combination with Kadcyla discussed above, Oncothyreon is considering an additional Phase 2 or Phase 3 trial of this combination potentially focused on patients with CNS metastases. Oncothyreon plans to discuss potential designs for this trial, together with the overall registration strategy for ONT-380, with regulatory authorities, including the United States Food and Drug Administration, in the first part of 2016.

On December 8, 2015 Spectrum Pharmaceuticals (NasdaqGS: SPPI), a biotechnology company with fully integrated commercial and drug development operations with a primary focus in Hematology and Oncology, reported key presentations of clinical and scientific data related to its products at the San Antonio Breast Cancer Symposium (SABCS), being held in San Antonio, Texas, from December 8-12, 2015 (Press release, Spectrum Pharmaceuticals, DEC 8, 2015, View Source [SID:1234508504]).

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For more information about the SABCS meeting and for a complete list of abstracts, please refer to the conference website at View Source

On December 9, 2015 Chugai Pharmaceutical Co., Ltd. (TOKYO: 4519) reported that it obtained approval from the Ministry of Health, Labour and Welfare on September 2, 2015 for "Alecensa Capsule 150mg," a high content preparation of the ALK inhibitor "Alecensa Capsule 20mg and 40mg" (generic name: alectinib hydrochloride) sold for the indication of "ALK fusion gene positive unresectable, advanced/recurrent non-small cell lung cancer (Press release, Chugai, DEC 8, 2015, View Source [SID:1234508505])." Following its National Health Insurance Drug Price listing on November 28, we launch the "Alecensa Capsule 150mg" today.

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Regarding Alecensa, the patients have been obliged to orally take in total of 8 capsules (7 capsules of 40mg preparation and 1 capsule of 20mg preparation) per time, twice daily. Considering great need of a high content preparation to improve convenience of patients, Chugai started developing a 150mg preparation and filed an application in September 2014.

Chugai is convinced that "Alecensa Capsule 150mg" will contribute to the improvement of patients’ convenience and satisfaction with treatment, and we continue to put our effort into the improvement of medical care for cancer and the satisfaction of unmet medical needs based on our business philosophy "Innovation all for the patients."

[Drug information of new Capsule]

Brand name: Alecensa Capsule 150mg
Generic name: alectinib hydrochloride
Indications: ALK fusion gene-positive unresectable, recurrent or advanced non-small cell lung cancer (NSCLC)
Dosage and administration: The usual adult dosage is 300mg alectinib administered orally twice daily.
Drug price: 6,614.60 yen/capsule
Package: 28 capsules (PTP)

On December 8, 2015 Pieris Pharmaceuticals, Inc. (NASDAQ: PIRS), a biotechnology company advancing novel bio therapeutics through its proprietary Anticalin technology platform, reported a research collaboration and license agreement with Roche in cancer immunotherapy (CIT) (Press release, Pieris Pharmaceuticals, DEC 8, 2015, View Source [SID:1234515041]). Under the terms of the agreement, Pieris will discover, characterize and optimize Anticalin-based drug candidates against an undisclosed target. Roche and Pieris will evaluate different drug formats against this target and advance them through preclinical development, with Roche being responsible for IND-enabling activities, clinical development and worldwide marketing of any resulting products. Pieris will receive an upfront payment of CHF 6.5 million (~$6.4 million USD) and committed research funding, and may receive development and regulatory-based milestone payments, sales-based milestone payments as well as mid single-digit to low double-digit royalties on any future product sales. If all milestones and other conditions are met, the total payments to Pieris could surpass CHF 415 million (~$409.3 million USD), excluding royalties.

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"Our partnership with Roche is a significant step forward for Pieris," commented Stephen Yoder, President and CEO of Pieris. "The decision by the leader in the development and commercialization of cancer biologics to collaborate with Pieris underscores the unique potential of Anticalin-based proteins as a differentiated class of immuno-oncology drugs. As we initiate this collaboration, we will continue to vigorously advance our fully proprietary programs, including our lead CD137-HER2 bispecific."

With its immuno-oncology PRS-300 Series, which remains proprietary to the Company, Pieris is developing bispecific Anticalin-based protein therapeutics against a variety of tumor and immunomodulatory targets. These compounds, including its lead program PRS-343 (CD137/HER2 bispecific), aim to activate the immune system in the tumor microenvironment, with the goal of increasing efficacy as well as improving safety compared to existing approaches. This collaboration represents Pieris’ first partnered immuno-oncology program and leverages Pieris’ capability to address a target in multiple ways through Anticalin-based drug candidates in different formats.

On December 8, 2015 Gilead Sciences, Inc. (Nasdaq: GILD) reported results from a prespecified interim analysis of a Phase 3 study (Study 115) evaluating Zydelig (idelalisib) in combination with bendamustine and rituximab (BR) for patients with previously treated CLL (Press release, Gilead Sciences, DEC 8, 2015, View Source;p=irol-newsArticle&ID=2120907 [SID:1234508483]). The analysis found a 67 percent reduction in the risk of disease progression or death (progression-free survival, PFS) in patients receiving Zydelig plus BR compared to BR alone (hazard ratio (HR) = 0.33; 95 percent CI: 0.24, 0.45; p<0.0001). Additionally, all secondary endpoints, including overall survival (OS), achieved statistical significance in this interim analysis. Detailed results were presented today during the late-breaking abstracts session at the Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in Orlando, Florida (#LBA-5).

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"These new findings add to the role of idelalisib-containing regimens for the treatment of relapsed CLL," said Andrew D. Zelenetz, MD, PhD, Medical Oncologist and Vice Chair, Medical Informatics, Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center. "In this Phase 3 study, adding idelalisib to BR provided not only statistically significant but clinically meaningful improvements in progression-free and overall survival compared to BR, a current standard of care in relapsed/refractory CLL. Further, idelalisib treatment also benefitted patients with genetic factors associated with a poorer prognosis."

Zydelig is approved in the United States in combination with rituximab for patients with relapsed CLL for whom rituximab alone would be considered appropriate therapy due to comorbidities. Based on the Study 115 results, Gilead plans to submit supplemental regulatory filings in the U.S. and Europe early next year.

Study 115 enrolled 416 adult patients with previously treated CLL whose disease had progressed less than 36 months following completion of prior therapy, and was not refractory to bendamustine. Eligible patients were randomized (1:1) to receive six cycles of BR over 24 weeks with either Zydelig 150 mg or placebo taken orally twice daily until disease progression or unacceptable toxicity. In November, the trial was unblinded following the recommendation of an independent Data Monitoring Committee.

The primary endpoint was PFS, defined as the time from randomization to definitive disease progression or death, as assessed by an independent review committee. Median PFS for patients receiving Zydelig plus BR was 23.1 months compared to 11.1 months for patients receiving placebo plus BR. Among patients with a 17p deletion or TP53 mutation (Zydelig plus BR: n=69; placebo plus BR: n=68), genetic abnormalities that have been linked to poor prognosis, there was a 50 percent reduction in the risk of disease progression or death (HR=0.50, 95 percent CI: 0.32, 0.77).

The study also found a statistically significant benefit in OS, with a 45 percent reduction in the risk of death among patients receiving Zydelig plus BR compared to those receiving BR alone (HR=0.55; 95 percent CI: 0.36, 0.86; p=0.008). Median OS has not been reached in either arm. The overall response rate (ORR) was 68 percent in the Zydelig arm and 45 percent for the control arm.

Grade ≥3 adverse events for the Zydelig plus BR and placebo plus BR arms, respectively, included neutropenia (60 versus 46 percent), febrile neutropenia (20 versus 6 percent) and diarrhea (7 versus 2 percent). Grade ≥3 elevations in ALT and AST occurred in 21 and 16 percent, respectively, of patients receiving Zydelig plus BR compared to 3 percent and 3 percent in patients receiving BR alone; see below for Important Safety Information, including BOXED WARNING.

Zydelig in combination with bendamustine and rituximab is an investigational regimen and its safety and efficacy have not been established.

About Zydelig (idelalisib)

Zydelig is an oral inhibitor of phosphoinositide 3-kinase (PI3K) delta, a protein that plays a role in the activation, proliferation and viability of B cells, a critical component of the immune system. PI3K delta signaling is active in many B-cell leukemias and lymphomas, and by inhibiting the protein, Zydelig blocks several cellular signaling pathways that drive B-cell viability.

Important U.S. Safety Information

BOXED WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, AND INTESTINAL PERFORATION

Fatal and/or serious hepatotoxicity occurred in 14 percent of Zydelig-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Zydelig as recommended.

Fatal and/or serious and severe diarrhea or colitis occurred in 14 percent of Zydelig-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue Zydelig as recommended.

Fatal and serious pneumonitis can occur. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue Zydelig as recommended.

Fatal and serious intestinal perforation can occur in Zydelig-treated patients. Discontinue Zydelig for intestinal perforation.

Contraindications

History of serious allergic reactions, including anaphylaxis and toxic epidermal necrolysis (TEN).
Warnings and Precautions

Hepatotoxicity: Findings were generally observed within the first 12 weeks of treatment and reversed with dose interruption. Upon rechallenge at a lower dose, ALT/AST elevations recurred in 26 percent of patients. In all patients, monitor ALT/AST every 2 weeks for the first 3 months, every 4 weeks for the next 3 months, and every 1 to 3 months thereafter. If ALT/AST is >3x upper limit of normal (ULN), monitor for liver toxicity weekly. If ALT/AST is >5x ULN, withhold Zydelig and monitor ALT/AST and total bilirubin weekly until resolved. Discontinue Zydelig for recurrent hepatotoxicity. Avoid concurrent use with other hepatotoxic drugs.

Severe diarrhea or colitis: Grade 3+ diarrhea can occur at any time and responds poorly to antimotility agents. Avoid concurrent use with other drugs that cause diarrhea.

Pneumonitis: Evaluate for pneumonitis in patients presenting with pulmonary symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates on radiologic exam, or oxygen saturation decline by ≥5 percent.

Intestinal perforation: Advise patients to promptly report any new or worsening abdominal pain, chills, fever, nausea, or vomiting.
Severe cutaneous reactions: One case of TEN occurred in a study of Zydelig in combination with rituximab and bendamustine. Other severe or life-threatening (Grade ≥3) cutaneous reactions have been reported. Monitor patients for the development of severe cutaneous reactions and discontinue Zydelig if a reaction occurs.

Anaphylaxis: Serious allergic reactions including anaphylaxis have been reported. Discontinue Zydelig permanently and institute appropriate supportive measures if a reaction occurs.

Neutropenia: Treatment-emergent Grade 3-4 neutropenia occurred in 31 percent of Zydelig-treated patients in clinical trials. In all patients, monitor blood counts ≥every 2 weeks for the first 3 months. In patients with neutrophil counts <1.0 Gi/L, monitor weekly.

Embryo-fetal toxicity: Zydelig may cause fetal harm. Women who are or become pregnant while taking Zydelig should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking Zydelig and to use effective contraception during and at least 1 month after treatment with Zydelig.

Adverse Reactions

Most common adverse reactions (incidence ≥20 percent; all grades) in clinical studies, when used alone or in combination with rituximab, were diarrhea, pyrexia, fatigue, nausea, cough, pneumonia, abdominal pain, chills, and rash.

Most frequent serious adverse reactions (SAR) in clinical studies in combination with rituximab were pneumonia (17 percent), pyrexia (9 percent), sepsis (8 percent), febrile neutropenia (5 percent), and diarrhea (5 percent); SAR were reported in 49 percent of patients and 10 percent of patients discontinued due to adverse reactions. Most frequent SAR in clinical studies when used alone were pneumonia (15 percent), diarrhea (11 percent) and pyrexia (9 percent); SAR were reported in 50 percent of patients and 53 percent of patients discontinued or interrupted therapy due to adverse reactions.

Most common lab abnormalities (incidence ≥30 percent; all grades) in clinical studies were neutropenia, hypertriglyceridemia, hyperglycemia, and ALT/AST elevations.

Drug Interactions

CYP3A inducers: Avoid coadministration with strong CYP3A inducers.
CYP3A inhibitors: When coadministered with strong CYP3A inhibitors, monitor closely for Zydelig toxicity.
CYP3A substrates: Avoid coadministration with CYP3A substrates.

Dosage and Administration

Adult starting dose: One 150 mg tablet twice daily, swallowed whole with or without food. Continue treatment until disease progression or unacceptable toxicity. The safe dosing regimen for patients who require treatment longer than several months is unknown.

Dose modification: Consult the Zydelig full Prescribing Information for dose modification and monitoring recommendations for the following specific toxicities: pneumonitis, ALT/AST elevations, bilirubin elevations, diarrhea, neutropenia, and thrombocytopenia. For other severe or life-threatening toxicities, withhold Zydelig until toxicity is resolved and reduce the dose to 100 mg, twice daily, upon resuming treatment. If severe or life-threatening toxicities recur upon rechallenge, Zydelig should be permanently discontinued.

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