On November 16, 2015 Starpharma (ASX: SPL, OTCQX: SPHRY) reported that treatment with its novel antibody-targeted DEP
conjugate resulted in complete tumour regression and 100% survival in an ovarian cancer model (Press release, Starpharma, NOV 16, 2015, View Source [SID:1234508250]).

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Starpharma’s antibody-targeted DEP conjugate (using Herceptin as the targeting group) significantly outperformed both Roche’s Kadcyla (T-DM1), a Herceptin antibody-drug conjugate (ADC), and the monoclonal antibody Herceptin (Trastuzumab)
itself in the pre-clinical ovarian cancer model.

The targeted DEP treated group showed vastly improved anticancer effectiveness and survival compared to both Kadcyla and Herceptin. The targeted DEP treated group exhibited complete regression after treatment which has been maintained for the duration of the experiment (60 days, experiment ongoing). In contrast, in the Kadcyla group, only tumour stasis was observed during treatment with a maximum inhibition of 32% at day 12, however soon after completion of dosing tumour regrowth occurred.

Survival statistics for the targeted DEP conjugate were also impressive with 100% of the targeted DEP treated group surviving at 60 days (study still ongoing), whereas by day 50, none of the Kadcyla treated group were alive. Survival results are presented
below.

"We are very excited by these latest results for our targeted DEP conjugates and feedback from commercial parties on this new data has been very positive indeed. Discussions are now underway with a number of pharmaceutical companies in relation
to this targeted DEP conjugate and the application of Starpharma’s targeted DEP platform to their proprietary drugs."

The top 3 antibody based treatments in cancer (Rituxan, Avastin and Herceptin) had total sales in excess of $US20B in 2014. Targeted therapies for cancer such as the ADCs Kadcyla and Adcetris had combined sales in excess of US$1billion in 2014, with
Kadcyla sales growing at 144% versus the previous year. The market for ADCs is expected to grow to US$9 billion annually by 2023.1

Targeted DEP Conjugates
Starpharma’s proprietary targeted DEP conjugate in this experiment consist of a dendrimer scaffold, a targeting group (in this case the monoclonal antibody trastuzumab (Herceptin)) and a "payload" of anticancer drug.

Targeted DEP conjugates have a number of important advantages over standard ADCs including higher drug loading and manufacturing advantages.

On November 16, 2015 Gilead Sciences reported following the recommendation by an independent Data Monitoring Committee (DMC), that its Phase 3 Study 115 evaluating Zydelig (idelalisib) added to standard therapy in previously-treated chronic lymphocytic leukemia (CLL) patients will be unblinded early (Press release, Gilead Sciences, NOV 16, 2015, View Source [SID:1234508249]).

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The DMC recommendation is based upon a predefined interim analysis indicating a statistically significant benefit in efficacy for progression-free survival (PFS) and overall survival (OS) in patients receiving Zydelig plus bendamustine and rituximab, compared to those receiving only bendamustine and rituximab. The safety profile of Zydelig was consistent with prior studies. Detailed results from this study will be presented during a late-breaking abstracts session (#LBA-5) at the Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in Orlando, Florida taking place December 5-8.

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.

"The clinical benefit observed in this Phase 3 study adds to the body of evidence demonstrating the potential of Zydelig-containing treatment regimens for patients with previously treated CLL," said Norbert W. Bischofberger, PhD, Gilead’s Executive Vice President, Research and Development and Chief Scientific Officer. "We look forward to sharing the detailed scientific data with the hematology community at the upcoming ASH (Free ASH Whitepaper) meeting."

Study 115 is a randomized, double-blind, placebo-controlled, Phase 3 study evaluating the efficacy and safety of Zydelig in combination with bendamustine and rituximab among 416 adult patients with previously treated CLL. Eligible patients were randomized (1:1) to receive six cycles of bendamustine and rituximab over 24 weeks combined with either Zydelig 150 mg or placebo taken orally twice daily continuously until disease progression or unacceptable toxicity. The primary endpoint is PFS.

Additional details contained in the Study 115 abstract are available at View Source Based on these results, Gilead plans to submit supplemental regulatory filings in the U.S. and Europe early next year.

The use of Zydelig in combination with bendamustine/rituximab is investigational and the safety and efficacy of this combination has 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% 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 ≥10 percent and ≥2 percent than rituximab alone, all grades) were pyrexia, nausea, pneumonia, diarrhea, chills, rash, vomiting and headache.

Most frequent serious adverse reactions (SAR) 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 common lab abnormalities (incidence ≥30 percent and ≥5 percent than rituximab alone; all grades) were neutrophils decreased, hypertriglyceridemia, hyperglycemia and ALT elevation.

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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On November 16, 2015 Clovis Oncology, Inc. (NASDAQ: CLVS) reported that during its regularly scheduled Mid-Cycle Communication Meeting held last week with the U.S. Food and Drug Administration (FDA), the agency requested additional clinical data for use in the efficacy analysis for both the 500mg and 625mg BID dose patient groups for rociletinib (Press release, Clovis Oncology, NOV 16, 2015, View Source [SID:1234508247]). The Company will provide this information in a Major Amendment to the FDA by close of business today.

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"We remain confident in rociletinib and its potential to treat patients with mutant EGFR T790M-positive lung cancer, said Patrick J. Mahaffy, President and CEO of Clovis Oncology. "We will continue to work diligently with the FDA on our NDA submission."

In the Mid-Cycle Communication meeting, the FDA emphasized that its efficacy analysis would focus solely on confirmed responses. The New Drug Application (NDA) submitted by Clovis to the FDA contained immature data sets based on both unconfirmed response rates and confirmed response rates. These data sets were updated in the 90 day efficacy update the Company submitted at the end of October.

As the rociletinib clinical trials were rapidly enrolling, Clovis presented interim data publicly and at medical meetings and these data therefore included a data set based primarily on unconfirmed responses. This was also true of the Company’s Breakthrough Therapy designation submission. In the Company’s NDA submission, both immature confirmed and unconfirmed response analyses were submitted. As the efficacy data have matured, the number of patients with an unconfirmed response who converted to a confirmed response was lower than expected.

In the intent to treat analysis of the 79 patients in the 500mg dose group, the current confirmed response rate is 28 percent, and 34 percent in the 170 patients in the 625mg dose group, with an encouraging duration of response in both doses. The most frequent reasons that patients’ responses were not confirmed in a subsequent scan were due to progression, often due to brain metastasis, and due to subsequent scans not demonstrating tumor shrinkage greater than 30 percent.

The Company anticipates that the review of this additional information will result in a delay of a potential approval. This additional review could lead to an extension of the Company’s March 30, 2016 Prescription Drug User Fee Act (PDUFA) date.

About Rociletinib
Rociletinib is the company’s novel, oral, targeted covalent (irreversible) mutant-selective inhibitor of EGFR in development for the treatment of NSCLC in patients with initial activating EGFR mutations, as well as the dominant resistance mutation T790M. Data from both the pivotal, single-arm TIGER-X and TIGER-2 clinical trials served as the basis for the U.S. and EU regulatory submissions for the treatment of advanced mutant EGFR T790M-positive lung cancer. Rociletinib was given Breakthrough Therapy designation by the FDA in May 2014.

On November 16, 2015 Array BioPharma Inc. (Nasdaq: ARRY) and Pierre Fabre treported a collaboration to globally develop and commercialize Array’s late-stage novel oncology products, binimetinib and encorafenib (Press release, Array BioPharma, NOV 16, 2015, View Source [SID:1234508245]). Binimetinib, a MEK inhibitor, and encorafenib, a BRAF inhibitor, are currently advancing in three, global Phase 3 trials for melanoma and ovarian cancer. Top-line results from NEMO, a Phase 3 study of binimetinib in patients with NRAS-mutant melanoma, are anticipated before the end of 2015. Array plans to host a conference call on November 16, 2015 at 9:00 am ET to discuss the collaboration.

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Under the terms of the agreement, Array will receive an upfront payment of $30 million and retains exclusive commercialization rights for binimetinib and encorafenib in the United States, Canada, Japan, Korea and Israel. Pierre Fabre will have exclusive rights to commercialize both products in all other countries, including Europe, Asia and Latin America. Array is entitled to receive up to $425 million if certain development and commercialization milestones are achieved, and is eligible for robust, tiered double-digit royalties. Array and Pierre Fabre have agreed to split future development costs on a 60:40 basis (Array:Pierre Fabre) with initial funding committed for new clinical trials in colorectal cancer and melanoma. All ongoing binimetinib and encorafenib clinical trials remain substantially funded through completion by Novartis.

Pierre Fabre Oncology, a business unit of the global 10,000-employee Pierre Fabre company, is supported by over 1,000 employees with a strong focus on European markets. In 2014, worldwide annual sales of Pierre Fabre Oncology products surpassed $200 million on the strength of the Oral Navelbine, Javlor and Busilvex brands. In addition, Pierre Fabre has a significant commitment and track record in pharmaceutical R&D, developing products for patients afflicted with lung, breast and other solid tumors and hematological cancers.

"In Pierre Fabre we selected a partner with a European and emerging market focus in oncology to develop and commercialize binimetinib and encorafenib in these geographies," said Ron Squarer, Chief Executive Officer, Array BioPharma. "With Phase 3 trials approaching data readouts, and over 30 additional Phase 1/2 trials underway, we are confident that binimetinib and encorafenib are well positioned for near-term regulatory submissions and significant commercial value."

"Pierre Fabre is strongly committed to develop and commercialize oncology products," said Frederic Duchesne, Chief Executive Officer, Pierre Fabre Pharmaceuticals. "This partnership with Array is aligned with our growth strategy in Pharmaceuticals, our geographic footprint, and our corporate mission to bring to the market novel oncology products which address unmet patient needs. Binimetinib and encorafenib will fit perfectly with our broad expertise in oncology and dermatology, and will strengthen our current portfolio and international presence."

The agreement remains subject to European Commission on Competition review and approval.

About Binimetinib and Encorafenib

RAF and MEK are key protein kinases in the RAS/RAF/MEK/ERK pathway. Research has shown this pathway regulates several key cellular activities including proliferation, differentiation, migration, survival and angiogenesis. Inappropriate activation of proteins in this pathway has been shown to occur in many cancers, such as non-small cell lung cancer, melanoma, colorectal, ovarian and thyroid cancers. Binimetinib is a small molecule MEK inhibitor and encorafenib is a small molecule BRAF inhibitor, both of which target key enzymes in this pathway. Three Phase 3 trials in advanced cancer patients continue to advance: NRAS-mutant melanoma (NEMO, with binimetinib), low-grade serous ovarian cancer (MILO, with binimetinib) and BRAF-mutant melanoma (COLUMBUS, with binimetinib and encorafenib). NRAS-mutant melanoma represents the first potential indication for binimetinib, with a projected regulatory filing estimated in the first half of 2016. Array also projects a regulatory filing of binimetinib in combination with encorafenib in BRAF melanoma in 2016.

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