On April 17, 2016 Ignyta, Inc. (Nasdaq: RXDX), a precision oncology biotechnology company, reported that updated results of its Phase 1 clinical trials of entrectinib, the company’s proprietary oral tyrosine kinase inhibitor targeting solid tumors harboring activating alterations to NTRK1, NTRK2, NTRK3, ROS1 or ALK, were presented in an oral plenary session at the 2016 Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) in New Orleans, Louisiana (Press release, Ignyta, APR 17, 2016, View Source [SID:1234510954]).

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"We continue to be excited by entrectinib’s ability to help patients with advanced cancer," said Jonathan Lim, M.D., Chairman and CEO of Ignyta. "With respect to efficacy, in the 25 patients in the Phase 1 trials who would meet the eligibility criteria for our Phase 2 clinical trial, we saw tumor regression in 20 patients, or 80%. Nineteen out of 24 patients with extracranial solid tumors had a confirmed RECIST response, representing a 79% overall response rate; and one patient with an astrocytoma had evidence of substantial tumor regression by volumetric measurement. These responses were observed in patients with each of NTRK, ROS1 and ALK rearrangements, and across six tumor histologies, including complete and/or durable responses in both primary and metastatic tumors of the central nervous system."

"With respect to safety, based upon a larger dataset of 119 patients, which included 45 patients treated at our Phase 2 dose of 600 mg continuous once daily dosing, we have been able to further substantiate entrectinib’s acceptable safety profile," continued Dr. Lim. "We have 19 patients who have been on study for longer than six months; of those, 11 patients have been on study for more than one year, including three patients for more than two years. We believe these data highlight the long-term tolerability and promising anti-tumor activity of entrectinib as we continue to enroll STARTRK-2, our ongoing, potentially registration-enabling Phase 2 clinical trial of entrectinib."

The Phase 1 clinical trials included the ALKA-372-001 study and the STARTRK-1 study, which is the first of the "Studies of Tumor Alterations Responsive to Targeting Receptor Kinases". Both trials were designed to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D), as well as preliminary anti-cancer activity, of single agent entrectinib in patients with solid tumors with the relevant target alterations: TrkA (encoded by NTRK1), ROS1 or ALK for ALKA-372-001 and TrkA/TrkB/TrkC (encoded by NTRK1/2/3), ROS1 or ALK for STARTRK-1.

The data cut-off for the AACR (Free AACR Whitepaper) presentation was March 7, 2016. Highlights of the data included:

Safety

A total of 119 patients with a range of solid tumors had been dosed across both clinical trials, with 45 patients treated at the RP2D of 600 mg, taken orally once per day (QD).

Entrectinib was well tolerated:

Across both studies, the most frequent (>10% incidence) treatment-related adverse events were fatigue (44%), dysgeusia (41%), paresthesia (28%), nausea (24%), and myalgia (22%).
The vast majority of treatment-related adverse events were Grade 1 or 2 in severity.
The most frequent (>2% incidence) Grade 3 treatment-related adverse events were fatigue (4%) and anemia (3%).
Adverse events were reversible with dose modification.
There was no evidence of cumulative toxicity, hepatic or renal toxicity, or QTc prolongation.
Efficacy

Across both studies, there were 25 patients treated who met the company’s Phase 2 clinical trial eligibility criteria, which include:

Presence of NTRK1/2/3, ROS1 or ALK gene rearrangements, as opposed to other types of molecular alterations (e.g., SNPs, amplifications, deletions);
ALK-inhibitor and/or ROS1-inhibitor naïve; and
Treatment at or above the RP2D.
Among the 25 patients treated who met the company’s Phase 2 clinical trial eligibility criteria, tumor regression was seen in 80% (20 out of 25 treated patients):

24 patients had tumors that were evaluable by RECIST criteria. The overall response rate was 79% (19 responses, including 2 complete responses, out of 24 treated patients, as assessed and confirmed by the clinical sites).
One patient had astrocytoma. Assessment by RECIST criteria demonstrated stable disease. However, since RECIST criteria are not validated for primary brain tumors, the clinical site performed three-dimensional volumetric analysis of this patient’s tumor to determine changes in tumor size, which resulted in an estimated 45% decrease in tumor size from baseline.
Many of these responses occurred rapidly, within the first four weeks of entrectinib treatment. Seventeen of the patients remained on study treatment, having received up to 27 months of treatment. Of note, three of four patients with primary or metastatic central nervous system (CNS) disease responded.

With respect to specific subsets of patients:

Trk patients

There were four patients included in the clinical studies with NTRK1/2/3 gene rearrangements that met the company’s Phase 2 eligibility criteria, including patients with non-small cell lung cancer (NSCLC), colorectal cancer (CRC), salivary gland cancer and astrocytoma. All four of these patients demonstrated tumor regression (three confirmed responses by RECIST and one by volumetric assessment).

Two of these Trk patients remained on study, one of whom had been on study for longer than 12 months.

In addition, the company included in the AACR (Free AACR Whitepaper) presentation a case study of a 20-month old baby boy with NTRK3-rearranged infantile fibrosarcoma that had metastasized to the brain and who had exhausted all available therapies. The patient was first dosed in February 2016, and after five weeks of treatment experienced a decrease in his brain lesions of approximately 58%, as estimated from radiology assessment, with accompanying clinical improvement.

Three of these five patients with NTRK1/2/3 gene rearrangements had either primary or metastatic CNS disease, and all three demonstrated substantial CNS tumor regression, underscoring the importance of entrectinib’s CNS penetration and clinical activity for this patient population.

ROS1 patients

There were 14 patients included in the clinical studies with ROS1 gene rearrangements who met the company’s Phase 2 eligibility criteria, including 13 patients with NSCLC and one patient with malignant melanoma.

Eleven of the 13 patients with NSCLC and the patient with melanoma responded, including two complete responses. The resultant overall response rate for these ROS1 patients was 86%, and the response rate for the subset of patients with NSCLC was 85%.

Eleven of the ROS1 responders remained on study in response, with the longest at 27 months; one ROS1 NSCLC patient has met the criteria for RECIST progression but has remained on study due to clinical benefit.

ALK patients

There were seven patients included in the clinical studies with ALK gene rearrangements who met the company’s Phase 2 eligibility criteria, including four patients with NSCLC, one patient with CRC, one patient with renal cell carcinoma (RCC) and one patient with a thoracic tumor of unknown primary.

Two of the four patients with NSCLC, the patient with CRC and the patient with RCC had clinical responses. Another NSCLC patient had stable disease. The resultant overall response rate for these ALK patients was 57%.

Two of the responders remained on study in response, as did the patient with stable disease.

On Monday, April 18, 2016, Ignyta will file a Form-8-K with the U.S. Securities and Exchange Commission (SEC) containing the entrectinib Phase 1 materials presented at the 2016 AACR (Free AACR Whitepaper) annual meeting. The company’s SEC filings can be found on the company’s website at www.ignyta.com and on the SEC’s website at www.sec.gov.

Reception and Webcast Presentation

In addition, Ignyta announced that it will host a reception in New Orleans, Louisiana, on Tuesday, April 19, 2016, during the AACR (Free AACR Whitepaper) annual meeting.

At the reception, Ignyta’s management team will make a presentation relating to the clinical data and plans for further development of entrectinib, as well as an overview of the company’s other product candidates and highlights.

The presentation will take place at 7:00 PM, Central time. A live webcast of the event will be available in the Investors section of the company’s website at View Source, and will be archived and available at that site for 14 days.

Current information on the incidence and prevalence of bone metastases in women with breast cancer is scarce. This study examined the occurrence and predictors of bone metastases, as well as post-metastasis survival in a prospective cohort of Canadian women with breast cancer. We included women treated for early-stage (stage I, II, or III) breast cancer at the Henrietta Banting Breast Centre (HBBC) in Toronto, Canada between 1987 and 2000. Data were abstracted from medical records and pathology reports in the HBBC database; follow-up extended to end of data availability or August 31, 2015. Actuarial survival analyses provided cumulative incidence of bone metastases at 5, 10, and 15 years after breast cancer diagnosis. Kaplan-Meier curves describe breast cancer mortality. Regression models assessed patient, tumor, and treatment characteristics as predictors of bone metastases with all-cause mortality as a competing risk. Among 2097 women studied, the 5-, 10-, and 15-year probability of bone metastasis was 6.5, 10.3, and 11.3 % for the first recurrence, and 8.4, 12.5, and 13.6 % for any bone recurrence. At median follow-up (12.5 years), 13.2 % of patients had bone metastases. Median survival was 1.6 years following bone metastasis, and shorter if both bone and visceral metastases occurred. Advanced age and adjuvant treatment with tamoxifen were protective against bone metastasis. In this representative cohort of women diagnosed with early-stage breast cancer in Ontario, Canada, with long follow-up, the incidence of bone metastases was consistent with longitudinal studies from the United Kingdom, Denmark, and the US.

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Epidermal growth factor receptor inhibitors such as panitumumab are associated with characteristic skin toxicities. We summarise data from three panitumumab clinical trials to investigate the potential impact of skin toxicity on quality of life (QoL) in patients with metastatic colorectal cancer (mCRC).
The studies were randomised, open-label trials comparing standard treatment (first-line FOLFOX4 [n = 456], second-line FOLFIRI [n = 381], or best supportive care [n = 114]) with or without panitumumab in adults with KRAS/NRAS (RAS) wild-type mCRC. QoL was assessed using the EuroQoL 5-domain health state index (HSI) and overall health rating (OHR) measures. Impact of skin toxicity on changes in QoL scores was estimated using a linear mixed-effects model. Worst skin toxicity was defined in separate models as a subgroup variable or as a measure over time.
Regardless of analysis method, there were no statistically significant differences between the panitumumab and comparator arms in any of the studies in terms of change in HSI or OHR scores. There were no statistically significant differences in QoL outcomes between patients with worst skin toxicity grade <3 and those with grade ≥3. In addition, there were no statistically significant differences between the panitumumab and comparator arms in subgroups of patients with worst skin toxicity of grade <3 and ≥3.
Addition of panitumumab to chemotherapy in RAS wild-type mCRC has no statistically significant negative effect on overall QoL, despite skin toxicity. Skin toxicity of worst grade ≥3 appeared to have similar impact on QoL as skin toxicity of grade <3.

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On April 17, 2016 Loxo Oncology, Inc. (Nasdaq:LOXO), a biopharmaceutical company innovating the development of highly selective medicines for patients with genetically defined cancers, reported new results from its Phase 1 open-label, dose-escalation trial of LOXO-101, a selective inhibitor of tropomyosin receptor kinase (TRK) (Press release, Loxo Oncology, APR 17, 2016, View Source [SID:1234510957]). A presentation at the 2016 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans on April 17, 2016 provided updated data from the Phase 1 trial, which was last reported at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) in November 2015.

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LOXO-101 Phase 1 study investigators reported that, as of the March 25, 2016 data cutoff date, 43 patients with solid tumors refractory to standard therapy had been enrolled and treated, including seven patients with cancers harboring TRK gene fusions. Data regarding the first three of these patients were initially reported at the AACR (Free AACR Whitepaper)-NCI-EORTC conference in November 2015.

Six patients with TRK fusion cancers had been on study sufficiently long for their first efficacy assessment, and all six exhibited significant tumor regressions. A seventh patient with a TRK fusion cancer was enrolled more recently and thus had not yet been evaluated for response as of the data cutoff date, though the patient remains on study. Five of the six efficacy evaluable patients achieved a confirmed partial response, as defined by standard RECIST criteria. The sixth patient demonstrated clear radiographic tumor regressions, including in the central nervous system, but has not met the threshold required for a RECIST response. Tumor regressions have been observed in five different anatomically-defined cancers: sarcoma, gastrointestinal stromal tumor, mammary analogue secretory cancer of the salivary glands, thyroid cancer and non-small cell lung cancer. No TRK fusion patients have progressed, with one patient in cycle 14, two patients in cycle 10 and three patients in cycle 7, as of the data cutoff date. In addition, LOXO-101 has been highly active and well-tolerated at doses that include the recommended Phase 2 dose of 100 mg BID. The majority of adverse events reported by the investigators have been mild to moderate. A maximum tolerated dose (MTD) has not been defined.

"The responses, durability and safety data with LOXO-101 clearly suggest that this is an important drug candidate for patients with TRK fusion cancers," said David Hong, M.D., deputy chair and associate professor in the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center in Houston and presenter of the LOXO-101 oral presentation. "We are excited to continue to follow these Phase 1 patients and treat additional TRK fusion patients in the LOXO-101 Phase 2 trial. I hope these data encourage my colleagues to test for TRK fusions and refer patients to a LOXO-101 study."

"The consistent efficacy of LOXO-101 in patients with TRK gene fusions, independent of tumor type, is very exciting," said Josh Bilenker, M.D., chief executive officer of Loxo Oncology. "The data update also provides an encouraging snapshot of response durability, particularly at the recommended Phase 2 dose of 100mg twice-daily. These data suggest that LOXO-101 can deeply inhibit its target at a well-tolerated dose and generate durable disease control in a diverse group of patients with TRK gene fusions."

LOXO-101 Phase 1 Results
LOXO-101 is currently being evaluated in an ongoing dose-escalation Phase 1 trial in patients with solid tumors refractory to standard therapy. As of March 25, 2016, 43 patients with advanced cancer had been treated at five dose levels: 50 mg QD, 100 mg QD, 100 mg BID, 150 mg BID and 200 mg QD. The median age of these patients is 57 (ranging from 28-76) and the median number of prior treatments is three (ranging from 0-11).

Safety Analysis
LOXO-101 has been well tolerated in the 43 patients treated, including 24 patients at a dose of 100mg BID. Adverse events reported regardless of attribution to study drug are generally consistent with those previously presented. Grade 1 and 2 adverse events include fatigue (33 percent), constipation (23 percent) and dizziness (23 percent). Grade 3 adverse events included fatigue, constipation, anemia, increased liver enzymes, dyspnea, abdominal pain, hypertension, hyperkalemia, delirium, pleural effusion, and syncope. No Grade 4 adverse events have been reported. The frequency of toxicities did not correlate with dose level. The maximum tolerated dose (MTD) has not yet been defined.

Efficacy Analysis
As of March 25, 2016, seven patients with cancers harboring TRK fusions have been enrolled, representing a broad range of tumor types: mammary analogue secretory cancer of the salivary glands (MASC, n=3), soft tissue sarcoma, gastrointestinal stromal tumor, thyroid carcinoma and non-small cell lung cancer. As of the March 25, 2016 data cutoff date, six patients had been evaluated for response, and five had achieved a confirmed objective response. All six patients experienced significant tumor regression, with response status summarized below:

Soft tissue sarcoma, LMNA-NTRK1 fusion: Confirmed partial response, remains on study in cycle 14 at a dose of 100 mg BID
Gastrointestinal stromal tumor, ETV6-NTRK3 fusion: Confirmed partial response, remains on study in cycle 10 at a dose of 150 mg BID
MASC, ETV6-NTRK3 fusion: Confirmed partial response, remains on study in cycle 10 at 100 mg BID
MASC, ETV6-NTRK3 fusion: Confirmed partial response, remains on study in cycle 7 at 100 mg QD; this patient started therapy on 100 mg BID and dose-reduced early in cycle 1 to 100 mg QD due to transient dizziness possibly related to drug
Papillary thyroid cancer, ETV6-NTRK3 fusion: Confirmed partial response, remains on study in cycle 7 at 100 mg BID
Non-small cell lung cancer, TPR-NTRK1 fusion: 18% tumor regression of bone-only RECIST evaluable disease (stable disease), remains on study in cycle 7 at 100mg BID
All six patients remain on study as of March 25, 2016. The seventh patient was recently enrolled and not yet evaluable for efficacy as of the data cutoff date, but also remains on study.

On Monday, April 18, 2016, Loxo Oncology plans to file a Form-8-K with the U.S. Securities and Exchange Commission (SEC) containing the LOXO-101 materials presented at the AACR (Free AACR Whitepaper) meeting. These materials will also be posted to the Loxo Oncology website.

Upcoming Milestones for Loxo Oncology
Loxo Oncology continues to make significant progress across its pipeline. Upcoming milestones are expected to include:

Continued enrollment of the LOXO-101 Phase 2 global, multi-center, single-arm, open-label basket trial in adult patients with solid tumors that harbor a TRK fusion, with an enrollment update expected in the second half of 2016.
Initiation of a Phase 1 study of a selective RET inhibitor in late 2016 or early 2017.
Initiation of a Phase 1 study of next-generation TRK inhibitor LOXO-195, addressing previously-treated patients with acquired resistance, in 2017.
Conference Call and Webcast Information
Loxo Oncology will host a conference call, live webcast with slides and Q&A on Monday, April 18, 2016 at 8:00 a.m. ET to discuss the LOXO-101 data and program updates. To participate in the conference call, please dial (877) 930-8065 (domestic) or (253) 336-8041 (international) and refer to conference ID 77038770. A live webcast of the presentation will be available at View Source A replay of the webcast will be available shortly after the conclusion of the call and archived on the company’s website for 30 days following the call.

About LOXO-101
LOXO-101 is a potent, oral and selective investigational new drug in clinical development for the treatment of patients with cancers that harbor abnormalities involving the tropomyosin receptor kinases (TRKs). Growing research suggests that the NTRK genes, which encode for TRKs, can become abnormally fused to other genes, resulting in growth signals that can lead to cancer in many sites of the body. In an ongoing Phase 1 clinical trial, LOXO-101 has demonstrated encouraging preliminary efficacy. LOXO-101 is also being evaluated in a global Phase 2 multi-center basket trial in patients with solid tumors that harbor TRK gene fusions and a Phase 1 trial in pediatric patients. For additional information about the LOXO-101 clinical trials, please refer to www.clinicaltrials.gov. Interested patients and physicians can contact the Loxo Oncology Physician and Patient Clinical Trial Hotline at 1-855-NTRK-123.

Isavuconazole, a novel triazole antifungal agent, has broad-spectrum activity against Aspergillus spp. and other pathogenic fungi. The isavuconazole exposure-response relationship in experimental invasive pulmonary aspergillosis using galactomannan index (GMI) suppression as a marker of disease clearance was explored.
The impact of exposure on GMI suppression in persistently neutropenic rabbits treated with isavuconazonium sulphate (isavuconazole-equivalent dosages of 20, 40 or 60 mg/kg every 24 h, after a 90 mg/kg loading dose) for 12 days was linked using mathematical modelling. Bridging to humans using population pharmacokinetic (PK) data from a clinical trial in invasive aspergillosis was performed using Monte Carlo simulations.
Mean plasma isavuconazole AUC/MIC (EC50) of 79.65 (95% CI 32.2, 127.1) produced a half-maximal effect in GMI suppression. The inhibitory sigmoid Emax curve dropped sharply after an AUC/MIC of ≥30 and was near maximum (EC80) at ∼130. Bridging the experimental PK/pharmacodynamic (PD) target to human population PK data was then used to return to the rabbit model to determine a clinically relevant PD endpoint. The clinical dosing regimen used in the trial would result in a mean GMI of 4.3 ± 1.8, which is a 50% reduction from the starting GMI in the experiment.
The clinical trial results showing the non-inferiority of isavuconazole to voriconazole for all-cause mortality further support the PK-PD endpoint, thereby demonstrating the usefulness of the rabbit model and endpoint for isavuconazole and implications on interpretive breakpoints. Importantly, the analysis supports this model as an important tool for development of antifungal agents.
© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected].

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