On November 8, 2015 Ignyta, Inc. (Nasdaq: RXDX) ("Ignyta"), a precision oncology biotechnology company, reported the exclusive license of worldwide rights relating to Eli Lilly and Company’s taladegib oncology development program in exchange for an upfront payment of $2.0 million in cash and the issuance to Lilly of approximately 1.2 million shares of Ignyta’s common stock (Press release, Ignyta, NOV 8, 2015, View Source [SID:1234509530]). Taladegib is a potent, orally bioavailable small molecule hedgehog/smoothened antagonist that has achieved clinical proof-of-concept and a recommended Phase 2 dose based on results from prior clinical studies. Ignyta also licensed exclusive worldwide rights to the topical formulation of taladegib, which is a late preclinical program being developed for the potential treatment of patients with superficial and nodular basal cell carcinoma.

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Concurrently with the license, Ignyta entered into a stock purchase agreement with Lilly under which Lilly will purchase a further 1.5 million shares of Ignyta common stock at a price of $20 per share in a private placement. Lilly has agreed not to sell or otherwise transfer any of the shares acquired from Ignyta until May 10, 2016, and Ignyta is required to register the resale of the shares issued to Lilly with the Securities and Exchange Commission (SEC) prior to such date.

Under the license agreement, Ignyta is obligated to pay to Lilly development and sales milestones related to taladegib products totaling up to approximately $38 million (a portion of which may be paid in Ignyta equity), along with royalties on net sales of taladegib products. Ignyta also granted back to Lilly exclusive rights to develop and commercialize taladegib-containing products in combination with certain Lilly compounds. Lilly is obligated to pay to Ignyta a royalty on net sales of such combination products it commercializes. Further financial terms were not disclosed.

"We are pleased to be working with Ignyta to further the development of taladegib and explore its potential to help patients across multiple tumor types," said Richard Gaynor, M.D., senior vice president, product development and medical affairs for Lilly Oncology. "Lilly continues to raise the bar on innovation by leveraging external relationships and expertise. Moreover, we are looking forward to working with Ignyta on potential combination therapies with other Lilly compounds."

"The exclusive license from Lilly of this clinical program with demonstrated compelling Phase 1 activity is well aligned with our strategic vision of developing first-in-class and/or best-in-class therapeutics that can potentially eradicate residual disease in precisely defined patient populations," said Jonathan Lim, M.D., Chairman and CEO of Ignyta. "This new targeted oncology program is a hedgehog/smoothened antagonist that complements our pipeline well and provides us with exciting potential monotherapy and combination therapy approaches across multiple solid tumor indications. We are grateful to Lilly for sharing Ignyta’s precision oncology vision and recognizing the strong strategic fit of taladegib with our pipeline and capabilities, which led to its $30 million investment in the company."

On November 08, 2015 Calithera Biosciences, Inc. (Nasdaq:CALA), a clinical stage biotechnology company focused on the development of novel cancer therapeutics, reported that it will announce new clinical data from the solid tumor expansion cohorts of its lead anti-cancer therapeutic candidate, CB-839, at the 2015 AACR (Free AACR Whitepaper)-NCI-EORTC International Conference on Molecular Targets in Boston, Massachusetts (Press release, Calithera Biosciences, NOV 8, 2015, View Source;p=RssLanding&cat=news&id=2110182 [SID:1234508340]). CB-839 is a potent, selective, orally bioavailable glutaminase inhibitor in phase I clinical trials. The data support earlier findings of the clinical activity, tolerability and unique mechanism of action of CB-839 in patients with solid tumors, as well as show one partial response according to RECIST criteria.

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The new data to be presented by Funda Meric-Bernstam, MD, from MD Anderson Cancer Center (Abstract #C49), demonstrate stable disease across a variety of tumor types, as well as a single agent partial response (PR, on study >5 months) in a renal cell carcinoma (RCC) patient. This patient showed a 32% reduction in target lesions by RECIST with generalized shrinkage of lymph node metastases. Among the fifteen evaluable patients with RCC, nine (60%) had stable disease lasting at least three cycles (63 days) or a partial response, with four patients remaining on study. Among efficacy-evaluable patients across a range of tumor types treated on the current dosing schedule of twice-daily with food, 22 of 50 patients (44%) experienced stable disease or better. Five stable disease patients currently on study have been treated with CB-839 for over 8 months without progression (2 triple negative breast cancer, 1 RCC, 1 mesothelioma and 1 IDH1 mutant chondrosarcoma).

"We are very encouraged by these findings in that they reinforce the published safety and efficacy profile of CB-839. We believe that this first partial response in solid tumors points to the potential of our novel agent’s efficacy in renal cell carcinoma, and we look forward to sharing data as our single agent and combination studies mature," said Susan Molineaux, PhD, President and Chief Executive Officer of Calithera. "We are currently expanding enrollment of CB-839 as a monotherapy in renal cell carcinoma patients, as well as dosing CB-839 in combination with everolimus."

The Phase 1 multi-center open label dose escalation study was designed to evaluate the safety and tolerability of CB-839 in locally advanced, metastatic and/or refractory solid tumors. Oral CB-839 was administered in doses of 100 mg to 1000 mg, in 21 day cycles using one of two regimens: TID or BID with food. As of October 1, 2015, 98 patients were enrolled in the solid tumor study (32 TID, 66 BID with food) and evaluable for safety; 77 were evaluable for efficacy. All future patients enrolled to the study will be dosed on the BID with food regimen.

Safety Data

Among 98 patients evaluable for safety, a maximum tolerated dose has not been established. CB-839 was generally well tolerated with the majority of treatment-emergent adverse events being mild to moderate, Grade 1/2 and reversible. Among patients in the BID with food regimen, 4.5% (3/66) experienced a Grade 3/4 adverse event suspected to be related to CB-839 and 3% discontinued due to drug-related adverse events (2/66). The rate of Grade 3 alanine aminotransferase (ALT) elevations of 1.5% (1/66) in the BID with food cohort was substantially reduced relative to that observed in the TID cohort 16% (5/32).

In addition, a preclinical poster was presented by Calithera’s collaborators. Details for the presentation are as follows:

Targeting glutamine metabolism in colorectal cancers with PIK3CA mutations

Abstract #C115
Zhenghe John Wang, Ph.D., Case Western Reserve University
Poster Session C

On November 08, 2015 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) signaling molecules, and the first preclinical data for its RET and FGFR programs (Press release, Loxo Oncology, NOV 8, 2015, View Source [SID:1234508117]). The data are being presented at the 2015 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 Boston.

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Providing a LOXO-101 Phase 1 update, study investigators reported that, as of the October 20, 2015 data cutoff date, 30 patients with solid tumors refractory to standard therapy had been enrolled and treated, including six patients with cancers harboring TRK fusions. Three of the six patients with TRK fusion cancers had been on study sufficiently long for their first efficacy assessment, and all three had achieved an objective response at the first response assessment, as defined by standard RECIST criteria. All three of these patients remain in response and on study. The other three patients with TRK fusion cancers were recently enrolled and thus had not yet been evaluated for response as of the data cutoff date, though they all remain on study. In addition, LOXO-101 has been well tolerated, including the 100 mg twice-daily dose, which has been selected for Phase 2 study and has shown efficacy in TRK fusion patients. The majority of adverse events reported by investigators have been mild to moderate. A maximum tolerated dose (MTD) has not been defined, though near-term Phase 1 enrollment will focus on further characterizing the pharmacokinetics and safety of the 100 mg twice-daily dose dosing.

"The efficacy we are seeing for LOXO-101, at a well-tolerated dose, is as compelling as any I have seen in Phase 1," 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. "As a community, we need to test for TRK fusions and make sure these patients find their way to a LOXO-101 study. I look forward to participating in the recently initiated Phase 2 trial."

"We are very encouraged by the rapid and dramatic responses we are seeing in TRK fusion patients, which demonstrate LOXO-101’s ability to effectively target these genetically defined tumors," said Josh Bilenker, M.D., chief executive officer of Loxo Oncology. "As we look into 2016, we are focused on continuing to execute on our clinical development strategy for LOXO-101 and plan to release additional data from our Phase 1 study at a medical meeting next year. In addition, our preclinical posters show the progress we have made, with our partners at Array BioPharma, in developing other selective, purpose-built molecules with differentiated and best-in-class potential against highly actionable targets in oncology."

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 October 20, 2015, 30 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 55 (ranging from 28-76) and the median number of prior treatments was three (ranging from 0-11).

Safety Analysis
LOXO-101 has been well tolerated in the 30 patients treated as of October 20, 2015. Adverse events are reported regardless of attribution to study drug. Adverse events are generally consistent with those described after the last data cutoff of March 26, 2015, consisting of Grade 1 and 2 fatigue (33 percent), dizziness (30 percent), anemia (20 percent) and nausea (20 percent). Grade 3 adverse events reported included fatigue, anemia, abdominal pain, increased liver enzymes, delirium and syncope. No Grade 4 adverse events have been reported. The frequency of toxicities did not correlate with dose level. MTD has not yet been defined.

Efficacy Analysis
To date, six 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=2), soft tissue sarcoma, gastrointestinal stromal tumor, thyroid carcinoma, and non-small cell lung cancer. As of the October 20, 2015 data cutoff date, three patients had been evaluated for response, and all had achieved an objective response at first response assessment. A patient with soft tissue sarcoma harboring an LMNA-NTRK1 fusion remains on study for greater than eight months at a dose of 100 mg BID. This patient was the subject of a peer-reviewed research brief published in Cancer Discovery in July 2015. A patient with a gastrointestinal stromal tumor (GIST) harboring an ETV6-NTRK3 fusion remains on study for greater than four months at a dose of 150 mg BID. A patient with a MASC tumor harboring an ETV6-NTRK3 fusion remains on study for greater than three months at 100 mg BID. All three of these responding patients remain in response and on study as of October 20, 2015. The other three patients (thyroid carcinoma, non-small cell lung cancer, MASC) were recently enrolled and not yet evaluable for efficacy as of the data cutoff date.

On Monday, November 9, 2015, Loxo Oncology will 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)-NCI-EORTC meeting. These materials will also be posted to the Loxo Oncology website.

Pipeline Program Updates
Loxo Oncology presented data from the company’s novel Rearranged during Transfection (RET) and Fibroblast Growth Factor Receptor (FGFR) programs showing potential best-in-class selectivity and target coverage. Loxo Oncology expects to advance a RET inhibitor as its next Investigational New Drug (IND) application.

Upcoming Milestones for Loxo Oncology
Loxo Oncology continues to make significant progress across its pipeline. Milestones in 2016 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.
Presentation of additional data from the ongoing Phase 1 study of LOXO-101 at a medical meeting in 2016.
Initiate Phase 1 study of LOXO-101 in pediatric cancer patients, including an oral liquid formulation, in the first half of 2016.
Initiate Phase 1 study of a selective RET inhibitor in late 2016 or early 2017.

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. For additional information about both 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.

On November 8, 2015 ImmunoGen, Inc. (Nasdaq: IMGN), a biotechnology company that develops targeted anticancer therapeutics using its antibody-drug conjugate (ADC) technology, reported findings with mirvetuximab soravtansine, its novel folate receptor alpha (FRα)-targeting ADC product candidate, being presented 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) (abstract #C47) (Press release, ImmunoGen, NOV 8, 2015, View Source [SID:1234508113]). Analysis of the association between the amount of FRα present on patient cancer cells and response to treatment with mirvetuximab soravtansine found nine of ten (90%) patients with high levels of FRα had an objective response on treatment.

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"These early findings are highly encouraging as they underscore the potential of mirvetuximab soravtansine to make an important difference for patients with ovarian cancer," said Dr. Charles Morris, chief development officer. "The data are from patients with heavily pretreated platinum-resistant ovarian cancer, which is a difficult disease to treat. We will be assessing mirvetuximab soravtansine as single-agent therapy for patients with pretreated FRα-positive ovarian cancer in our FORWARD I trial, a study we intend to use for registration purposes."

The findings presented today are from an analysis of 20 efficacy-evaluable patients with platinum-resistant ovarian cancer who received mirvetuximab soravtansine in Phase 1 testing at its selected dose. Patients were categorized as having high, medium or low amounts of FRα on their cancer cells.1 Enrollment criteria for the clinical study required all patients to have at least low expression.

Nine of the ten patients with high FRα expression had an objective response (2 complete responses/CRs, 7 partial responses/PRs by RECIST 1.1 criteria). Six of these responders remained on treatment for at least 24 weeks.

The six patients with medium expression all had tumor regression. One patient had an objective response (unconfirmed PR) and one had tumor shrinkage with new lesion formation (mixed response/MR). An additional patient remained on treatment for more than six months but did not have an objective response.

Four patients had low expression and none had an objective response. One patient was still on treatment at the time of data cut off for presentation.

The ORR was 50% for all 20 efficacy-evaluable patients. Among all 22 patients evaluable for tolerability, the majority of adverse events reported were low grade (grade 1 or 2), with diarrhea, blurred vision, vomiting, fatigue, and nausea the most common treatment-emergent events reported ( > 30% of patients).

ImmunoGen anticipates reporting mature data from the full 46-patient cohort in this study at a medical meeting in 2016.

The FORWARD I Trial

ImmunoGen’s FORWARD I trial will assess mirvetuximab soravtansine as single-agent therapy for the treatment of ovarian cancer previously treated with three to four prior regimens. Patients will have medium or high expression of FRα to qualify for enrollment in this Phase 2 study. Patient enrollment is expected to start in late 2015.

About Mirvetuximab Soravtansine

Mirvetuximab soravtansine (IMGN853) is a FRα-targeting ADC developed and wholly owned by ImmunoGen. It comprises a FRα-binding antibody conjugated to DM4, a potent cancer-killing agent created by ImmunoGen for use in ADCs. The antibody serves to target the DM4 specifically to FRα-positive cancer cells which the DM4 can then kill. FRα is highly expressed on many cases of epithelial ovarian cancer.2 It also is highly expressed on other types of solid tumors including endometrial cancer and some non-small cell lung cancers.

About Ovarian Cancer

Each year, there are approximately 21,300 new cases of ovarian cancer diagnosed in the US and more than 14,200 women die from the disease.3 Once the cancer has been treated with several lines of combination regimens, patients may be treated with single-agent therapy, which typically have response rates around 15-20%.4

On November 8, 2015 Ignyta, Inc. (Nasdaq: RXDX), a precision oncology biotechnology company, reported that interim results from the company’s ongoing Phase 1 clinical trial of RXDX-105, the company’s orally-available, small molecule multikinase inhibitor with potent activity against such key targets as RET and BRAF, were presented at the 27th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics in Boston, Massachusetts (Press release, Ignyta, NOV 8, 2015, View Source [SID:1234508112]).

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"We are excited by the data from our Phase 1 clinical trial of RXDX-105, including the overall safety profile and the recent partial response in a non-small lung cancer patient," said Pratik Multani, M.D., Chief Medical Officer of Ignyta. "We believe we are close to determining the recommended phase 2 dose (RP2D) and we look forward to further study of this product candidate in cancer histologies and molecular alterations of interest."

The dose escalation clinical trial was 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 RXDX-105 in patients with advanced or metastatic solid tumors that were not selected based on any molecular alteration.

As of the October 26, 2015, data cut-off for the presentation, the findings showed:

A total of 41 patients with a range of solid tumors were dosed in the clinical trial;
RXDX-105 was well tolerated to date:

The most frequent treatment-emergent adverse events were fatigue, vomiting, nausea, decreased appetite, constipation, diarrhea, hypertension and muscle spasms;

Three Grade 3 dose-limiting toxicities were observed: maculopapular rash, fatigue and diarrhea, each of which resolved upon study drug interruption;

There were no treatment-related serious adverse events. Two Grade 4 adverse events had occurred, consisting of intestinal obstruction and anemia, neither of which was considered to be treatment-related. No Grade 5 treatment-related adverse events or cumulative adverse events were observed;

The MTD and RP2D had not yet been determined;

Pharmacokinetic measurements showed increased exposure with increasing dose, with a half-life compatible with once-daily dosing. Dosing in the fed state appears to further increase exposure;

Exposure was reaching levels expected to be efficacious based on tumor growth inhibition in animal models of RET- and BRAF-driven tumors; and

Tumor regression was observed in six patients treated with 275 mg, including one confirmed partial response (40% reduction) in a patient with non-small cell lung cancer with a KRAS G12C mutation. Two additional patients with thyroid cancer and squamous cell lung cancer exhibited reductions of 20% and 27%, respectively. In patients with tumor regression, there appears to be an exposure/response correlation.

On Monday, November 9, 2015, Ignyta will file a Form-8-K with the U.S. Securities and Exchange Commission (SEC) containing the materials presented at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium. 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.

At the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium, Ignyta also presented a poster relating to the potent RET inhibitory activity of RXDX-105 in multiple preclinical models of RET-rearrangement driven cancer. This poster is available on the company’s website at www.ignyta.com.