On June 6, 2016 Kite Pharma, Inc. (Nasdaq:KITE) ("Kite") reported results to be presented at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting from a study of low-dose chemotherapy conditioning followed by anti-CD19 chimeric antigen receptor (CAR) T-cell therapy (Press release, Kite Pharma, JUN 6, 2016, View Source [SID:1234513027]). The results showed that CAR T-cell therapy was effective in inducing a high response rate in patients with advanced non-Hodgkin lymphoma (NHL). The results will be presented today as a Late Breaking Abstract by James N. Kochenderfer, M.D., an investigator in the Experimental Transplantation and Immunology Branch of the National Cancer Institute (NCI) Center for Cancer Research (Hall D2, Time: 4:42PM CDT, Abstract #3010).

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In this study of 22 patients (19 diffuse large B-cell lymphoma, 2 follicular lymphoma, and 1 mantle cell lymphoma), objective responses were seen in 16 patients (73%). Twelve of 22 patients (55%) achieved complete responses following low-dose chemotherapy conditioning regimen. Kite is using a similar conditioning regimen in its ZUMA-1 Study of KTE-C19, an anti-CD19 CAR T cell therapy. Nine of 19 patients (47%) with diffuse large B-cell lymphoma (DLBCL) achieved complete responses, which are all ongoing with a duration of 7+ to 20+ months. Additionally, the three patients with mantle cell lymphoma and follicular lymphoma achieved complete responses. Reversible grade 3 or 4 neurotoxicity including confusion, dysphasia, encephalopathy, and gait disturbances was observed in 55% of treated patients.

"Patients with chemorefractory DLBCL have few effective treatment options," said Jeff Wiezorek, M.D., M.S., Kite’s Senior Vice President, Clinical Development. "These early results are encouraging and served as the foundation for Kite’s ongoing KTE-C19 ZUMA-1 Study."

According to the American Cancer Society, NHL is one of the most common cancers in the United States and DLBCL is the most common form of the disease accounting for one out of every three cases of NHL.1 It is estimated that approximately 26,000 people will be diagnosed with DLBCL in the United States in 2016. DLBCL is an aggressive and fast growing lymphoma, but considered curable in patients who respond to initial treatment with a chemotherapy-based regimen. Patients with chemorefractory DLBCL face limited treatment options and historically poor outcomes.

This study was performed pursuant to a Cooperative Research and Development Agreement (CRADA) between the NCI and Kite.

On June 6, 2016 NewLink Genetics Corporation (NASDAQ:NLNK), a biopharmaceutical company focused on bringing novel immuno-oncology medicines to patients, reported the presentation of data from two studies on two posters highlighting the combination therapeutic potential of indoximod, an indoleamine-(2,3)-dioxygenase (IDO) pathway inhibitor, at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (Press release, NewLink Genetics, JUN 6, 2016, View Source [SID:1234513051]).

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Both posters are available online here.

Updates on Phase 1b/2 trial of the IDO inhibitor indoximod plus checkpoint inhibitors for the treatment of unresectable stage 3 or 4 melanoma

The trial design allows for the combination of indoximod with either ipilimumab or one of the PD-1 checkpoint inhibitors pembrolizumab or nivolumab. The combination of indoximod with other checkpoint inhibitors has been well tolerated thus far with no increase in toxicity noted in this Phase 1b/2 study. Overall, 40 patients had been enrolled in the combined Phase 1b/2 study long enough to have response data available at the time of data cut off. The poster data presented at ASCO (Free ASCO Whitepaper) were based on data via site reported RECIST criteria available from 28 subjects, the objective response rate, comprised of complete response plus partial response, for these patients is 36 percent (10 of 28) with three complete responses. Interestingly, the subset of 15 patients who received indoximod in combination with pembrolizumab had an objective response rate of 53 percent (8 of 15) with two complete responses (13 percent). The trial continues to enroll, with 55 patients currently enrolled in Phase 2.

"Although early, the 53 percent response rate in patients with metastatic melanoma treated with indoximod and pembrolizumab appears promising," said Zakharia Yousef, M.D., Assistant Professor of Medicine, Division of Hematology, Oncology and Blood & Marrow Transplantation at the University of Iowa and Holden Comprehensive Cancer Center.

Phase 2 trial of the IDO pathway inhibitor indoximod plus gemcitabine/nab-paclitaxel for the treatment of metastatic pancreas cancer: interim analysis

The combination of indoximod and gemcitabine/nab-paclitaxel continues to be well tolerated by patients with metastatic pancreatic cancer. These data come from the Phase 1/2 trial in which treatment-naïve metastatic pancreatic cancer patients were treated with the combination therapy in continuous four week cycles. As of the data cut off for the analysis, a total of 45 patients (Phase 1 and 2) were enrolled in the trial long enough to potentially have cycle 4 imaging available by the ASCO (Free ASCO Whitepaper) presentation. Data via site reported RECIST criteria were available on 31 patients. At the time of this analysis, objective response rate was 45 percent (14 of 31) and multiple durable responses ≥6 months were observed. Two patients achieved a complete response (6 percent), both at Cycle 8, showing delayed kinetics that may indicate an immune based mechanism. The trial continues to enroll patients and a biopsy cohort expansion is underway.

"The objective response rate, observance of complete responses, and delayed and durable response patterns are promising for this combination regimen for patients with metastatic pancreas cancer," said Andrea Wang-Gillam, M.D., Ph.D., Assistant Professor of Medicine, Division of Oncology, Section of Medical Oncology, at Washington University School of Medicine.

Further Study of Indoximod Combinations Planned

"These are promising data as indoximod continues to demonstrate potential in combination therapies with other checkpoint inhibitors and with chemotherapies for different cancers, with encouraging rates for objective responses while being well-tolerated," said Charles Link, Jr., M.D., Chairman and Chief Executive Officer. "We believe these data further support that the IDO pathway is one of the key immune checkpoint targets. We anticipate continued clinical progress in these and additional indoximod combinations during 2016."

About Indoximod

Indoximod is an orally available small molecule that has shown the potential to interfere with multiple targets within the indoleamine 2,3-dioxygenase (IDO) pathway. It is designed to be used in combination with other therapeutic agents to maximize the body’s immune response against a range of tumor types. Indoximod is currently in multiple Phase 2 clinical trials for the treatment of patients with breast, prostate, pancreatic, melanoma and brain cancers and in Phase 1 clinical trials for the treatment of pediatric patients with primary malignant brain tumors.

On June 6, 2016 Mirna Therapeutics, Inc. (Nasdaq: MIRN), a clinical stage biopharmaceutical company developing a broad pipeline of microRNA-based oncology therapeutics, reported the presentation of clinical data at the 52nd American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (Press release, Mirna Therapeutics, JUN 6, 2016, View Source [SID:1234513072]). Investigators reported on the clinical activity of an ongoing, dose-finding Phase 1 trial of MRX34 (miR-34 mimic), Mirna’s lead microRNA therapeutic, in patients with a variety of advanced solid tumors.

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In an oral presentation (Abstract # 2508 "MRX34, a Liposomal miR-34 Mimic, in Patients with Advanced Solid Tumors: Final Dose-Escalation Results from a First-in-Human Phase 1 Trial of microRNA Therapy"), David S. Hong, M.D., study author and Deputy Chair, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, presented results showing MRX34’s impact on a broad number of oncogenes and immune pathways, and on the investigational therapy’s safety profile and clinical activity.

"The potential of microRNA therapeutics to simultaneously repress multiple oncogenic and immune-evasion pathways represents an exciting new approach to treating cancer," commented Dr. Hong. "In this early study, we are seeing compelling anti-cancer activity, including tumor shrinkage with notable durations of response, supporting further clinical study of MRX34."

Data highlights include:

Manageable safety profile of MRX34 when administered at the maximum tolerated dose (MTD) with dexamethasone.
Broad, dose-dependent microRNA target engagement with MRX34, including delivery to tumor sites in patients.
Four confirmed partial responses (PRs) for up to 54 weeks in duration. This includes patients with late-stage, metastatic cancers including hepatocellular carcinoma (liver cancer), renal cell carcinoma (kidney cancer) and acral melanoma (skin cancer). Timing of these responses and the safety profile observed suggest a potential immune component to MRX34 antitumor activity.
Stable disease in an additional 15 patients for more than four cycles of therapy (approximately three months), ranging from 79-386 days.
Vincent O’Neill, M.D., Mirna’s Chief Medical Officer commented, "We’re pleased to report our clinical progress to date with the first microRNA candidate for cancer. MRX34 is a promising, first-in-class therapeutic candidate with potential as a single agent and in combination with targeted and immune therapies. With the safety profile and recommended dose established, we look forward to advancing the development of MRX34 into Phase 2 later in 2016."

The presentation may be accessed from the Events & Presentations section of the Company’s website.

On June 6, 2016 Castle Biosciences, Inc., a provider of molecular diagnostics to improve cancer treatment decisions, reported the results from a study evaluating the performance of its gene expression profile (GEP) test, DecisionDx-Melanoma, in 334 new melanoma patients (Press release, Castle Biosciences, JUN 6, 2016, View Source [SID:1234513096]). The data confirmed the positive results from two previously published multicenter clinical validation studies demonstrating the test’s ability to identify patients’ risk of melanoma recurrence in the 5 years following diagnosis. The data were presented in a poster session at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, IL. A second, independent, prospective study of DecisionDx-Melanoma was also presented further confirming the results of the three prior multicenter studies.

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Expanded Multicenter Performance Study

In a study titled "Performance of a 31-Gene Expression Profile in a Previously Unreported Cohort of 334 Cutaneous Melanoma Patients" (Abstract # 9581), 334 cutaneous melanoma tumors from 12 centers in the U.S. were analyzed using the DecisionDx-Melanoma test. Tumors were classified as either low-risk Class 1 or high-risk Class 2. The test’s prognostic results were compared to actual clinical outcomes over a 5-year period, as well as traditional methods for disease staging and prognosis including sentinel lymph node (SLN) biopsy, ulceration, Breslow thickness and mitotic rate. Study endpoints included recurrence-free survival (RFS), defined as time to either a regional or distant metastatic event; distant metastasis-free survival (DMFS), defined as time to any metastatic event beyond the regional node; and melanoma-specific survival (MSS), defined as time from diagnosis to death documented as specifically resulting from melanoma. A summary of the results is below:

RFS DMFS MSS
5-year rate # of events 5-year rate # of events 5-year rate # of events
Class 1 (n=181) 86% 29 91% 19 98% 5
Class 2 (n=153) 51% 69 60% 54 75% 31
The study also highlighted the GEP test’s ability to predict which patients are not likely to recur (Negative Predictive Value, or NPV) when used by itself, and in combination with other standard prognostic techniques such as SLN biopsy. While both the DecisionDx-Melanoma test and SLN biopsy were shown to have strong sensitivity to detect patients at risk of metastasis, a combination of the two was the most effective. Results include:

MSS SLN Status GEP Class SLN + GEP
Sensitivity 67% (49-81%) 86% (71-95%) 94% (81-99%)
Specificity 72% (66-77%) 59% (53-65%) 48% (42-54%)
PPV 22% (15-31%) 20% (14-28%) 18% (13-24%)
NPV 95% (91-97%) 97 (94-99%) 99% (95-100%)
95% confidence interval shown in parentheses

Study authors also combined previously studied populations, reviewing the total of 514 patient cases from validation and performance studies of the GEP test to date. Results from the Stage I/II and Stage III patients are shown below:

MSS Stage I/II (n=356) Stage III (n=158)
Sensitivity 80% (52-96%) 87% (70-96%)
Specificity 65% (60-70%) 32% (24-41%)
PPV 9% (5-15%) 24% (16-33%)
NPV 99% (96-100%) 91% (79-98%)
95% confidence interval shown in parentheses

"These study results confirm the prognostic accuracy of this GEP test, demonstrating its ability to provide prognostic information that is independent of and additive to conventional staging," commented Jonathan S. Zager, MD, FACS, lead study author and Professor of Surgery in the Cutaneous Oncology and Sarcoma Departments at the Moffitt Cancer Center. "For melanoma-specific survival, combining this GEP test with SLN status improves sensitivity to 94% and Negative Predictive Value to 99% over SLN status or the GEP test alone – providing support for low-risk management/surveillance plans for Class 1 patients. For Class 2 patients, increased surveillance per guidelines for high-risk patients appears to be warranted."

"We are extremely pleased with the continued strong performance of our GEP test," commented Federico A. Monzon, M.D., FCAP, Chief Medical Officer of Castle Biosciences. "The test, when used with standard melanoma staging tools, provides the most accurate prognostic information from which to plan follow-up care. In addition to improving patient care, the GEP test offers the opportunity to improve clinical trial design to advance adjuvant treatment in patients who have a Class 2, high-risk test result."

Second, Independent, Prospective Study Also Presented

Also at the meeting, a study titled "Prospective Validation of Gene Expression Profiling in Primary Cutaneous Melanoma" (Abstract #9565), was presented by Eddy C. Hsueh, M.D., Professor and Director, Division of Surgical Oncology, St. Louis University Hospital. This study evaluated 159 prospectively enrolled melanoma patients undergoing SLN biopsy and successful testing with the DecisionDx-Melanoma GEP test. The data show that GEP classification is significantly associated with early recurrence in patients diagnosed with melanoma. With a median follow-up time of 18 months, the study found a Negative Predictive Value of 98% for disease-free survival. To date, all Stage III patients with a Class 1 result are recurrence free. The DecisionDx-Melanoma test correctly identified 16 of 18 patients who had recurrence events as high-risk (Class 2). Overall the high-risk Class 2 group had a 38% recurrence rate. Patients who were both high-risk Class 2 and Stage III had a 77% recurrence rate compared to 43% with Stage III status alone.

"An important milestone in test development is demonstrated consistency in prospective studies," added Derek Maetzold, President and CEO of Castle Biosciences. "This prospective study represents the second such DecisionDx-Melanoma study presented in the last six weeks, and provides further independent confirmation for the consistent results seen in Castle Biosciences’ sponsored multicenter studies."

About Melanoma
Cutaneous melanoma is diagnosed in approximately 76,000 people in the U.S. each year, according to the American Cancer Society. Seventy-five percent are diagnosed as Stage I or II, meaning there is no evidence of the melanoma spreading beyond the primary tumor. It is not the most prevalent form of skin cancer, but it is the most aggressive. Unlike other more common skin malignancies such as basal cell and squamous cell carcinomas, melanoma often spreads to other parts of the body, either via the lymphatic or blood system, resulting in cancers of distant organs including the brain or lungs. So, while it represents just 4% of skin cancers, melanoma accounts for about 80% of skin cancer-related deaths.

On June 6, 2016 Peloton Therapeutics, Inc., a drug discovery and development company focused on advancing first-in-class, small molecule cancer therapies targeting unexploited molecular vulnerabilities, reported first-in-human Phase 1 clinical data on its lead investigational candidate, PT2385, at the annual meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago, IL (Press release, Peloton Therapeutics, JUN 6, 2016, View Source [SID:1234513120]). PT2385 is the first clinical stage antagonist of hypoxia inducible factor-2α (HIF-2α), a transcription factor implicated in the development and progression of kidney and other cancers.

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In an oral presentation titled "A Phase 1 Dose-Escalation Trial of PT2385, a first-in-class oral HIF-2α Inhibitor, in Patients with Advanced Clear Cell Renal Cell Carcinoma," it was shown that PT2385 was well tolerated with no dose-limiting toxicities and had pharmacologic activity with encouraging clinical efficacy.

Patients with advanced clear cell renal cell carcinoma (ccRCC) and at least one prior therapy with a VEGF inhibitor were treated with PT2385 to determine the recommended Phase 2 dose and evaluate safety, pharmacokinetics and pharmacodynamics.
Twenty-six patients were enrolled in dose escalation and received PT2385 from 100 to 1800 mg twice per day. Patients were heavily pretreated prior to study entry, with greater than 50 percent having four or more prior therapies. Exposure increased with doses up to the 800 mg cohort without a further increase from 800 to 1800 mg. No dose limiting toxicities were observed at any dose level. Circulating plasma levels of the HIF-2α transcriptional target erythropoietin (EPO) rapidly decreased with treatment with PT2385 and remained suppressed. Based on safety, pharmacokinetic and EPO pharmacodynamic data, 800 mg twice per day was selected as the recommended Phase 2 dose. An additional 25 patients were enrolled in an expansion cohort at the recommended Phase 2 dose.

Among the 51 patients in total, the most common all-grade adverse events (AEs) were anemia, peripheral edema and fatigue. No cardiovascular AEs were noted. To date, one patient had a complete response, three patients had a partial response, and 16 patients had stable disease for 16 or more weeks. Ten percent of patients remain in this ongoing clinical trial for at least one year.
"Research at our institution has shown than HIF-2α is strongly implicated in renal cell carcinoma. PT2385 is the first agent to target this transcription factor and is very well tolerated. Its efficacy in patients with advanced clear cell renal cell carcinoma is promising," said Toni Choueiri, M.D., from the Dana-Farber Cancer Institute and Harvard Medical School, the senior author of the study.
"We are encouraged by the initial efficacy results in this heavily pretreated population and the fact that PT2385 does not have the cardiovascular toxicities of most other kidney cancer treatments, most notably VEGFR tyrosine kinase inhibitors. In light of this favorable safety profile and preclinical evidence of synergistic activity of our HIF-2α antagonists in combination with immune checkpoint inhibitors shown at the recent AACR (Free AACR Whitepaper) conference, we have opened a clinical trial of PT2385 in combination with nivolumab (Opdivo). Additionally, we are planning clinical studies of PT2385 as monotherapy and with other combination regimens," said John Josey, Ph.D., Peloton’s Chief Executive Officer.

About PT2385
PT2385 is a first-in-class small molecule inhibitor of hypoxia-inducible factor-2α (HIF-2α), a transcription factor implicated in the development and progression of kidney cancer. It is currently being investigated in a Phase 1 clinical trial for the treatment of advanced or metastatic clear cell renal cell carcinoma (ccRCC). Loss of the von Hippel-Lindau tumor suppressor (VHL) is the key oncogenic event in up to 95% of patients with ccRCC. With the loss of the VHL protein (pVHL), the transcription factor HIF-2α accumulates and drives the unbalanced expression of numerous gene products. Preclinical data indicate that orally bioavailable PT2385 disrupts HIF-2α activity in ccRCC and thereby blocks the expression of multiple tumorigenic factors responsible for unrestrained cancer cell growth and proliferation, tumor angiogenesis, and suppression of anti-tumor immune responses characteristic of ccRCC.

About Renal Cell Cancer
The American Cancer Society estimates that more than 62,000 new cases of kidney cancer will be diagnosed and more than 14,000 people will die from this disease this year. The National Cancer Institute reports that the prognosis for any treated renal cell cancer patient with progressing, recurring, or relapsing disease is poor, regardless of cell type or stage.
About Peloton Therapeutics