On June 6, 2016 GlycoMimetics, Inc. (NASDAQ:GLYC) reported dosing of the first patient with relapsed/refractory acute myeloid leukemia in the Phase 2 portion of its ongoing Phase 1/2 clinical trial evaluating its novel E-selectin antagonist, GMI-1271, combined with induction chemotherapy (Press release, GlycoMimetics, JUN 6, 2016, View Source [SID:1234513101]).

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For the study’s Phase 2 portion, the optimal dose has been determined, and clinical investigators will expand the number of patients receiving GMI-1271 to obtain additional safety and efficacy data. Study enrollment is limited to patients at least 18 years old with relapsed or refractory AML and who would be treated with mitoxantrone, etoposide, and cytarabine (‘MEC’). All patients must be eligible to receive this chemotherapy regimen, and will be given GMI-1271 in addition to this combination chemotherapy. During the Phase 1 portion of the study, patients received a single cycle of treatment including GMI-1271. During this Phase 2 portion, certain patients will be eligible to receive an additional cycle of treatment.

"The data from the first cohorts point to both the safety and potential efficacy of GMI-1271 as a treatment for AML," said Helen Thackray, M.D., Chief Medical Officer of GlycoMimetics. "In the second half of this trial, we will further assess if patients with relapsed or refractory AML respond well to this combination approach while also including those who have been newly diagnosed with the disease in a separate arm of the study. If the second half confirms our earlier preclinical and clinical findings, we believe that GMI-1271 could well address the unmet needs of AML patients, beyond what can be done with currently available therapies."

This clinical trial is a multinational open-label study evaluating endpoints for safety, pharmacokinetics (PK) and efficacy of GMI-1271 in combination with induction chemotherapy in patients with high-risk AML. This trial is being conducted at a number of academic medical institutions in the United States, Ireland, and Australia. While the primary objective is to assess safety, additional endpoints include overall response rate, biomarkers of activity, durability of response and overall survival. This Phase 2 portion of the study is expected to include approximately 25 participants.

About GMI-1271

GMI-1271 is designed to block E-selectin (an adhesion molecule on cells in the bone marrow) from binding with AML cells as a targeted approach to disrupting well-established mechanisms of leukemic cell resistance within the bone marrow microenvironment. Preclinical research points to the drug’s potential role in moving cancerous cells out of the protective environment of the bone marrow where they hide and escape the effects of chemotherapy. In preclinical studies using animal models of AML, the results of which were presented at meetings of the American Society of Hematology (ASH) (Free ASH Whitepaper), GMI-1271 was also associated with a reduction of chemotherapy-induced neutropenia and chemotherapy-induced mucositis.

On June 6, 2016 Kolltan Pharmaceuticals, Inc., a privately held clinical-stage company focused on the discovery and development of novel antibody-based drugs targeting receptor tyrosine kinases (RTKs) for use in oncology and immunology, reported the presentation of clinical data related to KTN3379, the Company’s most advanced product candidate for the potential treatment of various solid tumors (Press release, Kolltan Pharmaceuticals, JUN 6, 2016, View Source [SID:1234513100]). These data were discussed in an oral presentation titled, "Safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity in a phase 1b study evaluating anti-ErbB3 antibody KTN3379 in adults with advanced tumors alone and with targeted therapies," at the 2016 ASCO (Free ASCO Whitepaper) Annual Meeting, which is taking place in Chicago, IL, June 3-7, 2016. KTN3379 is a novel antibody that blocks the activity of the ErbB3 (HER3) receptor by binding to a unique epitope and effectively locking the ErbB3 receptor in an inactive conformation. In addition, KTN3379 has been engineered to extend serum half-life. These features are believed to contribute to the favorable potency and pharmacology of KTN3379.

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"The data presented today are very encouraging and demonstrate that anti-tumor activity was observed in certain extensively pretreated patients when KTN3379 was administered in combination with other targeted therapeutics. The evidence from the Phase 1b clinical trial and several preclinical studies supports the initiation of a Phase 2 clinical trial in HNSCC, and we believe KTN3379 has the potential to provide clinical benefit across multiple tumor types where ErbB3 plays a role in tumor progression and therapeutic resistance. There exists an unmet medical need in cancer patients that have exhausted many or all treatment options, and we plan to advance the clinical development of KTN3379 to address this need," stated Gerald McMahon, Ph.D., President and Chief Executive Officer of Kolltan.

Study KTN3379-CL-001 (NCT02014909) has two parts. In Part 1, which was the subject of an oral presentation by Dr. Patricia LoRusso at the 26th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain, KTN3379 was administered to patients with advanced solid tumors as a single agent. In this part of the study, a maximum tolerated dose was not reached and KTN3379 demonstrated favorable tolerability and pharmacology profiles. In Part 2 of the study, the focus of today’s oral presentation, KTN3379 was evaluated in combination with four different targeted therapies. KTN3379 was administered at 15 and 20 mg/kg every three weeks in combination with cetuximab (N=16), erlotinib (N=8), vemurafenib (N=4), or trastuzumab (N=10). Safety monitoring and RECIST-based tumor assessments were conducted. Pharmacokinetic parameters and immunogenicity were evaluated. In addition, archival tumor tissue was tested for mRNA expression of neuregulin (NRG) in baseline tumor samples. Sixty percent of the patients had received at least four prior treatment regimens. Enrollment in the vemurafenib patient cohort is currently being expanded.

Joseph Paul Eder, M.D., Professor of Medicine (Medical Oncology) at the Yale Cancer Center, commented, "The ErbB family of receptors has been among the most successful targets in the treatment of cancer, resulting in therapies that are standard of care across a number of tumor types. The scientific rationale supporting the development of this anti-ErbB3 antibody, including its differentiated features and potency, together with durable responses observed in patients with resistant tumors, warrants the further development of KTN3379 in combination with targeted therapies."

Ronald Peck, M.D., Chief Medical Officer and Senior Vice President, Clinical Development at Kolltan added, "The responses reported in this trial were impressive, in particular the durable complete response in a HNSCC patient receiving the combination of KTN3379 and cetuximab after disease progression on single agent cetuximab and the durable partial response in a non-small cell lung cancer (NSCLC) patient receiving KTN3379 plus vemurafenib after progressing on another BRAF inhibitor and other prior therapy. These results, as well as extensive preclinical data, support the planned Phase 2 clinical trial of KTN3379 in combination with cetuximab in patients with advanced head and neck squamous cell carcinoma and the ongoing expansion of the Phase 1b BRAF-mutant tumor cohort receiving KTN3379 in combination with vemurafenib."

The results were presented by Gerald Falchook, M.D., Director of Drug Development at Sarah Cannon Research Institute at HealthONE in Denver, Colorado. Following is a summary of the key results:

38 total patients were treated in four cohorts with KTN3379 in combination with the following targeted therapies: cetuximab (N=16), erlotinib (N=8), vemurafenib (N=4), or trastuzumab (N=10);

The patient population enrolled in Part 2 of Study KTN3379-CL-001 was generally heavily pretreated, with approximately 97% of patients having received at least one prior treatment regimen and 60% of patients having received at least four prior treatment regimens;

The safety profile of the combination therapies was consistent with the safety profiles of the individual agents. The most common treatment related adverse events included diarrhea and rash, which were resolved with medical therapy or dose reduction;

Pharmacokinetic data demonstrated that all patients achieved serum concentrations of KTN3379 required for maximal anti-tumor activity in animal tumor models; and

Showed a consistent trend towards slower clearance and longer terminal half-life of KTN3379 compared to published data for other anti-ErbB3 antibodies

Anti-tumor activity was achieved in several patients with resistant tumors treated with KTN3379 in combination with cetuximab or vemurafenib

Cetuximab combination arm:

Anti-tumor activity was observed in certain of the nine patients with HNSCC treated with KTN3379 in combination with cetuximab including a patient with a durable complete response (CR) who had undergone extensive prior therapy including chemotherapy, radiation, and multiple surgeries; and

The patient with a CR had previously progressed five months after initiating single agent cetuximab. The patient’s CR with KTN3379 in combination with cetuximab persisted for 10.5 months after starting study therapy. The patient’s tumor was found to express the ErbB3 ligand, neuregulin.

Vemurafenib combination arm:
In four patients with BRAF-mutant cancers that were treated with KTN3379 in combination with vemurafenib, stable disease was reported in one patient with colorectal cancer and durable partial responses (PRs) were reported in two patients with NSCLC; and
Notably, one of the two NSCLC PRs was in a patient who underwent extensive prior therapy, which included combination chemotherapy, another BRAF-inhibitor (dabrafenib), and combination immunotherapy (an investigational regimen of an anti-CTLA4 and an anti-PDL-1). Previously, the patient had disease progression within two months of initiating dabrafenib. The patient’s PR persisted for 12 months after starting study therapy. The patient’s tumor was found to express neuregulin.

About KTN3379
KTN3379 is a human monoclonal antibody designed to block the activity of ErbB3 (HER3), a receptor tyrosine kinase (RTK) that belongs to the epidermal growth factor receptor, or EGFR, family. ErbB3 is believed to be an important receptor regulating cancer cell growth and survival. ErbB3 is expressed in many cancers, including head and neck, breast, lung, and gastric cancers, and melanoma. Kolltan is conducting multiple clinical trials evaluating KTN3379 in the treatment of solid tumors (NCT02014909, NCT02456701, and NCT02473731).

On June 6, 2016 Principia Biopharma Inc., a private clinical-stage biopharmaceutical company, reported that initial Phase 1 clinical data for its fibroblast growth factor receptor (FGFR) 1-4 inhibitor, PRN1371, was presented at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, Principia Biopharma, JUN 6, 2016, View Source [SID:1234513099]). PRN1371 is an oral, irreversible covalent FGFR 1-4 inhibitor currently being evaluated in a Phase 1 dose escalation trial in patients with solid tumors to be followed by a dose expansion phase.

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Clinical, pharmacokinetic and pharmacodynamic data from the ongoing international, multi-center trial were presented. The data demonstrated consistent pharmacokinetics with high apparent bioavailability, and robust pharmacodynamic impact on surrogate markers of serum phosphate and FGF23 levels. PRN1371 was well tolerated, with no dose limiting toxicities or any major off-target safety signals observed.

The presented poster will be available on the Scientific Publications section of Principia Biopharma’s website at View Source

About FGFR inhibition in cancer

FGFR genetic alterations occur in a wide range of cancers including lung, breast, stomach, liver and bladder. These alterations may be amenable to targeted therapy designed to inhibit the effects of the alteration in driving tumor growth. Highly selective and potent FGFR inhibitors, such as PRN1371, may be able to slow or reverse tumor growth with a lower rate of side effects compared with less selective drugs.

On June 6, 2016 IntegraGen, a leading provider of genomic solutions which transform molecular information into clinical action, reported the presentation of positive clinical results on its miR-31-3p biomarker during the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting being held in Chicago (Press release, Integragen, JUN 6, 2016, View Source [SID:1234513098]). The data presented demonstrates that IntegraGen’s proprietary miR-31-3p biomarker is predictive for both survival and treatment response in patients receiving anti-EGFR therapy. These results are based on an analysis of the expression of miR-31-3p in tumors from 370 RAS wild-type (WT) metastatic colorectal cancer (mCRC) patients enrolled in the FIRE-3 clinical trial (AIO KRK-0306). The data presented represents the first study comparing miR-31-3p expression in mCRC patients treated in first line with anti-EGFR vs. anti-VEGF therapy.

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In addition to confirming miR-31-3p is predictive of improved outcomes for mCRC patients treated with anti-EGFR therapy, the study also demonstrated that patients with a miR-31-3p expression below a pre-defined threshold treated with FOLFIRI plus cetuximab have a one year longer median overall survival, a 40% reduction in mortality risk, and a better treatment response compared to patients treated with FOLFIRI plus bevacizumab. No difference in outcomes were seen between the two groups in patients with miR-31-3p expression above the pre-defined threshold. These results suggest that testing miR-31-3p expression in RAS WT mCRC patients can help identify which 1st line biologic therapy may be most beneficial.

"Our results show that miR-31-3p can predict which mCRC patients will have improved outcomes when treated in first line with cetuximab compared to bevacizumab when combined with FOLFIRI therapy," said Professor Volker Heinemann, from the Department of Medical Oncology and Comprehensive Cancer Center at University Hospital Grosshadern in Munich, Germany and lead investigator for the FIRE-3 study. "These findings are extremely significant clinically since nearly two-thirds of the patients with RAS wild-type tumors in our study had low miR-31-3p expression levels and would therefore benefit from being treated with cetuximab versus bevacizumab as first line therapy for mCRC."

"The results from this study provide strong clinical evidence that IntegraGen’s miR-31-3p biomarker can predict the benefit of anti-EGFR therapy in mCRC patients," stated Dr. Bernard Courtieu, IntegraGen’s CEO. "The data presented at this year’s ASCO (Free ASCO Whitepaper) meeting in patients enrolled in the landmark FIRE-3 study demonstrates that RAS wild-type mCRC patients would benefit from the analysis of miR-31-3p expression prior to the determination of which biologic agent to utilize as first line therapy. This aligns with a more personalized approach to cancer care and contributes to the ability to tailor therapies to patients who are more likely to have clinical benefit of these therapies."

Dr. Courtieu also added that "IntegraGen is currently pursuing options for offering a commercial test based on the miR-31-3p biomarker to physicians and their patients, which we estimate represents a $100 million market opportunity worldwide."

ABOUT THE FIRE-3 CLINICAL TRIAL

The FIRE-3 clinical trial is an independent, randomized, controlled Phase III trial conducted in Europe and led by Ludwig-Maximilians University in Munich, Germany. The study compares outcomes of KRAS Exon 2 wild-type (WT) stage IV colorectal cancer patients randomized to receive FOLFIRI therapy (5-FU, folinic acid and irinotecan) in combination with either cetuximab or bevacizumab.

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.