On April 19, 2016 Cerulean Pharma Inc. (NASDAQ:CERU), a clinical-stage company developing nanoparticle-drug conjugates (NDCs), reported the presentation of clinical data in a late-breaker at the 2016 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting. Adrian Senderowicz, M.D., Senior Vice President and Chief Medical Officer of Cerulean will present results from the first 18 patients enrolled in an investigator-sponsored trial (Press release, Cerulean Pharma, APR 19, 2016, View Source [SID:1234511092]).

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The trial studies CRLX101 in combination with Avastin in patients with platinum-resistant ovarian cancer. The trial employs a Simon Two-Stage Design and has met the stage gate criteria for advancement into Stage 2. In order to advance to Stage 2, more than two events of progression-free survival at six months (PFS6) were needed. Eighteen patients were treated in Stage 1, and 25 patients will be enrolled in Stage 2. The study is sponsored by Massachusetts General Hospital. Cerulean and Genentech provide the trial with CRLX101 and Avastin, respectively.

"This arm of the study is designed to assess whether combining Avastin with CRLX101 improves the antitumor activity observed with CRLX101 in the monotherapy arm of the study," said Carolyn N. Krasner, M.D., principal investigator of the trial. "VEGF inhibitors such as Avastin starve tumors of oxygen, resulting in tumor shrinkage, but they may exacerbate the hypoxic conditions present in solid tumors, which would increase HIF-1α. CRLX101 inhibits HIF-1α and mitigates HIF-associated resistance to VEGF inhibitors. The Stage 1 results show that CRLX101 plus Avastin appears to provide a greater benefit than CRLX101 alone. I am pleased that the study has advanced into Stage 2."

"The increased tumor activity observed by combining CRLX101 with Avastin is encouraging," said Dr. Senderowicz. "We also are evaluating the combination of CRLX101 and Avastin in our randomized Phase 2 study in 3rd and 4th line renal cell carcinoma, and there are many other opportunities to combine our HIF-inhibitor with Avastin or other therapies, including TKIs, chemotherapy or radiation therapy."

Results from Stage 1 Arm of Phase 2 Trial of CRLX101 in Combination with Avastin in Platinum-Resistant Ovarian Cancer

In this open-label study, patients were dosed in two arms: a CRLX101 monotherapy arm (Group A) and a combination arm of CRLX101 with Avastin (Group B). Group A patients received CRLX101 at 15 mg/m2 every other week (presented at ASCO (Free ASCO Whitepaper) 2014) and Group B patients received CRLX101 at 15 mg/m2 with Avastin 10 mg/kg every other week. The primary endpoint for both groups was the rate of PFS6 using RECIST 1.1 criteria. Secondary endpoints were objective response rate (ORR), PFS, ≥50% reduction of CA125 over baseline, and safety. Adverse events (AEs) were assessed by CTCAE v4.0. Pre- and post-treatment tumor biopsies were collected from a cohort of patients on CRLX101 as monotherapy to evaluate relevant progressive disease endpoints.

In Stage 1 of Group B, a total of 18 platinum-resistant ovarian cancer patients were evaluated. PFS6 (defined as patients that are free of progression at six months) was demonstrated in 56% of patients (10 out of 18). The overall response rate was 17% (3 out of 18 patients). The overall stable disease rate was 78% (14 out of 18 patients). The clinical benefit rate (defined as patients that either achieved a partial response or stable disease) was 94% (17 out of 18). Median PFS (defined as time from first dose to discontinuation of treatment) is 6.2 months so far, and 2 of 18 patients have been on treatment after 11 months. A ≥ 50% decline in CA125 was demonstrated in 44% patients (8 out of 18). Thus far, Group B showed increased antitumor activity relative to Group A on all of the aforementioned dimensions.

AEs most commonly observed with the combination were anemia (10 patients, 56%); nausea (10 patients, 56%); fatigue (6 patients, 33%); and proteinuria (5 patients, 28%). The majority of AEs were Grade 1. There were four drug-related AEs that were Grade 3 or 4: Grade 3 anemia, elevated alanine transaminase levels, and non-infective cystitis, and Grade 4 febrile neutropenia.

Details of the AACR (Free AACR Whitepaper) late-breaking poster presentation are as follows:

Title:
Phase 2 trial of the NDC CRLX101 in combination with Avastin in patients with Platinum-Resistant OvarianCancer (PROC)
Date and Time:
Tuesday, April 19 – 8:00 am to 12:00 pm
Abstract number:
CT090
Location:
Section 13
Poster board number:
18

A copy of the poster will be available upon request following AACR (Free AACR Whitepaper) by emailing [email protected].

About CRLX101

CRLX101 is a nanoparticle-drug conjugate (NDC) designed to concentrate in tumors and slowly release its anti-cancer payload, camptothecin, inside tumor cells. CRLX101 inhibits topoisomerase 1 (topo 1), which is involved in cellular replication, and also inhibits hypoxia-inducible factor-1α (HIF-1α), which research suggests is a master regulator of cancer cell survival mechanisms. CRLX101 has shown activity in four different tumor types, both as monotherapy and in combination with other cancer treatments. CRLX101 is in Phase 2 clinical development and has been dosed in more than 350 patients. The U.S. FDA has granted CRLX101 Orphan Drug designation for the treatment of ovarian cancer and Fast Track designation in combination with Avastin in metastatic renal cell carcinoma.

On April 19, 2016 BioLineRx Ltd. (NASDAQ/TASE: BLRX) reported that detailed results from a study on the underlying mechanism of action of BL-8040, its lead platform for the treatment of multiple cancer and hematological indications, were presented by Prof. Amnon Peled at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) 2016 meeting in New Orleans (Press release, BioLineRx, APR 19, 2016, View Source;p=RssLanding&cat=news&id=2158220 [SID:1234511046]).

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The work presented, entitled "CXCR4 Controls BCL-2 Expression and Function by Regulating miR-15a/16-1 Expression in Tumor Cells," illustrates the mechanism by which the CXCR4 pathway controls malignant cell survival and death in preclinical studies. Specifically, the studies point out how BL-8040 increases the expression and activity of a special class of microRNA precursors termed miR-15a/16-1. These microRNA molecules have been previously linked to cancer, and shown to suppress the activity of several tumor-related pro-survival proteins, specifically BCL2, MCL1 and cyclin D1. The studies presented showed that BL-8040 increases the suppression of these three target proteins through miR-15a/16-1, thereby increasing tumor cell death.

The BL-8040 oncology platform is a short cyclic peptide that functions as a high-affinity antagonist for CXCR4, a chemokine receptor that is directly involved in tumor progression, angiogenesis, metastasis and cell survival. CXCR4 is overexpressed in the majority of cancer cells, and its degree of expression often correlates with disease severity.

Dr. Kinneret Savitsky, CEO of BioLineRx, stated, "We recently announced the successful top-line results for BL-8040, in combination with Cytarabine, one of the standard-of-care chemotherapies, in a Phase 2 study in relapsed or refractory AML. In that study, BL-8040 showed a triple effect on the leukemic cells. First, BL-8040 monotherapy triggered robust mobilization of AML cells from the bone marrow to the peripheral blood, thereby sensitizing these cells to the chemotherapy and improving its efficacy. Second, BL-8040 monotherapy showed a 3-4 fold increase in the direct apoptotic effect on the leukemia cells in the bone marrow. Last, BL-8040 monotherapy induced leukemia progenitor cells towards differentiation. As a result of these factors, we reported a 38% complete remission rate in the study, compared to historical remission rates in similar patient populations with similar treatment regimens of approximately 20% for Cytarabine on a stand-alone basis. We look forward to providing the full results of this study at an upcoming scientific conference."

"In this regard, we are pleased to announce the current study results presented at the AACR (Free AACR Whitepaper) meeting, which provide significant clarity regarding BL-8040’s mechanism of action relating to apoptosis. The data suggest that BL-8040 is able to indirectly suppress the activity of several tumor-promoting genes, by increasing the activity of the microRNA molecule miR-15a/16-1. Of note, one of these pro-survival proteins, BCL-2, is a validated anti-cancer target that is recently attracting a lot of interest in the drug development space."

"In order to further expand and enhance the potential of our unique oncology platform, BL-8040 is undergoing multiple clinical studies, including our recently announced immuno-oncology collaboration with Merck on a Phase 2 study to investigate BL-8040 in combination with KEYTRUDA for the treatment of pancreatic cancer," concluded Dr. Savitsky.

Link to AACR (Free AACR Whitepaper) On-Line Abstract

About BL-8040
BL-8040 is a clinical-stage drug candidate for the treatment of acute myeloid leukemia, as well as other hematological indications. It is a short cyclic peptide that functions as a high-affinity antagonist for CXCR4, a chemokine receptor that is directly involved in tumor progression, angiogenesis (growth of new blood vessels in the tumor), metastasis (spread of the disease to other organs or organ parts) and cell survival. CXCR4 is over-expressed in more than 70% of human cancers and its expression often correlates with disease severity. In a Phase 1/2, open-label, dose escalation, safety and efficacy clinical trial in 18 multiple myeloma patients, BL-8040, when combined with G-CSF, demonstrated an excellent safety profile at all doses tested and was highly effective in the mobilization of hematopoietic stem cells and white blood cells from the bone marrow to the peripheral blood. Additionally, in a Phase 1 stem-cell mobilization study in healthy volunteers, BL-8040 as a single agent was safe and well tolerated at all doses tested and resulted in efficient stem-cell mobilization and collection in all study participants. Importantly, the results of this study support the use of BL-8040 as one-day, single-dose collection regimen, which is a significant improvement upon the current standard of care.

BL-8040 also mobilizes cancer cells from the bone marrow and may therefore sensitize these cells to chemo- and bio-based anti-cancer therapy. Importantly, BL-8040 has also demonstrated a direct anti-cancer effect by inducing apoptosis. Pre-clinical studies show that BL-8040 inhibits the growth of various tumor types including multiple myeloma, non-Hodgkin’s lymphoma, leukemia, non-small cell lung carcinoma, neuroblastoma and melanoma. BL-8040 also significantly and preferentially stimulated apoptotic cell death of malignant cells (multiple myeloma, non-Hodgkin’s lymphoma and leukemia). Significant synergistic and/or additive tumor cell killing activity has been observed in-vitro and in-vivo when tumor cells were treated with BL-8040 together with Rituximab, Bortezomib, Imatinib, Cytarabine and the FLT-3 inhibitor AC-220 (in NHL, MM, CML, AML, and AML-FLT3-ITD models, respectively). In addition, the recently completed Phase 2 clinical trial in AML patients has demonstrated robust mobilization and apoptosis of cancer cells, along with a clinically meaningful response rate. BL-8040 was licensed by BioLineRx from Biokine Therapeutics and was previously developed under the name BKT-140.

Arthralgia is a common toxicity among women taking aromatase inhibitors (AIs) and can lead to premature discontinuation of therapy. We evaluated the association between arthralgia, co-morbid fatigue and/or insomnia, and inflammatory biomarkers among women taking AIs.
Women taking AIs for early-stage breast cancer completed a modified version of the Brief Pain Inventory, the Brief Fatigue Inventory, and the Insomnia Severity Index and provided blood samples for simultaneous assessment of 34 inflammatory biomarkers with a Luminex kit. Two-sided t tests were used to compare inflammatory biomarker concentrations for patients with or without moderate to severe arthralgia. Multivariate linear regression analyses were performed to evaluate the relationship between comorbid arthralgia, fatigue, and insomnia with identified biomarker concentrations.
Among 203 participants, the severity of arthralgia, fatigue, and insomnia were significantly correlated with each other (p < 0.001 for all comparisons). After controlling for race, chemotherapy history, non-steroidal anti-inflammatory drug use, age, and body mass index, the coexistence of arthralgia, fatigue, and insomnia was associated with elevated C-reactive protein (CRP) (β = 93.1; 95 % confidence interval (CI): 25.1-161.1; p = 0.008), eotaxin (β = 79.9; 95 % CI: 32.5-127.2; p = 0.001), monocyte chemoattractant protein (MCP)-1 (β = 151.2; 95 % CI: 32.7-269.8; p = 0.013), and vitamin D-binding protein (VDBP) (β = 19,422; 95 % CI: 5500.5-33,344; p = 0.006).
Among women taking AIs, the coexistence of arthralgia, fatigue, and insomnia was associated with increased levels of inflammatory biomarkers (elevated CRP, eotaxin, MCP-1, and VDBP). These findings suggest a possible shared inflammatory mechanism underlying these common symptoms.

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On April 19, 2016 Euclises Pharmaceuticals, Inc., a biopharmaceutical company focused on the discovery and development of novel COX-2 inhibitors for the treatment of cancer, reported that its Late-Breaking Abstract has been accepted for presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans on April 19, 2016 (Press release, Euclises, APR 19, 2016, View Source [SID:1234511093]).

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Entitled, "Anti-tumor effects of ECP-1014 in combination with erlotinib in HT-29 xenograft murine colon carcinoma model," the presentation will report the results of key preclinical experiments using Euclises’ COX-2 inhibitor candidate, ECP-1014. The study, conducted in collaboration with Guangzhou Institute of BioMedicine and Health, builds upon recent research demonstrating a role for overactive COX-2 in maintaining an immunosuppressive microenvironment for a variety of tumors, including colorectal and non-small cell lung cancers.

"The epidermal growth factor (EGFR) inhibitor erlotinib is the current standard of care for advanced colorectal cancer," said Dr. Bobby W. Sandage, Jr., Ph.D., CEO of Euclises. "In this preclinical study, we demonstrate a substantial additional benefit in tumor suppression from combining erlotinib with our third-generation COX-2 inhibitor."

"The research to be presented at AACR (Free AACR Whitepaper) strongly validates Euclises’ approach," added Rick Ryan, Ph.D., chairman of Euclises’ board. "These results comprise an important step towards the clinical translation and commercialization of effective COX-2 inhibitors for colorectal cancer patients."

Dr. Sandage will present the research on Tuesday morning, April 19, in Section 11 of the Late-Breaking Research: Experimental and Molecular Therapeutics 3 poster session.

On April 19, 2016 Kite Pharma, Inc. (Nasdaq:KITE) ("Kite") reported updated clinical results from the phase 1 portion of Kite’s ZUMA-1 trial of its lead product candidate, KTE-C19, in patients with chemorefractory, aggressive non-Hodgkin lymphoma (NHL) (Press release, Kite Pharma, APR 19, 2016, View Source [SID:1234511121]). KTE-C19 is an investigational therapy in which a patient’s T cells are genetically modified to express a chimeric antigen receptor (CAR) that is designed to target the antigen CD19, a protein expressed on the cell surface of B cell lymphomas and leukemias.

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David Chang, M.D., Ph.D., Kite’s Executive Vice President, Research and Development, and Chief Medical Officer, commented, "Today’s report affirms the early safety and efficacy profile of KTE-C19 in chemorefractory, aggressive NHL. We are encouraged by the ongoing complete remissions in patients with significant unmet need for new therapies. We remain on track to provide interim data from the pivotal phase 2 portion of the study later this year and to submit the KTE-C19 registration filing to the U.S. Food and Drug Administration (FDA) by the end of 2016."

"The data reported today are important because refractory DLBCL is incurable. Median survival for these patients is short and there is no standard therapy," noted Ronald Levy, M.D., Robert K. Summy and Helen K. Summy Professor of Medicine and Director of the Lymphoma Program at Stanford University School of Medicine and Associate Director of Translational Science for the Stanford Cancer Institute. "A rate of complete response and durability of response in the ranges of those reported today would be of profound clinical importance if replicated in the phase 2 portion of the ZUMA-1 study. Adoptive transfer of engineered T cells has the potential to become standard of care for patients with refractory NHL in the near future."

Updated Phase 1 Results from ZUMA-1: A Phase 1-2 Multi-Center Study Evaluating the Safety and Efficacy of KTE-C19 (Anti-CD19 CAR T Cells) in Subjects with Refractory Aggressive Non-Hodgkin Lymphoma (NHL)

Session: Early Clinical Trials Evaluating Cell-based, Checkpoint Inhibitors, and Novel Immunotherapeutics; Abstract Number: CT135; Presenter: Armin Ghobadi, M.D., Washington University, St. Louis, MO

Phase 1 of ZUMA-1 treated a total of 7 patients with chemorefractory, diffuse large B cell lymphoma (DLBCL)
KTE-C19 related adverse events consisted predominantly of cytokine release syndrome (CRS) and neurotoxicity which were generally reversible
Grade 3 or higher CRS was observed in 14% and neurotoxicity in 57%; all were reversible except in one patient with dose-limiting toxicity
KTE-C19 achieved rapid and durable responses in patients with chemorefractory disease (objective response rate 71%, complete response rate 57%)
Ongoing complete response (CR) observed in 3 of 7 patients. One ongoing CR as of 9-month study follow-up and 2 ongoing CRs as of 6-month study follow-up.
In addition, two posters on KTE-C19 engineered cell manufacturing and characteristics were presented at AACR (Free AACR Whitepaper) on April 18, 2016.

Manufacturing and Characterization of KTE-C19 in a Multicenter Trial of Patients with Refractory Aggressive Non-Hodgkin Lymphoma (NHL) (ZUMA-1)

Session: Adoptive Cell Therapy; Abstract Number: 2308; Presenter: John Rossi, M.S., Kite Pharma

The optimized GMP-manufacturing process generated anti-CD19 CAR T cells rapidly and without the need for pre-selection of a defined composition of T cells
Biologically active anti-CD19 CAR T cells were manufactured for all patients enrolled in the multicenter phase 1 ZUMA-1 trial.
Comparative Evaluation of Peripheral Blood T Cells and Resultant Engineered Anti-CD19 CAR T Cell Products from Relapsed/Refractory Non-Hodgkin’s Lymphoma (NHL) Patients

Session: Adoptive Cell Therapy; Abstract Number: 2305; Presenter: Timothy J. Langer, Kite Pharma

CAR T cells were successfully manufactured for all patients enrolled in the study at the National Cancer Institute, Surgery Branch
CAR T cell products were composed of both CD4+ and CD8+ T cells with a less differentiated phenotype than the starting leukapheresis products
CAR T cells were polyfunctional and produced a wide range of immune homeostatic, modulating and effector cytokines/chemokines in response to antigen-positive target cells.