On April 19 2016 Medigene AG (MDG1, Frankfurt, Prime Standard), a clinical stage immune-oncology company focusing on the development of T cell immuno-therapies for the treatment of cancer, reported that clinical data of a dendritic cell (DC) vaccine trial for the treatment of prostate cancer were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, LA, USA (Press release, MediGene, APR 19, 2016, View Source [SID:1234511089]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The clinical data were collected, utilising Medigene’s DC vaccine technology in part, in an ongoing clinical phase I/II study on dendritic cell (DC) vaccines for the treatment of prostate cancer at the Department of Cellular Therapy at the Oslo University Hospital, Norway, under the responsibility of Prof. Gunnar Kvalheim. The poster presented was entitled "Clinical results of a Phase I/II trial of adjuvant therapeutic vaccination in high risk resected prostate cancer patients using autologous dendritic cells loaded with mRNA from primary prostate cancer tissue, hTERT and survivin".

More than 50% of high risk prostate cancer patients will develop an early biochemical relapse, with no curative therapy presently available. Therefore, Prof. Gunnar Kvalheim and his team have chosen this patient population for their ongoing Phase I/II dendritic cell (DC) vaccine study. Dendritic cells from each of the 20 enrolled patients were differentiated from enriched monocytes and matured with one of two different maturation cocktails. The DCs were then transfected with mRNA from primary prostate cancer tissue, hTERT and Survivin and then frozen and stored until use. Based on encouraging clinical results with a new type of DCs in patients with different types of tumours treated in a compassionate use[1] programme, the DC vaccine protocol was changed to the use of new generation DCs. The last five of 20 treated patients received DCs that were matured with a new TLR7/8-agonist maturation cocktail developed by Medigene. Three of 15 patients given DC vaccines derived with the old (standard) maturation cocktail have experienced a biochemical relapse (raised levels of prostate-specific antigen, PSA) during the vaccination period of 3 years. None of the patients given the new type of DC vaccines has so far experienced a rise in PSA levels.

Prof. Gunnar Kvalheim, Head of Department of Cellular Therapy, Oslo University Hospital concluded on the results: "To our knowledge this is the first adjuvant DC vaccine study in high risk prostate cancer and we conclude that the study is feasible, safe and utmost promising."

Prof. Dolores J. Schendel, CEO/CSO of Medigene AG added: "We feel very encouraged by these preliminary data. The advanced method of making DC vaccines is identical with the method Medigene is also using in its own ongoing DC vaccine study in acute myeloid leukaemia."

More detailed information on the presented data can be found under the following link: View Source;sKey=ac456e79-efd5-416e-a7de-67382c67723a&cKey=2ab5cd11-b3d8-40a8-8087-b0c57f2e8034&mKey=1d10d749-4b6a-4ab3-bcd4-f80fb1922267

The Oslo University Hospital has an agreement with Medigene for use of Medigene`s new generation DC vaccines for their ongoing academic clinical studies.

About Medigene’s DC vaccines: The platform for the development of antigen-tailored DC vaccines is the most advanced platform of the highly innovative and complementary immunotherapy platforms of Medigene Immunotherapies. Currently, Medigene evaluates its DC vaccines in a company-sponsored phase I/II clinical trial in acute myeloid leukaemia (AML). Further studies utilising Medigene’s DC vaccine technology include two ongoing clinical investigator-initiated trials (IITs): a clinical phase I/II trial for treating acute myeloid leukaemia (AML) at Ludwig Maximilians University Hospital Grosshadern, Munich, and a clinical phase II trial of a treatment for prostate cancer at Oslo University Hospital. Moreover, compassionate use patients are treated with DC vaccines at the Department of Cellular Therapy at Oslo University Hospital.

Dendritic cells (DCs) are the most potent antigen presenting cells of our immune system. Their task is to take up, process and present antigens on their cell surface, which enables them to activate antigen-specific T cells for maturation and proliferation. This way T cells can recognise and eliminate antigen-bearing tumour cells. Dendritic cells can also induce natural killer cells (NK cells) to attack tumour cells. The team of Medigene Immunotherapies GmbH’s scientists has developed new, fast and efficient methods for generating dendritic cells ex-vivo, which have relevant characteristics to activate both T cells and NK cells. The DC vaccines are developed from autologous (patient-derived) precursor cells, isolated from the patient’s blood, and can be loaded with tumour-specific antigens to treat different types of cancer. Medigene’s DC vaccines are in development for the treatment of minimal residual disease or use in combination therapies.

RG7876 is a fully human (IgG2) agonistic antibody against CD40 (Company Pipeline, Hoffmann-La Roche , APR 19, 2016, View Source [SID:1234512462]). The antibody induces T cell-driven tumor killing by activation of CD40 on antigen-presenting cells which in turn prime T cells to attack the tumor. The antibody is being developed in combination with other immunotherapies and is currently being tested in combination with atezolizumab (anti-PD-L1, RG7446).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

On April 19, 2016 SignalRx Pharmaceuticals Inc., focused on developing more effective oncology drugs through molecular design imparting multiple target-selected inhibition, reported the presentation of scientific data on the company’s dual small-molecule PI3K/BRD4 inhibitor program in oncology (Press release, SignalRx, APR 19, 2016, http://www.ireachcontent.com/news-releases/signalrx-presents-at-aacr-annual-meeting-on-first-in-class-dual-pi3kbrd4-inhibitors-for-treating-cancer-576189881.html [SID1234527327]). The presentation by Dr. Donald L. Durden, MD, PhD, senior scientific advisor for SignalRx, was made at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, LA.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The presentation highlighted advancements in the development of SF2523, SF2535 and SF2558HA, all single small molecules that inhibit both PI3 kinase (PI3K) and the new epigenetic cancer target BRD4. Key breakthroughs are:

New crystal structures obtained for SF2523, SF2535 and SF2558HA with BRD4 protein providing insights on key dual inhibitor binding interactions.
First-time proof of MYC inhibition by enhancing MYC degradation via PI3K inhibition AND blocking MYC production via MYC transcription inhibition (BRD4 inhibition).
SF2523 exhibits desired in vivo anti-tumor effects with no toxicity in several mouse cancer models.
Inhibition of PI3K-gamma and delta isoforms by SF2523 function as checkpoint inhibitors and enhance immune-therapeutics.
BRD4 inhibition blocks tumor-specific super-enhancers activating the innate and adaptive immune response providing a novel strategy to treat cancer.
The company also demonstrated that SF2523 is safer to normal cells over the combination of single PI3K and BRD4 inhibitors making SF2523 an attractive anti-cancer candidate that can potentially overcome traditional toxicity issues associated with most combinations of oncology drugs.

SignalRx is also announcing that it is seeking a partner to accelerate the development of these novel small molecules into first-in-man clinical trials based on the promising profile of its PI3K/BRD4 inhibitors shown so far. Since these are single molecules with a single PK/PD and toxicity profile, there is a great opportunity to develop them as single therapeutics and streamline their development in combination therapies focused on companion diagnostics built around synthetic lethality discoveries in human cancers, e.g., kinome adaptation mediated by BRD4.

On April 19, 2016 Advaxis, Inc. (NASDAQ:ADXS), a clinical-stage biotechnology company developing cancer immunotherapies, hosted a Research Reception on Monday, April 18, 2016 at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, Louisiana (Press release, Advaxis, APR 19, 2016, View Source [SID:1234511045]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The Research Reception featured Rosemarie Krupar, M.D., of Baylor College of Medicine, presenting "Immunogenicity of Axalimogene Filolisbac in Head and Neck Cancer," a review of the late-breaking poster presentation (Abstract #LB-095). The phase 2 trial leveraged a 5-6 week window between diagnosis and trans-oral robotic surgery, administering two doses of treatment with Advaxis’ lead immunotherapy candidate, axalimogene filolisbac (AXAL), two weeks apart to eight patients with late-stage HPV-associated oropharyngeal cancer (HPVOPC). The study observed changes to the tumor immune microenvironment (TME), including cytotoxic T cell infiltration into the post-resection tumor, increased immune activation, a reduction of regulatory T cells, infiltration of cytotoxic T cells, and increased expression of inflammatory activation markers, suggesting that AXAL has the potential to cause positive immunologic responses for patients with HPV+ head and neck cancers.

Nicola Mason, Ph.D., BVetMed, Assistant Professor of Medicine at the University of Pennsylvania, presented "Immune Therapy with ADXS31-164 Prevents Metastatic Disease and Prolongs Overall Survival in Spontaneous Canine Osteosarcoma." In her presentation, Dr. Mason reviewed her experiences with ADXS31-164 in dogs with spontaneous osteosarcoma. In two separate studies, repeat administrations of up to 3.3 x 109 CFUs were well tolerated with transient low-grade side effects. Immune responses to HER2/neu were detected within 6 months in 15 of 18 dogs with minimal residual disease. In these dogs, metastatic disease was delayed or prevented. Radiographic progression of primary osteosarcoma lesions was prevented in a subset of dogs who were treated after palliative radiotherapy. Treated animals had tumor-specific T-cell responses in the tumor site and reduced numbers of Tregs and MDSCs in the tumor microenvironment.

Robert Petit, Ph.D., Chief Scientific Officer and EVP of Advaxis, presented "Effect of Advaxis’ Lm Immunotherapy on the STING Pathway." In his presentation, Dr. Petit discussed the potent triggering of STING (STimulator of Interferon Genes) built into every Advaxis vector and triggered by DNA, including 80-100 copies of DNA plasmids, that code for tumor target antigens. Advaxis Lm-LLO vectors escape into the cytosol of antigen-presenting cells (APCs) where the human STING receptor is triggered preferentially by DNA. Triggering STING results in the secretion of type I interferons and pro-inflammatory cytokines and has been linked to immune sensing of tumors, clinical responses to melanoma, and inflammation of the tumor microenvironment. Experiments in STING knock-out models demonstrate that triggering of STING contributes to part, but not all, of the ability of ADXS11-001 to control HPV+ tumors.

The Research Reception concluded with a final presentation by Robert Petit, "Cancer Neoepitope Immunotherapy: An Update on ADXS-NEO." Advaxis’ Lm Technology is being used to develop novel ADXS-NEO immunotherapies personalized to the specific and unique neo-epitopes found in an individual patient’s tumor. ADXS-NEO is projected to be available for patients in 6-8 weeks from biopsy to infusion. This platform is able to decrease Tregs and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment and can be used to combine tumor driver targets along with neoepitope targets. Data was presented from a mouse model, demonstrating the ability of ADXS-NEO to express multiple tumor neoantigens which were capable of controlling tumor growth. The data developed in this model confirms that ADXS-NEO can be successfully executed and administered and has the ability to control the tumors that were the source of the neoantigens. Advaxis is currently developing an Investigational New Drug Application for ADXS-NEO and is planning for upcoming clinical trials.

Advaxis is actively building collaborations in academia and industry to drive ADXS-NEO forward, including the MINE (My Immunotherapy Neo-Epitopes) collaboration with Memorial Sloan Kettering Cancer Center, focusing on preclinical and clinical development of neoepitope-based Lm treatments. The goal of MINE is to develop neo-epitope immunotherapies based on the specific and unique neo-epitopes found in an individual patient’s tumor. Advaxis is currently partnering with SGI-DNA for DNA synthesis and bioinformatics.

To view the presentation slides and to listen to the presenters, visit www.advaxis.com.

About Axalimogene Filolisbac

Axalimogene filolisbac (AXAL) is Advaxis’ lead Lm Technology immunotherapy candidate for the treatment of HPV-associated cancers and is in clinical trials for three potential indications: invasive cervical cancer, head and neck cancer, and anal cancer. In a completed randomized Phase 2 study in recurrent/refractory cervical cancer, axalimogene filolisbac showed apparent prolonged survival, objective tumor responses, and a manageable safety profile alone or in combination with chemotherapy, supporting further development of the company’s Lm Technology. Axalimogene filolisbac has Orphan Drug Designation in the U.S. for the treatment of anal cancer.

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]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

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.