On March 21, 2016 Oncolytics Biotech Inc. (TSX: ONC) (OTCQX: ONCYF) (FRA: ONY) ("Oncolytics" or the "Company") reported an update for a randomized Phase II clinical trial of its lead product, REOLYSIN, in combination with paclitaxel in patients with ovarian cancer (GOG-0186H) (Filing, 6-K, Oncolytics Biotech, MAR 21, 2016, View Source [SID:1234509813]).

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The study is being sponsored by the US National Cancer Institute ("NCI"). The update includes data from a Gynecologic Oncology Group (GOG) study summary report, and follows a presentation made by the principal investigator regarding the study at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer, which runs from March 19-22 in San Diego, CA.

Update Highlights

Response Using CA-125 Measurements by Treatment Among all Patients

CA-125 Response Treatment
Paclitaxel Paclitaxel+REOLYSIN Total
Full Response 1 (1.85%) 5 (9.26%) 6
Partial Response 9 (16.67%) 7 (12.96%) 16
Stable Disease 3 (5.56%) 12 (22.22%) 15
Progressive Disease 0 (0.00%) 2 (3.70%) 2
Indeterminate 16 (29.63%) 13 (24.07%) 29
Not Evaluable 25 (46.30%) 15 (27.78%) 40
Total 54 54 108
Source: GOG Study Summary Report

The Company performed an intent-to-treat analysis of tumour response, as assessed by CA-125 antigen levels, which showed statistically significantly higher full response rates and stable disease or better rates in the test arm versus the control arm. The rate of full responses in the test arm was 9.26%, compared with 1.85% in the control arm (p = 0.0196). The rate of stable disease or better in the test arm was 44.44%, compared with 24.08% in the control arm (p = 0.0096). The response rates were defined using a modified Rustin’s criteria. CA-125 levels are commonly used in clinical practice to assess response in ovarian cancer patients.

Response rates as measured by RECIST were performed on patients with measurable disease (n = 68 (of 108)). The proportion responding on the test arm was 17% whereas the proportion responding on the control arm was 20%.

An analysis of progression free survival ("PFS") stratified by measurable disease and platinum-free interval (test arm: n = 54, 43 events (progressions), and control arm: n = 54, 48 events) was performed and demonstrated a median PFS of 4.4 months for the test arm, and 4.3 months for the control arm.

An interim analysis of overall survival ("OS") (test arm: n = 54, 32 events (deaths), and control arm: n = 54, 32 events) was performed and demonstrated a median OS of 12.9 months for the test arm, and 15.0 months for the control arm. The OS was an interim analysis, as 44 (41%) patients out of a total of 108 patients were alive at the time of analysis. Given the number of patients still alive on the test and control arms with current survival less than the median, final median OS results are expected to change.

"This is one of a total of six randomized Phase II studies with REOLYSIN that were designed and sponsored by third parties. The results from these studies will determine clinical targets, endpoints, and study designs for follow on and registration studies conducted by Oncolytics. In the case of this ovarian cancer study, we are pleased that REOLYSIN has demonstrated a statistically significant reduction in tumour burden in ovarian cancer patients as measured by CA-125 levels," said Dr. Brad Thompson, President and CEO of Oncolytics. "This adds to our results in other indications that have shown improvement in tumour responses. In order to further our understanding of how REOLYSIN interacts with the immune system, we hope, in conjunction with the principal investigator, to analyze the PD-1 and CD8+ T lymphocyte levels of patients on entry and correlate these with overall survival and progression free survival."

Study Design Summary
The study (GOG-0186H) is a randomized Phase 2 clinical trial of paclitaxel versus paclitaxel plus REOLYSIN in patients with persistent or recurrent, ovarian, fallopian tube or primary peritoneal cancer. Patients received paclitaxel on days 1, 8 and 15 of each 28-day treatment cycle, with either REOLYSIN (test arm) or placebo (control arm) administered on days 1 through 5. One hundred and eight patients were randomized (1:1, 54 patients in the control arm, 54 patients in the test arm). The NCI study did not stratify on entry according to PD-L1 levels or infiltrating CD8+ T lymphocyte levels, nor were either of those levels measured post-treatment. However, pre-treatment tumour biopsies were taken from the majority of patients. The primary objectives are PFS and toxicity. The secondary objectives are median overall OS by treatment group, median PFS by treatment group, and tumour response as measured by RECIST criteria and CA-125 antigen levels. The study was sponsored by the US National Cancer Institute and conducted by the former GOG, now incorporated into NRG Oncology.

Analysis of the Relationship between Ovarian Cancer Patients’ Immune Status upon Study Entry and Survival
In order to further understand the effects of a patient’s immune status prior to treatment with REOLYSIN on PFS and OS, the principal investigator and the Company are working to quantify the levels of PD-L1 and CD8+ T lymphocytes in tumours at the time of enrolment. The Company wishes to conduct this analysis to be able to determine what component of PFS and OS is attributable to PD-L1 and CD8+ T lymphocyte levels on study entry, and what is attributable to REOLYSIN therapy.

The basis for this analysis is Hamanishi et al. (2007) (Programmed cell death 1 ligand 1 and tumour-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. PNAS 104(9):3360-3365), which found that the overall survival rates and progression free survival rates for ovarian cancer patients with high PD-L1 expression on entry were statistically significantly worse than those of patients with low PD-L1 expression on entry. They also noted that the overall survival rates and progression free survival rates for ovarian cancer patients with high intraepithelial CD8+ T lymphocyte counts on entry were statistically significantly better than those of patients with low CD8+ T lymphocyte counts.

On March 21, 2016 Genmab A/S (Nasdaq Copenhagen: GEN) reported that daratumumab will be investigated in early stage clinical studies (NCT02431208) in combination with atezolizumab (anti-PD-L1 antibody), in a solid tumor and multiple myeloma (Press release, Genmab, MAR 21, 2016, View Source [SID:1234509778]).

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The studies will be conducted under a clinical trial collaboration agreement between Genmab’s licensing partner for daratumumab, Janssen Biotech, Inc., and Genentech, a member of the Roche Group. Atezolizumab is an investigational monoclonal antibody designed to bind to a protein called PD-L1, which is expressed on tumor cells and tumor-infiltrating immune cells. Janssen will conduct a Phase Ib study of daratumumab in combination with atezolizumab to treat a solid tumor. Genentech will amend an ongoing Phase Ib study to assess atezolizumab in combination with daratumumab, with daratumumab and lenalidomide, and with daratumumab and pomalidomide in relapsed/refractory multiple myeloma (NCT02431208). The studies are expected to start enrolling patients later this year and information about the studies will be posted on www.clinicaltrials.gov.

"We are very excited about the start of the first study to investigate daratumumab in a solid tumor, potentially expanding its clinical utility beyond hematological cancers. We are equally excited about testing daratumumab in combination with an immune checkpoint inhibitor, such as Roche’s anti-PDL1, atezolizumab, in multiple myeloma. Both studies mark a key next step in the expansive clinical development of daratumumab in the hope to find even more effective treatment options for cancer patients," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

About DARZALEX (daratumumab)
DARZALEX (daratumumab) injection for intravenous infusion is indicated in the United States for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.1 DARZALEX is the first monoclonal antibody (mAb) to receive U.S. Food and Drug Administration (FDA) approval to treat multiple myeloma. For more information, visit www.DARZALEX.com.

Daratumumab is a human IgG1k monoclonal antibody (mAb) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. It is believed to induce rapid tumor cell death through programmed cell death, or apoptosis,1,2 and multiple immune-mediated mechanisms, including complement-dependent cytotoxicity,1,2 antibody-dependent cellular phagocytosis3,4 and antibody-dependent cellular cytotoxicity.1,2 In addition, daratumumab therapy results in a reduction of immune-suppressive myeloid derived suppressor cells (MDSCs) and a subset of regulatory T cells (Tregs) and B cells (Bregs), all of which express CD38. These reductions in MDSCs, Tregs, and Bregs were paralleled by increases in CD4+ and CD8+ T cell numbers in both the peripheral blood and bone marrow.1

Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license to develop, manufacture and commercialize daratumumab from Genmab. Five Phase III clinical studies with daratumumab in relapsed and frontline settings are currently ongoing, and additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases on which CD38 is expressed, such as smoldering myeloma and non-Hodgkin’s lymphoma.

On March 21, 2016 Onconova Therapeutics, Inc. (NASDAQ:ONTX), a clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer, reported the enrollment of the first European patient in Salzburg, Austria for the Phase 3 INSPIRE trial for IV rigosertib as a treatment for higher-risk myelodysplastic syndromes (HR-MDS) following failure of hypomethylating agent (HMA) therapy (Press release, Onconova, MAR 21, 2016, View Source [SID:1234509771]). The first patient in this global trial was enrolled at the MD Anderson Cancer Center in December 2015.

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"We are excited to expand enrollment for this important trial to Europe," said Dr. Steven Fruchtman, Chief Medical Officer of Onconova. "The recent publication in Lancet Oncology of results of the ONTIME study provides support for the present trial and highlights the urgent unmet medical needs of patients following failure of front-line treatment with HMAs. There are no approved therapies for HR-MDS patients whose disease has failed treatment with an HMA, and the clinical community is looking for novel drugs to address this treatment gap."

The INSPIRE trial is a multi-center, randomized controlled Phase 3 study to assess the efficacy and safety of IV rigosertib in HR-MDS patients who had progressed on, or failed to respond to, or relapsed, following previous treatment with HMAs. The trial will enroll approximately 225 patients randomized at a 2:1 ratio into two treatment arms: IV rigosertib plus Best Supportive Care versus Physician’s Choice plus Best Supportive Care. The primary endpoint of INSPIRE is overall survival and an interim analysis is anticipated.

The INSPIRE trial is actively screening patients at multiple sites in the United States and Europe, and additional sites are being initiated globally. Onconova’s collaboration partner in Japan and Korea, SymBio Pharmaceuticals, Ltd., intends to begin enrolling patients in Japan shortly.

About INSPIRE

The INternational Study of Phase III IV RigosErtib, or INSPIRE, is based on guidance received from the U.S. Food and Drug Administration and European Medicines Agency and derives from the findings of the ONTIME Phase 3 trial. INSPIRE is a multi-center, randomized controlled study to assess the efficacy and safety of IV rigosertib in HR-MDS patients who had progressed on, failed to respond to, or relapsed after previous treatment with an HMA within the first nine months of initiation of HMA treatment. This time frame optimizes the opportunity to respond to treatment with an HMA prior to declaring treatment failure, as per NCCN Guidelines.1 The trial will enroll approximately 225 patients randomized at a 2:1 ratio into two treatment arms: IV rigosertib plus Best Supportive Care versus Physician’s Choice plus Best Supportive Care. The primary endpoint of INSPIRE is overall survival and an interim analysis is anticipated. Full details of the INSPIRE trial, such as inclusion and exclusion criteria, as well as secondary endpoints, can be found on clinicaltrials.gov (NCT02562443).

About Rigosertib

Rigosertib is a small molecule inhibitor of cellular signaling and acts as a Ras mimetic. These effects of rigosertib appear to be mediated by direct binding of the compound to the Ras-binding domain (RBD) found in many Ras effector proteins, including the Raf kinases and PI3K. The therapeutic focus for rigosertib is myelodysplastic syndromes (MDS), a group of bone marrow disorders characterized by ineffective formation of blood cells that often converts into acute myeloid leukemia (AML). Clinical trials for rigosertib are being conducted at leading institutions in the United States, Europe, and the Asia-Pacific region. Rigosertib is protected by issued patents (earliest expiry in 2026) and has been awarded Orphan Designation for MDS in the United States, Europe and Japan.

On March 21, 2016 MabVax Therapeutics Holdings, Inc. (OTCQB: MBVX), a clinical-stage oncology drug development company, reported the initiation of a phase I clinical trial of HuMab-5B1 for patients with locally advanced or metastatic adenocarcinoma of the pancreas (PDAC) or other CA19-9 positive malignancies (Press release, MabVax, MAR 21, 2016, View Source [SID:1234509768]).

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The CA19-9 target is expressed on more than 90% of pancreatic cancers and is a validated biomarker for the disease. The Company filed an Investigational New Drug (IND) application for this product on November 30, 2015 and received U.S. Food and Drug Administration (FDA) authorization to proceed with the study on December 24, 2015.

The study is a phase I, open-label, multi-center, dose-escalation clinical trial. The primary objectives are to determine the safety, maximum tolerated dose (MTD), and the pharmacokinetics (PK) of HuMab-5B1. The phase I trial will also evaluate the tumor response rate based on RECIST 1.1 and the duration of response of HuMab-5B1 as a single agent or in combination with a standard of care chemotherapy regimen. The study will enroll up to approximately 60 patients at multiple centers in the United States.

On January 28, 2016 MabVax received authorization from FDA to proceed with a second phase I clinical trial with [Zr-89]-HuMab-5B1 as a new generation PET imaging agent in patients with pancreatic cancer. [Zr-89]-HuMab-5B1 combines a well-established PET imaging radiolabel [Zr-89] with the targeting specificity of the HuMab-5B1 antibody. Preclinical xenograft animal models demonstrated high image resolution of tumors, making [Zr-89]-HuMab-5B1 attractive as a potential diagnostic agent for use with the HuMab-5B1 therapeutic product. Some of the data was previously published in the Journal of Nuclear Medicine, Bioconjugate Chemistry, and the Proceedings of the National Academy of Sciences.

David Hansen, President and CEO, said, "Data generated in the early portions of these two Phase I trials could demonstrate important initial safety, PK and targeting specificity data of the antibody and signal the potential utility of the HuMab-5B1 antibody in the diagnosis and treatment of patients with this devastating disease. We anticipate reporting interim-study data from both trials in mid-year 2016. Additionally, we are excited about the potential applicability of our dual-product development approach in other cancers with HuMab-5B1, as well as with follow-on antibodies under development at MabVax."

About HuMab-5B1:

MabVax’s HuMab-5B1 antibody is fully human and was discovered from the immune response of cancer patients vaccinated with an antigen-specific vaccine during a Phase I trial at Memorial Sloan Kettering Cancer Center. In preclinical research, the 5B1 antibody has demonstrated high specificity and affinity, and has shown potent cancer cell killing capacity and efficacy in animal models of pancreatic, colon and small cell lung cancers. The antigen the antibody targets is expressed on more than 90% of pancreatic cancers making the antibody potentially broadly applicable to most patients suffering from this type of cancer.