On August 27, 2015 Onconova Therapeutics, Inc. (NASDAQ:ONTX), a clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer, reported that it has filed Clinical Trial Applications (CTAs) with the United Kingdom, German and Austrian regulatory agencies for IV rigosertib as a treatment in higher-risk myelodysplastic syndromes (HR-MDS) patients after failure of a hypomethylating agent (HMA) therapy (Press release, Onconova, AUG 27, 2015, View Source [SID:1234507348]). Upon clearance of the CTAs and the recently updated U.S. IND submission, Onconova intends to initiate a single randomized controlled pivotal Phase 3 trial, designated 04-30 or "INSPIRE", in patients with HR-MDS whose prior therapy with an HMA has failed. Additional filings in other European countries and in Japan are expected to follow shortly.

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"These filings follow our recent updated IND submission to the U.S. FDA," said Ramesh Kumar, Ph.D., President and CEO of Onconova. "Together, acceptance of these regulatory filings will allow Onconova to initiate a single global pivotal trial for IV rigosertib in HR-MDS. We anticipate enrollment in the new Phase 3 study will begin in the second half of 2015."

Per a development and licensing agreement with Baxalta (formerly the BioScience business of Baxter International Inc.), which grants Baxalta commercialization rights to rigosertib in the European Union and other countries in Europe, the company has elected to and Baxalta will fulfill its obligation under the agreement to pay for half of the costs for the trial of rigosertib in HR-MDS up to a specified cap.

Onconova has partnered with SymBio Pharmaceuticals, Ltd. for clinical development of rigosertib in Japan and Korea. SymBio plans to participate in the global Phase 3 trial by enrolling patients in Japan, which should accelerate the timing of regulatory filings in Japan and Korea.

"We completed a Phase 1 trial for oral rigosertib (SyB C-1101) in relapsed or refractory MDS last June and expect to complete the ongoing Phase 1 trial for IV rigosertib (SyB L-1101) in the treatment of relapsed or refractory HR-MDS patients this October. After consulting with the PMDA (Japanese Pharmaceuticals and Medical Devices Agency), it is our plan to participate in the global 04-30 trial, and to begin enrolling patients in Japan for this unmet medical need in HR-MDS," added Mr. Fuminori Yoshida, President and CEO of SymBio.

"Onconova is appreciative of the continued collaborations with Baxalta and SymBio to advance the INSPIRE Trial," continued Dr. Kumar. "We look forward to working closely with our partners in the development of IV rigosertib in HR-MDS in Europe and in Japan."

The INSPIRE Trial will enroll HR-MDS patients who had progressed on, or failed to respond to, previous treatment with an HMA. The primary endpoint of this study is overall survival, and an interim analysis is anticipated. This randomized trial of approximately 225 patients will be conducted at about 100 sites globally. Enrollment in this trial is expected to begin later this year.

On August 27, 2015 Genmab A/S (OMX: GEN) reported the New England Journal of Medicine (NEJM) has published the full data set from the initial Phase I/II study with daratumumab monotherapy treating patients with relapsed or refractory multiple myeloma (Press release, Genmab, AUG 27, 2015, View Source [SID:1234507347]).

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Patients that received 16 mg/kg in part 2 of the study had a median of 4 prior lines of therapy and 64% of these patients were refractory to both proteasome inhibitors (PIs) and immunomodulatory (IMiD) drugs, which are current standard of care treatments for multiple myeloma. The data showed a 36% response rate in the 16 mg/kg group in part 2 of the study, with responses that deepened over time. Sixty five percent of patients in this group that responded to treatment were progression-free twelve months following the start of treatment. For all patients in part 2, pneumonia and thrombocytopenia were the most common grade 3/4 adverse events (AEs; ≥5%). Infusion-related reactions were mild with no dose-dependent adverse events. In part 1 of the study, no maximum tolerated dose was identified up to 24 mg/kg.

Following this study, 16 mg/kg was chosen as the dose to be used in future daratumumab clinical studies. Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license to develop, manufacture and commercialize daratumumab from Genmab.

"Patients who have relapsed or refractory multiple myeloma currently have very limited treatment options. The results from this first-in-human study of daratumumab, presented in full in The NEJM, show an impressive response rate and duration of response, particularly when you consider that patients in the study had received a large number of prior treatments," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

Data from this study has been included in the Biologics License Application (BLA) submitted by Janssen to the U.S. Food and Drug Administration for daratumumab as a treatment for patients with multiple myeloma who have received at least three prior lines of therapy including both a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD) or who are double refractory to a PI and an IMiD. The BLA submission was completed on July 9th 2015.

About the study
This two-part, Phase I/II, open-label study enrolled 32 patients in part 1, and 72 patients in part 2, 42 of which were in the 16 mg/kg dose group. Part 1 was a dose-escalation study with patients receiving weekly doses of daratumumab between 0.005 and 24 mg/kg of daratumumab.

In part 2, 8 mg/kg and 16 mg/kg daratumumab were administered with different schedules. The primary endpoint of the study was safety. Secondary endpoints were pharmacokinetics, objective response according to International Myeloma Working Group (IMWG) uniform response criteria for myeloma, relative reductions in M-protein and free light chains, time to progression, response duration, progression-free and overall survival.

About multiple myeloma
Multiple myeloma is an incurable blood cancer that starts in the bone marrow and is characterized by an excess proliferation of plasma cells.1 Multiple myeloma is the third most common blood cancer in the U.S., after leukemia and lymphoma.2 Approximately 26,850 new patients will be diagnosed with multiple myeloma and approximately 11,240 people will die from the disease in the U.S. in 2015.3 Globally, it is estimated that 124,225 people will be diagnosed and 87,084 will die from the disease in 2015.4 While some patients with multiple myeloma have no symptoms at all, most patients are diagnosed due to symptoms which can include bone problems, low blood counts, calcium elevation, kidney problems or infections.5 Patients who relapse after treatment with standard therapies, including PIs or IMiDs, have poor prognoses and few treatment options.6

About daratumumab
Daratumumab is an investigational 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 induces rapid tumor cell death through multiple immune-mediated mechanisms7, including complement-dependent cytotoxicity7, antibody-dependent cellular phagocytosis8 and antibody-dependent cellular cytotoxicity7, as well as via induction of apoptosis9 . Five Phase III clinical studies with daratumumab in relapsed and frontline settings are currently ongoing. 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 lymphoma. Daratumumab has been granted Breakthrough Therapy Designation from the US FDA.

On August 27, 2015 Threshold Pharmaceuticals, Inc. (NASDAQ: THLD) reported that the company has initiated a Phase 2 clinical trial of tarloxotinib bromide, or "tarloxotinib" (TH-4000), for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) or skin (SCCS) (Press release, Threshold Pharmaceuticals, AUG 27, 2015, View Source [SID:1234507345]). Tarloxotinib is Threshold’s proprietary, hypoxia-activated, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor licensed from the University of Auckland, New Zealand.

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"New and effective treatment options are urgently needed for patients with squamous cell carcinomas," said Danny Rischin, M.D., Co-Director, Division of Cancer Medicine at Peter MacCallum Cancer Centre and Principal Investigator of the Phase 2 trial. "Tarloxotinib represents a novel treatment approach that may allow effective inhibition of EGFR signaling in the tumor microenvironment with relative sparing of normal tissues."

Elevated expression of wild-type EGFR and its stimulatory ligands occurs in the majority of squamous cell carcinomas. Aberrant EGFR signaling can lead to uncontrolled tumor cell growth. One mechanism likely to be involved is hypoxia, or low-oxygen conditions, which is a prevalent feature of solid tumors including squamous cell carcinomas. In preclinical studies hypoxia has been shown to increase EGFR signaling by upregulation, stabilization, and hyperphosphorylation of EGFR, through multiple mechanisms.1-6 Gene expression-based profiling of clinical samples supports the observations of a strong causal link between elevation in the tumor EGFR pathway and hypoxia signatures.7

"We are pleased that tarloxotinib is actively being investigated in two monotherapy Phase 2 proof-of-concept trials, the other being in patients with non-small cell lung cancer," said Tillman Pearce, M.D., Chief Medical Officer of Threshold. "These clinical settings, in which EGFR is already a validated therapeutic target, represent opportune development paths for tarloxotinib, which is designed to exploit the reported overlap between elevated EGFR signaling and tumor hypoxia. By selectively targeting the hypoxic tumor microenvironment, tarloxotinib has the potential to increase the therapeutic index and overcome limitations of current EGFR inhibitor therapy, which may lead to improved outcomes for patients with these EGFR-dependent cancers."

About the Phase 2 Clinical Trial
The Phase 2 clinical trial is a single-arm, open label study that will enroll up to 68 patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) or skin (SCCS). Eligible patients will receive tarloxotinib (150 mg/m2 by intravenous infusion) on Days 1, 8, 15 and 22 of a 28-day cycle. Prior anti-EGFR antibody therapy is permitted. RECIST response rate is the primary endpoint. Secondary endpoints include duration of response, progression-free survival, overall survival, safety, tolerability and pharmacokinetics. In addition to other target-specific biomarkers, hypoxia status will be measured at baseline using Threshold’s proprietary PET imaging agent [18F]-HX4. The study is planned to be opened at 10 sites in the U.S. and Australia.

About Squamous Cell Carcinoma of the Head and Neck (SCCHN)
Most head and neck cancers, which include cancers of the larynx (voice box), throat, lips, mouth, nose, and salivary glands, begin in the squamous cells that line the moist surfaces inside the head and neck, and are therefore referred to as squamous cell carcinomas of the head and neck (SCCHN). SCCHN is diagnosed in approximately 59,000 people in the U.S. annually and is responsible for some 12,000 deaths.8 Historically, tobacco and alcohol use have been the greatest risk factors; more recently, infection with the human papilloma virus (HPV) has been recognized as a risk factor with a more favorable prognosis. For patients with advanced disease who have progressed on the standard regimen of platinum-based chemotherapy with or without cetuximab anti-EGFR therapy, further therapy with chemotherapy or cetuximab monotherapy is the standard of care, but response rates are about ten percent and disease progression occurs within two to three months.9

About Squamous Cell Carcinoma of the Skin (SCCS)
Non-melanoma skin cancers typically resulting from chronic sun exposure or other sources of ultraviolet rays are the most common types of cancer. Twenty percent of these skin cancers originate from squamous cells normally present in the outer layers of the skin (SCCS); five percent of SCCS will become locally advanced, recur, or metastasize. In the U.S., approximately 2,000 deaths per year are attributed to SCCS.10 As with SCCHN, SCCS is associated with EGFR overexpression and appear to be responsive to EGFR inhibitor therapy.11

About Tarloxotinib Bromide
Tarloxotinib bromide, or "tarloxotinib", (TH-4000) is a hypoxia-activated, covalent (irreversible) epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) that targets the activating mutations of EGFR (L858R and Del19) and wild-type, or "normal", EGFR. Tarloxotinib is designed as a prodrug to selectively release its EGFR TKI upon encountering severe tumor hypoxia, a feature of many solid tumors. Accordingly, tarloxotinib has the potential to effectively shut down aberrant wild-type and mutant EGFR signaling in a tumor-selective manner, thus potentially avoiding or reducing the toxic side effects associated with currently available EGFR TKIs and systemic wild-type EGFR inhibition. In addition to this second trial in squamous cell carcinomas, tarloxotinib is currently being evaluated in a Phase 2 proof-of-concept trial for the treatment of patients with mutant EGFR-positive, T790M-negative advanced non-small cell lung cancer progressing on an EGFR TKI. Threshold licensed exclusive worldwide rights to tarloxotinib from the University of Auckland, New Zealand, in September 2014.