Oncoethix, the Swiss-based specialist in oncology drug development, reported that the first patient has been enrolled in an international, open-label, non-randomized, multicenter Phase 1b trial of OTX015 in advanced solid tumors (Press release OncoEthix, NOV 12, 2014, View Source [SID:1234501220]). The trial will be coordinated by Dr Lillian Siu, MD, of the Princess Margaret Hospital, Toronto, Canada, who is Professor of Medicine at the University of Toronto, and Director of the Phase 1 program.

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The trial seeks to enrol up to 98 patients across seven centers in five countries (Belgium, Canada, France, Spain and Switzerland), including the Institut Gustave-Roussy in Paris, where Professor Jean-Charles Soria is the Principal investigator. Three patients have already been enrolled. The trial aims to determine, in a first step, the suitability of five solid tumor indications under investigation (BRD-NUT Midline Carcinoma, Triple Negative Breast Cancer, Non-Small Cell Lung Cancer harbouring a rearrangement ALK gene/fusion protein or KRAS mutation, and Castrate-Resistant Prostate Cancer and Pancreatic Ductal Carcinoma) to be progressed into the Phase 2a part of the trial.

Dr Esteban Cvitkovic, MD, Founder and Chief Scientific Officer, Oncoethix, commented: "This multicenter Phase 1b trial is an important step for OTX015, as it will provide key safety and efficacy data in several solid tumor types, after having characterized its single agent safety and activity profile in the Acute Leukemias and Lymphomas in Phase 1 trial (OTX015_104). The solid tumor indications approach selected for OXT015 is based on compelling data from our own preclinical pharmacology program. We have also initiated a multicentric (France, Switzerland) Phase 2a trial in recurrent glioma."

OTX015 is a novel first-in-class synthetic small molecule inhibitor of BET bromodomain proteins 2/3/4. These proteins are considered potential cancer targets, as they play a pivotal role in regulating the transcription of growth-promoting and cell cycle regulators.

Coordinating investigator Dr Lillian Siu commented: "OTX015 is a promising drug that has shown outstanding early results in hematologic cancer studies and we are delighted to have commenced the solid tumor trial at the Princess Margaret Cancer Centre in Canada."

Bertrand Damour, Chief Executive Officer at Oncoethix, added "We believe that OTX015 has the potential to be an important new drug across a number of advanced solid tumors and the start of the Phase 1b is a key milestone for the Company. We are also ahead of schedule in our hematologic cancer program and will be releasing further data from this program at NCI/EORTC/AACR in November and the American Society of Hematology (ASH) (Free ASH Whitepaper) in December."

An analysis from Adam Feuerstein at TheStreetis skeptic on Oxigene’s positive Phase II ovarian cancer data (External Source FierceBiotech, OXiGENE, NOV 12, 2014, View Source;utm_source=internal [SID:1234500966]). A decision on using Avastin for ovarian cancer is looming, but hasn’t arrived yet, complicating any analysis of a combination drug study like this. Avastin, by the way, achieved a solid PFS but not a statistically significant overall survival benefit for ovarian cancer patients, which may not prevent its approval. If Avastin plus chemo becomes the standard of care in this area, then Oxigene will face some big challenges in designing a Phase III trial, notes Feuerstein. If the biotech decides to run a non-inferiority study, it will need a big and expensive patient population to examine. If it tries to beat Avastin/chemo, it faces a very tall order. And if Avastin is rejected, that makes Oxigene’s task even more difficult. Perhaps, suggests Feuerstein, the company should go a different route and try a combination with Votrient.

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On November 12, 2014 Clovis Oncology reported that the Phase 2 portion of the seamless Phase 2/3 TIGER-1 (Third-Generation Inhibitor of Mutant EGFR in Lung Cancer) study has commenced with the dosing of the first patient at a U.S. study site (Press release Clovis Oncology, NOV 12, 2014, View Source;p=RssLanding&cat=news&id=1989119 [SID:1234500959]). Rociletinib is the Company’s novel, oral, targeted covalent (irreversible) mutant-selective inhibitor of the epidermal growth factor receptor (EGFR) for the treatment of non-small cell lung cancer (NSCLC) in patients with initial activating EGFR mutations as well as the primary resistance mutation T790M.

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"I am pleased to lead the US trial of first-line rociletinib in patients with EGFR-mutant NSCLC," said Ross Camidge, MD, PhD, Associate Professor, Division of Medical Oncology, University of Colorado School of Medicine and the lead investigator for the TIGER-1 study in the United States. "The rociletinib clinical data observed to date in the second-line EGFR-mutant population after failure of drugs like erlotinib have been highly encouraging and consistent, really making the case to try this drug in these patients from the outset. The absence of side effects associated with wild-type EGFR inhibition from this drug is also likely to be welcomed by patients."

"It is exciting that less than five years after the initial TKI was confirmed as standard first-line treatment for EGFR-mutant NSCLC, we are ready to begin the first randomized study proving the role of a third-generation EGFR inhibitor in this population," said Tony Mok, Professor of Clinical Oncology, the Chinese University of Hong Kong, and the lead investigator for the TIGER-1 study in Asia. "Rociletinib is a very promising compound which targets both the activating mutations and the resistant exon 20 T790M mutation. It is our objective to prove a higher efficacy with rociletinib in the TIGER-1 study. With the high incidence of EGFR mutations in this region, I trust TIGER-1 will roar in Asia."

"Patients with EGFR-mutant lung cancer are hungry for a new treatment option that can extend progression-free survival beyond what is seen with the first-generation EGFR inhibitors available today, particularly an option without the rash that make current treatments difficult for many patients," said Bonnie J. Addario, founder of The Bonnie J. Addario Lung Cancer Foundation, one of the largest philanthropies (patient-founded, patient-focused, and patient-driven) devoted exclusively to eradicating Lung Cancer through research, early detection, education, and treatment. "The evident activity and clear lack of rash and other side effects associated with wild-type EGFR inhibition makes us very enthusiastic about the potential for this drug and this study. I believe the development of targeted therapies like rociletinib represents one of the most important scientific advances of this decade."

In pre-clinical testing, rociletinib demonstrated significant reductions in tumor volume in subcutaneous xenograft and genetically-engineered mouse models with each of the two activating mutations (exon 19 deletion, L858R mutation), collectively observed in approximately 85 percent of EGFR-mutant NSCLC patients. Consistent with rociletinib sparing wild-type EGFR, there was no reduction in body weight in the animals treated with rociletinib whereas body weight loss was observed in the animals treated with erlotinib or afatinib.

In approximately 60 percent of patients with EGFR-mutant NSCLC, acquired resistance to current EGFR TKIs is driven by a secondary T790M mutation in EGFR. In a front-line PC-9 (EGFRDel19) model rociletinib and erlotinib were compared over time to determine when resistance emerged. Resistant tumors emerged around day 30 in erlotinib-treated mice whereas no tumor regrowth was observed in mice treated up to 86 days with rociletinib.

On November 12, 2014 Advaxis reported that the Company has submitted an Investigational New Drug application (IND) to the United States Food and Drug Administration (FDA) to conduct a Phase 1/2 study of ADXS-HPV (ADXS11-001) alone or in combination with MedImmune’s investigational anti-PD-L1 immune checkpoint inhibitor, MEDI4736, for the treatment of advanced, recurrent or refractory human papillomavirus (HPV)-associated cervical cancer and HPV-associated head and neck cancer (Press release Advaxis, NOV 12, 2014, View Source [SID:1234500957]).

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This follows the press release issued in July 2014 announcing the clinical trial collaboration between Advaxis and MedImmune, the global biologics research and development arm of AstraZeneca.

ADXS-HPV is Advaxis’s lead Lm-LLO immunotherapy designed for the treatment of HPV-associated cancers. Preclinical evidence suggests that the combination of ADXS-HPV with a checkpoint inhibitor, such as MEDI4736, can enhance overall anti-tumour response.

Pending FDA’s acceptance of the IND submission, the proposed Phase 1/2 protocol is designed to evaluate the safety and efficacy of ADXS-HPV as monotherapy and in combination with MEDI4736. Specifically, the Phase 1 part of the trial is expected to establish a recommended dose regimen of ADXS-HPV with MEDI4736, and the Phase 2 portion will assess the safety and efficacy of the combination. The study is planned to begin in early 2015.

"The filing of our ADXS-HPV + MEDI4736 IND for HPV associated cervical and head and neck cancers is another significant advance in Advaxis’s clinical strategy as it adds to our rapidly growing pipeline and positions Advaxis as a clear leader in the immunotherapy-checkpoint inhibitor combination therapy market," commented Daniel J. O’Connor, President and Chief Executive Officer of Advaxis. "Additionally, the filing of this IND and the recently announced filing of the ADXS-PSA + KEYTRUDA (pembrolizumab) IND demonstrate Advaxis’s ability to rapidly transition partnering agreements to clinical programs. Since announcing our agreements with MedImmune and Merck in July and August, respectively, we have worked diligently with both companies’ research teams to develop IND filings involving each company’s checkpoint inhibitor that, upon acceptance by FDA, should enable us to initiate two Phase 1/2 trials in early 2015."

Within 30 calendar days of the IND filing, FDA will notify Advaxis of any questions it has or protocol revisions it requests which may delay this timing. Advaxis plans to work with the FDA review team to address any questions or requests that arise within this 30-day window.