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Oxigene’s positive PhII ovarian cancer data faces analyst’s skepticism

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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Clovis Oncology Announces First Patient Enrolled in TIGER-1 Study

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.

"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.

Advaxis Submits Investigational New Drug Application for Phase 1/2 Study of ADXS-HPV and MedImmune’s MEDI4736 for the Treatment of HPV-Associated Cervical and Head & Neck Cancer

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]).

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.

Blueprint Medicines Secures $50 Million in Series C Financing

On November 12, 2014 Blueprint Medicines reported the completion of a $50 million Series C financing (Press release Blueprint Medicines, NOV 12, 2014, View Source [SID:1234500956]). Proceeds from the financing will be used to advance Blueprint Medicines’ two lead product candidates through clinical trials in 2015 and fund the continued development of Blueprint Medicines’ kinase discovery platform and pipeline.

"The proceeds from this financing provide us with the financial strength to initiate clinical trials for our FGFR4 and KIT Exon 17 inhibitors in 2015 with the goal of establishing proof of concept rapidly and ultimately improving the lives of patients," said Jeffrey Albers, chief executive officer of Blueprint Medicines. "We are incredibly pleased to welcome such highly respected public investors to our shareholder base. Their investment provides strong endorsement for the quality of the platform, pipeline and team we’ve built at Blueprint Medicines over the past three years."

Blueprint Medicines’ Series C financing was led by Partner Fund Management and included additional new investors, Wellington Management Company, RA Capital, Tavistock Life Sciences, Perceptive Advisors, Sabby Capital, Cowen Investments and Redmile Group. The Company’s existing shareholders – Biotechnology Value Fund, Casdin Capital, Fidelity Biosciences, Nextech Invest and Third Rock Ventures – also participated in the financing.
"Blueprint Medicines’ proprietary kinase platform, which combines a first-of-its-kind chemical library and a novel genomics-based target discovery engine, holds significant value creation potential," said Alex Virgilio, Ph.D. of Partner Fund Management. "The team has achieved impressive results to date by rapidly discovering and advancing two first-in-class product candidates toward clinical development. We believe the team can sustainably replicate this success based on the strength of the platform in producing exquisitely selective inhibitors to novel genomically defined kinase targets."

Blueprint Medicines expects to initiate clinical trials in 2015 with its two lead product candidates:
 BLU-285 is the first known selective inhibitor of KIT Exon 17 mutants. The Company intends to initiate two clinical studies, including one for the underserved systemic mastocytosis patient population and another for genomically defined subsets of patients with gastrointestinal stromal tumors (GIST).
 BLU-554 is the first known selective FGFR4 inhibitor. Blueprint Medicines anticipates initiating a clinical study for patients suffering from hepatocellular carcinoma with aberrant FGFR4 pathway activation.

8-K – Current report

On November 11, 2014 Threshold Pharmaceuticals reported that the U.S. Food and Drug Administration (FDA) granted Fast Track designation for TH-302, an investigational anticancer drug, for the treatment of previously untreated patients with metastatic or locally advanced unresectable soft tissue sarcoma (STS) (Filing 8-K , Threshold Pharmaceuticals, NOV 12, 2014, View Source [SID:1234500955]).

The FDA established the Fast Track designation process to facilitate the development and expedite the review of drugs intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs. An important feature of Fast Track is that the FDA may consider a “rolling review” of completed sections of the New Drug Application (NDA) before the complete application is submitted.

“We are pleased that FDA has granted Fast Track status for TH-302 for the treatment of previously untreated patients with metastatic or locally advanced unresectable soft tissue sarcoma,” said Barry Selick, Ph.D., Chief Executive Officer of Threshold. “Our ongoing Phase 3 trial of TH-302 in these patients is being conducted under a Special Protocol Assessment with the FDA. If successful, the Fast Track designation may provide an added benefit of facilitating the NDA review process. Currently, we anticipate the primary analysis of overall survival of the Phase 3 trial to be conducted in the first quarter of 2016.”

About the Phase 3 Trial

Threshold is conducting this international, randomized pivotal Phase 3 clinical trial in partnership with the Sarcoma Alliance for Research through Collaboration (SARC) and under a Special Protocol Assessment (SPA) agreement with the U.S. FDA. The trial is designed to investigate the efficacy and safety of TH-302 in combination with doxorubicin, compared with doxorubicin alone, in previously untreated patients with metastatic or locally advanced unresectable STS. The primary endpoint of the trial is overall survival. Secondary endpoints include progression-free survival, overall response rate, pharmacokinetics and safety. Patients were randomized to either doxorubicin alone or to receive TH-302 300 mg/m2 administered intravenously on Days 1 and 8 with doxorubicin 75 mg/m2 on Day 1 of each 21-day cycle. After six cycles, patients with stable and/or responding disease could receive maintenance monotherapy with TH-302 according to the same dosing schedule, 300 mg/m2 Days 1 and 8 of each 21-day cycle. The trial enrolled a total of 640 patients across 81 study sites in Europe, Israel, North America and the Russian Federation.