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Blueprint Medicines Announces Proof-of-Concept Data from Phase 1 Clinical Trial of BLU-285 in Patients with Advanced Gastrointestinal Stromal Tumors

On November 30, 2016 Blueprint Medicines Corporation (NASDAQ: BPMC), a leader in discovering and developing targeted kinase medicines for patients with genomically defined diseases, reported data from its ongoing Phase 1 clinical trial evaluating BLU-285, an investigational medicine for the treatment of patients with advanced gastrointestinal stromal tumors (GIST). These data provide proof-of-concept for BLU-285, a potent, highly selective inhibitor of D842V mutant PDGFRα and Exon 17 mutant KIT. The data will be presented on Thursday, December 1, 2016 at the 28th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics in Munich, Germany (EORTC-NCI-AACR) (Free EORTC-NCI-AACR Whitepaper).

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"The clinical activity observed to date in the dose escalation portion of this Phase 1 study is promising," said Michael Heinrich, M.D., Oregon Health & Science University, an investigator for the clinical trial. "Advanced GIST is a devastating illness, marked by rapid disease progression. Seeing tumor shrinkage in 14 out of 15 PDGFRα-driven GIST patients at this point in the study is notable. I am also excited to see tumor shrinkage in four out of the six KIT-driven GIST patients treated at the higher dose levels, indicating the potential for increased clinical activity as we continue to dose-escalate. Given these encouraging early data for this investigational medicine, I believe BLU-285 could be transformative for patients with advanced GIST."

"These data help to validate Blueprint Medicines’ ability to craft targeted kinase inhibitors and to achieve rapid proof-of-concept for our investigational therapies in genomically-defined populations," said Andy Boral, M.D., Chief Medical Officer at Blueprint Medicines. "We are encouraged by the early evidence of clinical activity, with the majority of patients achieving stable disease or a partial response, and some patients having durable tumor reduction lasting at least eight months. I am also pleased that BLU-285 has been well-tolerated to date and that the pharmacokinetic profile supports once daily dosing. We continue to believe that BLU-285 has the potential to significantly impact the treatment paradigm for patients with GIST."

Data from the Ongoing Phase 1 Clinical Trial

BLU-285 is currently being evaluated in the dose escalation stage of a Phase 1 clinical trial in patients with unresectable PDGFRα-driven GIST and patients with treatment-resistant KIT-driven GIST. As of the data cutoff date of November 1, 2016, 36 patients had been treated in the dose escalation portion of the Phase 1 clinical trial at seven dose levels (ranging from 30 mg once daily (QD) to 400 mg QD), including 18 patients with PDGFRα-driven GIST and 18 patients with KIT-driven GIST. The median age was 61 (ranging from 41 to 77), and the median number of prior tyrosine-kinase inhibitor (TKI) regimens was 3.5 (ranging from zero to 12).

Preliminary pharmacokinetic analysis demonstrated relatively rapid absorption of BLU-285 and a mean half-life of over 24 hours that supports once daily dosing.

Preliminary Safety Data

As of the data cutoff date of November 1, 2016, BLU-285 was observed to be well-tolerated at all doses. The majority of adverse events (AEs) reported by investigators were Grade 1 or 2. Across all grades, AEs reported by investigators most commonly included nausea (42%), vomiting (33%), peripheral edema (31%), fatigue (28%) and constipation (22%). Investigators reported treatment-related Grade 3 AEs in three patients: nausea and vomiting (one patient); anemia and intratumoral hemorrhage (one patient); and hypophosphatemia (one patient). No dose-limiting toxicities or drug-related Grade 4 or 5 AEs were reported, and no patients discontinued BLU-285 due to treatment-related adverse events. A maximum tolerated dose (MTD) has not been reached, and enrollment in the dose escalation portion of the Phase 1 clinical trial is ongoing.

Preliminary Clinical Activity Data

As of the data cutoff date of November 1, 2016, 28 patients in the first six cohorts of the dose escalation portion of the clinical trial (at doses ranging from 30 mg QD to 300 mg QD) had completed at least two 28-day dosing cycles and were evaluable for response assessment. CT and MRI imaging was used to measure clinical activity by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1.

In PDGFRα-driven GIST, investigators observed radiographic tumor reduction in 14 of 15 evaluable patients with six patients achieving a partial response (PR) by RECIST (five confirmed, one unconfirmed). Tumor reduction was observed at the first dose level in the PDGFRα-driven subgroup of advanced GIST.
In KIT-driven GIST, investigators observed radiographic tumor reduction in five of the 13 evaluable patients, including one who achieved a PR by RECIST (confirmed). At the higher dose levels (greater than or equal to 135 mg), four out of six patients had tumor reduction, including the patient with a PR, suggesting increased clinical activity with increased dose. Tumor shrinkage was first observed at the fourth dose level in the KIT-driven subgroup of advanced GIST.
Among all 36 patients treated, 27 patients remained on BLU-285, including all 18 patients with PDGFRα-driven GIST, with a duration of treatment ranging from 0.8 months to 12.3 months.
Nine patients discontinued treatment with BLU-285 due to progressive disease.
Clinical Development Plans for BLU-285 in GIST

Based on the favorable safety profile and encouraging clinical activity observed to date in the Phase 1 clinical trial for BLU-285 for the treatment of advanced GIST, Blueprint Medicines will continue to enroll patients in the dose escalation portion of this clinical trial until a MTD or a lower recommended dose for further clinical evaluation has been established. Enrollment in the expansion cohorts for this Phase 1 clinical trial is expected to begin in the first half of 2017. Blueprint Medicines plans to enroll approximately 35 patients with advanced GIST in the expansion cohorts. We also plan to accelerate our evaluation of expanded development options for BLU-285 in GIST, including opportunities to move to earlier lines of therapy and possible combinations.

In January 2016, the U.S. Food and Drug Administration (FDA) granted orphan drug designation to BLU-285 for the treatment of GIST, and in October 2016, the FDA granted Fast Track designation to BLU-285 for the treatment of patients with unresectable or metastatic GIST that progressed following treatment with imatinib and a second TKI and for the treatment of patients with unresectable or metastatic GIST with the PDGFRα D842V mutation regardless of prior therapy. Blueprint Medicines plans to seek regulatory guidance on potential pathways for expedited clinical development of BLU-285 for the treatment of advanced GIST.

Celsion Announces Data Monitoring Committee Unanimously Recommends Continuation of Phase III OPTIMA Study of ThermoDox® for Primary Liver Cancer

On November 30, 2016 Celsion Corporation (NASDAQ:CLSN) reported that following a review of data from its multinational, randomized pivotal Phase III clinical study of ThermoDox in combination with optimized radiofrequency ablation (RFA) for primary liver cancer (the OPTIMA Study), the study’s Data Monitoring Committee (DMC) has unanimously recommended that the trial continue enrollment. With approximately 40% of patients currently enrolled in the trial, Celsion expects to complete patient enrollment in this 550 patient trial by early 2018 (Press release, Celsion, NOV 30, 2016, View Source [SID1234516849]).

"Following the recent presentation by the NIH confirming our hypothesis that ThermoDox in combination with optimized RFA can be a treatment with curative intent for HCC, we could not be more pleased that the DMC has recommended continuation of the OPTIMA Study without modification. Based on their review of all the available study data, the DMC has concluded that ThermoDox is safe for newly diagnosed, intermediate stage patients and that the study is being conducted according to the highest of clinical research standards," said Michael H. Tardugno, Celsion’s chairman, president and chief executive officer. "We remain optimistic and encouraged by this decision, and by the potential that ThermoDox has consistently demonstrated in patients with primary liver cancer, a patient population in dire need of new therapeutic options."

The DMC is comprised of an independent group of medical and scientific experts and is responsible for reviewing and evaluating patient safety and efficacy data for the Company’s Phase III OPTIMA Study. The DMC reviews study data at regular intervals in order to ensure the safety of all patients enrolled in the trial and to monitor the quality and overall conduct of the trial including each site’s compliance with the minimum RFA heating time of 45 minutes specified in the study protocol. The OPTIMA Study’s design and statistical plan calls for two interim analyses by the DMC with the intent of evaluating its safety and efficacy to determine if there is overwhelming evidence of clinical benefit or a low probability of treatment success (a futility analysis) to continue, modify or terminate the trial.

On November 29, 2016, the Company announced results from an independent retrospective analysis conducted by the National Institutes of Health (NIH) on the intent-to-treat population of the 701 patient HEAT Study of ThermoDox plus optimized RFA for the treatment of primary liver cancer. The NIH analysis, which sought to evaluate the correlation between RFA burn time per tumor volume (min/ml) and clinical outcome, concluded that increased burn time per tumor volume significantly improved overall survival (OS) in patients with solitary lesions treated with RFA + ThermoDox compared to patients treated with RFA alone. The NIH analysis included 437 patients with a single lesion from the Company’s HEAT Study, the same patient population being treated in the Company’s ongoing Phase III OPTIMA study. These findings are consistent with Celsion’s own analysis of the HEAT Study data, which demonstrated that over a 3.5 year period, there was a statistically significant two year survival benefit for patients treated with ThermoDox plus optimized RFA over the optimized RFA only group.

About the OPTIMA Study
The Phase III OPTIMA Study is expected to enroll up to 550 patients in up to 75 clinical sites in the United States, Europe, China and Asia Pacific, and will evaluate ThermoDox in combination with optimized RFA, which will be standardized to a minimum of 45 minutes across all investigators and clinical sites for treating lesions three to seven centimeters, versus standardized RFA alone. The primary endpoint for the trial is Overall Survival, which is supported by post-hoc analysis of data from the Company’s 701 patient HEAT Study, where optimized RFA has demonstrated the potential to significantly improve survival when combined with ThermoDox. The statistical plan calls for two interim efficacy analyses by an independent Data Monitoring Committee (iDMC).

Pfizer Announces Positive Top-Line Results from the Pivotal Comparative REFLECTIONS B3271002 Study for PF-05280014, a Potential Biosimilar to Herceptin®1 (trastuzumab)

On November 30, 2016 Pfizer Inc. (NYSE:PFE) reported that the pivotal REFLECTIONS B3271002 study, a comparative safety and efficacy study of PF-05280014 versus Herceptin (trastuzumab), met its primary endpoint (Press release, Pfizer, NOV 30, 2016, View Source [SID1234516846]). PF-05280014 is being developed by Pfizer as a potential biosimilar to Herceptin.

The trial demonstrated equivalence in the primary endpoint of objective response rate (ORR) of PF-05280014 versus Herceptin, taken in combination with paclitaxel, in first line patients with HER2-positive metastatic breast cancer. ORR is defined as the proportion of patients with tumor size reduction of a predefined amount and for a minimum period of time2.

"As the leading global biosimilars company, we are committed to advancing our robust pipeline of biosimilar therapies in hopes of expanding access to high-quality treatment options for patients living with serious, life-threatening conditions such as cancer," said Sumant Ramachandra, MD, PhD, MBA, Head of Research and Development, Pfizer Essential Health. "Favorable comparative clinical data between proposed biosimilars and their respective reference product contribute to physician and patient understanding of and confidence in the value and importance of biosimilars. We are encouraged by these data and look forward to sharing the complete results with health authorities and the oncology community once available."

A separate comparative, randomized, double-blind clinical trial [REFLECTIONS B3271004] in early breast cancer patients [N=226] also met its primary endpoint of steady-state Ctrough concentrations (PK) in patients treated with PF-05280014 and Herceptin.

About the REFLECTIONS B3271002 Study

REFLECTIONS B3271002 is a comparative, randomized, double blind, clinical trial[N=690] evaluating the efficacy, safety, pharmacokinetics (PK) and immunogenicity of PF-05280014 (a potential biosimilar to Herceptin [trastuzumab]) in combination with paclitaxel versus Herceptin in combination with paclitaxel in first line patients with HER2-positive metastatic breast cancer. The primary endpoint is objective response rate (ORR) by Week 25 of study treatment. ORR is defined as the proportion of patients with tumor size reduction of a predefined amount and for a minimum period of time2.

More information about the PF-05280014 REFLECTIONS B3271002 and B3271004 studies can be found at www.clinicaltrials.gov (link is external).

About PF-05280014

PF-05280014 is a monoclonal antibody (mAb) that is in development as a potential biosimilar for all currently approved indications of Herceptin (trastuzumab).

Herceptin is currently approved in the U.S., EU and other markets for HER2-positive breast cancer and gastric cancer.

PF-05280014 is an investigational compound and has not received regulatory approval in any country. Biosimilarity has not yet been established by regulatory authorities and is not yet claimed.

First clinical data for monalizumab as a single agent in cancer patients show favorable safety profile

On November 30, 2016 Innate Pharma SA (the "Company" – Euronext Paris: FR0010331421 – IPH) reported preliminary safety results from the dose-ranging part of a Phase I/II trial investigating monalizumab as a single agent in patients with advanced gynecologic malignancies (Press release, Innate Pharma, NOV 30, 2016, View Source [SID1234516844]).

The data are presented today as a poster at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Molecular Targets and Cancer Therapeutics Symposium (Munich, Germany) 10:15 a.m. – 5:00 p.m. CET and will be discussed by Dr Anna Tinker, Medical Oncologist (British Columbia Cancer Agency, Vancouver) on behalf of CCTG during the Spotlight session at 1:10 – 1:20 p.m. CET. Monalizumab is Innate Pharma’s first-in-class anti-NKG2A antibody partnered with AstraZeneca. The trial is sponsored and conducted by the Canadian Cancer Trials Group (CCTG).

In this dose-ranging part of the study, 18 patients with advanced, heavily pretreated ovarian cancer were randomized to receive three dose levels of monalizumab (1, 4 and 10 mg/kg, every two weeks – six patients at each dose level). The data showed that monalizumab was well tolerated in this patient population, with no dose-limiting toxicities observed. No major differences in terms of safety were observed across the different dose levels. The most common adverse events (AEs) reported include fatigue and headaches. AEs were mostly low grade and rarely resulted in treatment delays. Preliminary efficacy data showed short-term disease stabilization in 41% of patients, including one patient with a mixed response.

Lesley Seymour, MD, PhD, Professor in Oncology at Queen’s University in Kingston, Ontario and Director of the Investigational New Drug Program at CCTG, said: "Monalizumab was well tolerated in this patient population with advanced gynecologic malignancies. These refractory tumors are an area of unmet need, and are typically treated with cytotoxic chemotherapy which is often poorly tolerated. Building on these initial results, further investigation of monalizumab in these patients is warranted and we are therefore continuing to enroll patients with relapsed and refractory gynecologic malignancies into the expansion phase of the study."

Pierre Dodion, Chief Medical Officer of Innate Pharma, said: "These are the first clinical data reported with monalizumab in cancer patients and they suggest a favorable safety profile. Preliminary results support the continuation of the ongoing cohort expansion part of this study and we look forward to its results. A comprehensive exploratory clinical plan investigating monalizumab in several indications, as both a monotherapy and combination treatment, is underway. We look forward to reporting further data as we move into 2017."

The cohort expansion part of this trial (up to 98 patients) is ongoing at the recommended Phase II dose (10 mg/kg) in patients with platinum sensitive ovarian cancer, platinum-resistant ovarian cancer, epithelial endometrial cancer and squamous cell carcinoma of the cervix.

Poster Details

Poster title: "Dose ranging study of monalizumab (IPH2201) in patients with gynecologic malignancies: A trial of the Canadian Cancer Trials Group (CCTG): IND221"
Presenter: A. Tinker, Canadian Cancer Trials Group
Location: International Congress Center, Munich, Germany

Agenus Announces Commencement of Phase 1/2 Clinical Trial of anti-OX40 Checkpoint Antibody INCAGN1949 in Patients with Solid Tumors

On November 30, 2016 Agenus Inc. (NASDAQ: AGEN), an immuno-oncology company with a pipeline of immune checkpoint antibodies and cancer vaccines, reported that the first patient has been dosed in a Phase 1/2 clinical trial of the anti-OX40 agonist antibody INCAGN1949. The trial is being conducted by, and in collaboration with, Incyte Corporation (Press release, Agenus, NOV 30, 2016, View Source [SID1234516842])

The open-label, dose-escalation portion of the trial will evaluate the safety and tolerability of INCAGN1949 in patients with advanced or metastatic solid tumors and determine its pharmacologically active and/or maximum tolerated dose. Part 2 of the trial is planned to evaluate the recommended dose of INCAGN1949 in multiple tumor types.

"We are pleased with the progress of our fruitful alliance with Incyte and also anticipate advancing a number of Agenus programs outside of the Incyte collaboration, such as our PD-1 antagonist, AGEN2034, into clinical development in the coming months," said Garo H. Armen, Ph.D. Chairman and CEO of Agenus. "Our pipeline of proprietary and differentiated assets continues to offer opportunities for additional partnerships."

INCAGN1949 is an agonist antibody targeting OX40, otherwise known as CD134 or TNFRSF4. OX40 is a co-stimulatory receptor found on activated T cells. OX40 engagement has a two-pronged effect; it can stimulate proliferation of activated T cells that may promote tumor killing and inhibit the activity of regulatory T cells that mediate immune suppression. INCAGN1949 was discovered during an earlier collaboration with Ludwig Cancer Research. This antibody is being co-developed with Incyte.

"Immune checkpoint antibodies including those targeting PD-1/PD-L1 and CTLA-4 have shown clinical activity across multiple tumor types that supported their approval in a number of indications, but a significant proportion of patients are still in need of additional intervention," said Jean-Marie Cuillerot, M.D., VP and Global Head of Clinical Development. "OX40 is an important co-stimulatory checkpoint that contributes to the regulation of the immune anti-tumor response. We believe OX40 agonism provides a robust framework for combination therapy with a potential to make a meaningful difference to patients afflicted by this deadly disease."

Additional information about the trial can be found here.

About Checkpoint Antibodies

Monoclonal antibodies that bind to immune checkpoint receptors, such as CTLA-4 and PD-1, are proven immunotherapeutic targets. These molecules serve as gateways employed by the body to prevent an overt immune response or allow rapid activation of the immune response when needed. Unfortunately, these necessary mechanisms of control can hinder the anti-cancer immune response. They can be harnessed by cancer cells as a defense against immune attack. Agenus is developing a broad pipeline of antibodies that bind to key immune checkpoint proteins and activate or block their activities for use in cancer therapy.