November 2016 – Page 3 – 1stOncology™: Cancer Intelligence Service

Pre-clinical profile of Porcupine inhibitor RXC004 presented at EORTC-NCI-AACR 2016

On November 30, 2016Redx Pharma is pleased to announce that it will present the pre-clinical profile of its Porcupine inhibitor RXC004 at the 28th European Organisation for Research and Treatment of Cancer (EORTC), National Cancer Institute (NCI) and American Association for Cancer Research (AACR) (Free AACR Whitepaper) Symposium in Munich, Germany, on 30 November 2016 (Press release, Redx Pharma, NOV 30, 2016, View Source [SID1234524744]).

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Redx’s Porcupine inhibitor RXC004 exhibits potent and selective inhibition of the Wnt pathway in in vitro and in vivo models of Wnt dependant pancreatic cancer. Preliminary results indicate that RXC004 may also enhance the efficacy of checkpoint inhibitors, such as anti-PD-1 antibodies, by reducing the proportion of regulatory T cells in the tumour microenvironment and enhancing the ratio of cytotoxic T cells to regulatory T cells in tumour infiltrates.

Pre-clinical studies are ongoing to determine the effect of RXC004 on the immune response to cancer. The Company is progressing studies to prepare the RXC004 program for first-in-human clinical trials. The aim is to commence these, initially monotherapy, trials early 2017.

Dr Neil Murray, CEO of Redx, said: We’re delighted to present the compelling pre-clinical profile of our Porcupine inhibitor RXC004 at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium.

RXC004 has the potential to become a potent therapy for a subset of biliary, gastric and pancreatic cancer patients. It has also been shown to enhance the efficacy of checkpoint inhibitors, such as anti-PD-1 antibodies. We aim to initiate first-in-human clinical studies for RXC004 early 2017.

Details of the presentation:
Date: 30 November 2016
Time: 10:15-17:00
Poster Session: Immunotherapy
Poster Board Number: P131
Poster Title: Novel Porcupine inhibitor RXC004: Potent efficacy in animal models of cancer through direct tumour targeting and immunomodulatory mechanisms
Download the presentation poster: Novel Porcupine inhibitor RXC004

bluebird bio Announces Interim Phase 1 Dose Escalation Data for its Anti-BCMA CAR T Product Candidate in Patients with Relapsed/Refractory Multiple Myeloma

On November 30, 2016 bluebird bio, Inc. (Nasdaq: BLUE), a clinical-stage company committed to developing potentially transformative gene therapies for severe genetic diseases and T cell-based immunotherapies for cancer, reported that interim data from its ongoing Phase 1 clinical study of bb2121, the company’s investigational anti-BCMA CAR T cell product candidate in patients with relapsed/refractory multiple myeloma, will be presented on Thursday, December 1, 2016 at the 28th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Molecular Targets and Cancer Therapeutics Symposium in Munich, Germany (Press release, bluebird bio, NOV 30, 2016, View Source;p=RssLanding&cat=news&id=2226688 [SID1234516854]). bluebird bio is developing bb2121 in collaboration with Celgene Corporation.

"We are pleased that these early data from our ongoing Phase 1 study of bb2121 demonstrate objective anti-tumor responses in heavily pre-treated patients with multiple myeloma, with all patients in the 15.0 x 107 and 45.0 x 107 CAR+ T cell dose cohorts achieving responses, including among them, patients with stringent complete responses and elimination of minimal residual disease," said David Davidson, M.D., chief medical officer, bluebird bio. "We are also encouraged by the safety profile to date, particularly the lack of severe cytokine release syndrome or neurotoxicity. In light of these positive data, and thanks to the multiple participating clinical sites and centralized manufacturing infrastructure we and our partner Celgene have built for this program, we anticipate efficiently completing the dose escalation stage of the trial and initiating the expansion cohort."

Clinical remissions and limited toxicity in a first-in-human multicenter study of bb2121, a novel anti-BCMA CAR T cell therapy for relapsed/refractory multiple myeloma (Abstract #14, LBA)

Presenter: Yi Lin, M.D., Ph.D., Assistant Professor of Medicine and Oncology, Mayo Clinic Division of Hematology, Rochester, MN
Date: Thursday, December 1, 2016, 18:00 CET (12:00 pm ET)
Session: Plenary Session 7

The open-label Phase 1 CRB-401 study (NCT02658929) is investigating the administration of bb2121 anti-BCMA CAR T cells in patients with relapsed and/or refractory multiple myeloma. The primary endpoint of the study is incidence of adverse events (AEs) and abnormal laboratory test results, including dose-limiting toxicities (DLTs). The study also seeks to assess disease-specific response criteria including: complete response (CR), very good partial response (VGPR), and partial response (PR) according to the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma. The study also seeks to determine the recommended dose for further clinical trials. Patients on study were heavily pre-treated, with a median of six prior therapies (range: 5 – 13). As of the November 18th, 2016 data cut-off, 11 patients had been enrolled and dosed in four dose cohorts: 5.0 x 107, 15.0 x 107, 45.0 x 107 and 80 x 107 CAR+ T cells. All 11 dosed patients were evaluable for safety, and the first nine patients (5.0 x 107, 15.0 x 107, 45.0 x 107 dose cohorts) have undergone their first multiple myeloma tumor restaging and were evaluable for efficacy. This study is currently enrolling patients at seven sites in the U.S., with an anticipated total enrollment of 50 patients.

Patients received a conditioning regimen of cyclophosphamide and fludarabine, followed by an infusion of bb2121 anti-BCMA CAR T cells. The CAR T cells were produced from each patient’s own blood cells, which were modified using a lentiviral vector encoding the anti-BCMA CAR.

Results, as of November 18th, 2016 Data Cut-off:

Cohort 1 2 3
CAR+ T Cell dose 5.0 x 107 15.0 x 107 45.0 x 107
Overall Response
Rate in cohort

33% 100% 100%
Best Response PD
SD

sCR (time to response: 2 months)
sCR* (time to response: 4 months)
VGPR*

*Both patients with
a minimal residual
disease (MRD)
assessment at
Month 1 were MRD
negative

PR
PR

All patients in cohorts 2 and 3 with bone
marrow involvement at baseline had no
detectable multiple myeloma cells in their
bone marrow on Day 14 or beyond

Median Prior
Lines of Therapy

6 (range: 5-13); all patients had a prior autologous stem cell
transplant, as well as prior exposure to a proteasome inhibitor and
an immunomodulatory agent; 64 percent of patients had
previously received daratumumab or CD38 antibody

Safety
No dose-limiting toxicities and no Grade 3 or higher
neurotoxicities or Grade 3 or higher cytokine release syndrome
(CRS) have been observed. No patients received tocilizumab or
steroids.

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).

"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.

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Month: November 2016

Pre-clinical profile of Porcupine inhibitor RXC004 presented at EORTC-NCI-AACR 2016

bluebird bio Announces Interim Phase 1 Dose Escalation Data for its Anti-BCMA CAR T Product Candidate in Patients with Relapsed/Refractory Multiple Myeloma

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

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

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