On June 5, 2017 Celsion Corporation (NASDAQ:CLSN), an oncology drug development company, reported an update on its OVATION Study, a Phase Ib dose escalating clinical trial combining GEN-1, the Company’s DNA-based immunotherapy, with the standard of care for the treatment of newly-diagnosed patients with advanced (stage III/IV) ovarian cancer who will undergo neoadjuvant chemotherapy followed by interval debulking surgery. GEN-1 is an IL-12 DNA plasmid vector formulated as a nanoparticle in a non-viral delivery system to cause the sustained local production and secretion of the Interleukin-12 (IL-12) protein loco-regionally at the tumor site.

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The Company announced the latest clinical and translational data from the OVATION Study in a poster presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2017 Annual Meeting at McCormick Place in Chicago, IL. The poster presentation, entitled "Phase 1 study of the safety and activity of formulated IL-12 plasmid administered intraperitoneally in combination with neoadjuvant chemotherapy in patients with newly diagnosed advanced stage ovarian cancer," was presented on Saturday, June 3rd from 1:15 PM to 4:45 PM by Dr. Premal H. Thaker, Associate Professor, Obstetrics and Gynecology Division of Gynecologic Oncology, Washington University in St. Louis School of Medicine. The presentation summarized clinical findings and available translational data from all fourteen patients treated in the trial to-date.

"The OVATION study has accrued patients from four major research cancer centers. We have seen highly promising clinical findings including a patient with a complete pathological response along with a very high rate of R0 at time of debulking surgery. The translational research data in the poster presentation demonstrates that GEN-1 is producing beneficial cytokines and positively impacting T-cells in the tumor," said Dr. Premal Thaker. "This is strong early data and we believe that GEN-1 may be stimulating the immune system to improve tumor control in these patients. I am looking forward to continuing our clinical evaluation of GEN-1 in subsequent ovarian cancer studies."

Celsion reported encouraging clinical data from the first fourteen patients who have completed treatment in the OVATION Study. GEN-1 plus standard chemotherapy produced positive results, with no dose limiting toxicities and promising dose dependent efficacy signals which appear to correlate well with successful surgical outcomes as summarized below:
Of the fourteen patients treated to date in the entire study, two (2) patients demonstrated a complete response, ten (10) patients demonstrated a partial response and two (2) patients demonstrated stable disease, as measured by RECIST criteria. This translates to a 100% disease control rate ("DCR") and an 86% objective response rate ("ORR"). Of the five patients treated in the highest dose cohort, there was a 100% objective response rate with one (1) complete response and four (4) partial responses.

Fourteen patients had successful resections of their tumors, with nine (9) patients (64%) having an R0 resection, which indicates a microscopically margin-negative resection in which no gross or microscopic tumor remains in the tumor bed. Of the five patients treated at the highest dose cohort, all five patients (100%) experienced a R0 surgical resection.

One patient demonstrated a pathological complete response (pCR). pCRs are typically seen in less than 7% of patients receiving neoadjuvant chemotherapy followed by surgical resection, and have been associated with a median overall survival (OS) of 72 months, which is more than three years longer than those who do not experience a pCR.

All patients experienced a clinically significant decrease in their CA-125 protein levels as of their most recent study visit. CA-125 is used to monitor certain cancers during and after treatment. CA-125 is present in greater concentrations in ovarian cancer cells than in other cells.

Celsion also reported supportive translational research data from the first four patient cohorts who have completed treatment in the OVATION Study. The translational data provides further insight into GEN-1’s mechanism of action through the evaluation of dose-related changes in the tumor and peritoneal immune cell population, as well as through the peritoneal cytokine levels.

Treatment-Related Changes in IL-12 and Cytokine Levels in Peritoneal Fluid
The analysis of peritoneal fluid and blood samples collected immediately before and 24 hours after IP administration of multiple doses of GEN-1 (36, 47, 61, 79 mg/m2) and standard NACT (carboplatin every 21 days and Taxol weekly) shows clear evidence of IL-12 gene transfer and biological response following GEN-1 treatment on a dose-dependent basis.

The translational data also demonstrated significant increases in IFN-gamma and decreases in VEGF levels. The treatment-related changes in immune activating cytokines and pro-tumor VEGF levels followed a dose-dependent trend and were predominantly in the peritoneal fluid compartment with little to no changes observed in the patients’ systemic blood stream.

Treatment-Related Changes in the Density of Various T-cells in Tumors
The immuno-histochemical (IHC) analysis of tumor tissue collected before treatment (laparoscopy) and after completion of eight GEN-1 weekly treatments showed increased infiltration of CD3+, CD4+ CD8+ T-cells into tumor tissue of several patients. The most pronounced effects observed in the IHC analysis were decreases in the density of immunosuppressive T-cell signals (FoxP3+, PD-1+, PDL-1+, IDO-1+) in the tumor microenvironment. The ratio of CD8+ cells to immunosuppressive T-cells was increased in 60-80% of patients suggesting an overall shift in the immune environment to pro-immune stimulatory following treatment with GEN-1.

An intriguing effect of the treatment on tumor microenvironment is a substantial reduction in the immunosuppressive T-cell subsets and an overall shift in the T-cell environment to favoring immune stimulation.

"Now having completed enrollment, per protocol, of our OVATION Study, we are impressed with GEN-1’s apparent activity in combination with standard chemotherapy in newly diagnosed patients with stage III and IV ovarian cancer. These data appear to correlate with the notable, unexpected surgical outcomes among all patients completing the prescribed eight weekly treatments and reinforce our confidence in the promise of GEN-1’s ability to work safely and effectively in advanced ovarian cancer," said Michael H. Tardugno, Celsion’s chairman, president and CEO. "Given these encouraging findings, in addition to our plans to evaluate GEN-1 in combination with Avastin in 2 nd line, the Company will consider continuing our clinical trials in the underserved newly diagnosed patient population."

OVATION Study Design
The Phase Ib trial evaluated weekly intraperitoneal dosing of GEN-1 in combination with neoadjuvant chemotherapy, the standard of care for patients newly diagnosed with ovarian cancer. Concurrently with neoadjuvant chemotherapy, enrolled patients received escalating weekly doses of GEN-1, from levels beginning at 36mg/m², to 47mg/m², 61mg/m² and 79mg/m² weekly for 8 treatments in total, followed by interval debulking surgery. The regimen is primarily being evaluated for its safety and tolerability.

About GEN-1 Immunotherapy
GEN-1, designed using Celsion’s proprietary TheraPlas platform technology, is an IL-12 DNA plasmid vector encased in a nanoparticle delivery system, which enables cell transfection followed by persistent, local secretion of the IL-12 protein. IL-12 is one of the most active cytokines for the induction of potent anti-cancer immunity acting through the induction of T-lymphocyte and natural killer (NK) cell proliferation. The Company has previously reported positive safety and encouraging Phase I results with GEN-1 given as monotherapy in patients with peritoneally metastasized ovarian cancer, and recently completed a Phase Ib trial of GEN-1 in combination with PEGylated doxorubicin in patients with platinum-resistant ovarian cancer.

On June 5, 2017 Calithera Biosciences, Inc. (Nasdaq:CALA), a clinical stage biotechnology company focused on the development of novel cancer therapeutics, reported that clinical data from its product candidate CB-1158, a first-in-class arginase inhibitor, will be presented in an oral presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (ASCO) (Free ASCO Whitepaper), in Chicago, Illinois (Press release, Calithera Biosciences, JUN 5, 2017, View Source [SID1234519364]). The data demonstrate the safety, tolerability and target engagement of CB-1158 (INCB01158) in patients with advanced solid tumors.

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"Arginase-expressing tumor-infiltrating myeloid cells have been shown to play an important role in suppressing the immune system in the tumor microenvironment. In this first-in-human Phase 1 trial of the oral arginase inhibitor CB-1158, we have demonstrated CB-1158’s bioavailability and near complete inhibition of plasma arginase activity," said Susan Molineaux, PhD, President and Chief Executive Officer of Calithera. "We look forward to completing the monotherapy dose expansion in tumor types of interest, and initiating combination cohorts with other immune-modulatory therapies."

As of the data cut off of April 24, 2017, a total of 17 patients with advanced solid tumors had received single agent doses ranging from 50 to 150 mg twice a day (BID) in the ongoing Phase 1 trial. CB-1158 was generally well tolerated with no drug-related serious adverse events. Treatment related adverse events were limited to one case each of Grade 1 anemia, fatigue, increased ALT and myalgia. No Grade 3 treatment related adverse events were reported. Reversible, asymptomatic elevations of urinary orotic acid, a highly sensitive marker of urea cycle inhibition, were observed in two patients at 150 mg bid. Plasma levels of arginase were inhibited >90% in all patients, and in 10 of 11 patients plasma arginine increased 1.5 fold or more. The pharmacokinetics support BID dosing of CB-1158, as currently tested doses continuously maintained targeted levels of arginase inhibition. Preliminary observation of peripheral immune modulation will be further explored.

"CX-1158-101: A first-in-human phase 1 study of CB-1158, a small molecule inhibitor of arginase, as monotherapy and in combination with an anti-PD-1 checkpoint inhibitor in patients with solid tumors," by lead author Kyriakos Papadopoulos from South Texas Accelerated Research Therapeutics is in the developmental therapeutics session at 1:45 p.m. CT Monday, June 5, 2017 (Abstract #3005).

About Arginase

Arginase is an enzyme produced by immunosuppressive myeloid cells, including myeloid-derived suppressor cells (MDSCs) and neutrophils, which prevents T-cell and natural killer (NK) cell activation in tumors. Arginase exerts its immunosuppressive effect by depleting the amino acid arginine in the tumor microenvironment, which subsequently prevents activation and proliferation of the immune system’s cytotoxic T-cells and NK-cells. Inhibition of arginase activity reverses this immunosuppressive block and restores T-cell function. In preclinical models, arginase inhibition has been shown to enhance anti-tumor immunity and inhibit tumor growth. CB-1158 (INCB01158) is being developed in a global collaboration with Incyte Corporation.

On Jun 5, 2017 bluebird bio, Inc. (NASDAQ:BLUE), and Celgene Corporation (NASDAQ:CELG) reported that updated results from the ongoing CRB-401 Phase 1 clinical study of bb2121, an investigational anti-BCMA CAR T cell therapy, in 18 patients with relapsed/refractory multiple myeloma will be presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, Illinois (Press release, bluebird bio, JUN 5, 2017, View Source [SID1234519361]). The objective of this Phase 1 dose-escalation study is to evaluate safety and efficacy of bb2121 and determine a recommended Phase 2 dose. bluebird bio and Celgene are jointly developing bb2121.

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"It is impressive to see objective responses in all patients treated at dose levels of 150 x 106 CAR+ T cells or higher in such a heavily pretreated population, including those with high tumor burden. We are encouraged by the duration and depth of responses, and pleased that the safety profile remains readily manageable," said David Davidson, M.D., chief medical officer, bluebird bio. "Although these data are still early, it is encouraging that no patient in the active dose cohorts has had myeloma progression. In light of these results, we look forward to initiating the expansion phase of the CRB-401 study in the coming months."

"The heavily pretreated, relapsed/refractory patients in this study have few effective treatment options, highlighting the importance of this interim data. All patients previously underwent autologous HSCT, and received a median of 7 lines of prior therapy," said Michael Pehl, President, Hematology and Oncology for Celgene. "The consistency, depth and durability of these patients’ responses coupled with a manageable safety profile is very exciting, and we believe will provide hope for patients in this setting. Efforts are underway to advance the development of bb2121 for patients with relapsed/refractory multiple myeloma."

First-in-Human Multicenter Study of bb2121 anti-BCMA CAR T Cell Therapy for Relapsed/Refractory Multiple Myeloma: Updated Results. (Abstract #3010)

Presenter: Jesus G. Berdeja, M.D., Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN

Date: Monday, June 5, 2017, 4:45-6:00 pm CT (poster discussion); 8:00-11:30 am CT

Location: Hall D1

Session Title: Poster Discussion Session: Developmental Therapeutics—Immunotherapy

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 seven prior therapies (range: 3 – 14):

100% previously treated with lenalidomide and bortezomib
91% previously treated with pomalidomide and carfilzomib
71% previously treated with daratumumab
29% of patients were penta-refractory (bortezomib, lenalidomide, carfilzomib, pomalidomide, daratumumab)
All patients had at least one prior autologous stem cell transplant (ASCT)
As of the May 4, 2017 data cut-off, 21 patients had been enrolled and dosed in four dose cohorts: 50 x 106, 150 x 106, 450 x 106 and 800 x 106 CAR+ T cells. All 21 dosed patients were evaluable for safety, and 18 patients have undergone their first multiple myeloma tumor restaging and were evaluable for efficacy. This study has enrolled patients at seven sites in the U.S., with an anticipated total enrollment of up to 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.

bb2121 is an investigational compound that is not approved for any use in any country.

Results, as of May 4, 2017 Data Cut-off:


Cohort 1 2 3 4
CAR+ T Cell Dose 50 x 106 150 x 106 450 x 106 800 x 106
Number of
Patients
Evaluable for
Efficacy

3 4 8 3
Overall Response Rate in Cohort 33% 100% 100% 100%
Best Response PD (1 patient)
SD (1 patient)

PR (1 patient)


CR (2 patients; 1
patient MRD
negative)
VGPR (1 patient
MRD negative)
PR (1 patient)




CR (1 patient*)
VGPR (5
patients; 1 patient MRD
negative)
PR (2 patients;
1 patient MRD
negative)
*Patient died of
unrelated cardio
pulmonary arrest

VGPR (1 patient)
PR (1 patient)

CR (1 patient)


All patients in cohorts 2, 3 and 4 with bone marrow
involvement at baseline had no detectable multiple
myeloma cells in their bone marrow on Day 14 or beyond.
Of four patients evaluable for MRD status, all four were found to be
MRD-negative.



Median Prior
Lines of
Therapy


7 (range: 3-14); all patients had at least one prior autologous stem cell
transplant, as well as prior exposure to a proteasome inhibitor and an
immunomodulatory agent; 71% of patients had previously received
daratumumab or CD38 antibody.

Safety
15/21 (71%) of patients had CRS, mostly Grade 1 & 2; 2 patients with
Grade 3 CRS that resolved within 24 hours. 4 patients received
tocilizumab, 1 (Grade 2 CRS) received steroids. The most common
treatment-emergent Grade 3-4 AEs in 21 infused patients include
cytopenias commonly associated with cy/flu lymphodepletion, as well
as Grade 3 events of hyponatraemia (n=4), cytokine release syndrome
(n=2), upper respiratory infection (n=2), and syncope (n=2).

Nanjing Legend Biotech, a subsidiary of Chinese firm GenScript, presented stellar results at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting, showing 100% objective response rate to its BCMA-specific chimeric antigen receptor (CAR)-modified T (LCAR-B38M CAR-T cells) in a small trial of refractory/relapsed myeloma patients (Article, BioSeeker Group, JUN 5, 2017, http://www.1stoncology.com/blog/promising-car-t-data-at-asco-puts-bcma-in-the-spotlight-for-the-treatment-of-multiple-myeloma/ [SID1234519389]). Out of 19 patients, 18 (95%) reached complete remission or near complete remission status without a single event of relapse in a median follow-up of 6 months. The majority (14) of the patients experienced mild or manageable cytokine release syndrome, and the rest (5) were even free of diagnosable cytokine release syndrome.

Simultaneously, Bluebird Bio and partner Celgene reported similar positive data from its phase 1 trial of bb2121 in multiple myeloma at ASCO (Free ASCO Whitepaper). This is all very welcome news and also brings attention and expectation to the other 20 plus BCMA targeting drugs currently in active development for the treatment of multiple myeloma.

Testament to how fast the field of cancer drug development is moving, ASCO (Free ASCO Whitepaper) already presented the next generation to these therapies with Affimed’s and TeneoBio’s pursuit of bispecific BCMA antibodies. Affimed is developing AFM26 which is a BCMA/CD16A tetravalent, bispecific antibody designed to specifically enhance NK-cell anti-Multiple Myeloma activity by redirecting NK-cell lysis to BCMA. TeneoBio on their side are developing a bispecific antibody specific for human CD3 and BCMA using its Human Heavy Chain Antibodies (UniAbs) for the treatment of multiple myeloma. Both of these drug candidates are in preclinical stage of development.

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