On April 4, 2017 Roche (SIX: RO, ROG; OTCQX:RHHBY) reported it has received 510(k) clearance from the U.S. Food and Drug Administration (FDA) for the CINtec Histology test (Press release, Hoffmann-La Roche, APR 4, 2017, View Source [SID1234518467]). This test is the only clinically validated p16 biomarker test that, when used in conjunction with hematoxylin & eosin (H&E) staining, helps pathologists determine which women should receive treatment for cervical pre-cancer. This test is a part of the Roche Cervical Cancer Portfolio, which includes the cobas HPV Test and the CINtec PLUS Cytology3 test.

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"The CINtec Histology test will help physicians make informed decisions as to the best course of care for patients with high-grade pre-cancerous cervical disease," said Roland Diggelmann, CEO, Roche Diagnostics. "By improving the consistency of diagnosis across pathologists, it can help ensure the right patients are receiving the best possible treatment for this highly preventable disease."

As women positive for HPV are at greater risk for having or developing pre-cancerous cervical lesions, cervical cancer screening can help physicians find and treat these pre-cancerous lesions before they develop into invasive cancers. The CINtec Histology test plays a key role when a cervical tissue biopsy is taken as a result of an abnormal cervical cancer screening result, as it provides conclusive visual confirmation of the presence or absence of pre-cancerous lesions. These lesions, if untreated, could eventually lead to cervical cancer.

FDA clearance was based on the results generated in the CERTAIN4 (Cervical Tissue Adjunctive Analysis) study, which now joins the landmark ATHENA5 and PALMS6 trials in demonstrating the effectiveness of the products within the Roche Cervical Cancer Portfolio. Additionally, the use of p16 immunohistochemistry is recommended by the World Health Organization (WHO), the College of American Pathologists (CAP) and the American Society for Colposcopy and Cervical Pathology (ASCCP) to improve the detection of pre-cancerous cervical disease.

On April 4, 2017 Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") reported that it has presented the latest research data regarding a mechanism of action that led to increased anti-tumor activity in mouse models which had been dosed with a combination of the in-house developed anticancer agent lenvatinib mesylate (lenvatinib) and an anti-mouse PD-1 antibody, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 108th Annual Meeting (Press release, Eisai, APR 4, 2017, View Source [SID1234518466]).

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The results presented at the AACR (Free AACR Whitepaper) meeting 1 showed that when syngeneic model mice inoculated with mouse liver cancer, melanoma or colon cancer cell lines were dosed with a combination of lenvatinib (10 mg/kg, once daily) and an anti-mouse PD-1 antibody (500 g/mouse, twice a week), lenvatinib alone or an anti-mouse PD-1 antibody alone, a substantial inhibitory effect on tumor growth was observed in mice that had been dosed with the combination therapy compared to the single treatments.
Additionally, an increased number of mice in the combination therapy group showed Complete Response (CR) of tumor compared to the single treatment group. Specifically, in the combination therapy group, 7 out of 30 mice showed CR (colon cancer models: 2/10, melanoma models: 2/10, liver cancer models: 3/10), whereas in each single treatment group, 1 out of 30 mice showed CR (colon cancer models: 1/10, melanoma models: 0/10, liver cancer models: 0/10).

Furthermore, in the liver cancer mouse model, even when identical cancer cell lines were re-inoculated into mice with complete tumor remission, no in vivo growth was observed.

RNA analysis of the cancer tissue and other tests confirmed a reduction in immunosuppressive tumor associated macrophages, a reduction in immunosuppressive signal receptors, and an increase in the ratio of memory T cells in model mice dosed with lenvatinib.

This non-clinical research suggested synergistic anti-tumor activity when combining lenvatinib with an anti-mouse PD-1 antibody in the mouse models, based on an immunostimulatory response due to the reduction in tumor associated macrophages and the enhancement of the ratio of memory T cells by lenvatnib.

Eisai has positioned oncology as a key therapeutic area of focus and remains committed to providing further evidence for lenvatinib as it seeks to contribute further to addressing the diverse needs of, and increasing the benefits provided to, patients with cancer, their families, and healthcare providers.


1. About lenvatinib mesylate (generic name, "lenvatinib", product name: Lenvima / Kisplyx) Discovered and developed in-house, lenvatinib is an orally administered multiple receptor tyrosine kinase (RTK) inhibitor with a novel binding mode that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors (VEGFR1, VEGFR2 and VEGFR3) and fibroblast growth factor (FGF) receptors (FGFR1, FGFR2, FGFR3 and FGFR4) in addition to other proangiogenic and oncogenic pathway-related RTKs (including the platelet-derived growth factor (PDGF) receptor PDGFRα; KIT; and RET) involved in tumor proliferation.
Currently, Eisai has obtained approval for lenvatinib as a treatment for refractory thyroid cancer in over 50 countries including in the United States, Japan, in Europe, Korea, Mexico, and Brazil, and is undergoing regulatory review in other countries including South Africa and Indonesia. Specifically, Eisai has obtained approval for the agent in the United States for the treatment of locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer, in Japan for the treatment of unresectable thyroid cancer, and in Europe for the treatment of adult patients with progressive, locally advanced or metastatic differentiated (papillary, follicular, Hürthle cell) thyroid carcinoma (DTC), refractory to radioactive iodine, respectively.
Lenvatinib was also approved in the United States in May 2016 for an additional indication in combination with everolimus for the treatment of patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy. Furthermore, lenvatinib was approved in combination with everolimus for the treatment of adult patients with advanced RCC following one prior vascular endothelial growth factor (VEGF) targeted therapy in Europe in August 2016. Lenvatinib has been launched in Europe under the brand name Kisplyx for this indication.
Additionally, in January 2017, a Phase III clinical trial of lenvatinib as a first-line treatment for patients with unresectable hepatocellular carcinoma has achieved its primary endpoint.
A Phase III study of lenvatinib in separate combinations with everolimus and pembrolizumab in renal cell carcinoma (first-line) was initiated and is underway. Additionally, a Phase Ib/II study to investigate the agent in combination with pembrolizumab in select solid tumors including endometrial cancer, renal cell carcinoma, head and neck cancer, and urothelial cancer is also underway.


2. About memory T cells After being activated by an antigen presented on cancer cells or infected cells, CTL (cytotoxic T lymphocyte) cells turn into effector T cells, which can attack and eliminate the antigen. Afterwards, the majority of the effector T cells will die, but a portion of them remain in the body as memory T cells, which retain the "experience" of fighting off cancer cells or infection. If the same cancer cells or infection appear again, they will once again become effector T cells, and attack the invader with high efficiency

On April 4, 2017 Bellicum Pharmaceuticals, Inc. (Nasdaq:BLCM), a leader in developing novel, controllable cellular immunotherapies for cancers and orphan inherited blood disorders, reported two presentations of preclinical results on the Company’s proprietary dual-switch technology for use in CAR-T and TCR product candidates at the 2017 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Washington, D.C (Press release, Bellicum Pharmaceuticals, APR 4, 2017, View Source [SID1234518465]).

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"We’re excited to report compelling preclinical data on the first dual-switch technology designed to provide control over both the activity and safety of cell-based therapies," said Rick Fair, Chief Executive Officer of Bellicum Pharmaceuticals. "These data in both CAR-T and TCR constructs support our objective to continue leading the industry in developing novel, controllable cell therapies. We look forward to advancing product candidates incorporating this dual-switch technology into the clinic."

The Company’s dual molecular switch is designed to increase efficacy, durability and safety of adoptive cell therapies. T-cell proliferation is triggered by an inducible MyD88/CD40 (iMC) costimulatory switch, which when activated by the presence of both a target antigen and rimiducid, leads to enhanced T-cell activation and survival. A novel suicide switch, called RapaCIDeTM, is also engineered into the cell for use in the event of severe toxicities. RapaCIDe is activated via infusion of rapamycin, triggering immediate apoptosis of the modified cells. The dual-switch technology has been incorporated into the Company’s GoCAR-T and GoTCR platforms.

In a late-breaking poster presentation titled "Dual-switch HER2 CAR-T cells: Small molecule-regulated GO and STOP switches to target solid cancer in vivo," Bellicum scientists tested the novel dual-switch platform in solid tumors by combining both the iMC costimulatory and RapaCIDe apoptotic signaling switches inside a first-generation CAR targeting HER2. Results showed that the novel RapaCIDe switch was as effective as the Company’s CaspaCIDe switch at activating apoptosis, while the iMC costimulatory switch enhanced tumor killing and T-cell proliferation. This study demonstrated that the Company’s dual-switch GoCAR-T technology effectively controlled tumor growth, T-cell proliferation/persistence and elimination in a solid tumor model.

Additional data were reported in a second presentation on the Company’s dual-switch technology in a TCR targeting the cancer antigen PRAME (preferentially expressed antigen in melanoma). The TCR was engineered with the rimiducid-driven iMC costimulatory switch and the RapaCIDe suicide switch. Results reported in a poster presentation titled "Dual-switch TCR: A two-ligand system to control PRAME TCR-modified T-cell proliferation and death using inducible MyD88/CD40 and caspase-9," showed that T cells transduced with the dual-switch technology effectively enhanced T-cell proliferation/persistence in the presence of rimiducid, and exposure to rapamycin effectively triggered the RapaCIDe switch and induced apoptosis, eliminating the cells. This is the first reported prototype of a dual-switch TCR designed to increase efficacy, durability and safety of adoptive T-cell therapies.

The posters will be available in the Abstracts & Presentations section of the Bellicum website after the presentations.

AACR Presentation Details

Late-Breaking Presentation:

Abstract Number: LB-184 / 7
Presentation Title: "Dual-switch HER2 CAR-T cells: Small molecule-regulated GO and STOP switches to target solid cancer in vivo"
Presentation Date: Tuesday, April 4, 2017
Presentation Time: 8:00 AM – 12:00 PM ET
Section: 35
Additional Presentation:

Abstract Number: 3745 / 1
Presentation Title: "Dual-switch TCR: A two-ligand system to control PRAME TCR-modified T cell proliferation and death using inducible MyD88/CD40 and caspase-9"
Presentation Date: Tuesday, April 4, 2017
Presentation Time: 8:00 AM – 12:00 PM ET
Section: 30

On April 4, 2017 Puma Biotechnology, Inc. (Nasdaq: PBYI), a biopharmaceutical company, reported that interim results from a Phase II clinical trial of Puma’s investigational drug PB272 (neratinib) were presented at the 2017 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (AACR) (Free AACR Whitepaper) that is currently taking place in Washington, D.C (Press release, Puma Biotechnology, APR 4, 2017, View Source [SID1234518463]). The presentation, entitled "Effects of adding budesonide or colestipol to loperamide prophylaxis on neratinib-associated diarrhea in patients with HER2-positive early stage breast cancer: the CONTROL trial," was presented as a poster presentation.

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The main adverse event that has been seen to date in clinical trials of neratinib is diarrhea and more specifically grade 3 diarrhea. In the Phase III ExteNET trial of neratinib as extended adjuvant treatment of HER2-positive early stage breast cancer that has previously been treated with adjuvant Herceptin, 95.4% of the patients experienced all grade diarrhea and 39.8% of the patients experienced grade 3 or higher diarrhea (there was one event of grade 4 diarrhea). The CONTROL trial is an international, open-label, Phase II study investigating the use of loperamide prophylaxis with or without other agents in the reduction of neratinib-associated diarrhea that has a primary endpoint of the incidence of grade 3 diarrhea.

In the CONTROL trial, patients with HER2-positive early stage breast cancer who had completed trastuzumab-based adjuvant therapy received neratinib daily for a period of one year. High dose loperamide prophylaxis was given for the first 2 cycles (56 days) of treatment. Initially, the loperamide dosing used was 16 mg on day 1, then 12 mg on days 2 and 3 and then 6-8 mg on days 4-56 (original dosing). The protocol was later amended to simplify the regimen such that patients took 12 mg on days 1-14 and 8 mg on days 15-56 (modified dosing). The CONTROL trial was also expanded to include two additional cohorts. One cohort received the combination of loperamide and budesonide and the other cohort received the combination of loperamide plus colestipol. Budesonide is a locally acting corticosteroid that the Company believes targets the inflammation identified in a preclinical model of neratinib-induced diarrhea and colestipol is a bile acid sequestrant that the Company believes targets the bile acid malabsorption also seen in preclinical models of neratinib-induced diarrhea.

The interim analysis of the trial presented in the poster included a total of 137 patients who received neratinib plus loperamide prophylaxis (28 patients taking the original dosing and 109 patients taking the modified dosing), 64 patients who received neratinib plus loperamide prophylaxis for 2 cycles and budesonide for 1 cycle, and 26 patients who received neratinib plus loperamide prophylaxis for 1 cycle and colestipol for 1 cycle.

The results of the trial showed that the incidence of grade 3 diarrhea for the 137 patients who received the loperamide prophylaxis was 30.7%. For the 137 patients who received the loperamide prophylaxis, the median number of grade 3 diarrhea episodes per patient was 1 and the median cumulative duration of grade 3 diarrhea was 3 days. For the 137 patients who received loperamide prophylaxis, 20.4% discontinued neratinib due to diarrhea.

For the 64 patients who received the combination of loperamide plus budesonide, the results of the trial showed that the incidence of grade 3 diarrhea was 23.4%. The median number of grade 3 diarrhea episodes per patient was 1 and the median cumulative duration of grade 3 diarrhea was 2 days. For the 64 patients who received loperamide plus budesonide prophylaxis, 9.4% discontinued neratinib due to diarrhea.

For the 26 patients who received the combination of loperamide plus colestipol, the results of the trial showed that the incidence of grade 3 diarrhea was 11.5%. The median number of grade 3 diarrhea episodes per patient was 2 and the median cumulative duration of grade 3 diarrhea was 2 days. For the 26 patients who received loperamide plus colestipol prophylaxis, no patient (0%) discontinued neratinib due to diarrhea. Further information is provided in Table 1 below:

Table 1: Characteristics of Treatment-Emergent Diarrhea

Study CONTROL ExteNET
Antidiarrheal prophylaxis
Loperamide
Budesonide Colestipol

(original +
modified)
+
loperamide
+
loperamide

Loperamide
prn
N (at data cut-off) 137 64 26 1408
Diarrhea, %
Any grade 77.4 79.7 57.7 95.4
Grade 1 24.1 26.6 30.8 22.9
Grade 2 22.6 29.7 15.4 32.5
Grade 3 30.7 23.4 11.5 39.8
Grade 4 0 0 0 0.1

Median cumulative duration of diarrhea, days
Any grade 12.0 10.0 8.0 59.0
Grade ≥2 4.0 3.0 2.0 10.0
Grade ≥3a 3.0 2.0 2.0 5.0

Median episodes of diarrhea per patient, n
Any grade 2.0 4.0 3.0 8.0
Grade ≥2 2.0 2.0 2.0 3.0
Grade ≥3a 1.0 1.0 2.0 2.0

Median duration of neratinib treatment, months
Median 10.6 5.1 1.7 11.6


Tolerability related to neratinib diarrhea
Neratinib dose hold due to diarrhea, % 14.6 14.1 7.7 33.9
Neratinib dose reductions due to diarrhea, % 7. 3 1.6 3.8 26.4
Neratinib discontinuations due to diarrhea, % 20.4 9.4 0 16.8
Hospitalization due to diarrhea, % 1. 5 0 0 1.4
a
No grade 4 events in the CONTROL study; one grade 4 event in the ExteNET study.

In the ExteNET trial, higher grade (grade 2 and grade 3) diarrhea occurred early and persisted throughout the duration of the 12-month treatment period. In the CONTROL trial, in the loperamide prophylaxis, loperamide plus budesonide prophylaxis and loperamide plus colestipol prophylaxis arms, the results showed that higher grade diarrhea (grades 2 and 3) occurred early but did not typically recur. This is shown in more detail in Figure 1: Treatment Emergent Diarrhea, which is attached to this news release. In addition, a full copy of the poster that was presented at AACR (Free AACR Whitepaper) is available on the Puma Biotechnology website.

During the course of the CONTROL trial there has been an increase in the proportion of patients previously treated with pertuzumab (mainly in the neoadjuvant setting). For the 55 patients in the loperamide prophylaxis cohort who received prior pertuzumab, the grade 3 diarrhea rate was 38.2% (Table 2). For the 82 patients who did not receive prior pertuzumab, the grade 3 diarrhea rate was 25.6%. For the 39 patients in the budesonide cohort who received prior pertuzumab, the grade 3 diarrhea rate was 10.3%. For the 25 patients in the budesonide cohort who did not receive prior pertuzumab, the grade 3 diarrhea rate was 36.0%. This analysis suggests that prior pertuzumab exposure may have led to a higher rate of grade 3 diarrhea in the CONTROL trial that was not effectively managed by loperamide prophylaxis alone but was more effectively managed by loperamide plus budesonide.

Table 2: Incidence of Grade 3 Diarrhea in CONTROL by Prior Pertuzumab Treatment


Loperamide Cohort

Budesonide Cohort

Yes No Yes No
(n = 55)
(n = 82)
(n = 39)
(n = 25)

Grade 3 Diarrhea 38.2% 25.6% 10.3% 36.0%

Dr. Carlos H. Barcenas, Assistant Professor, Department of Breast Medical Oncology and Associate Medical Director, Breast Cancer Survivorship Clinic for the University of Texas MD Anderson Cancer Center, said, "We are pleased to see the reduction in incidence, severity and duration of neratinib-associated diarrhea when using the three antidiarrheal prophylaxis regimens tested so far in this study. When using either the loperamide prophylaxis, the loperamide plus budesonide prophylaxis or the loperamide plus colestipol prophylaxis, there appears to be a reduction in the incidence and severity of grade 3 diarrhea with neratinib. Importantly, the severe grade 2 and grade 3 diarrhea, when using the prophylaxis, appears to be acute, self-limiting and manageable. Although the study is still ongoing, we are encouraged that the addition of budesonide or colestipol appears to greatly improve the tolerability of neratinib as well. We look forward to completing the loperamide plus colestipol cohort."

Alan H. Auerbach, Chief Executive Officer and President of Puma Biotechnology, said, "We are pleased to see the reductions in the incidence of severe neratinib-related diarrhea in the CONTROL trial when using the loperamide, loperamide plus budesonide or loperamide plus colestipol regimens. The severe diarrhea appears to become more acute, whereby it does not typically recur after the first month. We are also very encouraged by the improvements in tolerability that have been seen to date in the budesonide and the colestipol cohorts. This is a marked improvement in tolerability over what was seen in the ExteNET trial and we look forward to continuing to monitor this in the loperamide plus colestipol cohort."

On April 4, 2017 Onconova Therapeutics, Inc. (Nasdaq: ONTX), a Phase 3 stage biopharmaceutical company focused on discovering and developing small molecule drug candidates to treat cancer, with a primary focus on Myelodysplastic Syndromes, reported promising pre-clinical data for first-in-class dual inhibitor of CDK4/6 + ARK5, as well as a Type 1 novel inhibitor of FLT3 and Src pathways as a novel strategy for Acute Myeloid Leukemia (AML) therapy at the 2017 AACR (Free AACR Whitepaper) Annual Meeting (Press release, Onconova, APR 4, 2017, View Source [SID1234518461]). The Company presented its findings in two poster presentations on April 3, 2017.

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ON 123300, an orally administered novel CDK4/6 + ARK5 inhibitor, exhibits potent antitumor activity in vivo: comparative studies with Palbociclib

ON 123300, a third-generation potent CDK4/6 inhibitor that also inhibits ARK5 with low nanomolar potency, was found to be as effective as Palbociclib (Pfizer’s Ibrance) in an Rb + ve xenograft model. Moreover, the molecule may have the potential advantage of reduced neutropenia when compared to Palbociclib. Both compounds decreased RBC and platelet counts, however in this model system, Palbociclib had a more prominent and statistically significant (P≤0.05) inhibitory effect on neutrophil counts when compared to ON 123300 (30.70 ± 3.55 vs. 45.10 ± 2.04).

"There is a need for next-generation CDK4/6 inhibitors such as ON 123300, given the limitations of second-generation compounds that depend on a second molecule for therapeutic use. We are particularly excited about ON 123300 because of its potential to act as a single agent, as a dual inhibitor of CDK 4/6 + ARK 5 and which could be suitable for indications that may not be amenable to Palbociclib-like compounds," said Dr. Ramesh Kumar, CEO of Onconova.

A full copy of the above AACR (Free AACR Whitepaper) poster can be accessed by visiting "Scientific Presentations" in the Investors and Media section of Onconova’s website.

Dual inhibition of FLT3 and Src pathways by ON 150030, a type 1 inhibitor, as a novel strategy for relapsed and refractory AML

Biological studies at the Icahn School of Mount Sinai reveal that ON 150030 specifically inhibits the growth of MV4-11 cells harboring the FLT3-ITD mutation (GI50: 10nM). Western blot analysis demonstrates that MAPK and PI3K/AKT pathways in these cells are inhibited with increasing dose of ON 150030. The JAK independent phosphorylation of STAT5 seen in the context of FLT3-ITD is also reduced in response to ON 150030. The poor survival rate among FLT3-ITD positive AML patients and the resistance associated with current treatment regimens highlight a need for a novel FLT3 inhibitor that will be effective in cells resistant to Quizartinib.

"We are excited by the positive data on these two preclinical compounds, which address dual targeting strategy to address difficult to treat diseases. These promising results underscore the depth of our clinical pipeline, which is led by rigosertib, an advanced Phase 3 stage innovation for the treatment of patients with myelodysplastic syndromes. Following the advancement of our late stage trials in 2016, rigosertib is positioned for multiple key milestones in 2017," concluded Dr. Kumar.