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Compugen Announces Lead Therapeutic Candidate COM902 for CGEN-15137/TIGIT Immuno-Oncology Program

On March 28, 2017 Compugen Ltd. (NASDAQ: CGEN), a therapeutic discovery company, reported the selection of COM902 as the lead clinical antibody candidate for its CGEN-15137/TIGIT T cell checkpoint inhibitor program in immuno-oncology (Press release, Compugen, MAR 28, 2017, View Source [SID1234518290]). COM902 follows COM701 into the Company’s preclinical development pipeline. COM701 is the Company’s lead therapeutic antibody targeting PVRIG, for which IND is anticipated later this year. As previously disclosed, PVRIG and TIGIT represent two distinct but complementary arms of the same biological pathway, and inhibition of the two results in increased activation of tumor infiltrating lymphocytes (TILs). This provides a strong clinical rationale for the combination of COM701 and COM902, in addition to monotherapy use, as immunotherapies to treat various cancer types.

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Anat Cohen-Dayag, PhD, CEO and President of Compugen, commented, "The addition of this lead clinical antibody candidate for CGEN-15137/TIGIT to our preclinical pipeline represents another important milestone as we continue to build toward becoming a clinical stage company. We began our TIGIT program in 2016 based on our data indicating the potential for enhanced efficacy for combination treatment with COM701, and with our prior finding that TIGIT and PVRIG operate in the same biological pathway. The knowledge and the expertise we gained through the development of COM701 were an important factor in the accelerated development and selection of COM902. COM902 is a high affinity antagonist antibody selected for its potential ability to activate immune responses, both alone and in combination with COM701."

Dr. Cohen-Dayag added, "Currently available immuno-oncology therapies are effective for only a select subset of cancer patients, and we believe that the combination of COM701 and COM902, as well as with other checkpoint inhibitors, could provide a new therapeutic venue for treating cancer patients, specifically those non-responsive to current therapies. As we continue our development toward the clinic, we look forward to sharing with you more data as it becomes available."

About TIGIT
TIGIT is an immune checkpoint in the B7/CD28 family which has recently gained broad industry interest in the field of immuno-oncology. TIGIT was discovered by Compugen utilizing its in silico predictive discovery infrastructure and experimentally validated as an immune checkpoint. These findings were published by Compugen in the October 2009 issue of the Proceedings of National Academy of Sciences (PNAS). In the same year, two other groups also published papers disclosing TIGIT as a new checkpoint. Antibodies targeting TIGIT being developed by others entered Phase I clinical studies in 2016.

TIGIT can inhibit both T cell and NK cell activation when bound to its ligand, PVR (also known as CD155). TIGIT expression is increased on tumor infiltrating lymphocytes (TILs), and inhibition of T cell activation by TIGIT has been reported to be mediated by its ability to disrupt DNAM-1 (also known as CD226) costimulatory signals. Recent preclinical studies have shown that antibody antagonists of TIGIT can potently inhibit tumor growth in mouse cancer models when combined with PD-1 pathway blockade.

DelMar Pharmaceuticals Announces Abstract Presentations for the American Association for Cancer Research (AACR) Annual Meeting in April 2017

On March 28, 2017 DelMar Pharmaceuticals (Nasdaq: DMPI) ("DelMar" and the "Company"), a biopharmaceutical company focused on the development and commercialization of new cancer therapies, reported that it will present three abstracts at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, DelMar Pharmaceuticals, MAR 28, 2017, View Source [SID1234518289]). The abstracts are based on research conducted with DelMar’s lead anti-cancer product candidate, VAL-083 (dianhydrogalactitol), a "first-in-class" small-molecule DNA-targeting agent. The AACR (Free AACR Whitepaper) Annual Meeting will be held April 1-5, 2017 in Washington, D.C.

Details of the poster presentations by DelMar and/or its collaborators are as follows:

Abstract #1429 – DNA damage response to dianhydrogalactitol (VAL-083) in p53-deficient non-small cell lung cancer cells
Section: Genomic Instability and Cancer Therapy
Date and Time: Monday, April 3, 2017, 8:00 a.m. – 12:00 p.m. Eastern Time

Abstract #2483 – Molecular mechanisms of dianhydrogalactitol (VAL-083) in overcoming chemoresistance in glioblastoma
Section: Homologous Recombination and DNA Double-Strand Break Repair
Date and Time: Monday, April 3, 2017, 1:00 p.m. – 5:00 p.m. Eastern Time

Abstract CT#054 – Phase II study of dianhydrogalactitol in patients with MGMT-unmethylated bevacizumab-naive recurrent glioblastoma
Section: Phase III Clinical Trials and Phase II/III Clinical Trials in Progress
Date and Time: Monday, April 3, 2017, 1:00 p.m. – 5:00 p.m. Eastern Time

The Company’s first two abstracts have been published and can be viewed on the AACR (Free AACR Whitepaper) Annual Meeting website.

About VAL-083
VAL-083 is a "first-in-class," small-molecule DNA-targeting agent that demonstrated clinical activity against a range of cancers including GBM in historical clinical trials sponsored by the U.S. National Cancer Institute. DelMar has demonstrated that VAL-083’s anti-tumor activity against GBM is unaffected by the expression of MGMT in vitro. Further details can be found at www.delmarpharma.com/scientific-publications.html.

VAL-083 has received an orphan drug designation in Europe for the treatment of malignant gliomas, and the U.S. FDA Office of Orphan Products has granted an orphan designation to VAL-083 for the treatment of glioma, medulloblastoma and ovarian cancer.

DelMar has also announced plans to advance VAL-083 into a pivotal randomized multi-center Phase 3 clinical trial for the treatment of bevacizumab-failed GBM. A separate Phase 2 trial for MGMT-unmethylated recurrent GBM is currently open for enrollment at the University of Texas MD Anderson Cancer Center and an international trial for newly diagnosed MGMT-unmethylated GBM is expected to commence enrollment upon receipt of required government approval.

DelMar believes that data from its clinical trials, if successful, will form the basis of a new treatment paradigm for the vast majority of GBM patients whose tumors exhibit features that make them unlikely to respond to currently available therapies.

About Glioblastoma Multiforme (GBM)
GBM is the most common as well as the most lethal form of brain cancer. Approximately 15,000 new cases of GBM are expected to be diagnosed in the United States during 2017. GBM progresses quickly and patients deteriorate rapidly. Common symptoms include headaches, seizures, nausea, weakness, paralysis and personality or cognitive changes such as loss of speech or difficulty in thinking clearly. The majority of GBM patients do not survive for more than two years following diagnosis, and the median survival in newly diagnosed patients with best available treatments is less than 15 months.

Astrazeneca to share its robust early science in oncology with the medical community at AACR 2017

On March 28, 2017 AstraZeneca, along with its global biologics research and development arm, MedImmune, reported it will present the strength and depth of its translational science, which is expected to deliver the Company’s next wave of innovative oncology medicines, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Washington DC, US, 1-5 April 2017 (Press release, AstraZeneca, MAR 28, 2017, View Source [SID1234518288]).

In addition to demonstrating a robust early oncology portfolio in DNA Damage Response (DDR) and Tumour Drivers and Resistance, AstraZeneca will highlight the continued progress being made in early Immuno-Oncology (IO) and Antibody-Drug Conjugate (ADC) science.

Susan Galbraith, Senior Vice President, Head of Oncology, Innovative Medicines and Early Development (IMED) Biotech Unit, said: "The progress we will report at AACR (Free AACR Whitepaper) 2017 highlights the rapid growth of our highly-differentiated DNA Damage Response portfolio that targets a broad range of key molecular pathways. Presentations will also show our progress within Tumour Drivers and Resistance with the development of molecules targeting two key mechanisms that tumours use to resist cell death, namely MCL-1 and CDK9."

David Berman, Senior Vice President, Head of Oncology Innovative Medicines at MedImmune, added: "AACR 2017 is an exciting moment for our next-generation oncology portfolio, demonstrating how our broad biologics pipeline is targeting the multiple ways cancer evades the immune system. We will update on our scientific progress in cancer Immuno-Oncology, including predictive biomarkers of response to immune checkpoint inhibitors. We also look forward to presenting the first clinical trial results for our TLR 7/8 agonist, an important mechanism for immunologically-silent tumours, and to sharing updates from our Antibody-Drug Conjugate platform, a key pillar of AstraZeneca’s oncology strategy."

Shedding new light on Tumour Drivers and Resistance

AstraZeneca was a pioneer in the development of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for patients with non-small cell lung cancer (NSCLC) (Iressa, Tagrisso), and continues to work on the unmet needs of patients who fail to respond, or respond for limited periods, to these compounds. An expanding programme of tumour cell-death research is targeting upregulation of key proteins that cancer cells use to evade death, including myeloid cell leukaemia 1 (MCL-1) and cyclin-dependent kinase 9 (CDK9) and is leveraging the sophistication of macrocyles – larger, cyclic compounds – to address the complexity of protein interactions.

Presentations include:

AZD4205, a potent inhibitor of Janus kinase 1 (JAK1), part of the JAK1/signal transducer and activator of transcription (STAT) axis, which is understood to play an important role in tumour escape from EGFR-targeted treatment (oral presentation; Abstract #979)
The first preclinical data presented on AZD5991 demonstrating the tumour cell-killing potential of this potent, selective macrocylic inhibitor of MCL-1 in blood cancers (oral presentation; Abstract #DDT01)
AZD4205 combined with Tagrisso (osimertinib) in patients with EGFR mutation-positive NSCLC to reduce residual tumour burden and prolong the benefit of osimertinib (Abstract #4046)
Preclinical data supporting the potential of the CDK9 inhibitor, AZD5576, alone and in combination with AstraZeneca’s potentially best-in-class Bruton’s tyrosine kinase (BTK) inhibitor, acalabrutinib, in the treatment of non-Hodgkin lymphoma (Abstract #4295).
A leading DNA Damage Response (DDR) position

With one approved medicine and four candidates in clinical development, AstraZeneca is extending its leadership in medicines that target novel DDR deficiencies to selectively kill cancer cells, while minimising the impact on normal cells.

Four oral presentations will include the following data:

Phase I/II studies exploring the combination of Lynparza (olaparib) and temozolomide (an alkylating chemotherapy) in patients with small-cell lung cancer (SCLC) following failure of prior chemotherapy (Abstract #CT048), and
A Phase I study of Lynparza and the alpha-specific PI3-kinase inhibitor BYL719, in patients with recurrent ovarian and breast cancer (Abstract #CT008)
Preclinical data uncovering a novel role for the bromodomain protein, BRD4, in regulating DNA replication-stress response, and the potential of the combination of the BRD4 inhibitor, AZD5153, and the ATR inhibitor, AZD6738, in the sustained delay of tumour growth (Abstract #1026)
The European paediatric precision medicine programme in recurrent tumours showing first results from the MAPPYACTS molecular profiling trial aimed at increasing the number of targetable genomic alternations for DDR therapies (Abstract #CT004)
Preliminary results will also be reported from a Phase I dose-escalation study of the ataxia-telangiectasia and Rad3 related (ATR) inhibitor, AZD6738, in advanced solid tumours (PATRIOT Part A) (Abstract #CT084).

Immuno-Oncology (IO): Activating the immune system via multiple approaches

Presentations will illustrate the depth of AstraZeneca’s IO capabilities beyond its comprehensive late-stage portfolio.

Key presentations include:

Oral presentation of innovative computer modelling to identify tumour and immune cell interactions during disease progression to predict susceptibility to checkpoint inhibitors and other compounds (Abstract #975)
Phase I data on the Toll-like receptor 7/8 (TLR7/8) agonist MEDI9197 in solid tumours (Abstract #CT091) and preclinical data showing its anti-tumour activity in combination with PD-L1 or CTLA-4 checkpoint inhibitors (Abstract #4697)
Phase I/II data showing that high pre-treatment levels of interferon gamma gene signature are associated with greater benefit with durvalumab in patients with NSCLC and urothelial bladder cancer (Abstract #1773).
Antibody-Drug Conjugates: Sophisticated targeting of toxic payloads

AstraZeneca will share data demonstrating the potential of a range of ADCs in targeting cytotoxic treatments to tumour cells. These include preclinical data with toxic pyrrolobenzodiazepine (PBD) or tubulysin payloads in combination with multiple immunotherapies (Abstract #4596), and data on the potent anti-tumour activity of ADCT-401/MEDI3726 when targeting prostate-specific membrane antigen (PSMA) in prostate cancer models (Abstract #3111A).

AbbVie and M2Gen Announce New Collaboration for the Oncology Research Information Exchange Network® (ORIEN) Avatar Research Program

On March 28, 2017 AbbVie, a global biopharmaceutical company, and M2Gen, a leading health informatics solutions company, reported that AbbVie has joined the Oncology Research Information Exchange Network (ORIEN) Avatar Research Program (Press release, AbbVie, MAR 28, 2017, View Source [SID1234518286]). Launched in April of 2016, the ORIEN Avatar Research Program fosters collaboration among key stakeholders in cancer research with the shared goal of discovering and developing novel therapies in clinical trials.

ORIEN Avatar is a collaboration between the 15 leading U.S. cancer hospitals that comprise ORIEN, leading pharmaceutical companies and M2Gen, which manages the program. AbbVie is the fourth pharmaceutical company to participate in the Avatar Program.

The ORIEN Avatar Research Program was borne out of the ORIEN Cancer Initiative, which launched in 2014. A first-of-its-kind effort in cancer research, ORIEN joins leading cancer centers across the U.S. to better study the disease and encourage collaboration in research and development across nearly 20 types of cancer. ORIEN Avatar’s current focus areas have the potential to affect more than 1.4 million newly diagnosed patients in the U.S. annually. Patients at participating ORIEN hospitals donate clinical and molecular data through their consent to the Total Cancer Care (TCC) Protocol, building a wealth of data that includes more than 150,000 patients to date.

The Avatar Program represents an unprecedented, pre-competitive approach to fighting cancer. Cancer researchers contribute samples and disease information from patients who have consented to the Total Cancer Care Protocol. This provides rich molecular data that helps identify eligible participants for clinical trials. Pharmaceutical companies contribute financial support, and both companies and ORIEN member institutions receive access to de-identified genetic and disease information that can be used to inform the discovery and clinical development of novel cancer therapeutics. By matching the right patient to the right trial, ORIEN Avatar helps to accelerate the discovery and development of novel therapies for millions of patients.

"The ORIEN Avatar Research Program offers a unique and important opportunity in the effort to develop new treatments and cures for cancer," said Steve Davidsen, Vice President, Oncology Discovery, AbbVie. "We see enormous potential to improve patient recruitment and targeting for clinical trials, especially more in specific subsets of patients. Through the collaborative efforts of the ORIEN Avatar participants, we can magnify the collective data on specific tumor types and biomarkers to catalyze future discoveries for patients in need."

"We are pleased to welcome AbbVie to the ORIEN Avatar Research Program, and inspired by their commitment, to oncology research and development," said William Dalton, PhD, MD, founder and CEO of M2Gen. "This program offers the opportunity to make great strides in how we treat cancer. AbbVie is a partner that clearly understands the potential of ORIEN Avatar; that common understanding and passion for the work will only further enable our success for cancer patients."

GERMAN FEDERAL JOINT COMMITTEE?(G-BA) CONFIRMS ADDITIONAL BENEFIT OF ANTICANCER AGENT KISPLYX(R) (LENVATINIB MESYLATE) IN TREATMENT OF ADVANCED RENAL CELL CARCINOMA

On March 28, 2017 Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") reported that the German Federal Joint Committee (G-BA) has confirmed the additional benefit of in-house developed anticancer agent Kisplyx (lenvatinib mesylate) in combination with everolimus for the treatment of advanced renal cell carcinoma (RCC) compared to everolimus alone in its assessment for insurance reimbursement (Press release, Eisai, MAR 28, 2017, View Source [SID1234518279]). Based on this additional benefit assessment, price negotiations with the Head Association of German Sick Funds (GKV-SV) will be conducted, and a reimbursement price has to be agreed.

The G-BA’s assessment was based on a Phase II clinical study (Study 205)1 that evaluated the safety and efficacy of Kisplyx in combination with everolimus in patients with unresectable advanced or metastatic RCC following one prior vascular endothelial growth factor (VEGF) targeted therapy. From the results of the study, the Kisplyx plus everolimus group demonstrated a significant extension in the study’s primary endpoint of progression free survival (PFS) compared to the everolimus alone group. Furthermore, the Kisplyx plus everolimus group demonstrated an extension in median overall survival (OS) compared to the everolimus alone group.2
The most common treatment-emergent adverse events (TEAEs) reported in the Kisplyx plus everolimus group were diarrhea, decreased appetite and fatigue. The most common TEAEs of Grade 3 or higher (Common Terminology Criteria for Adverse Events) were diarrhea, hypertension and fatigue.

The number of patients with renal cancer is estimated to be approximately 115,000 in Europe in 2012.3 Renal cell carcinoma comprises more than 90% of all malignancies of the kidney,4 and originates from malignant cells in the lining of the tubules of the kidney. The incidence of renal cell carcinoma in people over 55 years of age is rising, and it is more likely to affect men than women. For advanced or metastatic RCC that is difficult to treat with surgery, the standard treatment is molecular targeted drug therapy. However, with low 5-year survival rates, RCC remains a disease with a significant unmet medical need.

In Europe, lenvatinib mesylate has been designated as an orphan drug for thyroid cancer and is marketed as Lenvima for this indication.

Eisai positions oncology as a key therapeutic area, and is aiming to discover revolutionary new medicines with the potential to cure cancer. Eisai remains committed to expanding access to Kisplyx and maximizing value of the drug 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. Glossary of Terms
1) German Federal Joint Committee (G-BA)
The German Federal Joint Committee (Gemeinsamer Bundesausschuss, G-BA) is the highest decision-making body of the joint self-government of physicians, dentists, hospitals and health insurance funds in Germany. It issues directives for the benefit catalog of statutory health insurance funds (GKV) and thus specifies which drugs and medical services are reimbursed by the GKV.

2) About additional benefit assessment conducted by the G-BA
In Germany, the enactment of the Act on the Reform of the Market for Medical Products (Arzneimittelmarkt-Neuordnungsgesetz, AMNOG) came into effect on January 2011. Under this amendment, all eligible new drugs launched on the German market must undergo an additional benefit assessment conducted by the G-BA, with later price negotiations to be based on this assessment, and a reimbursement price to be agreed upon within one year from the drug’s launch.

Furthermore, when a new drug is launched, the pharmaceutical company must submit to the G-BA a benefit dossier demonstrating the drug’s additional benefit over a comparator. The G-BA then usually commissions the country’s Institute for Quality and Efficiency in Health Care (Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen: IQWiG) to evaluate the dossier to decide whether any additional benefit exists over the comparator. The pharmaceutical company is next given an opportunity to comment on the IQWiG’s evaluation, after which the G-BA carries out its final decision regarding any additional benefit of the drug.

If an additional benefit is recognized by the G-BA, the drug proceeds to the price negotiation stage with the lead association of the German sick funds (GKV-Spitzenverbandes: GKV-SV), and a reimbursement price has to be agreed upon based on the level of additional benefit as decided by the G-BA. On the other hand, if a drug is deemed to offer no recognized additional benefit or if the additional benefit cannot be proven, the drug is designated a reference price group as well as a reimbursement price based on the price of the comparator used during the benefit assessment.

2. About lenvatinib mesylate (brand names: Lenvima, Kisplyx, "lenvatinib")
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. Specifically, Eisai has obtained approval for the agent indicated 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 VEGF-targeted therapy in Europe in August 2016.

In Europe, lenvatinib has been designated as an orphan drug for thyroid cancer and is marketed as Lenvima for this indication. In Europe, renal cell carcinoma does not meet the criteria for orphan drug designation. Accordingly, under European regulations, any licensed medicine that previously received orphan drug designation for an indication and subsequently receives license for a non-orphan indication must be marketed under a different trade name. As such, lenvatinib will be marketed as Kisplyx in the European Union for the indication covering renal cell carcinoma.
Furthermore, Eisai is currently preparing global submissions for lenvatinib in the treatment of unresectable hepatocellular carcinoma (HCC). In addition, Eisai is currently conducting several clinical trials, including a Phase III clinical study of lenvatinib in combinations with both pembrolizumab and everolimus in RCC (first-line therapy), a Phase II clinical study in biliary tract cancer, and in combination with pembrolizumab for various types of cancer (Phase Ib/II).

3. About the Phase II Clinical Study (Study 205)1
Study 205 was a multicenter, randomized, open-label study of the combination of lenvatinib (18 mg) plus everolimus (5 mg), lenvatinib alone (24 mg), and everolimus alone (10 mg) in patients with unresectable advanced or metastatic renal cell carcinoma following one prior VEGF-targeted therapy, and was conducted in Europe and the United States. 153 patients were randomized in a 1:1:1 ratio to one of three treatment arms to compare the efficacy and safety of these three regimens.

From the results of the study, the combination of lenvatinib plus everolimus group demonstrated a significant extension in the study’s primary endpoint of progression free survival (PFS) compared to the everolimus alone group (median PFS for the lenvatinib plus everolimus group: 14.6 months vs median PFS for the everolimus alone group: 5.5 months; Hazard Ratio (HR) 0.40 [95% CI: 0.24-0.68], p=0.0005). Additionally, median PFS for the lenvatinib alone group was 7.4 months, demonstrating an extension in PFS compared to the everolimus alone group (HR: 0.61 [95% CI: 0.38-0.98]).

The study also assessed objective response rate (ORR) and overall survival (OS) as secondary endpoints. Regarding ORR, both the lenvatinib plus everolimus group and the lenvatinib alone group showed an improvement in ORR compared to the everolimus alone group (lenvatinib plus everolimus: 43%, lenvatinib alone: 27%, everolimus alone: 6%). Additionally, regarding OS, an updated analysis carried out in December 2014 suggested that lenvatinib plus everolimus extends OS compared to everolimus alone (HR 0.51 [95% CI=0.30-0.88]).

Furthermore, regarding OS, updated median overall survival in the study population was 25.5 months in the lenvatinib plus everolimus group compared with 15.4 months in the everolimus group (HR 0.59 [ 95% CI 0.36 – 0.97]).2
The most common any-grade treatment-emergent adverse events (TEAEs) reported in the lenvatinib plus everolimus group were diarrhea, decreased appetite and fatigue. The most common TEAEs of Grade 3 or higher (Common Terminology Criteria for Adverse Events) were diarrhea, hypertension and fatigue.