On December 8, 2021 Epic Sciences, Inc. (Epic)’s comprehensive liquid-biopsy platform reported that continues to deliver compelling cancer profiling information as data presented during the San Antonio Breast Cancer Symposium 2021 demonstrate (Press release, Epic Sciences, DEC 8, 2021, View Source [SID1234596626]).

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"These findings represent just some of the useful information novel liquid biopsies can provide" says Dr. Joyce O’Shaughnessy, Celebrating Women Chair of Breast Cancer Research, Baylor University Medical Center and Chair of Breast Cancer Program, Texas Oncology and the US Oncology Network. "Once patients begin treatment for metastatic disease, the cancer remodels itself to evade therapy, and it is difficult to assess the molecular changes that enable this process. New targeted therapies are driving heterogeneous resistance mechanisms, and insights from liquid biopsies analyzing circulating tumor cells can help oncologists decide when to change therapy, and how to sequence therapies."

Since 2018, the Epic platform has been providing clinically validated predictive information about selective hormone therapy resistance for patients with metastatic prostate cancer. Top academic and pharmaceutical research teams have leveraged the Epic platform to track drug target engagement, monitor response to treatment protocols, and select or stratify patients based on cell characterization.

"Epic’s comprehensive liquid-biopsy platform is uniquely suited to elucidate metastatic breast cancer biology", says Dr. Richard Wenstrup, Chief Medical Officer, Epic Sciences, Inc. "Frequent tissue biopsies from metastatic patients are usually not medically practical, but it is critical to obtain information about the current state of the patient’s disease. Genome-based liquid-biopsy options address a small part of this challenge, but it is the cell-based liquid biopsy analysis that completes the picture.

It has previously been shown that certain types of cell-based morphology confer poor prognosis for metastatic prostate cancer patients, and this data now confirms similar results for metastatic breast cancer patients. This cell imaging analysis identified heterogeneous disease and specific morphological phenotypes that predict for shortened survival.

"This is one of several of Epic’s collaborative studies that will produce new insights about metastatic breast cancer from the blood. Look for our forthcoming announcement about new breast-cancer offerings in our clinical lab and for our research partners," adds Lloyd Sanders, President and CEO, Epic Sciences.

Poster P2-02-03 Circulating tumor cells (CTCs), CTC heterogeneity and distinct morphological CTC phenotypes predict worse survival in metastatic breast cancer (MBC)

On December 8, 2021 Affimed N.V. (Nasdaq: AFMD) a clinical-stage immuno-oncology company committed to giving patients back their innate ability to fight cancer, reported the initiation of patient recruitment for the open-label, multi-center phase 1/2a study evaluating the safety, tolerability, pharmacokinetics and efficacy of the innate cell engager (ICE) AFM24 in combination with Roche’s atezolizumab, an anti-PD-L1 checkpoint inhibitor (Press release, Affimed, DEC 8, 2021, View Source [SID1234596608]). AFM24 is Affimed’s tetravalent, bispecific epidermal growth factor receptor (EGFR)- and CD16A-targeting ICE, developed for the treatment of patients with solid tumors.

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"Natural killer cells, which are part of the innate immune system, have the ability to recognise cancer cells. AFM24, a novel immunotherapy, aims to redirect and engage these natural killer cells by linking them to a protein called EGFR, which is expressed on many solid tumours, to increase their tumour killing potency," said Dr Juanita Suzanne Lopez, Consultant Medical Oncologist at The Royal Marsden and Clinical Researcher at The Institute of Cancer Research, London and principal investigator for the study. "By combining AFM24 with an immune checkpoint inhibitor, we aim to activate both the innate and the adaptive immune system to improve patient outcomes. This approach has exciting potential for a broad range of tumour types, including lung, gastroesophageal, liver and pancreatic cancers."

The study will consist of two parts. The first part is a dose escalation phase, aiming to determine the maximum tolerated dose/recommended phase 2 dose of AFM24 in combination with atezolizumab. In the second part, the expansion phase (phase 2a), the goal is to collect preliminary evidence of efficacy as well as to confirm the safety of the therapeutic combination. The trial will include patients with solid tumors, including non-small cell lung cancer (NSCLC, EGFR-wildtype), gastric- and gastroesophageal junction adenocarcinoma and pancreatic/hepatocellular/biliary tract cancer. All patients have failed ≥1 prior line of treatment before receiving the combination of AFM24 and atezolizumab.

"Initiation of this trial is an important step in our three-pronged approach for developing our ICE molecules. We are driven by the biology of the targets and cancer indications to identify the right approach evaluating AFM24 in monotherapy, together with NK cells or immunotherapy," said Dr. Andreas Harstrick, CMO at Affimed. "We believe that the combination with anti-PD-L1 has the potential to provide benefits to a broad population of cancer patients."

Preclinical studies of AFM24 have demonstrated a good safety profile and anti-tumor activity. AFM24 monotherapy is currently being investigated in adult patients with advanced EGFR-positive solid malignancies in an open-label, non-randomized, multi-center, multiple ascending dose escalation/expansion study.

A Phase 1b study of another ICE, AFM13, in combination with the anti-PD-1 checkpoint inhibitor pembrolizumab has been published in Blood last year (Bartlett et al. Blood 2020, 136 (21): 2401–09), demonstrating an objective response rate (ORR) of 88% and a complete response (CR) rate of 46% at the recommended dose level in patients with relapsed/refractory Hodgkin lymphoma. The high ORR and CR rate in this proof-of-concept study were considered highly encouraging for the combination of the ICE with a checkpoint inhibitor and indicated that the activation of innate immunity has the potential to improve current therapies.

About AFM24
AFM24 is a tetravalent, bispecific innate cell engager (ICE) that activates the innate immune system by binding to CD16A on innate immune cells and EGFR, a protein widely expressed on solid tumors, to kill cancer cells. Generated by Affimed’s fit-for-purpose ROCK platform, AFM24 represents a distinctive mechanism of action that uses EGFR as a docking site to engage innate immune cells for tumor cell killing through antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis.
In addition to the AFM24-102 study presented here (NCT05109442), Affimed is evaluating AFM24 as a monotherapy (AFM24-101) for patients with advanced EGFR-expressing solid malignancies whose disease has progressed after treatment with previous anticancer therapies. The first-in-human Phase 1/2a open-label, non-randomized, multi-center, multiple ascending dose escalation and expansion study and can be found at www.clinicaltrials.gov using the identifier NCT04259450.
Furthermore, Affimed and NKGen Biotech have initiated a Phase 1/2a study (AFM24-103) in November 2021, evaluating AFM24 in combination with SNK01, NKGen Biotech’s NK cell product (NCT05099549).

On December 8, 2021 GT Biopharma, Inc. (the "Company") (NASDAQ: GTBP), a clinical stage immuno-oncology company focused on developing innovative therapeutics based on the Company’s proprietary natural killer (NK) cell engager, TriKE protein biologic technology platform, reported that the Company’s mini-poster presentation abstract is now broadly available on the European Society for Medical Oncology ("ESMO") Immuno-Oncology ("IO") Congress 2021 abstracts webpage (Press release, GT Biopharma, DEC 8, 2021, View Source [SID1234596627]). The congress is being held from December 8-11, 2021, in Geneva Switzerland.

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"B7-H3 is a checkpoint molecule under intense investigation as an immune therapy target for solid and hematologic tumors. These proof of concept data via in vivo animal models validates GTB-5550’s candidacy for further investigation, noted Dr. Gregory Berk, President of R&D, Chief Medical Officer and Interim Chief Executive Officer. GT BioPharma’s diverse but focused pipeline of TriKE Nanobodies are highly targeted natural killer cell engagers, resulting in potent activation, proliferation, and persistence of the patient’s NK cells, without activation of T-cells, which are often responsible for the side effects of T-cell directed therapies. As such, we look forward to continuing the Company’s progress in the new year including the advancement of GTB-3650, second-generation TRIKE for patients with relapsed/refractory Acute Myelogenous Leukemia (AML) and high-risk Myelodysplastic Syndrome (MDS)."

The study was conducted by Dr. Jeff Miller’s lab, University of Minnesota where functional assays were conducted with various ovarian, prostate, and hematologic malignancy cell lines with varying levels of B7H3 expression from none to very high levels. Dr. Miller’s lab previously showed that dual camelid nanobody tri-specific killer engager (TriKE) (GTB-5550) specifically bound B7-H3 on PC3/C4-2 prostate cancer (PCa) cells and activated peripheral blood (PB) NK cells. We have since developed a dual camelid bispecific killer engager (BiKE) targeting B7-H3 and show that both GTB-5550, which harbors wild-type IL-15, and BiKE display broad activity against B7-H3-expressing tumors. Compared to monomeric IL-15, GTB-5550 shows CD16-dependent metabolic activation of NK cells.

Presentation highlights from the mini-poster titled, "Novel B7-H3 Targeting Dual-Nanobody NK Cell Engagers Display Robust Activity" include:

Study Background
BiKE and GTB-5550 were manufactured in a mammalian expression system and purified from supernatants.
Models were used to evaluate how the BiKE and GTB-5550 induce NK cell degranulation (CD107a) and interferon gamma production through a variety of cell lines including PCa cells harboring enzalutamide resistance with divergent mechanisms including 22RV1 (androgen ligand-independent AR-V7 splice variant) as well as a spontaneously resistant LNCaP model (AR hyper activation), as well as a CREB5 overexpressing (epithelial to mesenchymal transition) LNCaP model.
Metabolic stimulation was measured in NK-92 cell lines.
PB NK cells were robustly activated, compared to controls, when treated with GTB-5550 or BiKE and cultured with enzalutamide resistant PCa, osteosarcoma (U2OS, SaOS2), rhabdomyosarcoma (RH30), ovarian carcinoma (MA148, OVCAR8), AML (MV4;11, THP-1) and multiple myeloma (MM1S) cell lines.
GTB-5550 was approximately 2 times more potent than NCI IL-15 in terms of metabolic stimulation of CD16+ NK-92 cells, but not CD16- NK-92 cells. Spheroid killing assays and deeper metabolic analyses are in progress.
Results of the Study
The data demonstrated that the novel dual camelid nanobody BiKE and GTB-5550 induce NK cell activation against a broad spectrum of tumors expressing B7-H3. Furthermore, B7-H3 is expressed at high levels on prostate cancer cell lines demonstrating enzalutamide resistance, thus inducing efficient targeting of these therapy PCa refractory lines. This B7-H3 targeting NK platform demonstrates broad translational potential. GMP production of GTB-5550 has been initiated.
ESMO IO 2021 presentation details

e-Poster Display Title (#126P): Novel B7-H3 targeting dual nanobody NK cell engagers display robust activity against a broad spectrum of solid and hematologic malignancies

The full abstract has been published on ESMO (Free ESMO Whitepaper)-IO website and the Company has published the poster on the company’s website in the "Presentations" section of its corporate website.

For event details please visit: View Source

About Camelid Antibodies

Camelid antibodies are single domain antibodies (sdAbs) from the Camelidae family of mammals that include llamas, camels, and alpacas. These animals produce 2 main types of antibodies. One type of antibody camelids produce is the conventional antibody that is made up of 2 heavy chains and 2 light chains. They also produce another type of antibody that is made up of only 2 heavy chains and no light chain. This is known as heavy chain IgG (hcIgG). While these antibodies do not contain the CH1 region, they retain an antigen binding domain called the VHH region. VHH antibodies, also known as single domain antibodies, contain only the VHH region from the camelid antibody. Camelid antibodies have key characteristics, which include high affinity and specificity (equivalent to conventional antibodies), high thermostability, good solubility and strictly monomeric behavior, small size, relatively low production cost, ease of genetic engineering, format flexibility or modularity, low immunogenicity, and a higher penetration rate into tissues.

About GTB-5550

GTB-5550 TriKE product candidate is being developed for the treatment of B7H3+ solid tumor cancers. GTB-5550 is a single-chain, tri-specific scFv recombinant fusion protein conjugate composed of the variable regions of the heavy and light chains of anti-CD16 and anti-B7H3 antibodies and human IL-15.

About GTB-3650

GTB-3650 is the Company’s lead second-generation Tri-Specific Killer Engager TriKE program currently in preclinical development for the treatment of relapsed/refractory acute myelogenous leukemia (AML) and high-risk myelodysplastic syndrome (MDS).

On December 8, 2021 EpiAxis Therapeutics reported it is commencing a pre-clinical collaboration focused on inhibiting Protein Kinase C theta (PKC theta), which could provide a potential new approach to treating cancer (Press release, EpiAxis Therapeutics, DEC 8, 2021, View Source;utm_medium=rss&utm_campaign=epiaxis-expands-pkc-theta-pre-clinical-program [SID1234596591]).

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PKC theta is upregulated in a variety of solid and haematological cancers and is associated with promoting tumour aggressiveness, metastasis, and resistance to therapy. PKC theta also plays an important role in immune regulation.

EpiAxis is collaborating with Dr Hanna Y Irie, MD, PhD, Associate Professor of Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai and a leading research scientist in the PKC theta cancer sector. Under the collaboration, EpiAxis will provide Dr. Irie with its PKC theta inhibitors for evaluation in breast cancer models.

Mt Sinai oncology

"This is an important collaboration for EpiAxis as we expand our pre-clinical program to advance our PKC theta assets," said EpiAxis CEO Dr Jeremy Chrisp. "We are delighted to be collaborating with Dr Irie’s team at the Icahn School of Medicine as this complements and strengthens our existing focus on LSD1 in breast cancer."

"This is an exciting opportunity to validate novel inhibitors against a promising therapeutic target for triple negative breast cancer, a particularly aggressive subtype that we have been studying for many years," said Mount Sinai’s Dr Irie about the partnership with EpiAxis.. "Once validated, we hope to translate these inhibitors for the benefit of patients."

Dr Irie (above) is a physician-scientist at Mount Sinai’s Tisch Cancer Institute whose research program is focused on identifying, validating, and translating novel therapeutic targets for high-risk breast cancers, especially drug-resistant and metastatic disease. While maintaining an active clinical practice as a breast medical oncologist, she has led translational efforts at Mount Sinai’s Dubin Breast Center, including the creation of the Breast Tumor Biorepository and generation of patient-derived xenograft (PDX) models of high risk and metastatic breast cancers, particularly triple negative, from diverse populations. Dr Irie’s research team has used phenotypic, genetic, and pharmacologic screening strategies to identify novel candidate therapeutic targets for breast cancer cells that are resistant to current standard-of-care treatments.

Dr Irie has published research papers in Nature Communications, Cell Reports, Cancer Research, NPJ Breast Cancer, Breast Cancer Research and Oncotarget, and her research on PKC theta has been supported by the American Association for Cancer Research (AACR) (Free AACR Whitepaper) and the Breast Cancer Research Foundation.

She received her MD and PhD degrees from Harvard Medical School, where she also completed her post-doctoral research fellowship. Dr Irie completed her clinical fellowship in Medical Oncology at the Dana-Farber Cancer Institute and Massachusetts General Hospital.

On December 8, 2021 Novartis reported new Kisqali (ribociclib) data demonstrating a consistent overall survival (OS) benefit with Kisqali plus endocrine therapy (ET) across genomic subtypes of hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced or metastatic breast cancer (mBC), similarly in the indolent as well as in the aggressive, endocrine therapy (ET)-resistant subtypes6 (Press release, Novartis, DEC 8, 2021, View Source [SID1234596611]). The findings will be presented as a late-breaking oral presentation at the 2021 San Antonio Breast Cancer Symposium (SABCS).

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"The overall survival benefit seen even in HER2-enriched adds to the body of evidence supporting the need to test the hypothesis that ribociclib may alter tumor biology, resulting in a better response to ET across common HR+/HER2- subtypes," said Aleix Prat, President of SOLTI, Head of the Medical Oncology Department at Hospital Clínic of Barcelona, Head of the Translational Genomics Group and Targeted Therapies in Solid Tumors at IDIBAPS and Professor of Medicine at the University of Barcelona. "One of the most interesting aspects of these ribociclib data is the overall survival benefit seen across the spectrum of indolent, less proliferative disease compared to the aggressive and ET-resistant disease, assuring the overall survival benefit of ribociclib in patients regardless of their baseline prognosis."

A broad ad hoc exploratory analysis of nearly 1,000 tumor samples showed that Kisqali in combination with ET consistently provided significant OS benefit compared to ET alone across main intrinsic subtypes (Luminal A: n=542; HR=0.75; 95% CI: 0.58-0.96; p=.021; Luminal B: n=278; HR=0.69; 95% CI: 0.50-0.95; p=.023; and HER2-enriched: n=147; HR=0.60; 95% CI: 0.40-0.92; p=.018)6. Patients with the HER2-enriched subtype associated with endocrine resistance and poor prognosis in HR+/HER2- breast cancer, achieved a significant improvement in median OS of 40.3 months compared to 29.4 months for ET alone6. The longest survival benefit from Kisqali plus ET was seen in patients with the luminal A subtype, who achieved a median OS of 68.0 months compared to 54.6 months on ET alone6. Patients with basal-like subtype, which is known to behave more like triple-negative breast cancer, had poorer OS outcomes in both the Kisqali combination and ET alone groups with a median OS of 19.4 months and 21.2 months, respectively (n=30; HR=1.89; 95% CI: 0.80-4.47; p=.148)6. These data follow the biomarker analysis of the MONALEESA trials presented at SABCS 2020 and published in Journal of Clinical Oncology, in which Kisqali demonstrated-progression free survival (PFS) benefit across the most common intrinsic subtypes in metastatic breast cancer9-10.

The four intrinsic subtypes of breast cancer (Luminal A, Luminal B, HER2-enriched and basal-like) have revealed critical differences in terms of incidence, survival and response to treatment11-15. Additionally, the insights provided by genomic intrinsic subtypes complement and expand upon the information provided by standard clinical parameters and pathological markers.

"The consistent overall survival data presented at SABCS again show the unique profile of Kisqali, reinforcing the scientific rationale for initiating HARMONIA, the first Phase III, head-to-head trial evaluating Kisqali versus Ibrance in HR+/HER2- metastatic breast cancer," said Susanne Schaffert, PhD, President of Novartis Oncology. "We know that for people living with metastatic breast cancer, quality of life in addition to extending life is so important to them, so we are excited to share meaningful outcomes from a global quality of life assessment."

Additional research of interest to be presented at SABCS includes the following:

Abstract Title Abstract Number/
Presentation Details
Genomic profiling of PAM50-based intrinsic subtypes in HR+/HER2- advanced breast cancer across the MONALEESA studies17 PD2-05
Wednesday, December 8 7:00am CT
Analysis of first-line patients with de novo disease vs late relapse and all pts with vs without prior chemotherapy in the MONALEESA-3 trial18 P1-18-11
Wednesday, December 8,
7:00am CT

Overall survival subgroup analysis by metastatic site from the Phase III MONALEESA-2 study of first-line ribociclib + letrozole in postmenopausal patients with HR+/HER2− advanced breast cancer8 GS2-01
Wednesday, December 8
8:45am CT
Circulating tumor DNA (ctDNA) dynamics in patients with hormone receptor positive HR+/HER2- advanced breast cancer treated in first line with ribociclib and letrozole in the BioItaLEE trial19 GS3-07
Thursday, December 9
10:15am CT
Assessment of quality of life in patients with advanced breast cancer in clinical practice: a real-world multi-country survey16 P4-12-03
Thursday, December 9
5:00pm – 6:30pm CT
Visit View Source for the latest information from Novartis, including our commitment to the Oncology community, and access to our SABCS Virtual Scientific Program data presentations (for registered participants).

About Kisqali (ribociclib)
Kisqali is the CDK4/6 inhibitor with the largest body of clinical trial evidence demonstrating consistent and superior overall survival benefit compared to endocrine therapy alone. Overall survival results were presented previously: MONALEESA-7 (ASCO 2019) and MONALEESA-3 (ESMO 2019) and MONALEESA-2 (ESMO 2021); MONALEESA-7 and MONALEESA-3 were published in the New England Journal of Medicine, with updated exploratory analyses presented at SABCS 2020 and ASCO (Free ASCO Whitepaper) 2021, demonstrating Kisqali plus endocrine therapy significantly extends life in pre/perimenopausal or postmenopausal women with HR+/HER2- advanced breast cancer1-5.

Kisqali is approved by the US Food and Drug Administration (FDA) and by the European Commission (EC) as initial endocrine-based therapy for postmenopausal women with HR+/HER2- locally advanced or metastatic breast cancer in combination with an aromatase inhibitor. Kisqali in combination with an aromatase inhibitor is approved for the treatment of pre-, peri- or postmenopausal women as initial endocrine-based therapy, and also indicated for use in combination with fulvestrant as both first- or second-line therapy in postmenopausal women by the FDA and by the EC20. Kisqali is approved in over 95 countries21.

Novartis is continuing to reimagine cancer with additional trials of Kisqali. NATALEE is a large confirmatory clinical trial of Kisqali with endocrine therapy in the adjuvant treatment of HR+/HER2- early breast cancer being conducted in collaboration with Translational Research In Oncology (TRIO)22. Novartis is collaborating with the Akershus University Hospital in Norway on the NEOLETRIB-trial, a neoadjuvant phase II trial studying the effects of Kisqali in HR+/HER2- early breast cancer including effects on the gut microbiota and senescence21. Novartis is also collaborating with SOLTI, who is leading the Phase III HARMONIA clinical trial evaluating Kisqali compared to palbociclib in patients with HR+/HER2- advanced breast cancer with aggressive tumor biology, defined as HER2-enriched21.

Kisqali was developed by the Novartis Institutes for BioMedical Research (NIBR) under a research collaboration with Astex Pharmaceuticals.

About Novartis in Advanced Breast Cancer
Novartis tackles breast cancer with superior science, collaboration and a passion for transforming patient care. We’ve taken a bold approach to our research by including patient populations often neglected in clinical trials, identifying new pathways or mutations that may play a role in disease progression and developing therapies that not only maintain, but also improve, quality of life for patients. Our priority over the past 30 years and today is to deliver treatments proven to improve and extend lives for those diagnosed with advanced breast cancer.

Important Safety Information from the Kisqali EU SmPC
Kisqali (ribociclib) is a prescription medicine approved in combination with an aromatase inhibitor as initial endocrine – based therapy in women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer or fulvestrant as initial endocrine – based therapy or following disease progression on endocrine therapy in postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. It is not known if Kisqali is safe and effective in children or adolescents. Kisqali can cause a heart problem known as QT prolongation. This condition can cause an abnormal heartbeat and may lead to death. Kisqali is not indicated for concomitant use with tamoxifen due to an increased risk of QT prolongation. Patients should tell their health care provider right away if they have a change in their heartbeat (a fast or irregular heartbeat), or if they feel dizzy or faint. Kisqali can cause serious liver problems. Patients should tell their health care provider right away if they get any of the following signs and symptoms of liver problems: yellowing of the skin or the whites of the eyes (jaundice), dark or brown (tea-colored) urine, feeling very tired, loss of appetite, pain on the upper right side of the stomach area (abdomen), and bleeding or bruising more easily than normal. Low white blood cell counts are very common when taking Kisqali and may result in infections that may be severe. Patients should tell their health care provider right away if they have signs and symptoms of low white blood cell counts or infections such as fever and chills. Before taking Kisqali, patients should tell their health care provider if they are pregnant, or plan to become pregnant as Kisqali can harm an unborn baby. Females who are able to become pregnant and who take Kisqali should use highly effective birth control during treatment and for at least 3 weeks after the last dose of Kisqali. Do not breastfeed during treatment with Kisqali and for at least 3 weeks after the last dose of Kisqali. Patients should tell their health care provider about all of the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements since they may interact with Kisqali. Patients should avoid grapefruit or grapefruit juice while taking Kisqali. The most common side effects (incidence >=20%) include infections, white blood cell count decreases, headache, cough, nausea, tiredness, diarrhea, vomiting, constipation, hair loss and rash. The most common Grade 3/4 side effects (incidence >5%) were infections, low neutrophils, low leukocytes, low red blood cells, abnormal liver function tests, low lymphocytes, low phosphate levels and vomiting. Abnormalities were observed in hematology and clinical chemistry laboratory tests.