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Efficacy and Safety of Nanosomal Docetaxel Lipid Suspension-Based Chemotherapy in Sarcoma: A Multicenter, Retrospective Study

Efficacy and Safety of Nanosomal Docetaxel Lipid Suspension-Based Chemotherapy in Sarcoma: A... Hindawi Sarcoma Volume 2019, Article ID 3158590, 7 pages https://doi.org/10.1155/2019/3158590 Research Article Efficacy and Safety of Nanosomal Docetaxel Lipid Suspension-Based Chemotherapy in Sarcoma: A Multicenter, Retrospective Study 1 2 3 Prasad Narayanan, Palanki Satya Dattatreya, Rammohan Prasanna, 4 5 2 6 Sundaram Subramanian, Kunal Jain, Nirni Sharanabasappa Somanath, Nisarg Joshi, 6 6 6 7 Deepak Bunger, Mujtaba Ali Khan, Alok Chaturvedi, and Imran Ahmad Cytecare Cancer Hospitals, Yelahanka, Bengaluru, Karnataka 560064, India Omega Hospitals, Hyderabad, Telangana 500034, India Department of Medical Oncology, CBCC-GVN Cancer Center, Tiruchirapalli, Tamil Nadu 620005, India VS Hospital, Madras Cancer Institute, Advanced Cancer Care, Chennai, Tamil Nadu 600031, India American Oncology Institute, Dayanand Medical College & Hospital, Ludhiana, Punjab 141001, India Medical Affairs and Clinical Development, Intas Pharmaceuticals Ltd., Sola, Ahmedabad, Gujarat 380054, India Jina Pharmaceuticals Inc., Libertyville, Green Oaks, Illinois 60048, USA Correspondence should be addressed to Imran Ahmad; imran@jinapharma.com Received 11 September 2019; Accepted 25 October 2019; Published 15 November 2019 Academic Editor: John D. Reith Copyright © 2019 Prasad Narayanan et al. *is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Objective. To evaluate the efficacy and safety of nanosomal docetaxel lipid suspension (NDLS, DoceAqualip) based chemotherapy in patients with sarcoma. Methods. In this retrospective, multicenter (6 centers), observational study, we analyzed the medical charts of adult patients of either sex, who were treated with NDLS (75mg/m in 3-weekly cycles) based chemotherapy for the treatment of sarcoma. *e efficacy outcomes were overall response rate (ORR: complete response (CR)+partial response (PR)) and diseasecontrolrate(DCR: CR+PR+stable disease(SD))inpatientswho received NDLS-basedchemotherapyinneoadjuvant and metastatic settings. Overall survival (OS) and safety were evaluated for all settings. Results. Of 11 patients (neoadjuvant: 1, adjuvant: 3, and metastatic: 7) in this study, majority had leiomyosarcoma (63.6%, 7/11) followed by extraskeletal myxoid chondrosarcoma (EMC), high grade pleomorphic sarcoma of mandible, malignant fibrous histiocytoma of right thigh, and osteosarcoma of femur (9.1% each, 1/11 each). NDLS plus gemcitabine combination was used in 10 patients (90.9%), and NDLS plus cyclophosphamide was used in one patient with EMC (9.1%). Efficacy evaluation was performed for 7 patients (neoadjuvant: 1/1; metastatic: 6/7). Complete response was reported in one patient (soft tissue sarcoma of mandible) treated in neoadjuvant setting. In metastatic setting, ORR was 50% and DCR was 66.7% (CR:16.7% (1/6), PR: 33.3% (2/6), SD:16.7% (1/6)). At a median follow-up of 6.5 months (range: 0.06–20.2 months), median OS was not reached in neoadjuvant and adjuvant settings, but it was 15.8 months inmetastaticsetting.Atleast1 AEwasreported in7(63.6%)patients. Neutropenia,thrombocytopenia, lymphopenia, and anemia were the hematological AEs, whereas nausea, vomiting, and diarrhea were the most common nonhematological AEs. NDLS treatment was well tolerated without any new safety concerns. Conclusion. Nanosomal docetaxel lipid suspension-based chemotherapy was efficacious and well tolerated in the treatment of sarcoma. Further prospective trials are needed to confirm the data. 2 Sarcoma conducted after due approval from ethics committee and in 1. Introduction compliance with the protocol. Sarcomas are a rare heterogeneous group of solid tumors and are broadly classified as soft tissue sarcomas (STS) and 2.2. Statistical Considerations. Demographic and baseline bone sarcomas [1, 2]. *e incidence of sarcomas is 2–4/ characteristics were summarized using descriptive sta- 100,000 people [2]. It is common in children accounting for tistics. Categorical variables were summarized with fre- ∼15% of all cancers, whereasit accounts for∼1% of all cancer quency and percentage. Continuous variables were cases in adults [3]. *e incidence of STS was ∼10% as per summarized with count, mean, standard deviation, me- Indian reports [4]. *e most common sarcoma type is STS, dian, minimum, and maximum. Response rate was pre- and the most common sites of STS are extremities (lower sented as frequency and percentage of patients. χ test was limb>upper limb); thigh is the commonest site [2]. With used to compare the distribution of patients in each >50 subtypes available, the most common STSs are pleo- category. Survival analysis was performed to measure morphic sarcoma, gastrointestinal stromal tumors (GIST), lifetime or the length of time until the occurrence of an leiomyosarcoma, synovial sarcoma, liposarcoma, and ma- event (death in case of overall survival). Survival data were lignant peripheral nerve sheath tumors [3]. Osteosarcomas analyzed using a nonparametric procedure which per- are the most common bone sarcomas followed by Ewing’s formed PROC LIFETESTof SAS (version 9.4) to measure sarcomas, and these can present in all bones [5]. the duration of time until a specified event occurs. OS was Multimodality treatment approach, including sur- calculated and analyzed using Kaplan–Meier method and gery, radiation therapy, and chemotherapy, is recom- log-rank test to estimate the survival function from mended for sarcomas [6]. Among many regimens used in lifetime data after treatment. *e AEs were summarized as clinical practice, docetaxel alone [7] or in combination frequencies and percentages by type of reactions. with gemcitabine [8, 9] is recommended by several guidelines [10, 11]. Docetaxel has shown activity in the 3. Results treatment of sarcomas, but toxicity issues such as hy- persensitivity reactions, fluid retention, sensory neuro- 3.1. Patient Disposition and Demographics. Eleven patients toxicity, and anaphylactoid reactions observed in these with sarcoma, who were treated with NDLS-based che- patients [7] are known to be associated with the carrier motherapy, were retrospectively analyzed. Majority of the polysorbate 80 in the conventional docetaxel formula- patients had leiomyosarcoma (63.6%, 7/11). Extraskeletal tion. A solvent-free lipid-based formulation “nanosomal myxoid chondrosarcoma (EMC), high grade pleomorphic docetaxel lipid suspension (NDLS, DoceAqualip)” was sarcoma of mandible, malignant fibrous histiocytoma of the developed [12], which has shown effectiveness and tol- right thigh, and high grade osteosarcoma of femur were erability in the treatment of several cancers including diagnosed in 1 patient each (9.1% each). *e baseline sarcoma [13]. We report here a multicenter, retrospective characteristics of patients are summarized in Table 1. experience in real-life practice evaluating the effective- NDLS was used as 1 hour infusion in 3-weekly cycles at a ness and tolerability of NDLS in the treatment of dose of 75mg/m . NDLS was used as a second-line therapy sarcomas. in majority (8, 72.7%) of the patients; 2 patients (18.2%) received as first-linetherapy,and onepatient(9.1%) asthird- 2. Methods line therapy. Most (9, 81.8%) of the patients were admin- istered premedications; dexamethasone premedication was 2.1. Study Design, Patient Selection, and Endpoints. In this administered to 54.5% patients. All the patients received multicenter (6 centers), retrospective, observational study, G-CSF/Peg-GCSF as primary prophylaxis. NDLS was used we analyzed the medical charts of sarcoma patients who in combination with gemcitabine (dose range: 600–1100mg/ received NDLS-based chemotherapy as part of their routine 2 m ) in 90.9% patients and cyclophosphamide (dose: 600mg/ clinical care between February 2016 and March 2019. *e m ) in 9.1% patients. Table 2 presents the patient details with study endpoints included overall response rate (ORR: chemotherapy regimens used and efficacy evaluation. proportion of patients achieving complete response (CR) and partial response (PR)) and disease control rate (DCR: proportion of patients achieving CR+PR+stable disease 3.2. Efficacy. Patients who received NDLS-based regimen as (SD)) for patients treated in neoadjuvant and metastatic adjuvant chemotherapy (n=3) were considered for safety settings, whereas overall survival (time from treatment to and overall survival analysis. Of 8 patients in neoadjuvant death due to any cause) was evaluated for patients treated and metastatic settings, efficacy evaluation was available for in all settings. Treatment response was evaluated using 7 patients (neoadjuvant: 1 and metastatic: 6). One patient Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 treated in neoadjuvant setting showed complete response [14]. *e National Cancer Institute (NCI) Common Ter- (ORR and DCR: 100%). In the metastatic setting, NDLS- minology Criteria for Adverse Events (CTCAE) Criteria based chemotherapy resulted in an ORR of 50% (CR: 16.7% version 5 [15] were used to grade (where available) the (1/6), PR: 33.3% (2/6)) and DCR of 66.7% (CR: 16.7% (1/6), incidence of adverse events (AEs) recorded from the PR: 33.3% (2/6), SD: 16.7% (1/6)) (Figure 1). Disease pro- treatment charts. Data on death and discontinuations were gression was reported in 2 patients treated in the metastatic recorded from patients’ medical charts. *e study was setting. Sarcoma 3 Table 1: Patient disposition and baseline characteristics. Parameters All patients (N �11) Neoadjuvant setting (N �1) Adjuvant setting (N �3) Metastatic setting (N �7) Age (years), mean±SD, range 46.09±11.46 (19–59) 48 44±10.15 (35–55) 46.71±13.46 (19–59) BSA, kg/m , mean±SD 1.63±0.20 1.62 1.57±0.18 1.66±0.23 Gender, n (%) Men 4 (36.4) 1 (100) 2 (66.7) 1 (14.3) Women 7 (63.6) — 1 (33.3) 6 (85.7) Cancer stage, n (%) II 3 (27.3) — 3 (100) — III 1 (9.1) 1 (100) — — IV 7 (63.6) — — 7 (100) Metastasis site, n (%) Lungs — — — 3 (42.9) Lymph node — — — 2 (18.2) Bone — — — 1 (14.3) Brain — — — 1 (14.3) ECOG performance score 1 4 (36.3) — 1 (33.3) 3 (42.9) 2 7 (63.7) 1 (100) 2 (66.7) 4 (57.1) Comorbid disease, n (%) Hypertension 5 (45.5) 1 (100) 1 (33.3) 3 (42.9) Diabetes 1 (9.1) — — 1 (14.3) Hypothyroidism 1 (9.1) — — 1 (14.3) Abbreviations: BSA, body surface area; ECOG, Eastern Cooperative Oncology Group; SD, standard deviation. Table 2: Patient details with chemotherapy regimens and efficacy evaluation. Cancer Setting in which NDLS Overall response as per the No. Age Sex If others, please specify stage NDLS was used chemotherapy used RECIST (1.1) High-grade pleomorphic NDLS plus 1 48 Male III Neoadjuvant setting CR sarcoma of mandible gemcitabine NDLS plus 2 42 Male Leiomyosarcoma II Adjuvant setting Not applicable gemcitabine NDLS plus 3 35 Male Leiomyosarcoma II Adjuvant setting Not applicable gemcitabine NDLS plus 4 55 Female Leiomyosarcoma II Adjuvant setting Not applicable gemcitabine NDLS plus 5 49 Female Leiomyosarcoma IV Metastatic setting NE gemcitabine NDLS plus 6 44 Female Leiomyosarcoma IV Metastatic setting SD gemcitabine NDLS plus 7 46 Female Leiomyosarcoma IV Metastatic setting CR gemcitabine NDLS plus 8 58 Female Leiomyosarcoma IV Metastatic setting PR gemcitabine Malignant fibrous histiocytoma NDLS plus 9 59 Male IV Metastatic setting PR of right thigh gemcitabine Extraskeletal myxoid NDLS plus 10 52 Female IV Metastatic setting PD chondrosarcoma cyclophosphamide NDLS plus 11 19 Female Osteosarcoma of left femur IV Metastatic setting PD gemcitabine Note. Efficacy response was not evaluated for patients in adjuvant setting. Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NDLS, nanosomal docetaxel lipid suspension; NE, not evaluated. 3.3. Overall Survival. Overall, patient survival data were and adjuvant settings, but it was 15.8 months in metastatic collected from the administration of the first dose of setting (Figure 2). NDLS-based therapy till the last follow-up date for alive patients and date of death for patients who died. At a median follow-up of 6.5 months (range: 0.06–20.2 3.4. Safety. At least 1 AE was reported in 7 (63.6%) patients. months), there were 3 (18.18%) deaths (metastatic setting: 3 Grade 1 AEs were reported in 45.5% (5/11) patients, grade 2 in patients), the median OS was not reached in neoadjuvant 36.4% (4/11) patients; grade 3/4 AEs were not reported. 4 Sarcoma 80 Neutropenia, thrombocytopenia, lymphopenia, and anemia were the hematological AEs, whereas nausea, vomiting, and 70 66.7% diarrhea were the most common nonhematological AEs (Table 3). 50.0% 33.3% 4. Discussion 20 16.7% 16.7% *e current multicenter, retrospective study demonstrated the effectiveness and tolerability of solvent-free NDLS for- (n = 1) (n = 2) (n = 1) (n = 3) (n = 4) mulation in patients with sarcoma. NDLS (75mg/m ) as a CR PR SD ORR DCR part of different chemotherapy regimens (NDLS plus gemcitabine/cyclophosphamide) demonstrated complete Figure 1: Efficacy of NDLS-based chemotherapy for the treatment response in 1 patient treated in neoadjuvant setting and of sarcoma in metastatic setting (n �6). CR: complete response; showed an ORR of 50% and DCR of 66.7%, respectively, for DCR: disease control rate; NDLS: nanosomal docetaxel lipid suspension; ORR: overall response rate; PR: partial response. patients treated in metastatic setting. A median OS of 15.8 Disease progression was reported in 2 patients. months was reported in the metastatic setting, whereas median OS was not reached in neoadjuvant and adjuvant settings. NDLS, a lipid-based formulation of docetaxel, was de- 1.0 veloped with an intent to avoid the toxicity issues related to the carriers (polysorbate 80 and ethanol) used in the con- 0.8 ventional formulation. NDLS was developed based on the patented (worldwide (WO2008127358), Europe (2076244), 0.6 Japan (5917789), and Canada (CA2666322)) “NanoAqualip” technology [16] with generally recognized as safe (GRAS) lipids by the US Food and Drug Administration. *e re- 0.4 sultant nanosomal particles (<100nm) [16] may allow the docetaxel infiltration and entrapment in the weakened tu- 0.2 mor vasculature and necrotic tumor tissue collagen material, thus causing increased retention (enhanced permeability 0.0 retention (EPR) effect), leading to a greater systemic 0 100 200 300 400 500 availability of docetaxel [16, 17], and ultimately improved Days outcome [12], which may have potential in the treatment of Censored difficult to treat cancers such as sarcomas. NDLS has demonstrated effectiveness and tolerability in Figure 2: Kaplan–Meier estimates of overall survival in sarcoma in the treatment of various cancers such as breast, ovarian, metastatic (n �7) setting. cervical, penile, hormone refractory prostate, non-small cell lung cancers, and sarcoma [12, 18–22]. *e efficacy of NDLS in sarcoma patients (n=3) was demonstrated in a previous Table 3: Safety profile of NDLS based chemotherapy in sarcoma single-center retrospective study [18]. *e current multi- (n �11). center retrospective study further strengthens the efficacy and tolerability data of NDLS in the treatment of sarcoma. All grades, n Grade I, n Grade II, n Adverse event *e conventional docetaxel formulation has demonstrated (%) (%) (%) effectiveness in sarcoma in previous studies [7–9]. In the Hematological AEs benchmark study by EORTC Soft Tissue and Bone Sarcoma Neutropenia 2 (18.2) 2 (18.2) Group, single-agent docetaxel demonstrated an ORR of 17% *rombocytopenia 1 (9.1) 1 (9.1) Anemia 1 (9.1) 1 (9.1) in the treatment of advanced sarcoma patients (n=29). Lymphopenia 1 (9.1) 1 (9.1) Hypersensitivity, anaphylactoid reactions, fluid retention, Nonhematological AEs and sensory neurotoxicity along with the hematologic AEs Nausea 4 (36.4) 4 (36.4) (neutropenia, thrombocytopenia, anemia, and leucopenia) Vomiting 4 (36.4) 4 (36.4) were reported in this study [7], which are the frequently Diarrhea 3 (27.3) 3 (27.3) reported AEs with conventional docetaxel formulation. Mucositis 2 (18.2) 2 (18.2) NDLS was most commonly used in combination with Mouth ulcer 2 (18.2) 2 (18.2) gemcitabine in the current study. NDLS-gemcitabine Weakness 1 (9.1) combination was used in neoadjuvant setting in one patient, Alopecia 1 (9.1) 1 (9.1) which demonstrated complete response. *is result is Note. AEs in different grades may occur in≥1 patient; hence, the number of similar to a previous case report, wherein neoadjuvant cumulative number of patients in different grades may exceed the total treatment with docetaxel and gemcitabine combination number of patients with individual AEs. % of patients Survival probability Sarcoma 5 (n=122) were thrombocytopenia (40%), fatigue (16%), and showed near-complete pathologic response in a patient with locally advanced leiomyosarcoma of the bladder [23]. febrile neutropenia (5%) [8]. *e SARC phase III study showed a significantly higher rate of discontinuation due to In adjuvant setting, 45% patients with stages I–IV high grade uterine leiomyosarcoma were progression-free at 2 toxicity in patients receiving docetaxel and gemcitabine years with docetaxel-gemcitabine combination in a study combination versus gemcitabine alone (P<0.01) [31]. In the (n �25) by Hensley and colleagues; median OS was not current report, grade III/IV AEs were not reported with reached in this study at a median follow-up of 49 months NDLS and gemcitabine combination. *e major limitation [24]. A phase III NRG Oncology/Gynecologic Oncology of this study due toits retrospectivenature is data availability Group study compared adjuvant gemcitabine plus docetaxel with respect to survival and safety and the small pool of patients. followed by doxorubicin or observation for high-grade uterine leiomyosarcoma and showed similar treatment Overall, NDLS-based chemotherapy was effective and well tolerated in managing sarcoma. *ese real-world data outcomes for both the groups [25]. In our study, 3 patients with leiomyosarcoma received NDLS/gemcitabine combi- provide valuable insights into the effectiveness and safety of NDLS as a potential treatment option in the management of nation in adjuvant setting, and all the patients were still alive at the last follow-up. sarcoma, while these results need to be established in a larger In metastatic setting, the efficacy and safety of docetaxel- population in prospective trials. gemcitabine combination was evaluated in a phase III randomized GeDDiS study in patients with metastatic Data Availability sarcoma (n �128), which demonstrated that 46.4% patients were alive and progression-free at 24 weeks after treatment *e datasets analyzed to support the findings of this at a median follow-up of 22 months [26]. *e Sarcoma study are available from the corresponding author upon Alliance for Research through Collaboration study showed request. an ORR of 16% and median OS of 17.9 months with docetaxel-gemcitabine treatment in patients with metastatic Conflicts of Interest soft tissue sarcomas (n �122) [8]. Hensley and colleagues demonstrated an ORR of 53% and median OS of 17.9 Drs. Alok Chaturvedi, Mujtaba A. Khan, Deepak Bunger, months with docetaxel and gemcitabine combination for the and Nisarg Joshi are employees of Intas Pharmaceuticals treatment of unresectable leiomyosarcoma (n �34) [9]. In Ltd., India. Dr Imran Ahmad is an employee of Jina patients with metastatic or relapsed leiomyosarcoma Pharmaceuticals Inc., USA. (n �24), docetaxel-gemcitabine combination resulted in an ORR of 24% in TAXOGEM study [27]. Two retrospective Authors’ Contributions studies by Leu et al. (n �35) and Bay et al. (n �114) had ORR rates of 43% and 18%, and median OS of 13 months and 12.1 MAK, AC, DB, NJ, and IA conceived and designed the months, respectively, with docetaxel-gemcitabine combi- study, collected and analyzed/interpreted data, and nation in the treatment of sarcomas [28, 29]. *e afore- reviewed the manuscript; SS, SKDM and GB provided/ mentioned evidence suggests an ORR of 16%–53% and a interpreted data and reviewed the manuscript. All au- median OS of 12.1 months–17.9 months with docetaxel- thors met the ICMJE criteria, and all those who fulfilled gemcitabine combination in sarcoma patients in a metastatic those criteria are listed as authors. All authors had access setting. to the study data and contributed to the development of NDLS was most commonly administered in combina- this article. All authors read and approved the manu- tion with gemcitabine in metastatic setting in our study. script. All contributing authors approved the submission NDLS-based chemotherapy demonstrated an ORR of 50% of this version of the manuscript. and a median OS of 15.8 months in metastatic setting, which is comparable with the above data. In our study, NDLS plus Acknowledgments gemcitabine was administered to 4 patients with leiomyo- sarcoma in metastatic setting. *e response was available in We would like to thank Mr. Shreekant Sharma, MPharm, 3 patients, which showed CR, PR, and SD in one patient ISMPP CMPP (Lambda *erapeutic Research Ltd., each; the corresponding ORR was 66.7% (2/3), comparable Ahmedabad, Gujarat, India) for providing writing assis- with that reported by Hensley et al. [9]. tance and Dr. Venugopal Madhusudhana, MBBS, EPBM, Overall, NDLS-based regimens were found to be well ISMPP CMPP (Lambda *erapeutic Research Ltd., tolerated in sarcoma patients. *e safety profile of NDLS in Ahmedabad, Gujarat, India) for additional editorial as- this study is consistent with previous literature [12, 13, 30]. sistance for the development of this manuscript. *e Neutropenia, thrombocytopenia, lymphopenia, and anemia authors also thank the clinical data management and were the hematological AEs, whereas nausea, vomiting, and biostatistics department of Lambda *erapeutic Research diarrhea were the most common nonhematological AEs. All Ltd., for their contribution in the preparation of statistical the AEs were grade I or II. *e Sarcoma Alliance for Re- analysis report in this retrospective data collation and search through Collaboration Study 002 reported that most analysis. *is study was funded by an unrestricted re- common grade III/IV AEs with docetaxel and gemcitabine search grant by Intas Pharmaceuticals Ltd., Ahmedabad, combination in patients with metastatic soft tissue sarcoma Gujarat, India. 6 Sarcoma [16] A. Ahmad, S. Sheikh, S. M. Ali et al., “Development of References aqueous based formulation of docetaxel: safety and phar- [1] D. T. Nguyen and S. Shayahi, “Pazopanib: approval for soft- macokinetics in patients with advanced solid tumors,” Journal tissue sarcoma,” Journal of the Advanced Practitioner in of Nanomedicine & Nanotechnology, vol. 6, no. 3, p. 1, 2015. Oncology, vol. 4, no. 1, pp. 53–57, 2013. [17] L. D. Lewis, A. A. Miller, G. L. Rosner et al., “A comparison of [2] D. A. Vodanovich and P. 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Efficacy and Safety of Nanosomal Docetaxel Lipid Suspension-Based Chemotherapy in Sarcoma: A Multicenter, Retrospective Study

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Copyright © 2019 Prasad Narayanan et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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10.1155/2019/3158590
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Abstract

Hindawi Sarcoma Volume 2019, Article ID 3158590, 7 pages https://doi.org/10.1155/2019/3158590 Research Article Efficacy and Safety of Nanosomal Docetaxel Lipid Suspension-Based Chemotherapy in Sarcoma: A Multicenter, Retrospective Study 1 2 3 Prasad Narayanan, Palanki Satya Dattatreya, Rammohan Prasanna, 4 5 2 6 Sundaram Subramanian, Kunal Jain, Nirni Sharanabasappa Somanath, Nisarg Joshi, 6 6 6 7 Deepak Bunger, Mujtaba Ali Khan, Alok Chaturvedi, and Imran Ahmad Cytecare Cancer Hospitals, Yelahanka, Bengaluru, Karnataka 560064, India Omega Hospitals, Hyderabad, Telangana 500034, India Department of Medical Oncology, CBCC-GVN Cancer Center, Tiruchirapalli, Tamil Nadu 620005, India VS Hospital, Madras Cancer Institute, Advanced Cancer Care, Chennai, Tamil Nadu 600031, India American Oncology Institute, Dayanand Medical College & Hospital, Ludhiana, Punjab 141001, India Medical Affairs and Clinical Development, Intas Pharmaceuticals Ltd., Sola, Ahmedabad, Gujarat 380054, India Jina Pharmaceuticals Inc., Libertyville, Green Oaks, Illinois 60048, USA Correspondence should be addressed to Imran Ahmad; imran@jinapharma.com Received 11 September 2019; Accepted 25 October 2019; Published 15 November 2019 Academic Editor: John D. Reith Copyright © 2019 Prasad Narayanan et al. *is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Objective. To evaluate the efficacy and safety of nanosomal docetaxel lipid suspension (NDLS, DoceAqualip) based chemotherapy in patients with sarcoma. Methods. In this retrospective, multicenter (6 centers), observational study, we analyzed the medical charts of adult patients of either sex, who were treated with NDLS (75mg/m in 3-weekly cycles) based chemotherapy for the treatment of sarcoma. *e efficacy outcomes were overall response rate (ORR: complete response (CR)+partial response (PR)) and diseasecontrolrate(DCR: CR+PR+stable disease(SD))inpatientswho received NDLS-basedchemotherapyinneoadjuvant and metastatic settings. Overall survival (OS) and safety were evaluated for all settings. Results. Of 11 patients (neoadjuvant: 1, adjuvant: 3, and metastatic: 7) in this study, majority had leiomyosarcoma (63.6%, 7/11) followed by extraskeletal myxoid chondrosarcoma (EMC), high grade pleomorphic sarcoma of mandible, malignant fibrous histiocytoma of right thigh, and osteosarcoma of femur (9.1% each, 1/11 each). NDLS plus gemcitabine combination was used in 10 patients (90.9%), and NDLS plus cyclophosphamide was used in one patient with EMC (9.1%). Efficacy evaluation was performed for 7 patients (neoadjuvant: 1/1; metastatic: 6/7). Complete response was reported in one patient (soft tissue sarcoma of mandible) treated in neoadjuvant setting. In metastatic setting, ORR was 50% and DCR was 66.7% (CR:16.7% (1/6), PR: 33.3% (2/6), SD:16.7% (1/6)). At a median follow-up of 6.5 months (range: 0.06–20.2 months), median OS was not reached in neoadjuvant and adjuvant settings, but it was 15.8 months inmetastaticsetting.Atleast1 AEwasreported in7(63.6%)patients. Neutropenia,thrombocytopenia, lymphopenia, and anemia were the hematological AEs, whereas nausea, vomiting, and diarrhea were the most common nonhematological AEs. NDLS treatment was well tolerated without any new safety concerns. Conclusion. Nanosomal docetaxel lipid suspension-based chemotherapy was efficacious and well tolerated in the treatment of sarcoma. Further prospective trials are needed to confirm the data. 2 Sarcoma conducted after due approval from ethics committee and in 1. Introduction compliance with the protocol. Sarcomas are a rare heterogeneous group of solid tumors and are broadly classified as soft tissue sarcomas (STS) and 2.2. Statistical Considerations. Demographic and baseline bone sarcomas [1, 2]. *e incidence of sarcomas is 2–4/ characteristics were summarized using descriptive sta- 100,000 people [2]. It is common in children accounting for tistics. Categorical variables were summarized with fre- ∼15% of all cancers, whereasit accounts for∼1% of all cancer quency and percentage. Continuous variables were cases in adults [3]. *e incidence of STS was ∼10% as per summarized with count, mean, standard deviation, me- Indian reports [4]. *e most common sarcoma type is STS, dian, minimum, and maximum. Response rate was pre- and the most common sites of STS are extremities (lower sented as frequency and percentage of patients. χ test was limb>upper limb); thigh is the commonest site [2]. With used to compare the distribution of patients in each >50 subtypes available, the most common STSs are pleo- category. Survival analysis was performed to measure morphic sarcoma, gastrointestinal stromal tumors (GIST), lifetime or the length of time until the occurrence of an leiomyosarcoma, synovial sarcoma, liposarcoma, and ma- event (death in case of overall survival). Survival data were lignant peripheral nerve sheath tumors [3]. Osteosarcomas analyzed using a nonparametric procedure which per- are the most common bone sarcomas followed by Ewing’s formed PROC LIFETESTof SAS (version 9.4) to measure sarcomas, and these can present in all bones [5]. the duration of time until a specified event occurs. OS was Multimodality treatment approach, including sur- calculated and analyzed using Kaplan–Meier method and gery, radiation therapy, and chemotherapy, is recom- log-rank test to estimate the survival function from mended for sarcomas [6]. Among many regimens used in lifetime data after treatment. *e AEs were summarized as clinical practice, docetaxel alone [7] or in combination frequencies and percentages by type of reactions. with gemcitabine [8, 9] is recommended by several guidelines [10, 11]. Docetaxel has shown activity in the 3. Results treatment of sarcomas, but toxicity issues such as hy- persensitivity reactions, fluid retention, sensory neuro- 3.1. Patient Disposition and Demographics. Eleven patients toxicity, and anaphylactoid reactions observed in these with sarcoma, who were treated with NDLS-based che- patients [7] are known to be associated with the carrier motherapy, were retrospectively analyzed. Majority of the polysorbate 80 in the conventional docetaxel formula- patients had leiomyosarcoma (63.6%, 7/11). Extraskeletal tion. A solvent-free lipid-based formulation “nanosomal myxoid chondrosarcoma (EMC), high grade pleomorphic docetaxel lipid suspension (NDLS, DoceAqualip)” was sarcoma of mandible, malignant fibrous histiocytoma of the developed [12], which has shown effectiveness and tol- right thigh, and high grade osteosarcoma of femur were erability in the treatment of several cancers including diagnosed in 1 patient each (9.1% each). *e baseline sarcoma [13]. We report here a multicenter, retrospective characteristics of patients are summarized in Table 1. experience in real-life practice evaluating the effective- NDLS was used as 1 hour infusion in 3-weekly cycles at a ness and tolerability of NDLS in the treatment of dose of 75mg/m . NDLS was used as a second-line therapy sarcomas. in majority (8, 72.7%) of the patients; 2 patients (18.2%) received as first-linetherapy,and onepatient(9.1%) asthird- 2. Methods line therapy. Most (9, 81.8%) of the patients were admin- istered premedications; dexamethasone premedication was 2.1. Study Design, Patient Selection, and Endpoints. In this administered to 54.5% patients. All the patients received multicenter (6 centers), retrospective, observational study, G-CSF/Peg-GCSF as primary prophylaxis. NDLS was used we analyzed the medical charts of sarcoma patients who in combination with gemcitabine (dose range: 600–1100mg/ received NDLS-based chemotherapy as part of their routine 2 m ) in 90.9% patients and cyclophosphamide (dose: 600mg/ clinical care between February 2016 and March 2019. *e m ) in 9.1% patients. Table 2 presents the patient details with study endpoints included overall response rate (ORR: chemotherapy regimens used and efficacy evaluation. proportion of patients achieving complete response (CR) and partial response (PR)) and disease control rate (DCR: proportion of patients achieving CR+PR+stable disease 3.2. Efficacy. Patients who received NDLS-based regimen as (SD)) for patients treated in neoadjuvant and metastatic adjuvant chemotherapy (n=3) were considered for safety settings, whereas overall survival (time from treatment to and overall survival analysis. Of 8 patients in neoadjuvant death due to any cause) was evaluated for patients treated and metastatic settings, efficacy evaluation was available for in all settings. Treatment response was evaluated using 7 patients (neoadjuvant: 1 and metastatic: 6). One patient Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 treated in neoadjuvant setting showed complete response [14]. *e National Cancer Institute (NCI) Common Ter- (ORR and DCR: 100%). In the metastatic setting, NDLS- minology Criteria for Adverse Events (CTCAE) Criteria based chemotherapy resulted in an ORR of 50% (CR: 16.7% version 5 [15] were used to grade (where available) the (1/6), PR: 33.3% (2/6)) and DCR of 66.7% (CR: 16.7% (1/6), incidence of adverse events (AEs) recorded from the PR: 33.3% (2/6), SD: 16.7% (1/6)) (Figure 1). Disease pro- treatment charts. Data on death and discontinuations were gression was reported in 2 patients treated in the metastatic recorded from patients’ medical charts. *e study was setting. Sarcoma 3 Table 1: Patient disposition and baseline characteristics. Parameters All patients (N �11) Neoadjuvant setting (N �1) Adjuvant setting (N �3) Metastatic setting (N �7) Age (years), mean±SD, range 46.09±11.46 (19–59) 48 44±10.15 (35–55) 46.71±13.46 (19–59) BSA, kg/m , mean±SD 1.63±0.20 1.62 1.57±0.18 1.66±0.23 Gender, n (%) Men 4 (36.4) 1 (100) 2 (66.7) 1 (14.3) Women 7 (63.6) — 1 (33.3) 6 (85.7) Cancer stage, n (%) II 3 (27.3) — 3 (100) — III 1 (9.1) 1 (100) — — IV 7 (63.6) — — 7 (100) Metastasis site, n (%) Lungs — — — 3 (42.9) Lymph node — — — 2 (18.2) Bone — — — 1 (14.3) Brain — — — 1 (14.3) ECOG performance score 1 4 (36.3) — 1 (33.3) 3 (42.9) 2 7 (63.7) 1 (100) 2 (66.7) 4 (57.1) Comorbid disease, n (%) Hypertension 5 (45.5) 1 (100) 1 (33.3) 3 (42.9) Diabetes 1 (9.1) — — 1 (14.3) Hypothyroidism 1 (9.1) — — 1 (14.3) Abbreviations: BSA, body surface area; ECOG, Eastern Cooperative Oncology Group; SD, standard deviation. Table 2: Patient details with chemotherapy regimens and efficacy evaluation. Cancer Setting in which NDLS Overall response as per the No. Age Sex If others, please specify stage NDLS was used chemotherapy used RECIST (1.1) High-grade pleomorphic NDLS plus 1 48 Male III Neoadjuvant setting CR sarcoma of mandible gemcitabine NDLS plus 2 42 Male Leiomyosarcoma II Adjuvant setting Not applicable gemcitabine NDLS plus 3 35 Male Leiomyosarcoma II Adjuvant setting Not applicable gemcitabine NDLS plus 4 55 Female Leiomyosarcoma II Adjuvant setting Not applicable gemcitabine NDLS plus 5 49 Female Leiomyosarcoma IV Metastatic setting NE gemcitabine NDLS plus 6 44 Female Leiomyosarcoma IV Metastatic setting SD gemcitabine NDLS plus 7 46 Female Leiomyosarcoma IV Metastatic setting CR gemcitabine NDLS plus 8 58 Female Leiomyosarcoma IV Metastatic setting PR gemcitabine Malignant fibrous histiocytoma NDLS plus 9 59 Male IV Metastatic setting PR of right thigh gemcitabine Extraskeletal myxoid NDLS plus 10 52 Female IV Metastatic setting PD chondrosarcoma cyclophosphamide NDLS plus 11 19 Female Osteosarcoma of left femur IV Metastatic setting PD gemcitabine Note. Efficacy response was not evaluated for patients in adjuvant setting. Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NDLS, nanosomal docetaxel lipid suspension; NE, not evaluated. 3.3. Overall Survival. Overall, patient survival data were and adjuvant settings, but it was 15.8 months in metastatic collected from the administration of the first dose of setting (Figure 2). NDLS-based therapy till the last follow-up date for alive patients and date of death for patients who died. At a median follow-up of 6.5 months (range: 0.06–20.2 3.4. Safety. At least 1 AE was reported in 7 (63.6%) patients. months), there were 3 (18.18%) deaths (metastatic setting: 3 Grade 1 AEs were reported in 45.5% (5/11) patients, grade 2 in patients), the median OS was not reached in neoadjuvant 36.4% (4/11) patients; grade 3/4 AEs were not reported. 4 Sarcoma 80 Neutropenia, thrombocytopenia, lymphopenia, and anemia were the hematological AEs, whereas nausea, vomiting, and 70 66.7% diarrhea were the most common nonhematological AEs (Table 3). 50.0% 33.3% 4. Discussion 20 16.7% 16.7% *e current multicenter, retrospective study demonstrated the effectiveness and tolerability of solvent-free NDLS for- (n = 1) (n = 2) (n = 1) (n = 3) (n = 4) mulation in patients with sarcoma. NDLS (75mg/m ) as a CR PR SD ORR DCR part of different chemotherapy regimens (NDLS plus gemcitabine/cyclophosphamide) demonstrated complete Figure 1: Efficacy of NDLS-based chemotherapy for the treatment response in 1 patient treated in neoadjuvant setting and of sarcoma in metastatic setting (n �6). CR: complete response; showed an ORR of 50% and DCR of 66.7%, respectively, for DCR: disease control rate; NDLS: nanosomal docetaxel lipid suspension; ORR: overall response rate; PR: partial response. patients treated in metastatic setting. A median OS of 15.8 Disease progression was reported in 2 patients. months was reported in the metastatic setting, whereas median OS was not reached in neoadjuvant and adjuvant settings. NDLS, a lipid-based formulation of docetaxel, was de- 1.0 veloped with an intent to avoid the toxicity issues related to the carriers (polysorbate 80 and ethanol) used in the con- 0.8 ventional formulation. NDLS was developed based on the patented (worldwide (WO2008127358), Europe (2076244), 0.6 Japan (5917789), and Canada (CA2666322)) “NanoAqualip” technology [16] with generally recognized as safe (GRAS) lipids by the US Food and Drug Administration. *e re- 0.4 sultant nanosomal particles (<100nm) [16] may allow the docetaxel infiltration and entrapment in the weakened tu- 0.2 mor vasculature and necrotic tumor tissue collagen material, thus causing increased retention (enhanced permeability 0.0 retention (EPR) effect), leading to a greater systemic 0 100 200 300 400 500 availability of docetaxel [16, 17], and ultimately improved Days outcome [12], which may have potential in the treatment of Censored difficult to treat cancers such as sarcomas. NDLS has demonstrated effectiveness and tolerability in Figure 2: Kaplan–Meier estimates of overall survival in sarcoma in the treatment of various cancers such as breast, ovarian, metastatic (n �7) setting. cervical, penile, hormone refractory prostate, non-small cell lung cancers, and sarcoma [12, 18–22]. *e efficacy of NDLS in sarcoma patients (n=3) was demonstrated in a previous Table 3: Safety profile of NDLS based chemotherapy in sarcoma single-center retrospective study [18]. *e current multi- (n �11). center retrospective study further strengthens the efficacy and tolerability data of NDLS in the treatment of sarcoma. All grades, n Grade I, n Grade II, n Adverse event *e conventional docetaxel formulation has demonstrated (%) (%) (%) effectiveness in sarcoma in previous studies [7–9]. In the Hematological AEs benchmark study by EORTC Soft Tissue and Bone Sarcoma Neutropenia 2 (18.2) 2 (18.2) Group, single-agent docetaxel demonstrated an ORR of 17% *rombocytopenia 1 (9.1) 1 (9.1) Anemia 1 (9.1) 1 (9.1) in the treatment of advanced sarcoma patients (n=29). Lymphopenia 1 (9.1) 1 (9.1) Hypersensitivity, anaphylactoid reactions, fluid retention, Nonhematological AEs and sensory neurotoxicity along with the hematologic AEs Nausea 4 (36.4) 4 (36.4) (neutropenia, thrombocytopenia, anemia, and leucopenia) Vomiting 4 (36.4) 4 (36.4) were reported in this study [7], which are the frequently Diarrhea 3 (27.3) 3 (27.3) reported AEs with conventional docetaxel formulation. Mucositis 2 (18.2) 2 (18.2) NDLS was most commonly used in combination with Mouth ulcer 2 (18.2) 2 (18.2) gemcitabine in the current study. NDLS-gemcitabine Weakness 1 (9.1) combination was used in neoadjuvant setting in one patient, Alopecia 1 (9.1) 1 (9.1) which demonstrated complete response. *is result is Note. AEs in different grades may occur in≥1 patient; hence, the number of similar to a previous case report, wherein neoadjuvant cumulative number of patients in different grades may exceed the total treatment with docetaxel and gemcitabine combination number of patients with individual AEs. % of patients Survival probability Sarcoma 5 (n=122) were thrombocytopenia (40%), fatigue (16%), and showed near-complete pathologic response in a patient with locally advanced leiomyosarcoma of the bladder [23]. febrile neutropenia (5%) [8]. *e SARC phase III study showed a significantly higher rate of discontinuation due to In adjuvant setting, 45% patients with stages I–IV high grade uterine leiomyosarcoma were progression-free at 2 toxicity in patients receiving docetaxel and gemcitabine years with docetaxel-gemcitabine combination in a study combination versus gemcitabine alone (P<0.01) [31]. In the (n �25) by Hensley and colleagues; median OS was not current report, grade III/IV AEs were not reported with reached in this study at a median follow-up of 49 months NDLS and gemcitabine combination. *e major limitation [24]. A phase III NRG Oncology/Gynecologic Oncology of this study due toits retrospectivenature is data availability Group study compared adjuvant gemcitabine plus docetaxel with respect to survival and safety and the small pool of patients. followed by doxorubicin or observation for high-grade uterine leiomyosarcoma and showed similar treatment Overall, NDLS-based chemotherapy was effective and well tolerated in managing sarcoma. *ese real-world data outcomes for both the groups [25]. In our study, 3 patients with leiomyosarcoma received NDLS/gemcitabine combi- provide valuable insights into the effectiveness and safety of NDLS as a potential treatment option in the management of nation in adjuvant setting, and all the patients were still alive at the last follow-up. sarcoma, while these results need to be established in a larger In metastatic setting, the efficacy and safety of docetaxel- population in prospective trials. gemcitabine combination was evaluated in a phase III randomized GeDDiS study in patients with metastatic Data Availability sarcoma (n �128), which demonstrated that 46.4% patients were alive and progression-free at 24 weeks after treatment *e datasets analyzed to support the findings of this at a median follow-up of 22 months [26]. *e Sarcoma study are available from the corresponding author upon Alliance for Research through Collaboration study showed request. an ORR of 16% and median OS of 17.9 months with docetaxel-gemcitabine treatment in patients with metastatic Conflicts of Interest soft tissue sarcomas (n �122) [8]. Hensley and colleagues demonstrated an ORR of 53% and median OS of 17.9 Drs. Alok Chaturvedi, Mujtaba A. Khan, Deepak Bunger, months with docetaxel and gemcitabine combination for the and Nisarg Joshi are employees of Intas Pharmaceuticals treatment of unresectable leiomyosarcoma (n �34) [9]. In Ltd., India. Dr Imran Ahmad is an employee of Jina patients with metastatic or relapsed leiomyosarcoma Pharmaceuticals Inc., USA. (n �24), docetaxel-gemcitabine combination resulted in an ORR of 24% in TAXOGEM study [27]. Two retrospective Authors’ Contributions studies by Leu et al. (n �35) and Bay et al. (n �114) had ORR rates of 43% and 18%, and median OS of 13 months and 12.1 MAK, AC, DB, NJ, and IA conceived and designed the months, respectively, with docetaxel-gemcitabine combi- study, collected and analyzed/interpreted data, and nation in the treatment of sarcomas [28, 29]. *e afore- reviewed the manuscript; SS, SKDM and GB provided/ mentioned evidence suggests an ORR of 16%–53% and a interpreted data and reviewed the manuscript. All au- median OS of 12.1 months–17.9 months with docetaxel- thors met the ICMJE criteria, and all those who fulfilled gemcitabine combination in sarcoma patients in a metastatic those criteria are listed as authors. All authors had access setting. to the study data and contributed to the development of NDLS was most commonly administered in combina- this article. All authors read and approved the manu- tion with gemcitabine in metastatic setting in our study. script. All contributing authors approved the submission NDLS-based chemotherapy demonstrated an ORR of 50% of this version of the manuscript. and a median OS of 15.8 months in metastatic setting, which is comparable with the above data. In our study, NDLS plus Acknowledgments gemcitabine was administered to 4 patients with leiomyo- sarcoma in metastatic setting. *e response was available in We would like to thank Mr. Shreekant Sharma, MPharm, 3 patients, which showed CR, PR, and SD in one patient ISMPP CMPP (Lambda *erapeutic Research Ltd., each; the corresponding ORR was 66.7% (2/3), comparable Ahmedabad, Gujarat, India) for providing writing assis- with that reported by Hensley et al. [9]. tance and Dr. Venugopal Madhusudhana, MBBS, EPBM, Overall, NDLS-based regimens were found to be well ISMPP CMPP (Lambda *erapeutic Research Ltd., tolerated in sarcoma patients. *e safety profile of NDLS in Ahmedabad, Gujarat, India) for additional editorial as- this study is consistent with previous literature [12, 13, 30]. sistance for the development of this manuscript. *e Neutropenia, thrombocytopenia, lymphopenia, and anemia authors also thank the clinical data management and were the hematological AEs, whereas nausea, vomiting, and biostatistics department of Lambda *erapeutic Research diarrhea were the most common nonhematological AEs. All Ltd., for their contribution in the preparation of statistical the AEs were grade I or II. *e Sarcoma Alliance for Re- analysis report in this retrospective data collation and search through Collaboration Study 002 reported that most analysis. *is study was funded by an unrestricted re- common grade III/IV AEs with docetaxel and gemcitabine search grant by Intas Pharmaceuticals Ltd., Ahmedabad, combination in patients with metastatic soft tissue sarcoma Gujarat, India. 6 Sarcoma [16] A. Ahmad, S. Sheikh, S. M. Ali et al., “Development of References aqueous based formulation of docetaxel: safety and phar- [1] D. T. Nguyen and S. Shayahi, “Pazopanib: approval for soft- macokinetics in patients with advanced solid tumors,” Journal tissue sarcoma,” Journal of the Advanced Practitioner in of Nanomedicine & Nanotechnology, vol. 6, no. 3, p. 1, 2015. Oncology, vol. 4, no. 1, pp. 53–57, 2013. [17] L. D. Lewis, A. A. Miller, G. L. Rosner et al., “A comparison of [2] D. A. Vodanovich and P. 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