Original Study
Therapeutic Efficacy of a Novel Nanosomal Docetaxel Lipid Suspension Compared With Taxotere in Locally Advanced or Metastatic Breast Cancer Patients Ateeq Ahmad,1 Saifuddin Sheikh,1 Rakesh Taran,2 Shanti P. Srivastav,3 Krishna Prasad,4 Senthil J. Rajappa,5 Vijay Kumar,6 Mamillapalli Gopichand,7 Mahesh Paithankar,8 Manish Sharma,9 Rajendra C. Rane,10 Imran Ahmad1 Abstract Drug delivery systems are widely used to reduce toxicity of drugs and enhance the quality of a patient’s life. Nanosomal docetaxel lipid suspension (NDLS) is formulated based on an aqueous lipid delivery system. Patients with breast cancer were not required to be premedicated before administration of NDLS. Docetaxel administered using this delivery system also improves the response rate compared with commercially available docetaxel drug. Background: Nanosomal docetaxel lipid suspension formulation was developed to eliminate ethanol and polysorbate 80 from the currently used docetaxel (Taxotere) drug for treatment of cancer patients. NDLS clinical safety and efficacy was evaluated and compared with Taxotere at 75 mg/m2 in metastatic breast cancer patients. Patients and Methods: A total of 72 patients were randomized in a ratio of 2:1 (NDLS:Taxotere). Patients treated with NDLS were not premedicated with corticosteroids as required with solvent-based Taxotere. Disease status and tumor response was assessed after every 2 cycles of treatment using Response Evaluation Criteria in Solid Tumors 1.1 guidelines through cycle 6. Results: Overall therapeutic response (complete þ partial) rate in metastatic breast cancer patients treated with NDLS and Taxotere were 35.5% and 26.3%, respectively, indicating better response in patients treated with NDLS. Patients in the NDLS group were not premedicated but the safety results of NDLS were found to be comparable with Taxotere. Conclusion: NDLS formulation with no premedication provides an alternative treatment option for breast cancer patients. Clinical Breast Cancer, Vol. 14, No. 3, 177-81 ª 2014 Elsevier Inc. All rights reserved. Keywords: Complete response rate, Computed tomography, Lipid delivery system, Premedication, Safety
Introduction Taxanes are one of the most important cytotoxic agents discovered for the treatment of several types of cancer. Paclitaxel was the first taxane product for which clinical studies indicated an effective response rate and overall survival in breast, lung, ovarian, and gastric cancers.1 However, in some cancers like advanced pancreatic carcinomas, paclitaxel showed lower efficacy compared with docetaxel.2 Results of this study were presented, in part, at the American Society of Clinical Oncology meeting, May 31 - June 4, 2013.
In metastatic and recurrent head and neck cancer, the combination of paclitaxel and platinum showed lower response compared with docetaxel combination.3 Therefore, in some types of cancers the response rate in patients using paclitaxel treatment might be less compared with patients using docetaxel. Docetaxel is prepared by semisynthesis beginning with a precursor extracted from the renewable needle biomass of yew plants. It 8
Astron Research, Ltd, Ahmedabad, India Lambda Therapeutic Research Ltd, Ahmedabad, India 10 Intas Pharmaceuticals, Ltd, Ahmedabad, India 9
1
Jina Pharmaceuticals, Inc, Libertyville, IL CHL Apollo Hospital, Indore, India Lions Cancer Detection Centre, New Civil Hospital, Surat, India 4 Kasturba Medical College and Hospital, Mangalore, India 5 Indo-American Cancer Hospital and Research Institute, Hyderabad, India 6 M.V. Hospital and Research Center, Lucknow, India 7 City Cancer Center, Vijayawada, India 2 3
1526-8209/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2013.09.011
Submitted: Aug 26, 2013; Revised: Sep 17, 2013; Accepted: Sep 24, 2013; Epub: Sep 28, 2013 Address for correspondence: Imran Ahmad, PhD, Jina Pharmaceuticals, Inc, 28100 N Ashley Ct, Suite 103, Libertyville, IL 60048 Fax: 847-557-0770; e-mail contact: [email protected]
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Efficacy of Nanosomal Docetaxel Lipid Suspension is highly lipophilic and practically insoluble in water. Because of its insolubility, the currently marketed docetaxel (Taxotere) is formulated in polysorbate 80 and ethanol and have been approved by the Food and Drug Administration for the treatment of various cancers including locally advanced metastatic breast, nonesmall-cell lung, and ovarian cancer, and in combination with other drugs for several additional cancer types such as prostate, head and neck, and gastric adenocarcinoma.4-7 The use of ethanol and polysorbate 80 in Taxotere formulation causes infusion-related toxicities and hypersensitivity reactions in patients.8-10 Thus, the patients are premedicated with corticosteroids to minimize such toxicities before the treatment. To circumvent the toxicities related to polysorbate 80, several investigators developed formulations based on various delivery systems such as liposomes, polymeric micelles, protein, and nanospheres.11-17 Nanosomal docetaxel lipid suspension (NDLS) formulation was developed using lipids generally recognized as safe (GRAS) by the Food and Drug Administration and is absolutely free of polysorbate 80 and ethanol. A crossover study conducted at 75 mg/m2 with Taxotere in solid tumor patients showed greater systemic availability of docetaxel in patients treated with NDLS compared with Taxotere. In addition, no increase in toxicity was observed compared with Taxotere. The higher systemic availability of NDLS led us to conduct the current efficacy study in breast cancer patients. Results of this study were presented, in part, at the American Society of Clinical Oncology meeting, 2013.18 In this study, comparative clinical safety and efficacy of NDLS and Taxotere at 75 mg/m2were evaluated in metastatic breast cancer patients. The improved clinical efficacy of NDLS with no premedication reported here might transform NDLS as a new useful drug for the treatment of cancer.
Patients and Methods Chemicals and Reagents Docetaxel was obtained from Scinopharm, Taiwan. NDLS clinical batches were manufactured at a Food and Drug Administration-inspected facility of Intas Pharmaceutical Ltd, India. Soy phosphatidylcholine was procured from Lipoid LLC (Newark, NJ) and sodium cholesteryl sulfate was obtained from Genzyme Pharmaceuticals (Cambridge, MA). Polysorbate-based docetaxel was procured from Aventis Pharma, SA, Paris, France.
Study Design
178
-
This was an open label, randomized, multiple dose, parallel study in locally advanced or metastatic breast cancer patients in whom previous chemotherapy had failed. Women, from 18 to 65 years of age, with histopathologically/cytologically confirmed breast cancer, having locally advanced or metastatic breast cancer after failure of previous chemotherapy were enrolled in the study. These patients had Eastern Cooperative Oncology Group (ECOG) performance status 2, with adequate bone marrow, renal, and hepatic function, having at least 1 measurable lesion according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria and also had life expectancy of at least 6 months. The patients were randomized to receive either NDLS or Taxotere. A total of 72 patients were enrolled into the study at a ratio of 2:1 (NDLS:Taxotere). The mean age of the enrolled patients was 47 years and racial makeup of the study was 100% Asian. Patients were
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administered NDLS or Taxotere at 75 mg/m2 according to the randomization schedule, using intravenous (I.V.) infusion for 1 hour in each cycle of 21 days. Each patient received a maximum of 6 cycles of NDLS or Taxotere. Patients in the NDLS group were not premedicated. Sexually active women enrolled in the study, unless surgically sterile (at least 6 months before study drug administration) or postmenopausal for at least 12 consecutive months, used an effective method of avoiding pregnancy including oral, transdermal, or implanted contraceptive devices (any hormonal method in conjunction with a secondary method), intrauterine device, female condom with spermicide, diaphragm with spermicide, absolute sexual abstinence, use of condom with spermicide by sexual partner or sterile (at least 6 months before study drug administration) for at least 4 weeks before study drug administration, during study, and up to 30 days after the last dose of study drug. Results of the pregnancy test done at screening were required to be negative.
Treatment and Efficacy Assessments Each drug, NDLS or Taxotere was administered using I.V. infusion over 1 hour (10-minute deviation was allowed) at a dose of 75 mg/m2. Disease status and tumor response (computed tomography [CT] scan/magnetic resonance imaging) was assessed after every 2 cycles of treatment using RECIST 1.1 guidelines through cycle 6 (including confirmation of response if required); subsequent cycles followed institutional standards for tumor/disease assessment. Independent evaluation (blinded reading) of the images acquired in clinical trial was done at the Central Imaging Facility. Primary efficacy evaluation was based on the overall response rate (complete response [CR] þ partial response [PR]), defined as the proportion of patients whose best overall response was CR (disappearance of all target lesions) or PR after receiving at least 2 cycles of study treatment of NDLS or Taxotere. Patients without a confirmed CR or PR were considered as failure in computing the best overall response rates. The secondary efficacy end point of this study was overall response rate, defined as the proportion of patients in whom disease control rate (CR þ PR þ stable disease [SD] ¼ disease control rate) from best overall response was CR or PR or SD. Patients without a confirmed CR or PR or SD were considered as failure in computing best overall response rate. The data identified as CR, PR, SD, progressive disease, or not evaluable from independent reviewers was used for the primary and secondary efficacy analysis.
Safety Assessments Adverse events (AEs) were assessed every cycle for the duration of the trial and graded according to the National Cancer Institute Common Toxicity Criteria, version 4.02. Data on serious AEs were collected throughout the study. Medical history, demography, physical examination and vital signs, body measurement, ECOG, hepatic screening, b-human chorionic gonadotropin test (serum), hematology biochemistry, urine analysis, CT scan, bone scan, echocardiography, and electrocardiogram were carried out as a part of safety and efficacy evaluations.
Statistical Analysis Primary efficacy analyses are presented for per protocol population who had confirmed CR and PR from the best overall response
Ateeq Ahmad et al Table 1 Patient and Demographic Characteristics Taxotere (n [ 23)
NDLS (n [ 49)
Median
45.0
47.0
Range
28-63
33-64
Characteristic
Outcome
Age, Years
Weight, kg Median
47.0
51.5
Range
30-74
33-91.5
1.4
1.46
BSA, m2 Median Range
1.16-1.73
1.18-1.91
Height, cm Median Range
Table 2 Objective Response Rates of NDLS and Taxotere at 75 mg/m2
150 137-162
153 137-164
Abbreviations: BSA ¼ body surface area; NDLS ¼ nanosomal docetaxel lipid suspension.
and secondary efficacy analysis are presented for per protocol population who had confirmed CR, PR, and SD from the best overall response. A point estimate and a 2-sided 95% confidence interval were computed for the primary efficacy end point, response rates (CR þ PR) from best overall response of the 2 treatment groups and their difference. A point estimate and a 2-sided 95% confidence interval were computed for the secondary efficacy end point, disease control rate (CR þ PR þ SD) from best overall response of the 2 treatment groups and their difference. An approximate 95% confidence interval (CI) for the proportion is presented. Categorical variables were summarized as counts and percentage. All statistical analysis was performed using SAS Version 9.2 (SAS Institute Inc).
Conduct of the Study Written informed consent was obtained from all patients before enrollment and the study was conducted as per the protocol, International Conference on Harmonization Good Clinical Practice, based on the basic principles of Good Laboratory Practice, Indian Council of Medical Research Guidelines for Biomedical Research on Human subjects, and Declaration of Helsinki (Seoul 2008) on the rights of research participants.
Results
CR, % PR, % ORR, %
NDLS
Taxotere
4.2 31.3 35.5
0 26.3 26.3
Response Evaluation Criteria In Solid Tumors 1.1 was used for evaluation of efficacy in patients in whom previous chemotherapy treatment had failed. Abbreviations: NDLS ¼ nanosomal docetaxel lipid suspension; ORR ¼ overall response rate.
in Table 2. It was also observed that 1 patient even showed complete response (disappearance of all target lesions) in the NDLS arm compared with none in the Taxotere arm. Taxotere is approved at a dose range of 60 to 100 mg/m2 in the United States and 100 mg/m2 in Europe. In the current study, 75 mg/m2 dose was selected because of the reports indicating that higher doses are substantially more toxic and are only marginally more effective. In addition, the 100 mg/m2 dose is not feasible for some metastatic breast cancer patients heavily pretreated with chemotherapy. Therefore, a dose of 75 mg/m2 of NDLS was used in the present study and was found to be effective.
Safety The safety was monitored according to any clinically significant abnormalities (AEs) in treated patients. The post-dose AEs were reported in 91.30% (n ¼ 21) out of 23 patients who received Taxotere and 93.88% (n ¼ 46) AEs were reported out of 49 patients who received NDLS. The NDLS-treated patients were not given any premedication including corticosteroids. In the NDLS and Taxotere treatment groups, 1 or more grade 3 to 4 treatmentrelated AEs were observed in 77.55% and 52.17% of patients, respectively. The overall increased incidence of neutropenia in NDLS and other AEs were manageable. Most of the post-dose AEs were resolved without any sequelae despite the fact that patients were not premedicated in the NDLS treatment group. Harvey et al19 observed that a Taxotere dose of 75 mg/m2 in patients with advanced breast cancer who experienced treatment failure with previous chemotherapy resulted in 83.7% neutropenia. Greater AEs were reported at higher dose (100 mg/m2) of Taxotere.20 Overall, NDLS was found to be tolerable at 75 mg/m2 devoid of premedication with corticosteroids (Table 3).20
Patient Demographic Characteristics A total of 72 locally advanced or metastatic breast cancer patients were enrolled in the study after previous chemotherapy had failed. Baseline demographic and other characteristics between the 2 treatment arms are shown in Table 1.
Efficacy The results of the study were assessed in an independent radiologic review that demonstrated statistically and clinically superior efficacy of NDLS in terms of objective response rates in metastatic breast cancer patients. The NDLS regimen resulted in 35.5% (95% CI, 21.9-48.9%), a higher overall response rate than Taxotere with 26.3% (95% CI, 6.5-46.1%). The disease control rate (CR þ PR þ SD) was found to be 8% greater for patients receiving Taxotere compared with those who received NDLS. The results are presented
Discussion In the taxane family of cytotoxic drugs, docetaxel is one of the most promising drugs. The polysorbate 80 and ethanol-formulated docetaxel (Taxotere) have been used for the treatment of several types of cancer including breast, head and neck, prostate, non-small lung, and ovarian.7 Taxotere containing polysorbate 80 also affects the disposition of intravenously administered solubilized drugs and leach plasticizers from polyvinylchloride infusion sets. To minimize the infusion-related toxicities including hypersensitivity reactions, patients are required to receive corticosteroids before administration of the drug. This is due to the occurrence of unpredictable (acute) hypersensitivity reactions and cumulative fluid retention.21 Several formulations have been developed including albumin nanoparticles, polyglutamates, taxane analogues and prodrugs,
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Efficacy of Nanosomal Docetaxel Lipid Suspension Table 3 Summary of Adverse Events System Organ Class
Event
Taxotere,20 100 mg/m2
Blood and Lymphatic System Disorders
Neutropenia
98.5%
Gastrointestinal Skin
-
77.5%
Taxotere, 75 mg/m2 (n [ 23) 52.2%
Vomiting
23.4%
10%
22%
Diarrhea
42.6%
29%
22%
Alopecia
74.2%
35%
26%
emulsions, and liposomes, docetaxelefibrinogen-coated olive oil droplets, docetaxel-encapsulated nanoparticle-aptamer bioconjugates, and submicronic dispersion to have an alternative, solvent-free, delivery form for docetaxel.7,21 Most of these formulations are in the early stages of development and investigators have demonstrated less toxicity and greater efficacy primarily in animal studies. Hennenfent and Govindan7 reported that preclinical and clinical data from several of these formulations do not have significant advantages compared with Taxotere. The primary rationale for developing NDLS was to avoid premedication by eliminating polysorbate 80 and ethanol from the commercial Taxotere formulation. In NDLS, docetaxel is formulated with a mixture of well characterized naturally occurring GRAS lipids. The advantages of using lipids instead of polysorbate and ethanol were several fold. Despite premedication with corticosteroids and histamine antagonists, minor reactions (eg, flushing and rash) still occur in approximately 40% of all patients treated with Taxotere, and nearly 3% of patients still experience potentially lifethreatening reactions.9,22 The exact contribution of polysorbate 80 to antitumor effects has not been understood; however, several reports suggest that it might be linked to the release of oleic acid, a fatty acid known to interfere with malignant cell proliferation, and inhibition of angiogenesis.7,23,24 It was observed that GRAS lipids were better tolerated than polysorbate 80 and ethanol. Thus, NDLS was administered in patients without the need for premedication with corticosteroids. This also alleviates the danger of leaching plasticizers from infusion bags or tubing. The pharmaceutical use of lipids have been well documented in several pharmaceutical preparations for oral and for I.V. administration. High levels of lipids infused I.V. have also been shown to be safe.13,14,25 This is consistent with the results reported in the current study in which the NDLS drug appeared to be well tolerated by cancer patients, even as a multiple dose administration. Most of the AEs after dosing were resolved without any sequelae despite the fact that patients were not premedicated. An earlier pharmacokinetics study revealed that NDLS showed greater systemic availability compared with Taxotere, which potentially could translate into greater efficacy.18 The current efficacy trial was conducted at equal doses (75 mg/m2) of NDLS or Taxotere and showed an improved efficacy profile with NDLStreated patients. These findings suggest that the greater exposure of drug using NDLS results in an improved therapeutic outcome in patient populations. Importantly, this trial was conducted in patients in whom previous chemotherapy had failed. The overall response rates observed for Taxotere treatment in our study are similar to those reported by other investigators.19,22
180
NDLS, 75 mg/m2 (n [ 49)
Clinical Breast Cancer June 2014
Conclusion Nanosomal docetaxel lipid suspension improves clinical efficacy without any premedication. Thus, it provides a better treatment option for breast cancer patients.
Clinical Practice Points Nanosomal docetaxel lipid suspension is a new formulation
developed to overcome toxicity and hypersensitivity reactions caused by excipients (polysorbate 80 and ethanol) of commercially available docetaxel formulations. Treatment of breast cancer patients with the improved docetaxel formulation might benefit the patients by shortening the hospital stay required for premedication and resulting in better therapeutic outcome.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Jasmine N, Fauzee S, Dong Z, et al. Taxanes: promising anti-cancer drugs. Asian Pac J Cancer Prev 2011; 12:837-51. 2. Ryan DP, Grossbard ML. Pancreatic cancer: local success and distant failure. Oncologist 1998; 3:178-88. 3. Al-Sarraf M. Treatment of locally advanced head and neck cancer: historical and critical review. Cancer Control 2002; 9:387-99. 4. Valero V, Holmes FA, Walters RS, et al. Phase II trial of docetaxel: a new, highly effective antineoplastic agent in the management of patients with anthracyclineresistant metastatic breast cancer. J Clin Oncol 1995; 13:2886-94. 5. Pronk LC, Stoter G, Verweij J. Docetaxel (Taxotere): single-agent activity, development of combination treatment and reducing side-effects. Cancer Treat Rev 1995; 21:463-78. 6. Hortobagyi GN, Kris MG. Expanding horizons: an update on the use of docetaxel in non-small cell lung, ovarian, and breast cancer. Semin Oncol 2002; 29:1-3. 7. Hennenfent KL, Govindan R. Novel formulations of taxanes: a review. Old wine in a new bottle? Ann Oncology 2006; 17:735-49. 8. Masini E, Planchenault J, Pezziardi F, et al. Histamine-releasing properties of Polysorbate 80 in vitro and in vivo: correlation with its hypotensive action in the dog. Agents Actions 1985; 16:470-7. 9. Loos WJ, Baker SD, Verweij J, et al. Clinical pharmacokinetics of unbound docetaxel: role of polysorbate 80 and serum proteins. Clin Pharmacol Ther 2003; 74:364-71. 10. ten Tije AJ, Verweij J, Loos WJ, et al. Pharmacological effects of formulation vehicles: implications for cancer chemotherapy. Clin Pharmacokinet 2003; 42:665-85. 11. Esmaeili F, Dinarvand R, Ghahremani MH, et al. Docetaxel-albumin conjugates: preparation, in vitro evaluation and biodistribution studies. J Pharm Sci 2009; 98: 2718-30. 12. Feng SS, Mei L, Anitha P, et al. Poly(lactide)-vitamin E derivative/montmorillonite nanoparticle formulations for the oral delivery of docetaxel. Biomaterials 2009; 30:3297-306. 13. Sheikh S, Ali SM, Ahmad MU, et al. Nanosomal Amphotericin B is an efficacious alternative to Ambisome for fungal therapy. Int J Pharm 2010; 397:103-8. 14. Ali SM, Ahmad A, Sheikh S, et al. Polyoxyl 60 hydrogenated castor oil free nanosomal formulation of immunosuppressant Tacrolimus: pharmacokinetics, safety, and tolerability in rodents and humans. Int Immunopharmacol 2010; 10:325-30. 15. Hwang HY, Kim IS, Kwon IC, et al. Tumor targetability and antitumor effect of docetaxel-loaded hydrophobically modified glycol chitosan nanoparticles. J Control Release 2008; 128:23-31.
Ateeq Ahmad et al 16. Liu B, Yang M, Li R, et al. The antitumor effect of novel docetaxel-loaded thermosensitive micelles. Eur J Pharm Biopharm 2008; 69:527-34. 17. Du W, Hong L, Yao T, et al. Synthesis and evaluation of water-soluble docetaxel prodrugs-docetaxel esters of malic acid. Bioorg Med Chem 2007; 15:6323-30. 18. Ahmad A, Sheikh S, Taran R, et al. Effect of nanosomal docetaxel lipid suspension (NDLS) on response rate compared to docetaxel: a randomized phase II study in patients with locally advanced or metastatic breast cancer. J Clin Oncol 2013; 31 (abstract 577). 19. Harvey V, Mouridsen H, Semiglazov V, et al. Phase III trial comparing three doses of docetaxel for second-line treatment of advanced breast cancer. J Clin Oncol 2006; 24:4963-70. 20. Taxotere (docetaxel) Injection [prescribing information]. Bridgewater, NJ: Aventis Pharmaceuticals; 2003. 21. Engels FK, Mathot RA, Verweij J. Alternative drug formulations of docetaxel: a review. Anticancer Drugs 2007; 18:95-103.
22. Sparano JA, Makhson AN, Semiglazov VF, et al. Pegylated liposomal doxorubicin plus docetaxel significantly improves time to progression without additive cardiotoxicity compared with docetaxel monotherapy in patients with advanced breast cancer previously treated with neoadjuvant-adjuvant anthracycline therapy: results from a randomized phase III study. J Clin Oncol 2009; 27:4522-9. 23. Chajes V, Sattler W, Stranzl A, et al. Influence of n-3 fatty acids on the growth of human breast cancer cells in vitro: relationship to peroxides and vitamin-E. Breast Cancer Res Treat 1995; 34:199-212. 24. Kimura Y. Carp oil or oleic acid, but not linoleic acid or linolenic acid, inhibits tumor growth and metastasis in Lewis lung carcinoma-bearing mice. J Nutr 2002; 132:2069-75. 25. Rosenblatt MA, Abel M, Fischer GW, et al. Successful use of a 20% lipid emulsion to resuscitate a patient after a presumed bupivacaine-related cardiac arrest. Anesthesiology 2006; 105:217-8.
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Therapeutic Efficacy of a Novel Nanosomal Docetaxel Lipid Suspension Compared With Taxotere in Locally Advanced or Metastatic Breast Cancer Patients Ateeq Ahmad,1 Saifuddin Sheikh,1 Rakesh Taran,2 Shanti P. Srivastav,3 Krishna Prasad,4 Senthil J. Rajappa,5 Vijay Kumar,6 Mamillapalli Gopichand,7 Mahesh Paithankar,8 Manish Sharma,9 Rajendra C. Rane,10 Imran Ahmad1 Abstract Drug delivery systems are widely used to reduce toxicity of drugs and enhance the quality of a patient’s life. Nanosomal docetaxel lipid suspension (NDLS) is formulated based on an aqueous lipid delivery system. Patients with breast cancer were not required to be premedicated before administration of NDLS. Docetaxel administered using this delivery system also improves the response rate compared with commercially available docetaxel drug. Background: Nanosomal docetaxel lipid suspension formulation was developed to eliminate ethanol and polysorbate 80 from the currently used docetaxel (Taxotere) drug for treatment of cancer patients. NDLS clinical safety and efficacy was evaluated and compared with Taxotere at 75 mg/m2 in metastatic breast cancer patients. Patients and Methods: A total of 72 patients were randomized in a ratio of 2:1 (NDLS:Taxotere). Patients treated with NDLS were not premedicated with corticosteroids as required with solvent-based Taxotere. Disease status and tumor response was assessed after every 2 cycles of treatment using Response Evaluation Criteria in Solid Tumors 1.1 guidelines through cycle 6. Results: Overall therapeutic response (complete þ partial) rate in metastatic breast cancer patients treated with NDLS and Taxotere were 35.5% and 26.3%, respectively, indicating better response in patients treated with NDLS. Patients in the NDLS group were not premedicated but the safety results of NDLS were found to be comparable with Taxotere. Conclusion: NDLS formulation with no premedication provides an alternative treatment option for breast cancer patients. Clinical Breast Cancer, Vol. 14, No. 3, 177-81 ª 2014 Elsevier Inc. All rights reserved. Keywords: Complete response rate, Computed tomography, Lipid delivery system, Premedication, Safety
Introduction Taxanes are one of the most important cytotoxic agents discovered for the treatment of several types of cancer. Paclitaxel was the first taxane product for which clinical studies indicated an effective response rate and overall survival in breast, lung, ovarian, and gastric cancers.1 However, in some cancers like advanced pancreatic carcinomas, paclitaxel showed lower efficacy compared with docetaxel.2 Results of this study were presented, in part, at the American Society of Clinical Oncology meeting, May 31 - June 4, 2013.
In metastatic and recurrent head and neck cancer, the combination of paclitaxel and platinum showed lower response compared with docetaxel combination.3 Therefore, in some types of cancers the response rate in patients using paclitaxel treatment might be less compared with patients using docetaxel. Docetaxel is prepared by semisynthesis beginning with a precursor extracted from the renewable needle biomass of yew plants. It 8
Astron Research, Ltd, Ahmedabad, India Lambda Therapeutic Research Ltd, Ahmedabad, India 10 Intas Pharmaceuticals, Ltd, Ahmedabad, India 9
1
Jina Pharmaceuticals, Inc, Libertyville, IL CHL Apollo Hospital, Indore, India Lions Cancer Detection Centre, New Civil Hospital, Surat, India 4 Kasturba Medical College and Hospital, Mangalore, India 5 Indo-American Cancer Hospital and Research Institute, Hyderabad, India 6 M.V. Hospital and Research Center, Lucknow, India 7 City Cancer Center, Vijayawada, India 2 3
1526-8209/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2013.09.011
Submitted: Aug 26, 2013; Revised: Sep 17, 2013; Accepted: Sep 24, 2013; Epub: Sep 28, 2013 Address for correspondence: Imran Ahmad, PhD, Jina Pharmaceuticals, Inc, 28100 N Ashley Ct, Suite 103, Libertyville, IL 60048 Fax: 847-557-0770; e-mail contact: [email protected]
Clinical Breast Cancer June 2014
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Efficacy of Nanosomal Docetaxel Lipid Suspension is highly lipophilic and practically insoluble in water. Because of its insolubility, the currently marketed docetaxel (Taxotere) is formulated in polysorbate 80 and ethanol and have been approved by the Food and Drug Administration for the treatment of various cancers including locally advanced metastatic breast, nonesmall-cell lung, and ovarian cancer, and in combination with other drugs for several additional cancer types such as prostate, head and neck, and gastric adenocarcinoma.4-7 The use of ethanol and polysorbate 80 in Taxotere formulation causes infusion-related toxicities and hypersensitivity reactions in patients.8-10 Thus, the patients are premedicated with corticosteroids to minimize such toxicities before the treatment. To circumvent the toxicities related to polysorbate 80, several investigators developed formulations based on various delivery systems such as liposomes, polymeric micelles, protein, and nanospheres.11-17 Nanosomal docetaxel lipid suspension (NDLS) formulation was developed using lipids generally recognized as safe (GRAS) by the Food and Drug Administration and is absolutely free of polysorbate 80 and ethanol. A crossover study conducted at 75 mg/m2 with Taxotere in solid tumor patients showed greater systemic availability of docetaxel in patients treated with NDLS compared with Taxotere. In addition, no increase in toxicity was observed compared with Taxotere. The higher systemic availability of NDLS led us to conduct the current efficacy study in breast cancer patients. Results of this study were presented, in part, at the American Society of Clinical Oncology meeting, 2013.18 In this study, comparative clinical safety and efficacy of NDLS and Taxotere at 75 mg/m2were evaluated in metastatic breast cancer patients. The improved clinical efficacy of NDLS with no premedication reported here might transform NDLS as a new useful drug for the treatment of cancer.
Patients and Methods Chemicals and Reagents Docetaxel was obtained from Scinopharm, Taiwan. NDLS clinical batches were manufactured at a Food and Drug Administration-inspected facility of Intas Pharmaceutical Ltd, India. Soy phosphatidylcholine was procured from Lipoid LLC (Newark, NJ) and sodium cholesteryl sulfate was obtained from Genzyme Pharmaceuticals (Cambridge, MA). Polysorbate-based docetaxel was procured from Aventis Pharma, SA, Paris, France.
Study Design
178
-
This was an open label, randomized, multiple dose, parallel study in locally advanced or metastatic breast cancer patients in whom previous chemotherapy had failed. Women, from 18 to 65 years of age, with histopathologically/cytologically confirmed breast cancer, having locally advanced or metastatic breast cancer after failure of previous chemotherapy were enrolled in the study. These patients had Eastern Cooperative Oncology Group (ECOG) performance status 2, with adequate bone marrow, renal, and hepatic function, having at least 1 measurable lesion according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria and also had life expectancy of at least 6 months. The patients were randomized to receive either NDLS or Taxotere. A total of 72 patients were enrolled into the study at a ratio of 2:1 (NDLS:Taxotere). The mean age of the enrolled patients was 47 years and racial makeup of the study was 100% Asian. Patients were
Clinical Breast Cancer June 2014
administered NDLS or Taxotere at 75 mg/m2 according to the randomization schedule, using intravenous (I.V.) infusion for 1 hour in each cycle of 21 days. Each patient received a maximum of 6 cycles of NDLS or Taxotere. Patients in the NDLS group were not premedicated. Sexually active women enrolled in the study, unless surgically sterile (at least 6 months before study drug administration) or postmenopausal for at least 12 consecutive months, used an effective method of avoiding pregnancy including oral, transdermal, or implanted contraceptive devices (any hormonal method in conjunction with a secondary method), intrauterine device, female condom with spermicide, diaphragm with spermicide, absolute sexual abstinence, use of condom with spermicide by sexual partner or sterile (at least 6 months before study drug administration) for at least 4 weeks before study drug administration, during study, and up to 30 days after the last dose of study drug. Results of the pregnancy test done at screening were required to be negative.
Treatment and Efficacy Assessments Each drug, NDLS or Taxotere was administered using I.V. infusion over 1 hour (10-minute deviation was allowed) at a dose of 75 mg/m2. Disease status and tumor response (computed tomography [CT] scan/magnetic resonance imaging) was assessed after every 2 cycles of treatment using RECIST 1.1 guidelines through cycle 6 (including confirmation of response if required); subsequent cycles followed institutional standards for tumor/disease assessment. Independent evaluation (blinded reading) of the images acquired in clinical trial was done at the Central Imaging Facility. Primary efficacy evaluation was based on the overall response rate (complete response [CR] þ partial response [PR]), defined as the proportion of patients whose best overall response was CR (disappearance of all target lesions) or PR after receiving at least 2 cycles of study treatment of NDLS or Taxotere. Patients without a confirmed CR or PR were considered as failure in computing the best overall response rates. The secondary efficacy end point of this study was overall response rate, defined as the proportion of patients in whom disease control rate (CR þ PR þ stable disease [SD] ¼ disease control rate) from best overall response was CR or PR or SD. Patients without a confirmed CR or PR or SD were considered as failure in computing best overall response rate. The data identified as CR, PR, SD, progressive disease, or not evaluable from independent reviewers was used for the primary and secondary efficacy analysis.
Safety Assessments Adverse events (AEs) were assessed every cycle for the duration of the trial and graded according to the National Cancer Institute Common Toxicity Criteria, version 4.02. Data on serious AEs were collected throughout the study. Medical history, demography, physical examination and vital signs, body measurement, ECOG, hepatic screening, b-human chorionic gonadotropin test (serum), hematology biochemistry, urine analysis, CT scan, bone scan, echocardiography, and electrocardiogram were carried out as a part of safety and efficacy evaluations.
Statistical Analysis Primary efficacy analyses are presented for per protocol population who had confirmed CR and PR from the best overall response
Ateeq Ahmad et al Table 1 Patient and Demographic Characteristics Taxotere (n [ 23)
NDLS (n [ 49)
Median
45.0
47.0
Range
28-63
33-64
Characteristic
Outcome
Age, Years
Weight, kg Median
47.0
51.5
Range
30-74
33-91.5
1.4
1.46
BSA, m2 Median Range
1.16-1.73
1.18-1.91
Height, cm Median Range
Table 2 Objective Response Rates of NDLS and Taxotere at 75 mg/m2
150 137-162
153 137-164
Abbreviations: BSA ¼ body surface area; NDLS ¼ nanosomal docetaxel lipid suspension.
and secondary efficacy analysis are presented for per protocol population who had confirmed CR, PR, and SD from the best overall response. A point estimate and a 2-sided 95% confidence interval were computed for the primary efficacy end point, response rates (CR þ PR) from best overall response of the 2 treatment groups and their difference. A point estimate and a 2-sided 95% confidence interval were computed for the secondary efficacy end point, disease control rate (CR þ PR þ SD) from best overall response of the 2 treatment groups and their difference. An approximate 95% confidence interval (CI) for the proportion is presented. Categorical variables were summarized as counts and percentage. All statistical analysis was performed using SAS Version 9.2 (SAS Institute Inc).
Conduct of the Study Written informed consent was obtained from all patients before enrollment and the study was conducted as per the protocol, International Conference on Harmonization Good Clinical Practice, based on the basic principles of Good Laboratory Practice, Indian Council of Medical Research Guidelines for Biomedical Research on Human subjects, and Declaration of Helsinki (Seoul 2008) on the rights of research participants.
Results
CR, % PR, % ORR, %
NDLS
Taxotere
4.2 31.3 35.5
0 26.3 26.3
Response Evaluation Criteria In Solid Tumors 1.1 was used for evaluation of efficacy in patients in whom previous chemotherapy treatment had failed. Abbreviations: NDLS ¼ nanosomal docetaxel lipid suspension; ORR ¼ overall response rate.
in Table 2. It was also observed that 1 patient even showed complete response (disappearance of all target lesions) in the NDLS arm compared with none in the Taxotere arm. Taxotere is approved at a dose range of 60 to 100 mg/m2 in the United States and 100 mg/m2 in Europe. In the current study, 75 mg/m2 dose was selected because of the reports indicating that higher doses are substantially more toxic and are only marginally more effective. In addition, the 100 mg/m2 dose is not feasible for some metastatic breast cancer patients heavily pretreated with chemotherapy. Therefore, a dose of 75 mg/m2 of NDLS was used in the present study and was found to be effective.
Safety The safety was monitored according to any clinically significant abnormalities (AEs) in treated patients. The post-dose AEs were reported in 91.30% (n ¼ 21) out of 23 patients who received Taxotere and 93.88% (n ¼ 46) AEs were reported out of 49 patients who received NDLS. The NDLS-treated patients were not given any premedication including corticosteroids. In the NDLS and Taxotere treatment groups, 1 or more grade 3 to 4 treatmentrelated AEs were observed in 77.55% and 52.17% of patients, respectively. The overall increased incidence of neutropenia in NDLS and other AEs were manageable. Most of the post-dose AEs were resolved without any sequelae despite the fact that patients were not premedicated in the NDLS treatment group. Harvey et al19 observed that a Taxotere dose of 75 mg/m2 in patients with advanced breast cancer who experienced treatment failure with previous chemotherapy resulted in 83.7% neutropenia. Greater AEs were reported at higher dose (100 mg/m2) of Taxotere.20 Overall, NDLS was found to be tolerable at 75 mg/m2 devoid of premedication with corticosteroids (Table 3).20
Patient Demographic Characteristics A total of 72 locally advanced or metastatic breast cancer patients were enrolled in the study after previous chemotherapy had failed. Baseline demographic and other characteristics between the 2 treatment arms are shown in Table 1.
Efficacy The results of the study were assessed in an independent radiologic review that demonstrated statistically and clinically superior efficacy of NDLS in terms of objective response rates in metastatic breast cancer patients. The NDLS regimen resulted in 35.5% (95% CI, 21.9-48.9%), a higher overall response rate than Taxotere with 26.3% (95% CI, 6.5-46.1%). The disease control rate (CR þ PR þ SD) was found to be 8% greater for patients receiving Taxotere compared with those who received NDLS. The results are presented
Discussion In the taxane family of cytotoxic drugs, docetaxel is one of the most promising drugs. The polysorbate 80 and ethanol-formulated docetaxel (Taxotere) have been used for the treatment of several types of cancer including breast, head and neck, prostate, non-small lung, and ovarian.7 Taxotere containing polysorbate 80 also affects the disposition of intravenously administered solubilized drugs and leach plasticizers from polyvinylchloride infusion sets. To minimize the infusion-related toxicities including hypersensitivity reactions, patients are required to receive corticosteroids before administration of the drug. This is due to the occurrence of unpredictable (acute) hypersensitivity reactions and cumulative fluid retention.21 Several formulations have been developed including albumin nanoparticles, polyglutamates, taxane analogues and prodrugs,
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Efficacy of Nanosomal Docetaxel Lipid Suspension Table 3 Summary of Adverse Events System Organ Class
Event
Taxotere,20 100 mg/m2
Blood and Lymphatic System Disorders
Neutropenia
98.5%
Gastrointestinal Skin
-
77.5%
Taxotere, 75 mg/m2 (n [ 23) 52.2%
Vomiting
23.4%
10%
22%
Diarrhea
42.6%
29%
22%
Alopecia
74.2%
35%
26%
emulsions, and liposomes, docetaxelefibrinogen-coated olive oil droplets, docetaxel-encapsulated nanoparticle-aptamer bioconjugates, and submicronic dispersion to have an alternative, solvent-free, delivery form for docetaxel.7,21 Most of these formulations are in the early stages of development and investigators have demonstrated less toxicity and greater efficacy primarily in animal studies. Hennenfent and Govindan7 reported that preclinical and clinical data from several of these formulations do not have significant advantages compared with Taxotere. The primary rationale for developing NDLS was to avoid premedication by eliminating polysorbate 80 and ethanol from the commercial Taxotere formulation. In NDLS, docetaxel is formulated with a mixture of well characterized naturally occurring GRAS lipids. The advantages of using lipids instead of polysorbate and ethanol were several fold. Despite premedication with corticosteroids and histamine antagonists, minor reactions (eg, flushing and rash) still occur in approximately 40% of all patients treated with Taxotere, and nearly 3% of patients still experience potentially lifethreatening reactions.9,22 The exact contribution of polysorbate 80 to antitumor effects has not been understood; however, several reports suggest that it might be linked to the release of oleic acid, a fatty acid known to interfere with malignant cell proliferation, and inhibition of angiogenesis.7,23,24 It was observed that GRAS lipids were better tolerated than polysorbate 80 and ethanol. Thus, NDLS was administered in patients without the need for premedication with corticosteroids. This also alleviates the danger of leaching plasticizers from infusion bags or tubing. The pharmaceutical use of lipids have been well documented in several pharmaceutical preparations for oral and for I.V. administration. High levels of lipids infused I.V. have also been shown to be safe.13,14,25 This is consistent with the results reported in the current study in which the NDLS drug appeared to be well tolerated by cancer patients, even as a multiple dose administration. Most of the AEs after dosing were resolved without any sequelae despite the fact that patients were not premedicated. An earlier pharmacokinetics study revealed that NDLS showed greater systemic availability compared with Taxotere, which potentially could translate into greater efficacy.18 The current efficacy trial was conducted at equal doses (75 mg/m2) of NDLS or Taxotere and showed an improved efficacy profile with NDLStreated patients. These findings suggest that the greater exposure of drug using NDLS results in an improved therapeutic outcome in patient populations. Importantly, this trial was conducted in patients in whom previous chemotherapy had failed. The overall response rates observed for Taxotere treatment in our study are similar to those reported by other investigators.19,22
180
NDLS, 75 mg/m2 (n [ 49)
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Conclusion Nanosomal docetaxel lipid suspension improves clinical efficacy without any premedication. Thus, it provides a better treatment option for breast cancer patients.
Clinical Practice Points Nanosomal docetaxel lipid suspension is a new formulation
developed to overcome toxicity and hypersensitivity reactions caused by excipients (polysorbate 80 and ethanol) of commercially available docetaxel formulations. Treatment of breast cancer patients with the improved docetaxel formulation might benefit the patients by shortening the hospital stay required for premedication and resulting in better therapeutic outcome.
Disclosure The authors have stated that they have no conflicts of interest.
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