Docetaxel + Plinabulin Compared to Docetaxel + Placebo in Patients With Advanced NSCLC (DUBLIN-3)

• ClinicalTrials.gov Identifier: NCT02504489
• Recruitment Status: Completed
• First Posted: July 22, 2015
• Last Update Posted: September 10, 2022
• Sponsor: BeyondSpring Pharmaceuticals Inc.
• Information provided by (Responsible Party): BeyondSpring Pharmaceuticals Inc.

Study Description

Brief Summary:

To compare the overall survival of NSCLC patients receiving 2nd- or 3rd-line systemic therapy with docetaxel + plinabulin (DP Arm) to patients treated with docetaxel + placebo (D5W) (D Arm) for advanced or metastatic disease.

Secondary purposes of the study are:

• To compare overall response rate (ORR) of NSCLC patients receiving 2nd- or 3rd-line systemic therapy with docetaxel + plinabulin (DP Arm) to patients treated with docetaxel + placebo (D5W) (D Arm) for advanced or metastatic disease.
• To compare progression free survival (PFS) of NSCLC patients receiving 2nd- or 3rd-line systemic therapy with docetaxel + plinabulin (DP Arm) to patients treated with docetaxel + placebo (D5W) (D Arm) for advanced or metastatic disease.
• To compare incidence of Grade 4 neutropenia (absolute neutrophil count [ANC] < 0.5 × 109/L) on Day 8 (+/- 1 day) of Cycle 1 of NSCLC patients receiving 2nd- or 3rd-line systemic therapy with docetaxel + plinabulin (DP Arm) to patients treated with docetaxel + placebo (D5W) (D Arm) for advanced or metastatic disease.
• To compare 24-month and 36-month OS rate of NSCLC patients receiving 2nd- or 3rd-line systemic therapy with docetaxel + plinabulin (DP Arm) to patients treated with docetaxel + placebo (D5W) (D Arm) for advanced or metastatic disease.

Condition or disease	Intervention/treatment	Phase
Non-Small Cell Lung Cancer	Drug: Docetaxel + Plinabulin (DP); Drug: Docetaxel (D)	Phase 3

Detailed Description:

Lung cancer is the leading cause of cancer-related mortality worldwide. According to the World Health Organization's Global Cancer Observatory, there were an estimated 2.09 million new cases and 1.76 million deaths worldwide in 2018 (GLOBOCAN, 2018, Fact Sheet N⁰39). The lung cancer incidence and mortality in China is relatively high compared to most countries with an estimated 774,323 new cases and 690,567 deaths in 2018 (GLOBOCAN, 2018, Fact Sheet N⁰160 China). In the US, as per the estimates of the National Cancer Institute, there would be about 228,820 new cases and 135,720 deaths from lung cancer in 2020 accounting for approximately 22.4% of all cancer deaths (SEER program, 2020). About 84% of lung cancers are NSCLCs in the US (American Cancer Society, 2020).

The prognosis for patients with advanced or metastatic NSCLC, either at initial diagnosis or recurrence, remains grim. The standard of care has been chemotherapy with agents including platinum analogs, taxanes, vinca alkaloids, and pemetrexed with vascular endothelial growth factor inhibitors and for patients with appropriate disease genotypes, epidermal growth factor receptor (EGFR) inhibitors or anaplastic lymphoma kinase (ALK) inhibitors.

First-line Therapy: For patients without specific molecular target, first-line therapy is usually a programmed cell death protein 1 (PD-1)-inhibitor or a platinum-containing, double agent regimen. Platinum can be either cisplatin or carboplatin, and the most commonly used drugs combined with platinum include paclitaxel, docetaxel, gemcitabine, and vinorelbine; other drugs such as irinotecan, etoposide, and vinblastine.

The arrival of immunotherapy with the PD-1 inhibitor pembrolizumab effectively changed the first-line standard. Pembrolizumab is very effective, with a long Duration of Response (DoR), however response rates remain suboptimal (approximately 45% in first line [Keytruda® Prescribing Information. 2020]). Most patients will eventually fail first line therapy and docetaxel remains a valid treatment option when NSCLC patients fail to respond to targeted or immune-based therapies or become refractory to such therapies.

For patients intolerant to platinum-containing regimens, platinum-free double-agent chemotherapy regimens are used as an alternative. For patients with an Eastern Cooperative Oncology Group score of 2 and elderly patients, single-agent or double agent regimens are recommended. Approval has been obtained in China for the single agent gefitinib to be used in first-line treatment of locally advanced or metastatic NSCLC patients with sensitive mutation of EGFR tyrosine kinase gene.

Second-line Therapy: Drugs used for second-line treatment include docetaxel, pemetrexed, EGFR-tyrosine kinase inhibitor (TKI) for EGFR mutant patients, and the checkpoint inhibitors (such as nivolumab and pembrolizumab).

Several second-line treatment drugs and regimens (docetaxel, pemetrexed, and ramucirumab combined with docetaxel) have been approved as single agents or combination for second-line therapy for locally advanced or metastatic NSCLC with EGFR wild type with limited efficacy, characterized by limited clinical improvement or overall survival (OS). EGFR wild type represents around 85% of western NSCLC population, and around 70% of Asian NSCLC population. Checkpoint inhibition with PD 1/programmed death-ligand 1 (PD-L1) inhibitors in combination with chemotherapy or other checkpoint inhibitors have moved into first line and are increasingly not an option for 2nd/3rd line. This has created a situation where docetaxel-based regimens have become standard-of-care in 2nd/3rd line NSCLC. Therefore, the evaluation of plinabulin combined with docetaxel versus docetaxel alone has become highly relevant.

Docetaxel, a taxane, binds to and stabilizes tubulin, thereby inhibiting microtubule disassembly resulting in cell cycle arrest at the G2/M phase and subsequent cell death. In patients with NSCLC, previously treated with a platinum-based chemotherapy, second-line therapy with docetaxel afforded a median OS in the range from 5.7 to 7.5 months (Fossella, 2000; Shepherd, 2000). The most common AEs included infections, neutropenia, anemia, febrile neutropenia (FN), hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, and myalgia (Taxotere Prescribing Information, 2020). Since the approval of docetaxel in 1999 as the second-line treatment for advanced or metastatic NSCLC, other drugs, namely pemetrexed and erlotinib, have been approved for the same indication. However, despite the availability of newer treatments, patient survival has not improved over that achieved with docetaxel. The OS in these studies was found to remain in the range of 5.6 to 8.3 months (Hanna et al., 2004; Kim et al., 2008; Shepherd et al., 2005).

A retrospective analysis of the plinabulin Phase 2 study suggests that plinabulin prolongs survival in NSCLC patients with measurable lung tumors. The expectation is that patients with a measurable lung lesion may still harbor antigens that are immunogenic, thus capable of still stimulating the immune system. Docetaxel treatment is expected to release these immunogens and plinabulin is expected to enhance presentation of these immunogens via dendritic cell activation, to the T-cell repertoire.

This plinabulin study investigates the efficacy and safety of plinabulin and docetaxel combination in patients with EGFR wild type NSCLC and progressing tumors requiring second- or third- line therapy for advanced or metastatic disease after failing a platinum-containing regimen. The primary endpoint is OS, with docetaxel monotherapy as an active comparator.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 559 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Masking Description: placebo
• Primary Purpose: Treatment
• Official Title: Randomized Blinded Phase III Assessment of Second or Third-Line Chemotherapy With Docetaxel + Plinabulin Compared to Docetaxel + Placebo in Patients With Advanced Non-Small Cell Lung Cancer and With at Least One Measurable Lung Lesion
• Actual Study Start Date: December 2015
• Actual Primary Completion Date: March 23, 2021
• Actual Study Completion Date: May 23, 2021

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Docetaxel (D); A treatment cycle is 21 days. Treatment will be repeated until disease progression is detected by imaging studies or unacceptable toxicities are encountered. On Day 1, all patients will receive docetaxel 75 mg/m2 by intravenous (IV) infusion over 1 hour. Oral dexamethasone (16 mg, given as 8 mg twice daily) will be given on the day prior to, the day of (Day 1), and the day following docetaxel infusion (Day 2). Antiemetic prophylaxis will be administered according to institutional guideline for docetaxel. Institutional guideline/practice should be followed in the event of infusion/hypersensitivity reaction. Diphenhydramine and dexamethasone infusion may be administered in the event of infusion reaction.	Drug: Docetaxel (D); Docetaxel 75 mg/m2 IV; Other Name: Taxotere
Experimental: Docetaxel + Plinabulin (DP); The treatment regimen for Docetaxel (D) will be followed for this arm. In addition, on Days 1 and 8 of the 21 day cycle, patients will receive Plinabulin (P) administered via IV infusion over 60 minutes. On Day 1, the infusion begins 2 hours from the starting time of docetaxel infusion, i.e, approximately 60 minutes from the end of docetaxel infusion. On Day 8, patients must be given an anti-emetic prophylactically before the plinabulin infusion. If emesis persists after Day 8, with a grade >1, plinabulin will be reduced to 20 mg/m2. Patients from the DP Arm who stop treatment with docetaxel due to toxicity or another medically acceptable reason, may continue treatment with plinabulin alone as previously described.	Drug: Docetaxel + Plinabulin (DP); Docetaxel 75 mg/m2 IV + Plinabulin 30 mg/m2; Other Name: BPI-2358, NPI-2358; Drug: Docetaxel (D); Docetaxel 75 mg/m2 IV; Other Name: Taxotere

Outcome Measures

Primary Outcome Measures :

1. Overall Survival [ Time Frame: Mid-February 2021 (Approximately 2 years after study initiation) ]
   Overall survival of NSCLC patients receiving 2nd- or 3rd-line systemic therapy

Secondary Outcome Measures :

1. ORR [ Time Frame: Approximately 2 years after study initiation. ]
   Overall response rate
2. PFS [ Time Frame: Approximately 2 years after study initiation. ]
   Progress-free survival
3. Severe Neutropenia [ Time Frame: Day 8 of Cycle 1 ]
   Percent of patients without severe neutropenia on Day 8 of Cycle 1
4. Month 24 OS Rate [ Time Frame: 24-month after study initiation ]
   To compare 24-month overall survival rate
5. Month 36 OS Rate [ Time Frame: 36 month after study initiation ]
   To compare 36-month overall survival rate
6. DoR [ Time Frame: Approximately 2 years after study initiation. ]
   Duration of response
7. Quality of Life (EORTC QLQ-C30) [ Time Frame: Approximately 2 years after study initiation. ]
   Average Quality of Life score over all observed weeks (scale 0 - 30, higher value represents better outcome)
8. Q-TWiST [ Time Frame: Approximately 2 years after study initiation. ]
   To compare the mean difference in quality-adjusted time without symptoms of disease and toxicity
9. QoL (QLQ-LC13) [ Time Frame: Approximately 2 years after study initiation. ]
   To compare the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 global health status/QoL and the combined symptom scales/items (excluding financial difficulties)
10. Proportion of patients who received docetaxel [ Time Frame: During 1st 21-day cycle ]
    To compare proportion of patients who received docetaxel >8 cycles, >10 cycles, and >12 cycles
11. Month 18 OS Rate [ Time Frame: 18 month after study initiation ]
    To compare 18-month overall survival rate
12. RDI [ Time Frame: First 4, 6, 8, 10, and 12 cycles ]
    To compare relative dose intensity [where dose intensity is defined as dose in mg/m2/week] of docetaxel
13. Month 12 OS Rate [ Time Frame: 12 month after study initiation ]
    To compare 12-month overall survival rate

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

INCLUSION CRITERIA:

1. Males and females ≥ 18 years of age
2. ECOG performance status ≤ 2.
3. Histopathologically or cytologically confirmed non-squamous or squamous NSCLC.
4. Disease progression during or after treatment with one or two treatment regimen(s) Treatment regimens can be chemotherapy, targeted therapy, biological therapy, or immunotherapy for advanced (Stage IIIB) or metastatic disease (Stage IV). Modification of a regimen to manage toxicity with a different drug does not constitute a new regimen. Maintenance therapy following platinum-based chemotherapy is not considered as a separate regimen. Adjuvant or neoadjuvant chemotherapy and/or chemo-radiation for early stage disease do not count as prior systemic therapy. Prior radiation therapy is not exclusionary. Prior immunotherapy with a PD-1/PD-L1 inhibitor is not exclusionary. Prior treatment for advanced or metastatic disease must have included a platinum-based regimen. (Treatment of early stage disease [Stage IIIA or earlier] with a platinum-containing therapy does not count).
5. Patients with active brain metastasis or leptomeningeal involvement with brain metastases who are asymptomatic, and whose lesions by imaging are at least stable and without interim development of new lesions for at least 4 weeks may be enrolled. Patients who require continued therapy with steroid medication for management for their brain metastases are eligible; dosing must be stable for at least 4 weeks prior to randomization;
6. Patients must have at least one measurable lung lesion of ≥10 mm by CT or MRI per RECIST 1.1 criteria. Radiographic tumor assessment is to be performed within 28 days prior to randomization;
7. All patients with non-squamous NSCLC must have been tested for 19 deletion and exon 21 L858R substitution mutation. Only patients without EGFR sensitizing mutations are eligible, and they must have progressed on platinum-based chemotherapy. Patients with known ALK-rearrangements should be treated with an appropriate tyrosine kinase inhibitor (TKI) before entering the study. The TKI regimen would count as a line of treatment.
8. All adverse events of any prior systemic therapy, surgery, or radiotherapy, must have resolved to CTCAE (v4.03) Grade ≤2, except for neurological adverse events that must have resolved to Grade ≤1;

9. The following laboratory results from the central laboratory within 14 days prior to Cycle 1 Day 1 study drug administration.

   • Hemoglobin ≥9 g/dL independent of transfusion or growth factor support;
   • Absolute neutrophil count ≥1.5 x 109/L independent of growth factor support;
   • Platelet count ≥100 x 109/L independent of transfusion or growth factor support;
   • Serum total bilirubin ≤ ULN, unless the patient has a diagnosis of Gilbert's disease in which case serum bilirubin ≤3.0 times ULN;
   • AST and ALT ≤2.5 x ULN (≤1.5 x ULN if alkaline phosphatase is >2.5 x ULN);
   • Serum creatinine ≤1.5 x ULN;
10. Life expectancy more than 12 weeks;

11. Female patients of childbearing potential have a negative pregnancy test at baseline. Females of childbearing potential are defined as sexually mature women without prior hysterectomy or who have had any evidence of menses in the past 12 months. However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, anti-estrogens, or ovarian suppression.

    1. Women of childbearing potential (i.e., menstruating women) must have a negative urine pregnancy test (positive urine tests are to be confirmed by serum test) documented within the 24-hour period prior to the first dose of study drug.
    2. Sexually active women of childbearing potential enrolled in the study must agree to use two forms of accepted methods of contraception during the course of the study and for 3 months after their last dose of study drug. Effective birth control includes (a) intrauterine device (IUD) plus one barrier method; (b) on stable doses of hormonal contraception for at least 3 months (e.g., oral, injectable, implant, transdermal) plus one barrier method; (c) 2 barrier methods. Effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm); or (d) a vasectomized partner.
    3. For male patients who are sexually active and who are partners of premenopausal women: agreement to use two forms of contraception as in criterion 11b above during the treatment period and for at least 3 months after the last dose of study drug.
12. Signed informed consent.

EXCLUSION CRITERIA: Patients with any of the following:

1. Administration of chemotherapy, immunotherapy, biological, targeted, or radiation therapy or investigational agent (therapeutic or diagnostic) within 3 weeks prior to receipt of study medication. Major surgery, other than diagnostic surgery, within 4 weeks before first study drug administration.

2. Significant cardiac history:

   • History of myocardial infarction or ischemic heart disease within 1 year (within a window of 18 days) before first study drug administration;
   • Uncontrolled arrhythmia;
   • History of congenital QT prolongation;
   • ECG findings consistent with active ischemic heart disease;
   • New York Heart Association Class III or IV cardiac disease;
   • Uncontrolled hypertension: blood pressure consistently greater than 150 mm Hg systolic and 100 mm Hg diastolic in spite of antihypertensive medication.
3. Patients who have received prior treatment with docetaxel.
4. Prior transient ischemic attack or cerebrovascular accident within the past year (within an 18-day window). Any neurologic toxicities ≥ Grade 2 within 3 weeks of randomization.
5. History of hemorrhagic diarrhea, inflammatory bowel disease or active uncontrolled peptic ulcer disease. (Concomitant therapy with ranitidine or its equivalent and/or omeprazole or its equivalent is acceptable). History of ileus or other significant gastrointestinal disorder known to predispose to ileus or chronic bowel hypomotility.
6. Active uncontrolled bacterial, viral, or fungal infection requiring systemic therapy.
7. Known infection with human immunodeficiency virus (HIV) or active hepatitis A, B, or C.
8. Known prior hypersensitivity reaction to any product containing polysorbate 80, polyoxyethylene 15 hydroxystearate/Macrogol 15 hydroxystearate (Solutol HS 15/ Kolliphor HS 15).
9. Female subject who is pregnant or lactating.
10. Second malignancy unless in remission for >5 years. (Non-melanoma skin cancer or carcinoma in situ of the cervix treated with curative intent is not exclusionary).
11. Any medical conditions that, in the Investigator's opinion, would impose excessive risk to the patient. Examples of such conditions include uncontrolled diabetes, infection requiring parenteral anti-infective treatment, liver failure, any altered mental status or any psychiatric condition that would interfere with the understanding of the informed consent form.
12. Unwilling or unable to comply with procedures required in this protocol.

Contacts and Locations

Locations

United States, Arizona

Ironwood Cancer & Research Centers

Chandler, Arizona, United States, 85224

United States, California

Pacific Cancer Medical Center, Inc.

Anaheim, California, United States, 92801

Innovative Clinical Research Institute

Whittier, California, United States, 90603

United States, Colorado

Memorial Health Care System

Colorado Springs, Colorado, United States, 80909

United States, Connecticut

Cancer Center of Central Connecticut

Plainville, Connecticut, United States, 06062

United States, Georgia

Peachtree Hematoloy-Oncology Consultants, PC

Atlanta, Georgia, United States, 30318

United States, Illinois

Orchard Healthcare Research Inc.

Skokie, Illinois, United States, 60077

Carle Cancer Center

Urbana, Illinois, United States, 61801

United States, Kansas

Kansas University Medical Center

Westwood, Kansas, United States, 00913

United States, Kentucky

University of Louisville-Brown Cancer Center

Louisville, Kentucky, United States, 40202

United States, Michigan

Henry Ford Hospital

Detroit, Michigan, United States, 48202

Michigan Center of Medical Research

Farmington Hills, Michigan, United States, 48334

United States, Mississippi

Hattiesburg Clinic Hematology/Oncology

Hattiesburg, Mississippi, United States, 39401

United States, Missouri

Central Care Cancer Center

Bolivar, Missouri, United States, 65613

United States, North Carolina

Wake Forest Baptist Health

Winston-Salem, North Carolina, United States, 27157

United States, Ohio

University of Cincinnati

Cincinnati, Ohio, United States, 45267

Toledo Cancer Center

Toledo, Ohio, United States, 43623

United States, Pennsylvania

Allegheny Health Network

Pittsburgh, Pennsylvania, United States, 15212

United States, Tennessee

Cookeville Regional Medical Center Cancer Center

Cookeville, Tennessee, United States, 61801

Australia, New South Wales

Blacktown Cancer Centre

Blacktown, New South Wales, Australia, 2148

Border Medical Oncology Research Unit

East Albury, New South Wales, Australia, 2640

Gosford Hospital

Gosford, New South Wales, Australia, 2250

Australia, Queensland

Adult Mater Hospital

South Brisbane, Queensland, Australia, 4101

Australia, Victoria

Peninsula and South East Oncology

Melbourne, Victoria, Australia, 3199

Epworth Hospital

Richmond, Victoria, Australia, 3121

Australia, Western Australia

Fiona Stanley Hospital

Murdoch, Western Australia, Australia, 6150

Perth Oncology/Mount Hospital

Perth, Western Australia, Australia, 6000

St John of God Hospital, Subiaco

Subiaco, Western Australia, Australia, 6008

China, Anhui

Anhui Provincial Hospital

Hefei, Anhui, China, 230000

China, Beijing

Cancer Hospital Chinese Academy of Medical Science

Beijing, Beijing, China, 100021

Beijing Cancer Hospital

Beijing, Beijing, China, 100142

The PLA General Hospital

Beijing, Beijing, China, 100853

China, Fujian

The First Affiliated Hospital of Xiamen University

Xiamen, Fujian, China, 361000

Zhongshan Hospital Xiamen University

Xiamen, Fujian, China, 361000

China, Guizhou

Guizhou Provincial Hospital

Guiyang, Guizhou, China, 550002

China, Hebei

The Fourth Hospital of Hebei Medical University

Shijiazhuang, Hebei, China, 050011

China, Heilongjiang

Affiliated Cancer Hospital of Harbin Medical Unive

Ha'erbin, Heilongjiang, China, 150040

China, Henan

Henan Cancer Hospital

Zhengzhou, Henan, China, 450008

China, Hunan

The Second Xiangya Hospital of Central South Unive

Changsha, Hunan, China, 410011

China, Jiangsu

Jiangyin People's Hospital

Jiangyin, Jiangsu, China, 214400

Jiangsu Cancer Hospital

Nanjing, Jiangsu, China, 210009

Nantong Tumor Hospital

Nantong, Jiangsu, China, 226361

China, Jiangxi

Jiangxi Provincial Tumor Hospital

Nanchang, Jiangxi, China, 330000

China, Jilin

Jilin Province Cancer Hospital

Changchun, Jilin, China, 100013

China, Liaoning

Liaoning Cancer Hospital & Institute

Shenyang, Liaoning, China, 110042

China, Shaanxi

The First Affiliated Hospital of Xi'an Jiaotong U

Xi'an, Shaanxi, China, 710061

China, Shangdong

Shandong Cancer Hospital

Jinan, Shangdong, China, 250117

527-Linyi Cancer Hospital

Linyi, Shangdong, China, 276000

Yantai Yuhuangding Hospital

Yantai, Shangdong, China, 264000

China, Shanghai

Shanghai Chest Hospital, Shanghai Jiaotong Univers

Shanghai, Shanghai, China, 200030

The Fifth People's Hospital of Shanghai

Shanghai, Shanghai, China, 200240

China, Sichuan

West China Hospital of Sichuan University

Chendu, Sichuan, China, 610041

China, Tianjin

Tianjin People's Hospital

Tianjin, Tianjin, China, 300060

China, Xinjiang

Affiliated Tumor Hospital of Xinjiang Medical Univ

Ürümqi, Xinjiang, China, 830011

China, Zhejiang

Sir Run Run Shaw Hospital, Zhejiang University

Hangzhou, Zhejiang, China, 310016

Zhejiang Cancer Hospital

Hangzhou, Zhejiang, China, 310022

The First Affiliated Hospital, Zhejiang University

Hanzhou, Zhejiang, China, 310003

Sponsors and Collaborators

BeyondSpring Pharmaceuticals Inc.

More Information

Additional Information:

BeyondSpring Pharmaceuticals, Inc. Web-site 

• Responsible Party: BeyondSpring Pharmaceuticals Inc.
• ClinicalTrials.gov Identifier: NCT02504489
• Other Study ID Numbers: BPI-2358-103
• First Posted: July 22, 2015
• Last Update Posted: September 10, 2022
• Last Verified: September 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Docetaxel; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action