A Study of IMC-A12 or Ramucirumab Plus Mitoxantrone and Prednisone in Prostate Cancer

• ClinicalTrials.gov Identifier: NCT00683475
• Recruitment Status: Completed
• First Posted: May 23, 2008
• Results First Posted: June 18, 2014
• Last Update Posted: October 16, 2014
• Sponsor: Eli Lilly and Company
• Information provided by (Responsible Party): Eli Lilly and Company

Study Description

Brief Summary:

The purpose of this study is to determine whether IMC-A12 or IMC-1121B (ramucirumab) with Mitoxantrone and Prednisone is effective in the treatment of metastatic androgen- independent prostate cancer (APIC).

Condition or disease	Intervention/treatment	Phase
Prostate Cancer	Biological: IMC-A12; Drug: Mitoxantrone; Drug: Prednisone; Biological: IMC-1121B (ramucirumab)	Phase 2

Detailed Description:

Prostate cancer is the most frequently diagnosed cancer in men and the second leading cause of cancer-related death in men in the United States. Chemotherapy, either as a single agent or in combination, may lead to clinical response, pain control, and/or improved quality of life. Docetaxel is now the first-line standard therapy for AIPC. Mitoxantrone was approved in 1996 for use in combination with corticosteroids as initial chemotherapy for pain related to advanced Hormone Refractory Prostate Cancer (HRPC). Hormonal manipulations and docetaxel-based chemotherapy are often effective in metastatic prostate cancer; however, disease becomes refractory to these interventions in the majority of men. Although mitoxantrone continues to be a significant agent in the treatment of HRPC, there exists a need for more efficacious therapy in docetaxel-refractory- AIPC. Because of the potential contribution of Insulin Like Growth Factor Receptor (IGF-IR) and VEGFR-2 mediated pathways in prostate cancer pathogenesis, it is hypothesized that each of these biological agents in combination with mitoxantrone and prednisone will result in clinically meaningful activity in AIPC. Therefore, ImClone plans to conduct a randomized Phase 2 trial to assess the safety and efficacy of IMC-A12 or IMC-1121B (ramucirumab) in combination with mitoxantrone and prednisone in participants with AIPC.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 138 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Multicenter, Randomized Study of IMC-A12 or IMC-1121B Plus Mitoxantrone and Prednisone in Metastatic Androgen-Independent Prostate Cancer (AIPC) Following Disease Progression on Docetaxel-Based Chemotherapy
• Study Start Date: August 2008
• Actual Primary Completion Date: September 2011
• Actual Study Completion Date: September 2011

Arms and Interventions

Arm	Intervention/treatment
Experimental: IMC-1121B (ramucirumab) + Mitoxantrone + Prednisone	Drug: Mitoxantrone; Mitoxantrone is to be administered as an I.V. infusion, at 12 milligrams/square meter (mg/m^2) over 5-15 minutes on Day 1 during a 3-week (21-day) cycle. Mitoxantrone treatment is to be continued for a maximum of 12 cycles (total cumulative dose of mitoxantrone is restricted to ≤ 144 mg/m^2) or until there is evidence of disease progression, death, or intolerable toxicity.; Drug: Prednisone; Prednisone (5 mg) is to be self-administered PO BID, each day of the 21-day cycle.; Biological: IMC-1121B (ramucirumab); IMC-1121B (ramucirumab) is to be administered as an intravenous (IV) infusion, 6 milligrams/kilogram (mg/kg) over 1 hour on Days 1, 8, and 15 of each 3-week (21-day) cycle. Ramucirumab treatment is to continue until there is evidence of disease progression, death, intolerable toxicity, or other withdrawal criteria are met.; Other Names: ramucirumab; IMC-1121B; LY3009806
Experimental: IMC-A12 + Mitoxantrone + Prednisone	Biological: IMC-A12; IMC-A12 is to be administered as an I.V. infusion, 6 mg/kg over 1 hour on Days 1, 8, and 15 of each 3-week (21-day) cycle. IMC-A12 treatment is to continue until there is evidence of disease progression, death, intolerable toxicity, or other withdrawal criteria are met.; Other Names: cixutumumab; LY3012217; Drug: Mitoxantrone; Mitoxantrone is to be administered as an I.V. infusion, at 12 milligrams/square meter (mg/m^2) over 5-15 minutes on Day 1 during a 3-week (21-day) cycle. Mitoxantrone treatment is to be continued for a maximum of 12 cycles (total cumulative dose of mitoxantrone is restricted to ≤ 144 mg/m^2) or until there is evidence of disease progression, death, or intolerable toxicity.; Drug: Prednisone; Prednisone (5 mg) is to be self-administered PO BID, each day of the 21-day cycle.

Outcome Measures

Primary Outcome Measures :

1. Composite Progression-free Survival (cPFS) [ Time Frame: Randomization to composite progressive disease, up to 23.4 months ]

   Defined as the median time from randomization to the earliest of:

   1. Tumor progression by Response Evaluation Criteria in Solid Tumors (RECIST);
   2. Evidence of progression by bone scan, performed after completion of the first 3 cycles, demonstrating the appearance of >=2 new lesions;
   3. New skeletal events (New pathologic bone fracture in the region of metastatic disease; New bone lesion requiring radiation or surgery; Spinal cord or nerve root compression)
   4. Symptomatic progression (for participants without measurable disease);
   5. Other clinical events attributable to prostate cancer that require major interventions; or
   6. Death from any cause

   Participants who were ongoing with no progression or who discontinued treatment for reasons other than progression were censored at date of last assessment. Participants who started new anticancer treatment before progression were censored at date of last assessment before start of new anti-cancer therapy.

Secondary Outcome Measures :

1. Summary Listing of Participants Reporting Treatment-Emergent Adverse Events [ Time Frame: Randomization to 36.3 months ]
   Data presented are the number of participants who experienced A12 or 1121B (ramucirumab) related treatment-emergent adverse events (TEAE), treatment related serious adverse events (SAE), or any Grade 3 or higher TEAE; any TEAE leading to discontinuation of A12 or 1121B (ramucirumab) treatment, and any TEAE leading to dose modification of A12 or 1121B (ramucirumab). A summary of SAEs and other nonserious AEs, regardless of causality, is located in the Reported Adverse Event section.
2. Time to Radiographic Evidence of Disease Progression [ Time Frame: Randomization to date of radiographic progression, up to 36.3 months ]

   Time between date of randomization and earliest date of radiographic progression defined as either:

   1. Tumor progression by RECIST;
   2. Evidence of progression by bone scan;
   3. New skeletal events (New pathologic bone fracture in the region of metastatic disease; New bone lesion requiring radiation or surgery; Spinal cord or nerve root compression).

   Participants who were ongoing with no radiographic evidence of disease progression, who discontinued treatment for reasons other than progression,or died before progression were censored at date of last tumor or bone radiographic assessment. Participants who started a new anticancer treatment before progression were censored at date of last tumor or bone radiographic assessment before start of new anti-cancer therapy.

3. Prostate Specific Antigen (PSA) Response Rate [ Time Frame: Baseline up to data cut-off date (up to 36.3 months) ]
   PSA response rate is defined as the percentage of participants with a decrease in PSA >= 50 percent from baseline.
4. Composite Progression-free Survival (cPFS) at 6-months [ Time Frame: 6 months ]

   Data presented are the percentage of participants without disease progression at 6 months.

   Participants who were ongoing with no progression or who discontinued treatment for reasons other than progression were censored at date of last assessment. Participants who started new anticancer treatment before progression were censored at date of last assessment before start of new anti-cancer therapy.

5. Composite Progression-free Survival (cPFS) at 9-months [ Time Frame: 9 months ]

   Data presented are the percentage of participants without disease progression at 9 months.

   Participants who were ongoing with no progression or who discontinued treatment for reasons other than progression were censored at date of last assessment. Participants who started new anticancer treatment before progression were censored at date of last assessment before start of new anti-cancer therapy.

6. Composite Progression-free Survival (cPFS) at 12-months [ Time Frame: 12 months ]

   Data presented are the percentage of participants without disease progression at 12 months.

   Participants who were ongoing with no progression or who discontinued treatment for reasons other than progression were censored at date of last assessment. Participants who started new anticancer treatment before progression were censored at date of last assessment before start of new anti-cancer therapy.

7. Overall Survival (OS) [ Time Frame: First dose to death due to any cause up to 36.3 months ]
   Overall survival is defined as the time from randomization to the date of death due to any cause. Participants who were alive at the time of study completion were censored at the time the participant was last known to be alive.
8. Objective Response Rate (ORR) [ Time Frame: Baseline to date of progressive disease or death up to 36.3 months ]

   Objective response is Complete Response (CR) + Partial Response (PR), as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST) guidelines. CR is a disappearance of all target and non-target lesions; PR is at least a 30% decrease in the sum of the longest diameter of target lesions without new lesions and progression of non-target lesions.

   Objective response rate is calculated as a total number of participants with CR or PR divided by the total number of participants with measurable disease, multiplied by 100.

9. Maximum Concentration (Cmax) at Study Day 1 [ Time Frame: Day 1 ]

   Maximum Concentration (Cmax) of Ramucirumab.

   All samples were assayed 36 months post sample collection, which exceeds the established long-term serum stability period for ramucirumab. Therefore, concentration data were invalid and pharmacokinetic (PK) analyses could not be conducted.

10. Maximum Concentration (Cmax) at Study Day 15 [ Time Frame: Day 15 ]

    Maximum concentration (Cmax) of Ramucirumab.

    All samples were assayed 36 months post sample collection, which exceeds the established long-term serum stability period for ramucirumab. Therefore, concentration data were invalid and pharmacokinetic (PK) analyses could not be conducted.

11. Maximum Concentration (Cmax) at Study Day 16 [ Time Frame: Day 16 ]

    Maximum concentration (Cmax) of Ramucirumab.

    All samples were assayed 36 months post sample collection, which exceeds the established long-term serum stability period for ramucirumab. Therefore, concentration data were invalid and pharmacokinetic (PK) analyses could not be conducted.

12. Maximum Concentration (Cmax) at Study Day 30 [ Time Frame: Day 30 ]

    Maximum concentration (Cmax) of Ramucirumab.

    All samples were assayed 36 months post sample collection, which exceeds the established long-term serum stability period for ramucirumab. Therefore, concentration data were invalid and pharmacokinetic (PK) analyses could not be conducted.

13. Minimum Concentration (Cmin) at Study Day 1 [ Time Frame: Day 1 ]

    Minimum concentration (Cmin) of Ramucirumab.

    All samples were assayed 36 months post sample collection, which exceeds the established long-term serum stability period for ramucirumab. Therefore, concentration data were invalid and pharmacokinetic (PK) analyses could not be conducted.

14. Minimum Concentration (Cmin) at Study Day 15 [ Time Frame: Day 15 ]

    Minimum concentration (Cmin) of Ramucirumab.

    All samples were assayed 36 months post sample collection, which exceeds the established long-term serum stability period for ramucirumab. Therefore, concentration data were invalid and pharmacokinetic (PK) analyses could not be conducted.

15. Minimum Concentration (Cmin) at Study Day 16 [ Time Frame: Day 16 ]

    Minimum concentration (Cmin) of Ramucirumab.

    All samples were assayed 36 months post sample collection, which exceeds the established long-term serum stability period for ramucirumab. Therefore, concentration data were invalid and pharmacokinetic (PK) analyses could not be conducted.

16. Minimum Concentration (Cmin) at Study Day 30 [ Time Frame: Day 30 ]

    Minimum concentration (Cmin) of Ramucirumab.

    All samples were assayed 36 months post sample collection, which exceeds the established long-term serum stability period for ramucirumab. Therefore, concentration data were invalid and pharmacokinetic (PK) analyses could not be conducted.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• The participant has histologically-confirmed adenocarcinoma of the prostate
• The participant has radiographic evidence of metastatic prostate cancer (stage M1 or D2)
• The participant has prostate cancer unresponsive or refractory to hormone therapy (androgen-independent)
• The participant has had disease progression (clinical or radiographic) while receiving docetaxel, or within 120 days of receiving docetaxel-based chemotherapy and in the opinion of the investigator is unlikely to derive significant benefit from additional docetaxel-based therapy, or was intolerant to therapy with this agent

• The participant must have evidence of progressive disease defined as at least one of the following;

  1. Progressive measurable disease: using conventional solid tumor criteria
  2. Bone scan progression: at least two new lesions on bone scan
  3. Increasing PSA: at least two consecutive rising PSA values over a reference value (PSA #1) taken at least 1 week apart. A third PSA (PSA #3) is required to be greater than PSA #2; if not, a fourth PSA (PSA #4) is required to be greater than PSA #2
• The participant has a PSA ≥ 2 ng/mL
• The participant has prior surgical or medical castration with a serum testosterone of <50 ng/mL. If the method of castration is luteinizing hormone releasing level hormone (LHRH) agonists, the participant must be willing to continue the use of LHRH agonists during protocol treatment
• The participant has an Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2
• The participant has adequate hematologic function (absolute neutrophil count [ANC]≥1500/uL, hemoglobin ≥9 g/dL, and platelets ≥100,000/uL)
• The participant has adequate hepatic function (bilirubin ≤ 1.5 times the upper limit of normal (ULN), Aspartate Transaminase (AST) and Alanine Transaminase (ALT) ≤ 3 times the ULN, or ≤ 5 times the ULN if liver metastases are present)
• The participant has adequate renal function (creatinine ≤ 1.5 x ULN or calculated creatinine clearance > 40 mL/min)
• The participant's urinary protein is ≤ 1+ on dipstick or routine urinalysis (UA). If urine dipstick or routine analysis indicates ≥ 2+ proteinuria, then a 24-hour urine must be collected and must demonstrate < 1000 mg of protein in 24 hours to allow participation in the study
• The participant has adequate coagulation function (an international normalized ratio [INR] ≤ 1.5 and a Partial Thromboplastin Time [PTT] ≤ 5 seconds above the ULN [unless on oral anticoagulant therapy]). Participants receiving full-dose anticoagulation therapy are eligible provided they meet all other criteria, are on a stable dose of oral anticoagulant or low molecular weight heparin (and if on warfarin have a therapeutic INR between 2 and 3)
• The participant has a fasting serum glucose level of < 160 mg/dL, or below the ULN

Exclusion Criteria:

• The participant has received more than one prior cytotoxic chemotherapy regimen for metastatic disease. (Participants who have had a treatment break followed by a second docetaxel-based regimen with subsequent disease progression are eligible.)
• The participant has received prior therapy with mitoxantrone for advanced prostate cancer (prior adjuvant therapy with mitoxantrone is permitted)
• The participant has a history of symptomatic congestive heart failure or has a pre-study echocardiogram or multigated acquisition (MUGA) scan with left ventricular ejection fraction (LVEF) that is ≥ 10% below the LLN
• The participant has received radiotherapy ≤ 21 days prior to first dose of IMC-A12 or Ramucirumab
• The participant is receiving corticosteroids (dexamethasone, prednisone, or others) at a dose > 5 mg prednisone orally (PO) two times per day (BID) or equivalent. Participants receiving corticosteroids at higher doses may be eligible if their corticosteroid therapy is tapered to study levels (prednisone 5 mg PO BID) prior to first dose of study medication, without concomitant clinical deterioration
• The participant has known or suspected brain or leptomeningeal metastases
• The participant has uncontrolled or poorly controlled hypertension
• The participant has poorly controlled diabetes mellitus. Inclusion Criteria:
• The participant has histologically-confirmed adenocarcinoma of the prostate
• The participant has radiographic evidence of metastatic prostate cancer (stage M1 or D2)
• The participant has prostate cancer unresponsive or refractory to hormone therapy (androgen-independent)
• The participant has had disease progression (clinical or radiographic) while receiving docetaxel, or within 120 days of receiving docetaxel-based chemotherapy and in the opinion of the investigator is unlikely to derive significant benefit from additional docetaxel-based therapy, or was intolerant to therapy with this agent

• The participant must have evidence of progressive disease defined as at least one of the following;

  1. Progressive measurable disease: using conventional solid tumor criteria
  2. Bone scan progression: at least two new lesions on bone scan
  3. Increasing PSA: at least two consecutive rising PSA values over a reference value (PSA #1) taken at least 1 week apart. A third PSA (PSA #3) is required to be greater than PSA #2; if not, a fourth PSA (PSA #4) is required to be greater than PSA #2
• The participant has a PSA ≥ 2 ng/mL
• The participant has prior surgical or medical castration with a serum testosterone of <50 ng/mL. If the method of castration is luteinizing hormone releasing level hormone (LHRH) agonists, the participant must be willing to continue the use of LHRH agonists during protocol treatment
• The participant has an Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2
• The participant has adequate hematologic function (absolute neutrophil count [ANC]≥1500/uL, hemoglobin ≥9 g/dL, and platelets ≥100,000/uL)
• The participant has adequate hepatic function (bilirubin ≤ 1.5 times the upper limit of normal (ULN), aspartate transaminase [AST] and alanine transaminase [ALT]≤ 3 times the ULN, or ≤ 5 times the ULN if liver metastases are present)
• The participant has adequate renal function (creatinine ≤ 1.5 x ULN or calculated creatinine clearance > 40 mL/min)
• The participant's urinary protein is ≤ 1+ on dipstick or routine urinalysis (UA). If urine dipstick or routine analysis indicates ≥ 2+ proteinuria, then a 24-hour urine must be collected and must demonstrate < 1000 mg of protein in 24 hours to allow participation in the study
• The participant has adequate coagulation function (an international normalized ratio [INR] ≤ 1.5 and a partial thromboplastin time [PTT] ≤ 5 seconds above the ULN [unless on oral anticoagulant therapy]). Participants receiving full-dose anticoagulation therapy are eligible provided they meet all other criteria, are on a stable dose of oral anticoagulant or low molecular weight heparin (and if on warfarin have a therapeutic INR between 2 and 3)
• The participant has a fasting serum glucose level of < 160 mg/dL, or below the ULN

Exclusion Criteria:

• The participant has received more than one prior cytotoxic chemotherapy regimen for metastatic disease. (Participants who have had a treatment break followed by a second docetaxel-based regimen with subsequent disease progression are eligible.)
• The participant has received prior therapy with mitoxantrone for advanced prostate cancer (prior adjuvant therapy with mitoxantrone is permitted)
• The participant has a history of symptomatic congestive heart failure or has a pre-study echocardiogram or multigated acquisition (MUGA) scan with left ventricular ejection fraction (LVEF) that is ≥ 10% below the LLN
• The participant has received radiotherapy ≤ 21 days prior to first dose of IMC-A12 or Ramucirumab
• The participant is receiving corticosteroids (dexamethasone, prednisone, or others) at a dose > 5 mg prednisone orally (PO) two times per day (BID) or equivalent. Participants receiving corticosteroids at higher doses may be eligible if their corticosteroid therapy is tapered to study levels (prednisone 5 mg PO BID) prior to first dose of study medication, without concomitant clinical deterioration
• The participant has known or suspected brain or leptomeningeal metastases
• The participant has uncontrolled or poorly controlled hypertension
• The participant has poorly controlled diabetes mellitus. Participants with a history of diabetes are allowed to participate, provided that their blood glucose is within normal range (fasting < 120 mg/dL or below ULN) and that they are on a stable dietary or therapeutic regimen for this condition
• The participant has a known human immunodeficiency virus infection or acquired immunodeficiency syndrome-related illness with a history of diabetes are allowed to participate, provided that their blood glucose is within normal range (fasting < 120 mg/dL or below ULN) and that they are on a stable dietary or therapeutic regimen for this condition
• The participant has a known human immunodeficiency virus infection or acquired immunodeficiency syndrome-related illness

Contacts and Locations

Locations

United States, California

ImClone Investigational Site

La Jolla, California, United States, 92093

United States, Connecticut

ImClone Investigational Site

New Haven, Connecticut, United States, 06520

United States, Florida

ImClone Investigational Site

Boca Raton, Florida, United States, 33486

ImClone Investigational Site

Port St. Lucie, Florida, United States, 34952

United States, Georgia

ImClone Investigational Site

Atlanta, Georgia, United States, 30318

United States, Illinois

ImClone Investigational Site

Chicago, Illinois, United States, 60611

ImClone Investigational Site

Chlcago, Illinois, United States, 60637

ImClone Investigational Site

Evanston, Illinois, United States, 60201

ImClone Investigational Site

Maryville, Illinois, United States, 62062

United States, Iowa

ImClone Investigational Site

Cedar Rapids, Iowa, United States, 52402

United States, Louisiana

ImClone Investigational Site

Metairie, Louisiana, United States, 70006

United States, Michigan

ImClone Investigational Site

Ann Arbor, Michigan, United States, 48109

United States, Minnesota

ImClone Investigational Site

Rochester, Minnesota, United States, 55905

United States, Missouri

ImClone Investigational Site

St Louis, Missouri, United States, 63110

United States, Montana

ImClone Investigational Site

Billings, Montana, United States, 59101

United States, New Jersey

ImClone Investigational Site

Roseland, New Jersey, United States, 07068

United States, New York

ImClone Investigational Site

Buffalo, New York, United States, 14263

ImClone Investigational Site

East Setauket, New York, United States, 11733

ImClone Investigational Site

New York, New York, United States, 10016

ImClone Investigational Site

New York, New York, United States, 10019

ImClone Investigational Site

New York, New York, United States, 10021

ImClone Investigational Site

New York, New York, United States, 10032

United States, North Carolina

ImClone Investigational Site

Durham, North Carolina, United States, 27710

United States, Ohio

ImClone Investigational Site

Cleveland, Ohio, United States, 44195

United States, Pennsylvania

ImClone Investigational Site

Philadelphia, Pennsylvania, United States, 19111

ImClone Investigational Site

Pittsburgh, Pennsylvania, United States, 15232

United States, South Carolina

ImClone Investigational Site

Greenville, South Carolina, United States, 29605

United States, Tennessee

ImClone Investigational Site

Knoxville, Tennessee, United States, 37920

ImClone Investigational Site

Nashville, Tennessee, United States, 37203

United States, Texas

ImClone Investigational Site

Abilene, Texas, United States, 79606

ImClone Investigational Site

Dallas, Texas, United States, 75246

ImClone Investigational Site

Houston, Texas, United States, 77030-4009

ImClone Investigational Site

Houston, Texas, United States, 77030

United States, Washington

ImClone Investigational Site

Seattle, Washington, United States, 98104

ImClone Investigational Site

Seattle, Washington, United States, 98109

United States, Wisconsin

ImClone Investigational Site

Madison, Wisconsin, United States, 53792

Sponsors and Collaborators

Eli Lilly and Company

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST); Eli Lilly and Company

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Hussain M, Rathkopf D, Liu G, Armstrong A, Kelly WK, Ferrari A, Hainsworth J, Joshi A, Hozak RR, Yang L, Schwartz JD, Higano CS. A randomised non-comparative phase II trial of cixutumumab (IMC-A12) or ramucirumab (IMC-1121B) plus mitoxantrone and prednisone in men with metastatic docetaxel-pretreated castration-resistant prostate cancer. Eur J Cancer. 2015 Sep;51(13):1714-24. doi: 10.1016/j.ejca.2015.05.019. Epub 2015 Jun 13.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT00683475
• Other Study ID Numbers: 13924; CP18-0601 ( Other Identifier: ImClone Systems ); I4T-IE-JVBS ( Other Identifier: Eli Lilly and Company )
• First Posted: May 23, 2008
• Results First Posted: June 18, 2014
• Last Update Posted: October 16, 2014
• Last Verified: October 2014

Keywords provided by Eli Lilly and Company:

Prostate Cancer

Additional relevant MeSH terms:

Prostatic Neoplasms; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Prostatic Diseases; Prednisone; Mitoxantrone; Ramucirumab; Antibodies, Monoclonal; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Immunologic Factors