Study Evaluating the Safety and Efficacy of Eribulin Mesilate in Combination With Irinotecan Hydrochloride in Children With Refractory or Recurrent Solid Tumors

• ClinicalTrials.gov Identifier: NCT03245450
• Recruitment Status: Completed
• First Posted: August 10, 2017
• Results First Posted: June 28, 2022
• Last Update Posted: June 28, 2022
• Sponsor: Eisai Inc.
• Information provided by (Responsible Party): Eisai Inc.

Study Description

Brief Summary:

The Phase 1 part of the study is conducted to determine the maximum tolerated dose (MTD) and Recommended Phase 2 Dose (RP2D) of eribulin mesilate in combination with irinotecan hydrochloride in pediatric participants with relapsed/refractory solid tumors (excluding central nervous system [CNS] tumors).

The Phase 2 part of the study is conducted to assess the objective response rate (ORR) and duration of response (DOR) of eribulin mesilate in combination with irinotecan hydrochloride in pediatric participants with relapsed/refractory rhabdomyosarcoma (RMS), non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) and ewing sarcoma (EWS).

Condition or disease	Intervention/treatment	Phase
Refractory or Recurrent Solid Tumors; Rhabdomyosarcoma; Non-Rhabdomyosarcoma Soft Tissue Sarcoma; Ewing Sarcoma	Drug: Eribulin mesilate; Drug: Irinotecan hydrochloride	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 40 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1/2 Single-arm Study Evaluating the Safety and Efficacy of Eribulin Mesilate in Combination With Irinotecan in Children With Refractory or Recurrent Solid Tumors
• Actual Study Start Date: March 5, 2018
• Actual Primary Completion Date: May 17, 2021
• Actual Study Completion Date: May 17, 2021

Arms and Interventions

Arm

Intervention/treatment

Experimental: Eribulin mesilate plus irinotecan hydrochloride; In Schedules A and B, eribulin mesilate at the dose of 1.4 milligrams per meters squared (mg/m^2) will be administered as an intravenous (IV) infusion on Days 1 and 8 of each 21-day cycle. In Schedule A, irinotecan hydrochloride at the doses of 20 mg/m^2 or 40 mg/m^2 will be administered as an IV infusion on Days 1 to 5 of a 21-day cycle. In Schedule B, irinotecan hydrochloride at the doses of 100 mg/m^2 or 125 mg/m^2 will be administered as an IV infusion on Days 1 and 8 of a 21-day cycle.

Drug: Eribulin mesilate; IV infusion; Other Name: E7389; Drug: Irinotecan hydrochloride; IV infusion; Other Name: (S)-4,11-diethyl-39 3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3',4':6,7]-indolizino[1,2-b]quinolin-9-4-yl-[1,4'-bipiperidine]-1'-carboxylate, monohydrochloride, trihydrate

Outcome Measures

Primary Outcome Measures :

1. Phase 1: Recommended Phase 2 Dose (RP2D) of Eribulin Mesilate in Combination With Irinotecan Hydrochloride [ Time Frame: First dose of study drug up to Cycle 1 (Cycle length=21 days) ]
   The RP2D was evaluated based on a review of the outcomes of safety (including dose limiting toxicities [DLTs]), tumor assessments, and pharmacokinetic (PK) in Phase 1 by investigators and the study team.
2. Phase 2: Objective Response Rate (ORR) [ Time Frame: From date of first dose of study drug until disease progression, development of unacceptable toxicity, withdrawal of consent, or up to approximately 2 years 4 months ]
   ORR was defined as the percentage of participants achieving best overall response (BOR) of confirmed partial response (PR) or complete response (CR) determined by investigator assessment per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR was defined as disappearance of all target and non-target lesions. All pathological (whether target or non-target) must have a reduction in their short axis less than (<) 10 millimeter (mm). PR was at least a 30 percent (%) decrease in the sum of diameter (SOD) of target lesions, taking as reference the baseline sum diameters.

Secondary Outcome Measures :

1. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: From first dose of study drug up to approximately 2 years 4 months ]
   A TEAE was defined as an AE that emerged during treatment, having been absent at pretreatment, or reemerged during treatment, having been present at pre-treatment (baseline) but stopped before treatment, or worsened in severity during treatment relative to the pretreatment state, when the AE was continuous. AE was defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment.
2. Number of Participants With Serious Adverse Event (SAE) [ Time Frame: Up to approximately 2 years and 4 months ]
   SAE was defined as any untoward medical occurrence at any dose if it resulted in death or life-threatening AE or required inpatient hospitalization or prolongation of existing hospitalization or resulted in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions or was a congenital anomaly/birth defect.
3. Phase 1, Cmax: Maximum Observed Plasma Concentration of Eribulin, Irinotecan and Its Active Metabolite SN-38 [ Time Frame: For eribulin, Cycle 1 Day 1: 0-120 hours post-eribulin infusion; For irinotecan and its metabolite, Cycle 1 Day 1: 0-24 hours post-irinotecan infusion (cycle length=21 days) ]
4. Phase 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Eribulin, Irinotecan and Its Active Metabolite SN-38 [ Time Frame: For eribulin, Cycle 1 Day 1: 0-120 hours post-eribulin infusion; For irinotecan and its metabolite, Cycle 1 Day 1: 0-24 hours post-irinotecan infusion (cycle length=21 days) ]
5. Phase 1, T1/2: Half-life of Eribulin, Irinotecan and Its Active Metabolite SN-38 [ Time Frame: For eribulin, Cycle 1 Day 1: 0-120 hours post-eribulin infusion; For irinotecan and its metabolite, Cycle 1 Day 1: 0-24 hours post-irinotecan infusion (cycle length=21 days) ]
   Half-life for irinotecan and metabolite SN-38 could not be estimated for phase 1:schedule A, eribulin mesilate 1.4 mg/m^2 + irinotecan 20 mg/m^2 and phase 1: schedule A, eribulin mesilate 1.4 mg/m^2 + irinotecan 40 mg/m^2 arm as the slope of the terminal phase of the concentration-time profiles could not be determined.
6. Phase 1, Total Clearance (CL) of Eribulin and Irinotecan [ Time Frame: For eribulin, Cycle 1 Day 1: 0-120 hours post-eribulin infusion; For irinotecan, Cycle 1 Day 1: 0-24 hours post-irinotecan infusion (cycle length=21 days) ]
   CL for irinotecan could not be estimated for phase 1:schedule A, eribulin mesilate 1.4 mg/m^2 + irinotecan 20 mg/m^2 and phase 1: schedule A, eribulin mesilate 1.4 mg/m^2 + irinotecan 40 mg/m^2 arm because it was not possible to calculate half-life as the slope of the terminal phase of the concentration-time profiles could not be determined.
7. Phase 1, Volume of Distribution (Vz) of Eribulin and Irinotecan [ Time Frame: For eribulin, Cycle 1 Day 1: 0-120 hours post-eribulin infusion; For irinotecan, Cycle 1 Day 1: 0-24 hours post-irinotecan infusion (cycle length=21 days) ]
   Vz for irinotecan could not be estimated for phase 1: schedule A, eribulin mesilate 1.4 mg/m^2 + irinotecan 20 mg/m^2 and phase 1: schedule A, eribulin mesilate 1.4 mg/m^2 + irinotecan 40 mg/m^2 arm because it was not possible to calculate half-life as the slope of the terminal phase of the concentration-time profiles could not be determined.
8. Phase 1, AUC(0-t): Area Under the Concentration-time Curve From Zero (Pre-dose) to Time of Last Quantifiable Concentration of Eribulin, Irinotecan and Its Active Metabolite SN-38 [ Time Frame: For eribulin, Cycle 1 Day 1: 0-120 hours post-eribulin infusion; For irinotecan and its metabolite, Cycle 1 Day 1: 0-24 hours post-irinotecan infusion (cycle length=21 days) ]
9. Phase 1, AUC(0-inf): Area Under the Concentration-time Curve From Zero (Pre-dose) Extrapolated to Infinite Time of Eribulin, Irinotecan and Its Active Metabolite SN-38 [ Time Frame: For eribulin, Cycle 1 Day 1: 0-120 hours post-eribulin infusion; For irinotecan and its metabolite, Cycle 1 Day 1: 0-24 hours post-irinotecan infusion (cycle length=21 days) ]
   AUC(0-inf) for irinotecan and metabolite SN-38 could not be estimated for phase 1: schedule A, eribulin mesilate 1.4 mg/m^2 + irinotecan 20 mg/m^2 and phase 1: schedule A, eribulin mesilate 1.4 mg/m^2 + irinotecan 40 mg/m^2 arm because it was not possible to calculate half-life as the slope of the terminal phase of the concentration-time profiles could not be determined.
10. Phase 2: Progression Free Survival (PFS) [ Time Frame: From the date of first dose to the date of first documentation of PD, or date of death, whichever occurred first up to approximately 2 years 4 months ]
    PFS was defined as the time from date of first dose to the date of disease progression (PD). PFS was assessed based on the investigators' assessments utilizing RECIST 1.1. PD was defined as at least 20% increase or 5 mm increase in the sum of diameters of target lesions recorded since the treatment started or the appearance of 1 or more new lesions. PFS was estimated and analyzed using Kaplan-Meier method.
11. Phase 2: Clinical Benefit Rate (CBR) [ Time Frame: From the date of first dose to the date of first documentation of PD, or date of death, whichever occurred first up to approximately 2 years 4 months ]
    CBR was defined as the percentage of participants with BOR of CR, PR, or durable stable disease (SD) based on RECIST 1.1 (durable SD was defined as SD with duration of greater than [>] 11 weeks). CR was defined as disappearance of all target and non-target lesions. All pathological (whether target or non-target) must have a reduction in their short axis <10 mm. PR was defined as at least 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters.
12. Model Predicted Apparent Total Body Clearance (CL) of Eribulin [ Time Frame: Cycle 1 Day 1: 0.5-120 hours after eribulin infusion; Cycle 1 Day 8: pre-dose and at the end of the eribulin infusion (cycle length=21 days) ]
    Per the planned PK analysis, PK samples were collected and analyzed using a population PK approach to estimate PK parameters. Eribulin plasma concentration data from this study were pooled from studies (NCT00069264, NCT00069277, NCT00326950, NCT00706095, NCT01000376, NCT01106248, NCT02171260, NCT00413192, NCT01458249, NCT03441360 and NCT01327885), and a population PK model was applied to the pooled dataset. The data presented are the CL parameter estimates, with Measure Type "Number" defining the eribulin PK model. They are population PK model predictions and have been estimated using non-linear mixed effects model.
13. Volume of Distribution Estimates From the Population PK Model for Eribulin [ Time Frame: Cycle 1 Day 1: 0.5-120 hours after eribulin infusion; Cycle 1 Day 8: pre-dose and at the end of the eribulin infusion (cycle length=21 days) ]
    Per the planned PK analysis, PK samples were collected and analyzed using a population PK approach to estimate PK parameters. Eribulin plasma concentration data from this study were pooled from studies (NCT00069264, NCT00069277, NCT00326950, NCT00706095, NCT01000376, NCT01106248, NCT02171260, NCT00413192, NCT01458249, NCT03441360 and NCT01327885), and a population PK model was applied to the pooled dataset. Data presented are the volume of distribution of the central compartment (V1), volume of distribution of the first peripheral compartment (V2), and volume of distribution of the second peripheral compartment (V3) parameter estimates with Measure Type "Number" defining the eribulin PK model. They are population PK model predictions and have been estimated using non-linear mixed effects model.

Eligibility Criteria

• Ages Eligible for Study: 6 Months to 25 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Participants must be

• >=12 months to less than or equal to (<=) 25 years old at the time of consent [no more than 25 percent (%) of participants between the ages of 18 and 25 years will be enrolled in this study].
• In Phase 1, >6 months and <12 months at the time of consent (Schedule A only) participants will be enrolled one dose level behind the >=12 months participant in order to maximize safety for infant participants. In Phase 2, participants aged >6 months and <12 months at the time of consent will be enrolled to Schedule A with a modified dose of eribulin with the irinotecan dose maintained in order to maximize safety for infant participants.

Inclusion Criteria:

• Phase 1: Participants must be diagnosed with histologically confirmed solid tumors (excluding CNS tumors), which is relapsed or refractory, and for which there are no currently available therapies.
• Phase 2: Participants must be diagnosed with histologically confirmed RMS, NRSTS or EWS which is relapsed or refractory having received at least 1 prior therapy, including primary treatment.
• Phase 1: Participants must have either measurable or evaluable disease as per RECIST 1.1.
• Phase 2: Participants must have measurable disease as per RECIST 1.1.
• Participant's current disease state must be one for which there is no known curative therapy.
• Participant's performance score must be >=50% Karnofsky (for participants >16 years of age) or Lansky (for participants <=16 years of age).Participants who are unable to walk because of paralysis and/or previous surgeries, but who are in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.

• Participants must have fully recovered from the acute toxic effects of all prior anticancer treatments prior to study drug administration:

  • Must not have received myelosuppressive chemotherapy within 21 days prior to study drug administration (42 days if prior nitrosourea).
  • Must not have received a long-acting growth factor (example, Neulasta) within 14 days or a short-acting growth factor within 7 days.
  • Must not have received an antineoplastic targeted therapy within 14 days.
  • Must not have received immunotherapy, example, tumor vaccines, within 42 days.
  • Must not have received monoclonal antibodies within at least 3 half-lives of the antibody after its last dose.
  • Must not have received radiotherapy (XRT) within 14 days prior to study drug administration (small field) or 42 days for craniospinal XRT, or if >=50% radiation of pelvis.
  • At least 84 days must have elapsed after stem cell infusion prior to study drug administration
  • No evidence of active graft-versus-host disease (GVHD) and at least 100 days must have elapsed after allogeneic bone marrow transplant or stem cell infusion prior to study drug administration

• Participants must have adequate bone marrow function, defined as:

  • Peripheral absolute neutrophil count (ANC) >=1.0*10^9/liter (L).
  • Platelet count >=100*10^9/L (not receiving platelet transfusions within a 7-day period prior to study drug administration).
  • Hemoglobin (Hb) at least 8.0 grams per deciliter (g/dL) at baseline (blood transfusions are allowed during the screening period to correct Hb values <8.0 g/dL).

• Participants must have adequate renal function, defined as:

  • A serum creatinine based on age/gender, derived from the Schwartz formula for estimating glomerular filtration rate (GFR), per protocol-specified criteria.
  • Serum creatinine clearance or GFR >=50 milliliters/minute/1.73 m^2, based on a 12 or 24 hours (h) urine creatinine collection.

• Participants must have adequate liver function, defined as:

  • Bilirubin (sum of conjugated + unconjugated) <=1.5 times the upper limit of normal (ULN) for age.
  • Alkaline phosphatase, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <=3*ULN (in the case of liver metastases <=5*ULN), unless there are bone metastases, in which case liver-specific alkaline phosphatase must be separated from the total and used to assess the liver function instead of the total alkaline phosphatase.
  • Serum albumin >=2 g/dL.
• All participants and/or their parents or guardians must sign a written informed consent.
• Participants must be willing to comply with all aspects of the protocol.

Exclusion Criteria:

• Females who are breastfeeding or pregnant at Screening or Baseline. A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 h before the first dose of study drug.

• Females of childbearing potential who:

  • Do not agree to use a highly effective method of contraception for the entire study period and for 6 months after study drug discontinuation, that is:
  • Total abstinence (if it is their preferred and usual lifestyle)
  • An intrauterine device (IUD) or intrauterine system (IUS)
  • A contraceptive implant
  • An oral contraceptive OR
  • Do not have a vasectomized partner with confirmed azoospermia.
• Males who have not had a successful vasectomy (confirmed azoospermia) or they and their female partners do not meet the criteria above (that is, not of childbearing potential or practicing highly effective contraception throughout the study period or for 3 months after study drug discontinuation). No sperm donation is allowed during the study period or for 3 months after study drug discontinuation.

• Concomitant Medications:

  • Participants receiving corticosteroids who have not been on a stable dose for at least 7 days prior to study drug administration.
  • Participants who are currently receiving other anticancer agents.
  • Participants who are receiving cyclosporine, tacrolimus or other agents to prevent GVHD post bone marrow transplant.
  • Participants who are receiving strong cytochrome P450 3A4 (CYP3A4) inhibitors and inducers including traditional herbal medicinal products (example, St. John's Wort).
• Phase 1: Received prior therapy with eribulin mesilate within 6 months prior to study drug administration.
• Phase 2: Received prior therapies with eribulin mesilate or irinotecan hydrochloride (for prior irinotecan hydrochloride, participants can be included if there was no tumor progression during irinotecan therapy).
• Any other malignancy that required treatment (except non-melanoma skin cancer, or histologically confirmed complete excision of carcinoma in situ), within 2 years prior to study drug administration.
• Has hypersensitivity to either study drug or any of the excipients.
• Has a known prior history of viral hepatitis (B or C) as demonstrated by positive serology (presence of antigens) or have an uncontrolled infection requiring treatment
• Has >Grade 1 peripheral sensory neuropathy or >Grade 1 peripheral motor neuropathy graded according to the Modified ("Balis") Pediatric Scale of Peripheral Neuropathies.

• Has cardiac pathology, defined as:

  • Participants with known congestive heart failure, symptomatic or Left ventricular (LV) ejection fraction <50% or shortening fraction <27% and participants with congenital long QT syndrome, bradyarrhythmias, or QT interval (QTc)>480 milliseconds on at least 2 separate electrocardiograms (ECGs).
• Has CNS disease: Participants with brain or subdural metastases are not eligible unless the metastases are asymptomatic and do not require treatment or have been adequately treated by local therapy and have discontinued the use of corticosteroids for this indication for at least 28 days prior to study drug administration. Participants must be clinically stable. It is not the intention of this protocol to treat participants with active brain metastases.

Note: Screening CNS imaging for participants with a known history of CNS disease is required.

• Have had or are planning to have the following invasive procedures:

  • Major surgical procedure or significant traumatic injury within 28 days prior to study drug administration.
  • Laparoscopic procedure or open biopsy within 7 days prior to study drug administration
  • Central line placement or subcutaneous port placement is not considered major surgery.
  • Core biopsy, including bone marrow biopsy within 2 days prior to study drug administration.
  • Fine needle aspirate within 3 days prior to study drug administration.
• Participants with known human immunodeficiency virus (HIV); due to lack of available safety data for eribulin therapy in HIV infected participants.
• Has any serious concomitant illness that in the opinion of the investigator(s) could affect the participant's safety or interfere with the study assessments (including active or severe chronic inflammatory bowel disease or bowel obstruction).
• Has received a live-virus vaccination within 30 days of planned start of study therapy. Seasonal flu vaccines that do not contain live virus are permitted.

Contacts and Locations

Locations

France

Hopitaux de La Timone

Marseille, Bouches-du-Rhône, France, 13385

Centre Oscar Lambret

Lille, Nord, France, 59020

Centre Léon Berard

Lyon, Rhône, France, 69008

Germany

Eisai Trial Site 4

Freiburg, Baden-Württemberg, Germany, 79106

Eisai Trial Site 2

Frankfurt, Hessen, Germany, 60590

Eisai Trial Site 5

Gottingen, Niedersachsen, Germany, 37075

Eisai Trial Site 1

Aachen, Nordrhein-Westfalen, Germany, 52074

Eisai Trial Site 3

Berlin, Germany, 13353

Eisai Trial Site 6

Essen, Germany, 45122

Greece

Aghia Sophia' Children's General Hospital of Athens

Athens, Attiki, Greece, 115 27

AHEPA University General Hospital of Thessaloniki

Thessaloníki, Greece, 546 36

Italy

Azienda Ospedaliero Universitaria Di Bologna - Policlinico S Orsola Malpighi

Bologna, Emilia-Romagna, Italy, 40138

Ospedale Pediatrico Bambino Gesù

Roma, Lazio, Italy, 00165

Fondazione Policlinico Universitario A Gemelli

Roma, Lazio, Italy, 00168

Istituto G Gaslini Ospedale Pediatrico IRCCS

Genova, Liguria, Italy, 16147

Ospedale Infantile Regina Margherita

Torino, Piemonte, Italy, 10126

Azienda Ospedaliera A Meyer

Firenze, Toscana, Italy, 50139

Azienda Ospedaliera Di Padova

Padova, Veneto, Italy, 35128

Istituto Nazionale Dei Tumori

Milan, Italy, 20133

Poland

Uniwersytecki Szpital Kliniczny im. Jana Mikulicza Radeckiego we Wroclawiu

Wrocław, Dolnoslaskie, Poland, 50-556

Instytut Pomnik Centrum Zdrowia Dziecka

Warszawa, Mazowieckie, Poland, 04-730

Spain

Hospital Universitario Vall d'Hebron - PPDS

Barcelona, Cataluña, Spain, 08035

Hospital Sant Joan de Deu

Esplugues De Llobregat, Cataluña, Spain, 08950

Hospital Infantil Universitario Niño Jesus

Madrid, Spain, 28009

Hospital Universitario La Paz

Madrid, Spain, 28046

Hospital Universitario Virgen del Rocio

Sevilla, Spain, 41013

Hospital Universitari i Politecnic La Fe de Valencia

Valencia, Spain, 46026

Switzerland

Kinderspital Zürich - Eleonorenstiftung

Zürich, Switzerland, CH-8032

United Kingdom

Addenbrooke's Hospital

Cambridge, Cambridgeshire, United Kingdom, CB2 0QQ

Southampton General Hospital

Southampton, Hampshire, United Kingdom, SO16 6YD

Alder Hey Childrens Hospital

Liverpool, Merseyside, United Kingdom, L12 2AP

John Radcliffe Hospital

Oxford, Oxfordshire, United Kingdom, OX3 9DU

Royal Marsden Hospital - Surrey

Sutton, Surrey, United Kingdom, SM2 5PT

Birmingham Children's Hospital

Birmingham, West Midlands, United Kingdom, B4 6NH

The Leeds Teaching Hospitals Charitable Foundation - Leeds Childrens Hospital (LCH)

Leeds, Yorkshire, United Kingdom, LS1 3EX

University College London

London, United Kingdom, NW1 2BU

Royal Manchester Childrens Hospital

Manchester, United Kingdom, M13 9WL

The Christie NHS Foundation Trust

Manchester, United Kingdom, M20 4BX

Royal Victoria Infirmary

Newcastle, United Kingdom, NE1 4LP

Sponsors and Collaborators

Eisai Inc.

  Study Documents (Full-Text)

Documents provided by Eisai Inc.:

Study Protocol  [PDF] March 29, 2021

Statistical Analysis Plan  [PDF] June 25, 2021

More Information

• Responsible Party: Eisai Inc.
• ClinicalTrials.gov Identifier: NCT03245450
• Other Study ID Numbers: E7389-G000-213; 2016-003352-67 ( EudraCT Number )
• First Posted: August 10, 2017
• Results First Posted: June 28, 2022
• Last Update Posted: June 28, 2022
• Last Verified: June 2021

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

Keywords provided by Eisai Inc.:

eribulin mesilate; irinotecan; combination therapy; children

Additional relevant MeSH terms:

Sarcoma; Rhabdomyosarcoma; Sarcoma, Ewing; Recurrence; Disease Attributes; Pathologic Processes; Neoplasms; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Myosarcoma; Neoplasms, Muscle Tissue; Osteosarcoma; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Irinotecan; Topoisomerase I Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents