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Veliparib, Pembrolizumab, and Combination Chemotherapy in Treating Patient With Locally Advanced Rectal Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02921256
Recruitment Status : Recruiting
First Posted : October 3, 2016
Last Update Posted : September 18, 2018
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This randomized phase II trial studies how well veliparib or pembrolizumab work with combination chemotherapy and radiation therapy in treating patients with rectal cancer that has spread from where it started to nearby tissue or lymph nodes (locally advanced). Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as modified (m)FOLFOX6 regimen, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. Giving veliparib or pembrolizumab with combination chemotherapy and radiation therapy may kill more tumor cells, make the tumor smaller, and reduce the amount of normal tissue that needs to be removed.

Condition or disease Intervention/treatment Phase
Rectal Adenocarcinoma Stage II Rectal Cancer AJCC v7 Stage III Rectal Cancer AJCC v7 Drug: Capecitabine Drug: Fluorouracil Radiation: Intensity-Modulated Radiation Therapy Drug: Leucovorin Calcium Drug: Oxaliplatin Biological: Pembrolizumab Drug: Veliparib Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 348 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Clinical Trial Platform of Sensitization Utilizing Total Neoadjuvant Therapy (TNT) in Rectal Cancer
Actual Study Start Date : October 12, 2016
Estimated Primary Completion Date : April 30, 2019

Arm Intervention/treatment
Active Comparator: Arm I (mFOLFOX6, RT, capecitabine)
Patients receive mFOLFOX6 regimen consisting of oxaliplatin IV over 2 hours on day 1, leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV continuously over 46-48 hours on days 1-2. Treatment repeats every 2 weeks for 8 courses in the absence of disease progression or unacceptable toxicity. 3-4 weeks after last does of mFOLFOX6 patient undergo RT and receive capecitabine PO BID Monday-Friday for 5 weeks in the absence of disease progression or unacceptable toxicity.
Drug: Capecitabine
Given PO
Other Names:
  • Ro 09-1978/000
  • Xeloda

Drug: Fluorouracil
Given IV
Other Names:
  • 5-Fluoro-2,4(1H, 3H)-pyrimidinedione
  • 5-Fluorouracil
  • 5-Fluracil
  • 5-FU
  • AccuSite
  • Carac
  • Fluoro Uracil
  • Fluouracil
  • Flurablastin
  • Fluracedyl
  • Fluracil
  • Fluril
  • Fluroblastin
  • Ribofluor
  • Ro 2-9757
  • Ro-2-9757

Radiation: Intensity-Modulated Radiation Therapy
Undergo intensity modulated radiation therapy
Other Names:
  • IMRT
  • Intensity Modulated RT
  • Intensity-Modulated Radiotherapy

Drug: Leucovorin Calcium
Given IV
Other Names:
  • Adinepar
  • Calcifolin
  • Calcium (6S)-Folinate
  • Calcium Folinate
  • Calcium Leucovorin
  • Calfolex
  • Calinat
  • Cehafolin
  • Citofolin
  • Citrec
  • citrovorum factor
  • Cromatonbic Folinico
  • Dalisol
  • Disintox
  • Divical
  • Ecofol
  • Emovis
  • Factor, Citrovorum
  • Flynoken A
  • Folaren
  • Folaxin
  • FOLI-cell
  • Foliben
  • Folidan
  • Folidar
  • Folinac
  • Folinate Calcium
  • folinic acid
  • Folinic Acid Calcium Salt Pentahydrate
  • Folinoral
  • Folinvit
  • Foliplus
  • Folix
  • Imo
  • Lederfolat
  • Lederfolin
  • Leucosar
  • leucovorin
  • Rescufolin
  • Rescuvolin
  • Tonofolin
  • Wellcovorin

Drug: Oxaliplatin
Given IV
Other Names:
  • 1-OHP
  • Ai Heng
  • Aiheng
  • Dacotin
  • Dacplat
  • Diaminocyclohexane Oxalatoplatinum
  • Eloxatin
  • Eloxatine
  • JM-83
  • Oxalatoplatin
  • Oxalatoplatinum
  • RP 54780
  • RP-54780
  • SR-96669

Experimental: Arm II (mFOLFOX6, RT, capecitabine, veliparib)
Patients receive mFOLFOX6 regimen consisting of oxaliplatin IV over 2 hours on day 1, leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV continuously over 46-48 hours on days 1-2. Treatment repeats every 2 weeks for up to 8 courses in the absence of disease progression or unacceptable toxicity. 3-4 weeks after last does of mFOLFOX6 patient undergo RT and receive capecitabine PO BID and veliparib PO BID Monday-Friday for 5 weeks in the absence of disease progression or unacceptable toxicity.
Drug: Capecitabine
Given PO
Other Names:
  • Ro 09-1978/000
  • Xeloda

Drug: Fluorouracil
Given IV
Other Names:
  • 5-Fluoro-2,4(1H, 3H)-pyrimidinedione
  • 5-Fluorouracil
  • 5-Fluracil
  • 5-FU
  • AccuSite
  • Carac
  • Fluoro Uracil
  • Fluouracil
  • Flurablastin
  • Fluracedyl
  • Fluracil
  • Fluril
  • Fluroblastin
  • Ribofluor
  • Ro 2-9757
  • Ro-2-9757

Radiation: Intensity-Modulated Radiation Therapy
Undergo intensity modulated radiation therapy
Other Names:
  • IMRT
  • Intensity Modulated RT
  • Intensity-Modulated Radiotherapy

Drug: Leucovorin Calcium
Given IV
Other Names:
  • Adinepar
  • Calcifolin
  • Calcium (6S)-Folinate
  • Calcium Folinate
  • Calcium Leucovorin
  • Calfolex
  • Calinat
  • Cehafolin
  • Citofolin
  • Citrec
  • citrovorum factor
  • Cromatonbic Folinico
  • Dalisol
  • Disintox
  • Divical
  • Ecofol
  • Emovis
  • Factor, Citrovorum
  • Flynoken A
  • Folaren
  • Folaxin
  • FOLI-cell
  • Foliben
  • Folidan
  • Folidar
  • Folinac
  • Folinate Calcium
  • folinic acid
  • Folinic Acid Calcium Salt Pentahydrate
  • Folinoral
  • Folinvit
  • Foliplus
  • Folix
  • Imo
  • Lederfolat
  • Lederfolin
  • Leucosar
  • leucovorin
  • Rescufolin
  • Rescuvolin
  • Tonofolin
  • Wellcovorin

Drug: Oxaliplatin
Given IV
Other Names:
  • 1-OHP
  • Ai Heng
  • Aiheng
  • Dacotin
  • Dacplat
  • Diaminocyclohexane Oxalatoplatinum
  • Eloxatin
  • Eloxatine
  • JM-83
  • Oxalatoplatin
  • Oxalatoplatinum
  • RP 54780
  • RP-54780
  • SR-96669

Drug: Veliparib
Given PO
Other Names:
  • ABT-888
  • PARP-1 inhibitor ABT-888

Experimental: Arm III (mFOLFOX6, RT, capecitabine, pembrolizumab)
ARM III: Patients receive mFOLFOX6 regimen consisting of oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV continuously over 46-48 hours on days 1-2. Treatment repeats every 2 weeks for 8 courses in the absence of disease progression or unacceptable toxicity. 3-4 weeks after last does of mFOLFOX6 patient undergo RT and receive capecitabine PO BID Monday-Friday for 5 weeks. They also receive pembrolizumab IV over 30 minutes every 3 weeks beginning on day 1 of RT for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Drug: Capecitabine
Given PO
Other Names:
  • Ro 09-1978/000
  • Xeloda

Drug: Fluorouracil
Given IV
Other Names:
  • 5-Fluoro-2,4(1H, 3H)-pyrimidinedione
  • 5-Fluorouracil
  • 5-Fluracil
  • 5-FU
  • AccuSite
  • Carac
  • Fluoro Uracil
  • Fluouracil
  • Flurablastin
  • Fluracedyl
  • Fluracil
  • Fluril
  • Fluroblastin
  • Ribofluor
  • Ro 2-9757
  • Ro-2-9757

Radiation: Intensity-Modulated Radiation Therapy
Undergo intensity modulated radiation therapy
Other Names:
  • IMRT
  • Intensity Modulated RT
  • Intensity-Modulated Radiotherapy

Drug: Leucovorin Calcium
Given IV
Other Names:
  • Adinepar
  • Calcifolin
  • Calcium (6S)-Folinate
  • Calcium Folinate
  • Calcium Leucovorin
  • Calfolex
  • Calinat
  • Cehafolin
  • Citofolin
  • Citrec
  • citrovorum factor
  • Cromatonbic Folinico
  • Dalisol
  • Disintox
  • Divical
  • Ecofol
  • Emovis
  • Factor, Citrovorum
  • Flynoken A
  • Folaren
  • Folaxin
  • FOLI-cell
  • Foliben
  • Folidan
  • Folidar
  • Folinac
  • Folinate Calcium
  • folinic acid
  • Folinic Acid Calcium Salt Pentahydrate
  • Folinoral
  • Folinvit
  • Foliplus
  • Folix
  • Imo
  • Lederfolat
  • Lederfolin
  • Leucosar
  • leucovorin
  • Rescufolin
  • Rescuvolin
  • Tonofolin
  • Wellcovorin

Drug: Oxaliplatin
Given IV
Other Names:
  • 1-OHP
  • Ai Heng
  • Aiheng
  • Dacotin
  • Dacplat
  • Diaminocyclohexane Oxalatoplatinum
  • Eloxatin
  • Eloxatine
  • JM-83
  • Oxalatoplatin
  • Oxalatoplatinum
  • RP 54780
  • RP-54780
  • SR-96669

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475




Primary Outcome Measures :
  1. Change in neoadjuvant rectal cancer (NAR) score [ Time Frame: Baseline to up to 3 years ]
    A linear regression model that controls for the stratification factors (cT-stage and cN-stage) will be used. Mean NAR scores along with standard errors and confidence intervals will be reported by treatment.


Secondary Outcome Measures :
  1. Overall survival [ Time Frame: Time from start of study treatment, assessed up to 3 years ]
    Analyzed using the stratified log rank test with strata cT-stage and cN-stage. Kaplan-Meier plots will illustrate the distribution of these endpoints by treatment. Cox regression models will be used to estimate hazard ratios and associated confidence intervals.

  2. Disease free survival [ Time Frame: Time from start of study treatment, assessed up to 3 years ]
    Analyzed using the stratified log rank test with strata cT-stage and cN-stage. Kaplan-Meier plots will illustrate the distribution of these endpoints by treatment. Cox regression models will be used to estimate hazard ratios and associated confidence intervals.

  3. Rate of pathologic complete response (nodes and tumor) ypT0 and ypN0 [ Time Frame: Up to 3 years ]
    Analyzed by a logistic regression model that controls for the stratification factors (cT-stage and cN-stage). Observed proportions along with confidence intervals will be presented by treatment.

  4. Rate of sphincter preservation [ Time Frame: Up to 3 years ]
    Analyzed by a logistic regression model that controls for the stratification factors (cT-stage and cN-stage). Observed proportions along with confidence intervals will be presented by treatment.


Other Outcome Measures:
  1. Rate of disease progression during chemotherapy (prior to chemoradiation) [ Time Frame: Up to 3 years ]
    Analyzed by a logistic regression model that controls for the stratification factors (cT-stage and cN-stage). Observed proportions along with confidence intervals will be presented by treatment.

  2. Rate of clinical complete response rate, ycT0 [ Time Frame: Up to 3 years ]
    Analyzed by a logistic regression model that controls for the stratification factors (cT-stage and cN-stage). Observed proportions along with confidence intervals will be presented by treatment.

  3. Rate of negative circumferential margin [ Time Frame: Up to 3 years ]
    Analyzed by a logistic regression model that controls for the stratification factors (cT-stage and cN-stage). Observed proportions along with confidence intervals will be presented by treatment.

  4. Rate of completion of all cycles of neoadjuvant chemotherapy [ Time Frame: Up to 3 years ]
    Analyzed by a logistic regression model that controls for the stratification factors (cT-stage and cN-stage). Observed proportions along with confidence intervals will be presented by treatment.

  5. Rate of completion of full course of chemoradiation [ Time Frame: Up to 3 years ]
    Analyzed by a logistic regression model that controls for the stratification factors (cT-stage and cN-stage). Observed proportions along with confidence intervals will be presented by treatment.

  6. Incidence of toxicity including patient-reported toxicities using Common Terminology for Adverse Events (CTCAE) version 4.0 (CTCAE version 5.0 beginning April 1, 2018) [ Time Frame: 30 days after last study treatment ]
  7. Correlative molecular predictors of response and distant failure [ Time Frame: Up to 3 years ]
    Cox regression models will be used to evaluate markers for time-to-event variables. Logistic regression models will be used for binary variables. Models will control for stratification factors and possibly other prognostic variables (e.g. gender or treatment).

  8. Relationship between radiographic findings and pathologic outcomes [ Time Frame: Up to 3 years ]
    Will explore the relationship between radiographic findings and pathologic outcomes.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

Inclusion Criteria:

  • The patient must have signed and dated an Institutional Review Board (IRB)-approved consent form that conforms to federal and institutional guidelines
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
  • Diagnosis of adenocarcinoma of the rectum with the major portion of the tumor intact; Note: prior to randomization, the investigator must specify and document each of the following:

    • Distance of the lowest tumor margin from the anal verge; and
    • Intent for sphincter sparing or non-sphincter sparing surgical resection according to the primary surgeon; and
    • The majority of the untreated tumor must be < 12 cm from the anal verge or below the peritoneal reflection as determined by the treating surgeon
  • The tumor must be clinically determined to be locally advanced stage II or stage III rectal cancer, and must also meet any ONE of the following criteria:

    • Distal location (as defined by measurement on magnetic resonance imaging [MRI], transrectal ultrasound [ERUS]/pelvic computed tomography [CT] [with IV contrast] scan or palpable on digital rectal examination [DRE]): cT3-4 =< 5 cm from the anal verge, any N
    • Bulky: any cT4 or evidence that the tumor is adjacent to (defined as within 3 mm of) the mesorectal fascia on MRI or ERUS/pelvic CT (with IV contrast) scan
    • High risk for metastatic disease with 4 or more regional lymph nodes (cN2); clinical nodal or "cN" status for eligibility includes the total number of nodes (N2 = 4 or more) in the mesorectal and superior rectal stations measuring >= 1.0 cm in any axis on cross sectional or endoscopic imaging; Note: nodes must measure 1.0 cm or greater to be considered positive for this eligibility requirement
    • Not a candidate for sphincter-sparing surgical resection prior to neoadjuvant therapy (as planned by the primary surgeon)

      • Note: clinical stage of the primary tumor and nodes may be determined locally by rectal endoscopic ultrasound or pelvic MRI (MRI is strongly preferred); CT scan with IV contrast is acceptable provided there is evidence of T4 and/or N2 disease
  • Patients must have the ability to swallow and retain oral medication
  • Absolute neutrophil count (ANC) must be >= 1200/mm^3 within 28 days before randomization
  • Platelet count must be >= 100,000/mm^3 within 28 days before randomization
  • Hemoglobin must be >= 10 g/dL within 28 days before randomization
  • Total bilirubin must be =< ULN (upper limit of normal) for the lab unless the patient has a bilirubin elevation > ULN to 1.5 x ULN due to Gilbert's disease or similar syndrome involving slow conjugation of bilirubin within 28 days before randomization
  • Alkaline phosphatase must be =< 3 x ULN for the lab within 28 days before randomization
  • Aspartate aminotransferase (AST) must be =< 3 x ULN for the lab within 28 days before randomization;

    • Note: if alanine aminotransferase (ALT) is performed instead of AST (per institution's standard practice), the ALT value must be =< 3 x ULN; if both were performed, the AST must also be =< 3 x ULN; if AST and/or ALT is >= ULN but =< 3 x ULN, serologic testing for hepatitis B and C must be performed and results for viral infection must be negative
  • Serum creatinine =< ULN for the lab and measured or calculated creatinine clearance > 60 mL/min within 28 days before randomization
  • Serum potassium, magnesium, and calcium levels within 28 days before randomization must be within normal limits (WNL) for the lab within 28 days before randomization
  • International normalized ratio of prothrombin time (INR) within 28 days before randomization must be =< ULN for the lab; patients who are therapeutically treated with an agent such as warfarin may participate if they are on a stable dose and no underlying abnormality in coagulation parameters exists per medical history
  • Patients with acquired immunodeficiency syndrome (AIDS-related illnesses) or known human immunodeficiency virus (HIV) disease must:

    • Have a cluster of differentiation (CD)4 count >= 200 cells/uL within 30 days before beginning study therapy
    • Be off all antiretroviral therapy (prophylaxis/treatment) more than 60 days before beginning study therapy, and
    • Have no evidence of opportunistic infections
  • Pregnancy test (urine or serum beta-human chorionic gonadotropin [HCG]) done within 72 hours before randomization must be negative (for women of childbearing potential only); if urine pregnancy results are positive or cannot be confirmed as negative, a serum pregnancy test will be required

Exclusion Criteria:

  • Rectal cancer histology other than adenocarcinoma (i.e., sarcoma, lymphoma, squamous cell carcinoma, mucosal melanoma, etc.)
  • Definitive clinical or radiologic evidence of metastatic disease; required imaging studies must have been performed within 28 days prior to randomization; Note: Distant clinical staging to exclude patients with overt metastatic disease is determined by:

    • Chest: CT scan (preferred); chest x-ray posterioranterior (PA) and lateral (acceptable); or positron emission tomography (PET) scan (acceptable)
    • Abdomen: CT scan with IV contrast (preferred); or MRI (acceptable)
    • Pelvis: MRI (preferred) or CT scan with IV contrast (acceptable)

      • (It is recommended that the same imaging tests that are performed before randomization be used at follow-up time points; Note: CT scans of the abdomen and pelvis must be performed with IV contrast)
  • History of prior invasive rectal malignancy, regardless of disease-free interval
  • Cardiac disease that would preclude the use of any of the drugs included in the GI002 treatment regimen; this includes but is not limited to:

    • Clinically unstable cardiac disease, including unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, active myocardial ischemia, or indwelling temporary pacemaker
    • Ventricular tachycardia or supraventricular tachycardia that requires treatment with class Ia antiarrhythmic drugs (e.g., quinidine, procainamide, disopyramide) or class III antiarrhythmic drug (e.g., sotalol, amiodarone, dofetilide); use of other antiarrhythmic drugs is permitted
    • Second- or third-degree atrioventricular (AV) block unless treated with a permanent pacemaker
    • Complete left bundle branch block (LBBB)
    • History of long QT syndrome
    • Corrected QT (QTc) >= 450ms
  • Sensory or motor neuropathy >= grade 2
  • History of, or any evidence of active, non-infectious pneumonitis
  • Active inflammatory bowel disease (i.e., patients requiring current medical interventions or who are symptomatic) or have a history of abdominal surgery or other medical condition that may, in the opinion of the treating physician, interfere with gastrointestinal motility or absorption
  • Active autoimmune disease that has required systemic treatment within the past 2 years (i.e., with use of modifying agents, corticosteroids, or immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
  • History of active TB (Bacillus tuberculosis)
  • Active or chronic infection requiring systemic therapy
  • Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study therapy; the use of physiologic doses of corticosteroids may be approved after consultation with the study principal investigator (PI)
  • Active seizure disorder uncontrolled by medication
  • Any antineoplastic therapy for this cancer before randomization
  • Synchronous colon cancer
  • Other invasive cancer within 5 years before randomization; exceptions are colonic polyps, non-melanoma skin cancer or carcinoma-in-situ of the cervix
  • Antineoplastic therapy (e.g. chemotherapy or targeted therapy) for other invasive cancer within 5 years before randomization; (for the purposes of this study, hormonal therapy is not considered chemotherapy)
  • Prior treatment with an investigational compound being tested in this study (e.g., poly ADP ribose polymerase [PARP] inhibitor, anti-PD-1, anti-PD-L1, or anti-PD-L2)
  • Receipt of live vaccination within 28 days before randomization; seasonal flu vaccines that do not contain live virus are permitted
  • Major surgery within 4 weeks before randomization
  • Any therapeutic pelvic radiation
  • Known homozygous DPD (dihydro pyrimidine dehydrogenase) deficiency
  • Pregnant women
  • Nursing women who are unwilling to discontinue nursing
  • Men or women of childbearing potential who are unwilling to employ adequate contraception (e.g., hormonal or barrier method of birth control; abstinence) for the duration of study treatment and for 4 months after the last dose of study therapy
  • Co-morbid illnesses or other concurrent disease that, in the judgement of the clinician obtaining informed consent, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens or prevent required follow-up

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02921256


  Show 566 Study Locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Thomas George NRG Oncology

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02921256     History of Changes
Other Study ID Numbers: NCI-2016-00222
NCI-2016-00222 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NRG-GI002
s17-00197
NRG-GI002 ( Other Identifier: NRG Oncology )
NRG-GI002 ( Other Identifier: CTEP )
U10CA180868 ( U.S. NIH Grant/Contract )
First Posted: October 3, 2016    Key Record Dates
Last Update Posted: September 18, 2018
Last Verified: August 2018

Additional relevant MeSH terms:
Adenocarcinoma
Rectal Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Rectal Diseases
Calcium, Dietary
Capecitabine
Fluorouracil
Oxaliplatin
Pembrolizumab
Veliparib
Leucovorin
Levoleucovorin
Folic Acid
Bone Density Conservation Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents