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Study to Compare Neoadjuvant Combination of Trastuzumab and Pertuzumab With Concurrent Taxane Chemotherapy or Endocrine Therapy and Quality of Life Assessment Under Adjuvant Therapy in Operable HER2+/HR+ Breast Cancer Patients (TP-II)

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03272477
Recruitment Status : Active, not recruiting
First Posted : September 5, 2017
Last Update Posted : May 30, 2019
Sponsor:
Collaborators:
Roche Pharma AG
WSG WOMEN´S HEALTHCARE STUDY GROUP
CANKADO
Information provided by (Responsible Party):
Palleos Healthcare GmbH

Brief Summary:
This is a prospective, phase IIa, multicenter, randomized, open-label study comparing a pre-surgical combination of trastuzumab and pertuzumab with concurrent weekly paclitaxel chemotherapy or endocrine therapy given for 12 weeks with a quality of life assessment for 40 additional weeks in patients with operable HER2+/HR+ breast cancer.

Condition or disease Intervention/treatment Phase
Breast Neoplasms Drug: Perjeta Injectable Product Drug: Herceptin Drug: Tamoxifen Drug: Paclitaxel Drug: Epirubicin Drug: Cyclophosphamide Drug: Anastrozole Drug: Letrozole Drug: Exemestane Drug: Leuprorelin acetate Drug: Goserelin Drug: Leuporelin acetate Diagnostic Test: Biopsy Procedure: Surgery Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 257 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Prospective, Randomized, Multicenter, Open-label Comparison of Pre-surgical Combination of Trastuzumab and Pertuzumab With Concurrent Taxane Chemotherapy or Endocrine Therapy Given for Twelve Weeks With a Quality of Life Assessment of Trastuzumab, Pertuzumab in Combination With Standard (Neo)Adjuvant Treatment in Patients With Operable HER2+/HR+ Breast Cancer.
Actual Study Start Date : October 5, 2017
Estimated Primary Completion Date : March 15, 2020
Estimated Study Completion Date : February 28, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Active Comparator: Paclitaxel+Trastuzumab+Pertuzumab

Neoadjuvant therapy: Trastuzumab and Pertuzumab in a 3-weekly schedule in combination with standard Taxane chemotherapy.

Adjuvant Therapy: Standard of care

Drug: Perjeta Injectable Product
Single dose of 840mg (loading dose) day1 cycle 1, 420mg at day1 of each subsequent cycle, every 3 weeks. (The latter cycle is called cycle of treatment and is to be given 4 times in the neoadjuvant phase and 14 times in the adjuvant therapy phase.)
Other Name: Pertuzumab

Drug: Herceptin
Single dose of 8mg/kg (loading dose) day1 cycle 1; 6mg/kg at day1 of each subsequent cycle body weight every 3 weeks. (This is called cycle of treatment and is to be given four times in the neoadjuvant phase and 14 times in the adjuvant therapy phase.)
Other Name: Trastuzumab

Drug: Tamoxifen
20 mg per day for a total of 40 weeks in the adjuvant therapy phase.

Drug: Paclitaxel
80mg/sqm, day one of each cycle, every week. This is called a cycle of treatment and is to be given for 12 weeks in neoadjuvant therapy phase.

Drug: Epirubicin
12 weeks (4cycles) of max. 90mg/sqm in adjuvant therapy phase

Drug: Cyclophosphamide
12 weeks (4cycles) of 600 mg/sqm i.v. on day 1+8 or 12 weeks (4cycles) of 500 mg/sqm i.v. on day 1 in adjuvant therapy phase

Drug: Anastrozole
1mg per day for a total of 40 weeks in adjuvant therapy phase

Drug: Letrozole
2,5 mg/day for a total of 40 weeks in adjuvant therapy phase

Drug: Exemestane
25mg/day for a total of 40 weeks in adjuvant therapy phase

Drug: Leuprorelin acetate
One injection of 3,75mg every month or 4 weeks in pre-menopausal women treated with aromatase inhibitors Anastrozole or Letrozole or Exemestane, for a total of 40 weeks in the adjuvant therapy phase.

Drug: Goserelin
3,6mg every 28 days or 4 weeks in pre-menopausal women treated with aromatase inhibitors Anastrozole or Letrozole or Exemestane, for a total of 40 weeks in the adjuvant therapy phase.

Diagnostic Test: Biopsy
Core biopsy at screening (outside of protocol), at week 4 after randomization, (at week 14 in addition if neoadjuvant phase is prolonged)

Procedure: Surgery
Surgery at week 14 after randomization (or later, if neoadjuvant phase is prolonged)

Experimental: Endocrine+Trastuzumab+Pertuzumab

Neoadjuvant therapy: Trastuzumab and Pertuzumab in a 3-weekly schedule in combination with endocrine therapy.

Adjuvant Therapy: Standard of care

Drug: Perjeta Injectable Product
Single dose of 840mg (loading dose) day1 cycle 1, 420mg at day1 of each subsequent cycle, every 3 weeks. (The latter cycle is called cycle of treatment and is to be given 4 times in the neoadjuvant phase and 14 times in the adjuvant therapy phase.)
Other Name: Pertuzumab

Drug: Herceptin
Single dose of 8mg/kg (loading dose) day1 cycle 1; 6mg/kg at day1 of each subsequent cycle body weight every 3 weeks. (This is called cycle of treatment and is to be given four times in the neoadjuvant phase and 14 times in the adjuvant therapy phase.)
Other Name: Trastuzumab

Drug: Epirubicin
12 weeks (4cycles) of max. 90mg/sqm in adjuvant therapy phase

Drug: Cyclophosphamide
12 weeks (4cycles) of 600 mg/sqm i.v. on day 1+8 or 12 weeks (4cycles) of 500 mg/sqm i.v. on day 1 in adjuvant therapy phase

Drug: Anastrozole
1mg per day for 12 weeks in neoadjuvant therapy phase; 1mg per day for a total of 40 weeks max. in adjuvant therapy phase

Drug: Letrozole
2,5 mg per day for 12 weeks in neoadjuvant therapy phase; 2,5 mg perday for a total of 40 weeks max. in adjuvant therapy phase

Drug: Exemestane
25mg/day for 12 weeks in neoadjuvant therapy phase; 25mg/day for a total of 40 weeks max. in adjuvant therapy phase

Drug: Paclitaxel
80mg/sqm, day one of each cycle, every week. This is called a cycle of treatment an is to be given for 12 weeks in the adjuvant phase

Drug: Tamoxifen
20mg per day (given over 12 weeks in the neoadjuvant therapy phase and over 40 weeks max. in the adjuvant therapy phase.

Drug: Leuporelin acetate
One injection of 3,75mg every month or 4 weeks in pre-menopausal women treated with aromatase inhibitors Anastrozole or Letrozole or Exemestane (given over 12 weeks in the neoadjuvant therapy phase and over 40 weeks max. in the adjuvant therapy phase).

Drug: Goserelin
3,5mg every 28 days or 4 weeks in pre-menopausal women treated with aromatase inhibitors Anastrozole or Letrozole or Exemestane (given over 12 weeks in the neoadjuvant therapy phase and over 40 weeks max. in the adjuvant therapy phase).

Diagnostic Test: Biopsy
Core biopsy at screening (outside of protocol), at week 4 after randomization, (at week 14 in addition if neoadjuvant phase is prolonged)

Procedure: Surgery
Surgery at week 14 after randomization (or later, if neoadjuvant phase is prolonged)




Primary Outcome Measures :
  1. Pathological complete response (pCR) [ Time Frame: 14 weeks after start of therapy treatment ]
    14 weeks after start of therapy treatment, tumor and lymph node biopsy is performed to reach the primary endpoint of pathological complete response (pCR) which is defined as the absence of residual invasive cancer of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (ypT0/is ypN0 in the current AJCC staging system). As secondary endpoint, also other response states will be taken into account: no invasive tumor in the complete resected breast specimen irrespective of the lymph node state following completion of neoadjuvant systemic therapy (ypT0/is, any ypN).


Secondary Outcome Measures :
  1. Health-related quality of life using EORTC QBL-BR-23 scale [ Time Frame: During the neoadjuvant treatment phase at baseline (week 1) and at week 13. In the adjuvant therapy phase, every 3 month, up to 12 months (from date of randomization) or date of drop out, whatever comes first ]
    Assessment of quality of life questions during the past week or during the past 4 weeks (depending on the questions) are measured on a 4 level-scale: 1 (not at all); 2 (a little); 3 (quite a bit); 4 (very much)

  2. Health-related quality of life using EQ5D-5L scale [ Time Frame: During the neoadjuvant treatment phase at baseline (week 1) and at week 13. In the adjuvant therapy phase, every 3 month, up to 12 months (from date of randomization) or date of drop out, whatever comes first ]
    • questions about "self care", "usual activities", "pain /discomfort", anxiety/depression" are assessed on a 5 level-scale using tick boxes : "I have no problem"; "I have slight problems"; "I have moderate problems"; "I have severe problems" "I am unable"
    • assessment of the patient health (good or bad) is measured on a scale numbered from 0 to 100 (100 means the best heath and 0 means the worst)

  3. Health-related quality of life using EORTC QLQ-C30 scale [ Time Frame: During the neoadjuvant treatment phase at baseline (week 1) and at week 13. In the adjuvant therapy phase, every 3 month, up to 12 months (from date of randomization) or date of drop out, whatever comes first ]
    • Assessment of quality of life questions (activities, breath, pain, sleep, appetite, vomiting, constipation, others..) are measured on a 4 level-scale: 1 (not at all); 2 (a little); 3 (quite a bit); 4 (very much)
    • Assessment of Overall health and overall quality of life during the past week is measured on a 7 level-scale going from 1 (very poor) to 7 (excellent)

  4. Tumor size reduction by mammography [ Time Frame: at screening visit and 12 weeks after start of therapy treatment ]
    The diameters of the tumors in the breast will be measured in millimeter by mammography as part of clinical response measure. The tumor size measurement 13 weeks after start of therapy is also used to reach a secondary endpoint: near pCR, defined as tumor sized ypT1a/is, any ypN with tumor size.

  5. Tumor size reduction by palpation and ultrasound [ Time Frame: at screening visit and 4, 7 and 13 weeks after start of therapy treatment ]
    The diameters of the tumors in the breast will be measured in millimeter by palpation and ultrasound as part of clinical response measure. The tumor size measurement 13 weeks after start of therapy is also used to reach a secondary endpoint: near pCR, defined as tumor sized ypT1a/is, any ypN with tumor size.

  6. Overall survival [ Time Frame: From date of randomization until the date of death from any cause, assessed up to 60 months ]
    The overall survival is defined as time (days) between study treatment allocation and death of patient due to any cause.

  7. Duration of invasive disease-free survival [ Time Frame: From date of treatment allocation until the date of first documented progression or secondary tumor or date of death from any cause, whichever came first, assessed up to 60 months (study duration including follow up) ]
    Duration of invasive disease-free survival is defined as time (days) between study treatment allocation and relapse, secondary tumor event or death.

  8. Number of mastectomies [ Time Frame: 14 weeks after start of therapy treatment ]
    The number of mastectomies will be determined at time of surgery (week 14 and week 18)

  9. Ki67 level [ Time Frame: 4 weeks after start of therapy treatment ]
    The level of Ki67 in biopsie material will be measured at week 4 of neoadjuvant therapy

  10. cDNA composition [ Time Frame: at baseline, 3 weeks, 4 weeks and 6, 18, 24, 36 48 and 60 months after start of therapy treatment ]
    The composition of cDNA in blood samples will be measured



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.


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

Inclusion Criteria:

  • Female patients, age at diagnosis 18 years and older
  • Histologically confirmed unilateral primary invasive carcinoma of the breast
  • Patients must qualify for neoadjuvant treatment as follows:

    • No clinical evidence for distant metastasis (M0)
    • Clinical cT1c-T4a-c (participation of patients with tumors > cT2 is strongly recommended) and no evidence for distant metastases (M0)
    • All clinical N (participation of patients with cN+, also in case of cT1c, is strongly recommended)
    • Known positive HR-status and centrally confirmed HER2+-status by IHC/FISH
    • Patients need to fulfill adequate blood count and organ function to receive chemotherapy (see exclusion criteria).
  • Tumor block available for central pathology review
  • Performance Status ECOG ≤ 1 or KI ≥ 80%
  • Negative pregnancy test (urine or serum) within 7 days prior to registration in premenopausal patients
  • Patients of childbearing potential must accept to implement a highly effective (less than 1% failure rate according to Pearl index) non-hormonal contraceptive measures during the study treatment and for 6 months following the last dose of study treatment (trastuzumab and pertuzumab) such as:

    • Intrauterine device (IUD)
    • bilateral tubal occlusion
    • vasectomised partner
    • sexual abstinence
  • Written informed consent prior to beginning specific protocol procedures, including expected cooperation of the patients for the treatment and follow-up, must be obtained and documented according to the local regulatory requirements
  • The patient must be accessible for treatment and follow-up
  • LVEF > 55%; LVEF within normal limits of each institution measured by echocardiography (within 42 days prior to randomization)
  • Normal ECG (within 42 days prior to randomization)

Exclusion Criteria:

  • Known hypersensitivity reaction to the compounds or incorporated substances
  • Prior malignancy with a disease-free survival of < 10 years, except curatively treated basalioma of the skin, pTis of the cervix uteri
  • Non-operable breast cancer including inflammatory breast cancer
  • Previous or concurrent treatment with cytotoxic agents for any reason
  • Concurrent treatment with other experimental drugs and participation in another clinical trial or clinical research project within 30 days prior to study entry is excluded
  • Male breast cancer
  • Concurrent pregnancy
  • Breastfeeding
  • Sequential breast cancer
  • Reasons indicating risk of poor compliance
  • Known polyneuropathy ≥ grade 2
  • Severe and relevant co-morbidity that would interact with the application of cytotoxic agents or the participation in the study including but not confined to:

    • Uncompensated chronic heart failure or systolic dysfunction (LVEF < 55%, CHF NYHA classes II-IV),
    • unstable arrhythmias requiring treatment i.e., atrial tachycardia with a heart rate ≥ 100/min at rest, significant ventricular arrhythmia (ventricular tachycardia) or higher-grade AV-block,
    • Angina pectoris within the last 6 months requiring anti-anginal medication,
    • Clinically significant valvular heart disease,
    • Evidence of myocardial infarction on electrocardiogram (ECG),
    • Poorly controlled hypertension (e.g., systolic > 180 mm Hg or diastolic > 100 mm Hg).
  • Inadequate organ function including but not confined to:

    • hepatic impairment (Child Pugh Class C)
    • pulmonary disease (severe dyspnea at rest requiring oxygen therapy)
  • Abnormal blood values:

    • Thrombocytopenia > CTCAE grade 1
    • Increases in ALT/AST > CTCAE grade 1
    • Hypokalaemia > CTCAE grade 1
    • Neutropenia > CTCAE grade 1
    • Anaemia > CTCAE grade 1

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): NCT03272477


Locations
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Germany
Evangelisches Krankenhaus Bethesda Mönchengladbach
Mönchengladbach, Germany, 41061
Sponsors and Collaborators
Palleos Healthcare GmbH
Roche Pharma AG
WSG WOMEN´S HEALTHCARE STUDY GROUP
CANKADO
Investigators
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Study Director: Stefan Dröse, PhD Palleos Healthcare GmbH

Publications:
Loibl S, von Minckwitz G, Blohmer J, et al: pCR as a Surrogate in HER2-Positive Patients Treated with Trastuzumab. Supplement to Cancer Research 71:[S5-4] 2011
Harbeck N, Gluz O, Christgen M, Kates RE, Braun M, Küemmel S, Schumacher C, Potenberg J, Kraemer S, Kleine-Tebbe A, Augustin D, Aktas B, Forstbauer H, Tio J, von Schumann R, Liedtke C, Grischke EM, Schumacher J, Wuerstlein R, Kreipe HH, Nitz UA. De-Escalation Strategies in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Early Breast Cancer (BC): Final Analysis of the West German Study Group Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early BC HER2- and Hormone Receptor-Positive Phase II Randomized Trial-Efficacy, Safety, and Predictive Markers for 12 Weeks of Neoadjuvant Trastuzumab Emtansine With or Without Endocrine Therapy (ET) Versus Trastuzumab Plus ET. J Clin Oncol. 2017 Sep 10;35(26):3046-3054. doi: 10.1200/JCO.2016.71.9815. Epub 2017 Jul 6.
Gianni L, Pienkowski T, Im Y-H, et al: Five-year analysis of the phase II NeoSphere trial evaluating four cycles of neoadjuvant docetaxel (D) and/or trastuzumab (T) and/or pertuzumab (P). ASCO Meeting Abstracts 33:505, 2015
Rimawi MF, Niravath PA, Wang T, et al: Abstract S6-02: TBCRC023: A randomized multicenter phase II neoadjuvant trial of lapatinib plus trastuzumab, with endcorine therapy and without chemotherapy, for 12 vs. 24 weeks in patients with HER2 overexpressing breast cancer. Cancer Research 75:S6-02, 2015
Gluz O, Nitz U, Liedtke C, et al: Abstract S6-07: Comparison of 12 weeks neoadjuvant Nab-paclitaxel combined with carboplatinum vs. gemcitabine in triple- negative breast cancer: WSG-ADAPT TN randomized phase II trial. Cancer Research 76:S6-07, 2016
Ellis M, Luo J, Tao Y, et al: Tumor Ki67 Proliferation Index within 4 Weeks of Initiating Neoadjuvant Endocrine Therapy for Early Identification of Non-Responders. Cancer Res 69, 2010
Von Minckwitz G, Untch M, Nueesch E, et al: Impact of treatment characteristics on response of different breast cancer subtypes: Pooled multilayer analysis of the German neoadjuvant chemotherapy trials. J Clin Oncol (Meeting Abstracts) 28:501-, 2010
Perez E, Suman V, Davidson N, et al: Results of Chemotherapy Alone, with Sequential or Concurrent Addition of 52 Weeks of Trastuzumab in the NCCTG N9831 HER2-Positive Adjuvant Breast Cancer Trial. Cancer Res 69:Abstract 80, 2010
Untch M, Fasching P, Konecny G, et al: Pathological Complete Response after Neoadjuvant Chemotherapy + Trastuzumab Treatment Predicts Survival and Detects a Patient Subgroup at High Need for Improvement of Anti-HER2 Therapy. Three Year Median Follow-Up Data of the TECHNO Trial. Cancer Res 71:P1-11-03, 2011
Von Minckwitz G, Kaufmann M, Kuemmel S, et al: Correlation of various pathologic complete response (pCR) definitions with long-term outcome and the prognostic value of pCR in various breast cancer subtypes: Results from the German neoadjuvant meta-analysis. J Clin Oncol 29:abstr 1028, 2011
Gianni L, Pienkowski T, Im Y-H, et al: Neoadjuvant Pertuzumab (P) and Trastuzumab (H): Antitumor and Safety Analysis of a Randomized Phase II Study ('NeoSphere'). Cancer Res 71:[S3-2], 2011
Schneeweiss A, Chia S, Hickish T, et al: Neoadjuvant Pertuzumab and Trastuzumab Concurrent or Sequential with an Anthracycline-Containing or Concurrent with an Anthracycline-Free Standard Regimen: A Randomized Phase II Study (TRYPHAENA). Supplement to Cancer Research 71:[S5-6] 2011
Hurvitz SA, Martin M, Symmans WF, et al: Pathologic complete response (pCR) rates after neoadjuvant trastuzumab emtansine (T-DM1 [K]) + pertuzumab (P) vs docetaxel + carboplatin + trastuzumab + P (TCHP) treatment in patients with HER2-positive (HER2+) early breast cancer (EBC) (KRISTINE). ASCO Meeting Abstracts 34:500, 2016
Guarneri V, Chavez-Mac Gregor M, Hsu L, et al: Use of Ki-67 in residual disease following preoperative chemotherapy to predict of recurrence and death in breast cancer patients. J Clin Oncol (Meeting Abstracts) 28:621-, 2010
Whelan TJ, Olivotto I, Ackerman I, et al: NCIC-CTG MA.20: An intergroup trial of regional nodal irradiation in early breast cancer. J Clin Oncol Suppl:LBA1003, 2011
Gourgou-Bourgade S, Cameron D, Poortmans P, Asselain B, Azria D, Cardoso F, A'Hern R, Bliss J, Bogaerts J, Bonnefoi H, Brain E, Cardoso MJ, Chibaudel B, Coleman R, Cufer T, Dal Lago L, Dalenc F, De Azambuja E, Debled M, Delaloge S, Filleron T, Gligorov J, Gutowski M, Jacot W, Kirkove C, MacGrogan G, Michiels S, Negreiros I, Offersen BV, Penault Llorca F, Pruneri G, Roche H, Russell NS, Schmitt F, Servent V, Thürlimann B, Untch M, van der Hage JA, van Tienhoven G, Wildiers H, Yarnold J, Bonnetain F, Mathoulin-Pélissier S, Bellera C, Dabakuyo-Yonli TS; Definition for the Assessment of Time-to-event Endpoints in Cancer Trials Initiative. Guidelines for time-to-event end point definitions in breast cancer trials: results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials)†. Ann Oncol. 2015 May;26(5):873-9. doi: 10.1093/annonc/mdv106. Epub 2015 Feb 27. Review. Erratum in: Ann Oncol. 2015 Dec;26(12):2505-6.

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Responsible Party: Palleos Healthcare GmbH
ClinicalTrials.gov Identifier: NCT03272477     History of Changes
Other Study ID Numbers: PH002-TP-II
First Posted: September 5, 2017    Key Record Dates
Last Update Posted: May 30, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Palleos Healthcare GmbH:
hormone receptor positive
human epidermal growth factor receptor 2 positive
Early breast cancer
HR+/HER2+
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Tamoxifen
Paclitaxel
Albumin-Bound Paclitaxel
Cyclophosphamide
Trastuzumab
Letrozole
Epirubicin
Anastrozole
Exemestane
Pertuzumab
Taxane
Goserelin
Leuprolide
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents