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Carfilzomib in Combination With Daratumumab, Lenalidomide and Dexamethasone in Transplant-ineligible NDMM Patients (KyDaR)

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ClinicalTrials.gov Identifier: NCT04065789
Recruitment Status : Recruiting
First Posted : August 22, 2019
Last Update Posted : August 22, 2019
Sponsor:
Information provided by (Responsible Party):
Tel-Aviv Sourasky Medical Center

Brief Summary:
Patients with newly diagnosed multiple myeloma (NDMM) who failed to achieve at least a minimal response (MR) after 2 cycles or a partial response (PR), after 4 cycles of a bortezomib-containing therapy, or progress on therapy during first 4 cycles (response defined by international Myeloma Working Group [IMWG] criteria), will be treated with a quadruple regimen comprised of: Daratumumab 16 mg/Kg weekly during cycles 1-2, q14 days during cycles 3-6, thereafter monthly (1st dose cycle 1 may be split over 2 days); Once-weekly intravenous (IV) administration of Carfilzomib on days 1, 8, 15, of cycle numbers 1-9 and Days 1 and 15 only of cycle numbers 10-18, at a dose of 20 mg/m2 on day 1 of cycle 1; at dose of 56 mg/m2 on all subsequent once weekly dosing days, alongside concomitant treatment with twice-weekly IV or oral dexamethasone 20mg administered on Days 1-2, 8-9, 15-16, and 22-23 of a 28-day cycle, for cycles 1-2 followed by weekly 20 mg dexamethasone on subsequent cycles; and oral Lenalidomide 25 mg, administered on days 1-21 of a 28-day cycle. On treatment days that require both Carfilzomib and Daratumumab infusions, Carfilzomib will be administrated prior to Daratumumab administration. All patients will undergo frailty assessment based on IMWG recommendations, and will be classified as fit, intermediate-fit and frail. Frail patients will receive Lenalidomide dose adjustment to 15 mg (throughout the study, from cycle 1 and on), and dexamethasone at 10 mg x 2/week cycles 1-2 followed by 10 mg/week for subsequent cycles. The quadruple regimen will be administered for 18 cycles, followed by long-term follow-up in which patients will receive standard of care treatment with Lenalidomide/dexamethasone (Rd) treatment, unless disease progression, the physician decides otherwise, the patient suffers from unacceptable toxicity, withdraws consent, or dies (whichever occurs first).

Condition or disease Intervention/treatment Phase
Myeloma Multiple Myeloma, Plasma-Cell Myeloma-Multiple Plasma Cell Myeloma Drug: Carfilzomib Drug: Daratumumab Drug: Lenalidomide Drug: Dexamethasone Phase 2

Detailed Description:

Patients with newly diagnosed multiple myeloma (NDMM) who failed to achieve at least a minimal response (MR) after 2 cycles or a partial response (PR), after 4 cycles of a bortezomib-containing therapy, or progress on therapy during first 4 cycles (response defined by international Myeloma Working Group [IMWG] criteria), will be treated with a quadruple regimen comprised of: Daratumumab 16 mg/Kg weekly during cycles 1-2, q14 days during cycles 3-6, thereafter monthly (1st dose cycle 1 may be split over 2 days); Once-weekly intravenous (IV) administration of Carfilzomib on days 1, 8, 15, of cycle numbers 1-9 and Days 1 and 15 only of cycle numbers 10-18, at a dose of 20 mg/m2 on day 1 of cycle 1; at dose of 56 mg/m2 on all subsequent once weekly dosing days, alongside concomitant treatment with twice-weekly IV or oral dexamethasone 20mg administered on Days 1-2, 8-9, 15-16, and 22-23 of a 28-day cycle, for cycles 1-2 followed by weekly 20 mg dexamethasone on subsequent cycles; and oral Lenalidomide 25 mg, administered on days 1-21 of a 28-day cycle. On treatment days that require both Carfilzomib and Daratumumab infusions, Carfilzomib will be administrated prior to Daratumumab administration. All patients will undergo frailty assessment based on IMWG recommendations, and will be classified as fit, intermediate-fit and frail. Frail patients will receive Lenalidomide dose adjustment to 15 mg (throughout the study, from cycle 1 and on), and dexamethasone at 10 mg x 2/week cycles 1-2 followed by 10 mg/week for subsequent cycles. The quadruple regimen will be administered for 18 cycles, followed by long-term follow-up in which patients will receive standard of care treatment with Lenalidomide/dexamethasone (Rd) treatment, unless disease progression, the physician decides otherwise, the patient suffers from unacceptable toxicity, withdraws consent, or dies (whichever occurs first). All patients will be required to receive either thromboprophylaxis or anticoagulation therapy in parallel. Patients will receive prophylaxis to herpes zoster and pneumocystis infection according to institutional guidelines, as well as proton pump inhibitors on dexamethasone treatment days only, according to institutional guidelines.

Patients will be assessed for response, to be determined by multiple myeloma (MM) biomarker profiling, on day 1 of cycle 2 and then every 56 ±4 days thereafter, irrespective of treatment delays or the timing of treatment cycles. Disease status will be followed until confirmed progressive disease (PD).

Long-term follow-up for disease status (only in cases where patients discontinued treatment prior to PD or patients completing all 18 cycles without signs of PD) and for survival (after reaching PD) will continue after treatment discontinuation until the patient has withdrawn consent for further participation, is lost to follow-up, has died, or the sponsor makes a decision to terminate the study. For patients who discontinued treatment before completing 18 cycles , without PD occurred, disease response assessments shall be performed every 56 days (±4 days), according to the original scheduled days of assessment, until disease progression. Patients completing all 18 cycles without signs of PD will be followed-up for disease response every 84±7 days. Follow-up for survival will be performed approximately every 3 months, or as needed, for all surviving patients until study closure. For any patient who is lost to follow-up, the study site will attempt to ascertain survival information via public database search.

The control group in this study (Historical Control) will consist of 144 consecutive patients from a subset of participating centers and will include transplant ineligible NDMM diagnosed between 2011 to 2017 with failure to respond to a bortezomib based induction (as defined in the prospective trial). Control group patients must meet the protocol inclusion and exclusion criteria.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Safety, Tolerability, and Efficacy of Once Weekly Carfilzomib in Combination With Daratumumab, Lenalidomide and Dexamethasone, in Transplant-ineligible Multiple Myeloma Patients Non-responsive to a Bortezomib Based Induction
Actual Study Start Date : May 2, 2018
Estimated Primary Completion Date : January 2022
Estimated Study Completion Date : January 2023


Arm Intervention/treatment
Experimental: Carfilzomib,Daratumumab,revlimid and dexamethasone
Carfilzomib, Daratumumab, Lenalidomide, Dexamethasone
Drug: Carfilzomib
Carfilzomib on Days 1, 8, 15, of cycle numbers 1-9 and Days 1 and 15 only of cycle numbers 10-18, at a dose of 20 mg/m2 on day 1 of cycle 1; at dose of 56 mg/m2 on all subsequent once weekly dosing days. The quadruple regimen treatment will be administered for 18 cycles.
Other Name: Kyprolis

Drug: Daratumumab
Daratumumab : 16 mg/Kg weekly for 8 weeks, then every 2 weeks for 16 weeks, and then every 4 weeks thereafter. The quadruple regimen treatment will be administered for 18 cycles.
Other Name: Darzalex

Drug: Lenalidomide
Lenalidomide (25 mg), administered on days 1-21 of 28-day cycle.In frail patients, Lenalidomide dose will be reduced according to 15 mg . The quadruple regimen treatment will be administered for 18 cycles.
Other Name: Revlimid

Drug: Dexamethasone
Patients will be treated with IV or oral dexamethasone (20 mg for fit and INT-FIT, 10 mg for frail), administered on Days 1-2, 8-9, 15-16, and 22-23 of each 28-day cycle for cycles 1-2 followed by weekly 20 mg dexamethasone on subsequent cycles; In frail patients, dexamethasone will be reduced to 10 mg . The quadruple regimen treatment will be administered for 18 cycles.




Primary Outcome Measures :
  1. Proportion of patients who experience any AE incidence, grade > 2 drug-elicited toxicities, peripheral neuropathy events (Grade 2 or higher). [ Time Frame: from screening through month 20 ]
    Determined by adverse events, vital signs and clinical laboratory parameters in relation to study intervention.


Secondary Outcome Measures :
  1. PFS [ Time Frame: From treatment initiation to the earlier of disease progression or death due to any cause. Up to 2 years from last patient enrollment ]
    Progression Free Survival (PFS)

  2. OS [ Time Frame: From treatment initiation to date of death (whatever the cause). Up to 2 years from last patient enrollment ]
    Overall Survival (OS)

  3. Overall response rate (ORR) [ Time Frame: From Screening and up to 2 years from last patient enrollment ]
    The fraction of patients who experience a partial response (PR), very good partial response (VGPR), complete response (CR), or stringent complete response (sCR) per IMWG 2016 criteria.

  4. Duration of response (DOR) [ Time Frame: From initiation of treatment and up to 2 years from last patient enrollment ]
    Time of first evidence of PR or better to confirmation of PD or death due to any cause

  5. Time to progression (TTP) [ Time Frame: From initiation of treatment and up to 2 years from last patient enrollment ]
    From initiation of treatment to documented PD

  6. Clinical benefit response (CBR) rate [ Time Frame: From initiation of treatment and up to 2 years from last patient enrollment ]
    Defined as ORR or minimal response (MR)

  7. Disease control rate (DCR), [ Time Frame: From initiation of treatment and up to 2 years from last patient enrollment ]
    Defined as ORR or minimal response (MR) or stable disease (SD) lasting at least 8 weeks.

  8. Changes in Global Health Status and Quality of Life [ Time Frame: From Screening and up to 2 years from last patient enrollment ]
    The European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire Module QLQ-MY20 will be used to evaluate Global Health Status/QoL. Questionnaire Module QLQ-MY20 include 20 questions (items). Score scale is starting from minimum of 1 and up to a maximum of 4. Higher values represent a worse outcome.It is the complementary module of the QLQ-C30 which is specific for Multiple Myeloma patients.

  9. Changes in Global Health Status and Quality of Life [ Time Frame: From Screening and up to 2 years from last patient enrollment ]

    The European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire Module QLQ-C30 will be used to evaluate Global Health Status/QoL. Questionnaire Module QLQ-C30 include 30 questions score scale is starting from minimum of 1 and up to a maximum of 7. In most items (1-28) Higher values represent a worse outcome.The exceptions are the items contributing to the global health status / QoL - 2 items (29-30) In which Higher values represent a better outcome .

    It incorporates five functional scales (physical, role, cognitive, emotional, and social), three symptom scales (fatigue, pain, and nausea and vomiting), a global health status / QoL scale, and a number of single items assessing additional symptoms commonly reported by cancer patients (dyspnoea, loss of appetite, insomnia, constipation and diarrhoea) and perceived financial impact of the disease.


  10. Changes in Frailty Status [ Time Frame: From Screening and up to 4 month from last patient enrollment ]

    Frailty assessment, for this study will be based only on 4 components : age, the Charlson Comorbidity Scoring System, the Katz Index of Independence in Activities of Daily Living and the Lawton Instrumental Activities of Daily Living Scale.

    All above 4 components are summed up and combined into one MM Frailty score - The score system (range 0-5, higher values represent a worse outcome), identifies 3 groups of patients:

    fit (score=0) intermediate-fitness (score=1) frail (score≥2)



Other Outcome Measures:
  1. exploratory genomic profiling [ Time Frame: From Screening and up to 2 years from last patient enrollment ]
    mutational transcriptional and post translational changes associated with drug sensitivity and resistance, clonal evolution



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:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Diagnosed with multiple myeloma and started induction therapy within 6 months prior to study entry
  2. Received bortezomib-based induction therapy, with corticosteroids, with or without alkylators
  3. Determined by investigator to be transplant-ineligible
  4. Failed to achieve a minimal response (MR) after 2 cycles or a partial response (PR), after 4 cycles of a bortezomib-containing therapy, or progress on therapy during first 4 cycles (response defined by international Myeloma Working Group [IMWG] criteria)
  5. Measurable disease at time of enrolment including:

    • Serum M-protein ≥ 0.5 g/dL, or
    • Urine M-protein ≥ 200 mg/24 hour, or
    • Serum free light chain (SFLC) ≥ 100 mg/L (involved light chain) and an abnormal serum kappa/lambda ratio, or
    • In patients with immunoglobulin A (IgA) type MM, whose disease can only be reliably measured by serum quantitative immunoglobulin (qIgA), qIgA ≥ 750 mg/dL (0.75 g/dL)
  6. Male/female, ≥ 18 years of age
  7. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-2
  8. Adequate hepatic function within 28 days prior to treatment initiation, with bilirubin < 1.5 times the upper limit of normal (ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 times the ULN
  9. Left ventricular ejection fraction ≥ 40%
  10. Absolute neutrophil count (ANC) ≥ 1500/mm3 within 28 days prior to enrollment, and reconfirmed within 7 days prior to first dose. Screening ANC should be independent of growth factor support for ≥ 1 week.
  11. Hemoglobin ≥ 8.0 g/dL within 28 days prior to treatment initiation, and reconfirmed within 7 days prior to first dose. Use of erythropoietic stimulating factors and red blood cell (RBC) transfusions per institutional guidelines is allowed, however most recent RBC transfusion may not have been done within 7 days of obtaining Screening hemoglobin.
  12. Platelet count ≥ 50,000/mm3 (≥ 30,000/mm3 if myeloma involvement in the bone marrow is > 50%) within 28 days prior of treatment initiation, and reconfirmed within 7 days prior to first dose. Patients should not have received platelet transfusions for at least 1 week prior to obtaining the Screening platelet count.
  13. Calculated or measured creatinine clearance (CrCL) of ≥ 30 mL/min within 28 days prior to treatment initiation. Calculation should be based on standard formula such as the Cockcroft and Gault: [(140 - Age) x Mass (kg) / (72 x Creatinine mg/dL)]; multiply result by 0.85 if female.
  14. Written informed consent in accordance with local regulations
  15. Females of childbearing potential (FCBP) must have a negative serum pregnancy test within 21 days prior to treatment initiation and agree to use an effective method of contraception throughout the treatment period and for 3 months following last dose. Female of childbearing potential is defined as a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).
  16. Male patients must use an effective barrier method of contraception during the treatment period and for 3 months following the last dose, if sexually active with a FCBP -

Exclusion Criteria:

  1. Prior therapy with any immunomodulatory drug (IMiD) or with Carfilzomib
  2. Any unresolved Grade 2 or higher toxicity from bortezomib based induction treatment
  3. Multiple myeloma of immunoglobulin M (IgM) subtype
  4. POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) syndrome
  5. Plasma cell leukemia or circulating plasma cells ≥ 2 × 10e9/L
  6. Waldenström macroglobulinemia
  7. Patients with known amyloidosis
  8. Focal radiation therapy within 7 days prior to treatment initiation; radiation therapy to an extended field, involving a significant volume of bone marrow, within 21 days prior to enrollment (i.e., prior radiation must have been to less than 30% of the bone marrow)
  9. Major surgery (excluding kyphoplasty) within 28 days prior to treatment initiation
  10. Active congestive heart failure (New York Heart Association [NYHA] Class III to IV), symptomatic ischemia, or conduction abnormalities uncontrolled by conventional intervention; myocardial infarction within 4 months prior to treatment initiation
  11. Acute active infection requiring systemic antibiotics, antiviral (except antiviral therapy directed at hepatitis B) or antifungal agents within 14 days prior to treatment initiation
  12. Known human immunodeficiency virus (HIV) seropositive, hepatitis C infection, and/or hepatitis B (except for patients with hepatitis B surface antigen [SAg] and core antibody receiving and responding to antiviral therapy directed at hepatitis B; these patients are allowed).
  13. Patients with known cirrhosis
  14. Second malignancy within the past 3 years except:

    A. Adequately treated basal cell or squamous cell skin cancer B. Carcinoma in situ of the cervix C. Prostate cancer Gleason score ≤ 6 with stable prostate-specific antigen (PSA) over 12 months D. Breast carcinoma in situ with full surgical resection E. Treated medullary or papillary thyroid cancer

  15. Patients with myelodysplastic syndrome
  16. Female patients who are pregnant or lactating
  17. Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize Carfilzomib)
  18. Patients with hypersensitivity to Carfilzomib,
  19. Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to antiviral drugs, or intolerance to hydration due to pre-existing pulmonary or cardiac impairment
  20. Patients with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to treatment initiation
  21. Subject has either one of the following:

    1. Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal. Note that FEV1 testing is required for subjects suspected of having COPD and subjects must be excluded if FEV1 is <50% of predicted normal.
    2. Known moderate or severe persistent asthma, within the past 2 years, uncontrolled asthma of any classification. Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate in the study.
  22. Patients who discontinued bortezomib due to bortezomib related adverse events.
  23. Any other clinically significant medical disease or psychiatric condition that, in the investigator's opinion, may interfere with protocol adherence or a patient's ability to give informed consent
  24. Any prior treatment with investigational anti-MM drugs -

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): NCT04065789


Contacts
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Contact: Yael Cohen, MD +972-3-6947655 Yaelcoh@tlvmc.gov.il
Contact: yuval piltz, MSc +972-3-6974143 yuvalp@tlvmc.gov.il

Locations
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Israel
Haemek Medical Center Recruiting
Afula, Israel
Contact: Chubar Evgeny, Dr.    972-4-6495440    chubar_ev@clalit.org.il   
Contact: Lior Hadar-Ifargan    972-4-6494052    lior_hif@clalit.org.il   
Barzilai Medical Center Recruiting
Ashkelon, Israel
Contact: Anatoly Nemetz, Dr.    972-8-6745796    anatolyn@bmc.gov.il   
Contact: Sigal Tapuhi    972-8-6745535    sigalt@bmc.gov.il   
Soroka Medical Center Recruiting
Be'er Sheva, Israel
Contact: Ori Rubio, Dr.    972-8-6403788    rubio@bgu.ac.il   
Contact: Margareta Shilo       Margarets@clalit.org.il   
Bnai-Zion Medical Center Recruiting
Haifa, Israel
Contact: Tamar Tadmor, Prof.    972-4-8359407    tamar.tadmor@b-zion.org.il   
Contact: Dana Weizer    972-4-8359405    dana.weizer@b-zion.org.il   
Carmel Medical center Recruiting
Haifa, Israel
Contact: Mouna Balan, Dr.    972-54-4345589    MounaBa@clalit.org.il   
Contact: Liat Dizingof       liatmd@clalit.org.il   
Rambam medical Center Recruiting
Haifa, Israel
Contact: Lavi Noa, Dr.    972-4-7772541    n_lavi@rambam.health.gov.il   
Contact: Naama Thsionsky    972-4-7771374    N_THSIONSKY@rambam.health.gov.il   
Hadassah Ein-Karem Medical Center Recruiting
Jerusalem, Israel
Contact: Moshe Gat, Dr.    972-2-6779268    Rmoshg@hadassah.org.il   
Contact: Reut Maimon    972-2-6779267    reutm@hadassah.org.il   
Shaare Zedek medical Center Recruiting
Jerusalem, Israel
Contact: Chezi Ganzel, Dr.    972-2-6666448    ganzelc@szmc.org.il   
Contact: Neta Dor    972-2-6555567    researchhem@szmc.org.il   
Meir Medical Center Recruiting
Kfar Saba, Israel
Contact: Osnat Jarchowsky, Dr.    972-9-7471904    osnat.jarchowsky@clalit.org.il   
Contact: Neta Shmueli    972-9-7472534    neta.shmueli@clalit.org.il   
Rabin Medical Center Recruiting
Petah tikva, Israel
Contact: Julia vaxman, Dr.    972-3-9240145    sjuliava@gmail.com   
Contact: Aviva Marsha       avivama1@clalit.org.il   
Kaplan Medical center Completed
Reẖovot, Israel
Hematology Department Sourasky Medical Center Recruiting
Tel Aviv, Israel, 6423906
Contact: Yael Cohen, MD    +972-3-6947655    Yaelcoh@tlvmc.gov.il   
Assuta Medical Center Completed
Tel Aviv, Israel
Ziv Medical Center Recruiting
Zefat, Israel
Contact: Nagib Dally, Dr.    972-54-5613114    nagib.d@ziv.health.gov.il   
Contact: Ayala Yaron       ayala.y@ziv.health.gov.il   
Sponsors and Collaborators
Tel-Aviv Sourasky Medical Center
Investigators
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Principal Investigator: Yael Cohen, MD Tel-Aviv Sourasky Medical Center

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Responsible Party: Tel-Aviv Sourasky Medical Center
ClinicalTrials.gov Identifier: NCT04065789     History of Changes
Other Study ID Numbers: 0101-17-TLV
MOH_2018-01-18_001958 ( Other Identifier: Israel MOH# )
First Posted: August 22, 2019    Key Record Dates
Last Update Posted: August 22, 2019
Last Verified: August 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 Tel-Aviv Sourasky Medical Center:
multiple myeloma (MM)
Myeloma
NDMM
RRMM
Additional relevant MeSH terms:
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Multiple Myeloma
Daratumumab
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone
Dexamethasone acetate
Lenalidomide
BB 1101
Antibodies, Monoclonal
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal