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Study to Assess Enzastaurin + R-CHOP in Subjects With DLBCL With the Genomic Biomarker DGM1™

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. Identifier: NCT03263026
Recruitment Status : Recruiting
First Posted : August 28, 2017
Last Update Posted : April 19, 2019
Information provided by (Responsible Party):
Denovo Biopharma LLC

Brief Summary:
This randomized, placebo-controlled phase 3 study is planned to enroll approximately 235 treatment-naïve subjects with high-risk Diffuse Large B-Cell Lymphoma (DLBCL). Subjects will be randomized 1:1 to R-CHOP plus enzastaurin or R CHOP (plus placebo during induction). All subjects will receive up to 6 cycles (3 weeks per cycle) of treatment. PET/ CT will be used to assess radiographic response at the end of treatment. Each subject's treatment assignment will be unblinded after initial phase of treatment. Subjects randomized to the enzastaurin arm who have a response will be offered maintenance treatment of the study drug for up to 2 additional years.

Condition or disease Intervention/treatment Phase
Diffuse Large B-Cell Lymphoma Drug: Enzastaurin Hydrochloride Other: R-CHOP + placebo Phase 3

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Detailed Description:

Diffuse Large B-Cell Lymphoma (DLBCL) is the most common of the Non-Hodgkin's Lymphomas, accounting for between 30%-40% of all cases. The incidence of DLBCL generally increases with age and roughly half of all patients are over the age of 60 at the time of diagnosis.

DLBCL is classified as an aggressive lymphoma meaning that its clinical course can progress rapidly to death. Nevertheless, patients with DLBCL can be cured with the appropriate treatment. The current standard of care treatment for DLBCL consists of rituximab added to the anthracycline-containing combination chemotherapy regimen of cyclophosphamide, doxorubicin, vincristine and prednisone (NCCN Treatment Guidelines). This regimen is referred to as R-CHOP immunochemotherapy. For DLBCL as a whole, R-CHOP immunochemotherapy has resulted in cure rates of approximately 60%. However, for individual patients 5-year survival rates can range from 90% for low-risk patients to less than 50% for high-risk patients.

Most important, for those subjects refractory to R-CHOP therapy less than 10% achieve a durable remission with secondary therapy. Thus, while R-CHOP remains the standard treatment for high-risk, advanced-stage DLBCL, approximately 30-40% of patients fail front-line therapy with most not achieving complete response or with early relapse. An essential step to move forward and improve the outcomes of these patients is to increase the rate of complete response to front-line R-CHOP therapy.

For this reason, there has been a great deal of effort placed on attempting to define disease characteristics that predispose patients to a poorer prognosis with R-CHOP therapy. Molecular and gene expression profiling of tumors and a variety of clinical prognostic indices have been used to identify patients at higher risk of failing R-CHOP immunochemotherapy. While this work has identified subgroups of patients who do not respond well to R-CHOP, to date these efforts have not resulted in substantial gains in response to front-line therapy.

Denovo Biopharma (Denovo) has pioneered an alternative approach to this challenging problem. Denovo has developed a model that employs sophisticated pharmacogenomic testing to detect somatic biomarkers that identify those subjects who responded to a particular study treatment with the aim of re-studying the drug of interest, in this case enzastaurin, in an enriched population.

Applying this technology to archived DNA samples from completed studies of enzastaurin in subjects with DLBCL, Denovo has identified a somatic biomarker that reliably identified subjects for whom the study treatment significantly prolonged survival. Enzastaurin is an oral serine/threonine kinase inhibitor, that targets the PKC, and phosphoinositide 3-kinase (PI3K) and AKT pathways to inhibit tumor cell proliferation, induce tumor cell apoptosis, and suppress tumor-induced angiogenesis.

The purpose of the current study is to prospectively assess the effect on survival of adding enzastaurin to R-CHOP immunochemotherapy in the front-line treatment of an enriched population of subjects with DLBCL.

Enzastaurin, an acyclic bisindolylmaleimide, is a potent and selective inhibitor of PKC-beta. At plasma concentrations achieved clinically, enzastaurin and its metabolites suppress signaling not only through PKC, but also through the PI3K/AKT pathway; these pathways promote tumor-induced angiogenesis, as well as tumor cell survival and proliferation. Accordingly, inhibition of signaling pathways by enzastaurin suppresses the phosphorylation of glycogen synthase kinase 3 beta (GSK3-beta) at ser9, induces cell death (apoptosis), and suppresses proliferation in cultured cell lines from human colon cancers, glioblastoma and lymphomas. Oral dosing with enzastaurin to achieve exposure levels similar to that in human clinical studies suppresses vascular endothelial growth factor (VEGF)-induced angiogenesis and the growth of human colon cancer and glioblastoma xenografts. These studies have demonstrated that enzastaurin can suppress tumor growth through multiple mechanisms: the direct effect of inducing tumor cell death, suppressing tumor cell proliferation, and the indirect effect of suppressing tumor-induced angiogenesis.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 235 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Subjects will be randomly assigned to receive one of the following: R-CHOP plus enzastaurin or R-CHOP plus placebo, during two treatment periods: induction and maintenance. Induction phase: all subjects will receive R-CHOP for up to six, 21-day cycles. Subjects in the enzastaurin arm will receive a 1125 mg loading dose on Day 2 followed by 500 mg daily. Subjects in the placebo arm will take an identical number of tablets.

After 4-<6 cycles of induction therapy treatment assignment will be unblinded. Subjects in the enzastaurin arm who have achieved a response will have the opportunity to continue in the single-agent, maintenance phase of the study, and will receive single-agent enzastaurin at 500 mg/day for up to 2 years. Eligible subjects must begin the maintenance phase of the study within 6 weeks of completing induction therapy.

Masking: Triple (Participant, Care Provider, Investigator)
Masking Description: Denovo Biopharma, the study Sponsor, will also be blinded.
Primary Purpose: Treatment
Official Title: A Randomized Phase 3 Study to Evaluate the Efficacy and Safety of Enzastaurin Plus R-CHOP Versus R-CHOP in Treatment-Naive Subjects With High-Risk Diffuse Large B-Cell Lymphoma Who Possess the Novel Genomic Biomarker DGM1™
Actual Study Start Date : March 20, 2018
Estimated Primary Completion Date : October 2020
Estimated Study Completion Date : September 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arm Intervention/treatment
Active Comparator: R-CHOP + enzastaurin hydrochloride
Subjects in the R-CHOP + enzastaurin Arm will receive R-CHOP (Rituximab-375 mg/m2 i.v., Cyclophosphamide-750 mg/m2 i.v., Doxorubicin-50 mg/m2 i.v., Vincristine-1.4 mg/m2 i.v. (2 mg max), and Prednisone-100 mg p.o.), as directed, plus a 1125 mg loading dose of enzastaurin on Day 2 followed by 500 mg daily.
Drug: Enzastaurin Hydrochloride
R-CHOP + Enzastaurin (Kinenza®) 125 mg
Other Name: Kinenza®

Placebo Comparator: R-CHOP + placebo
Subjects in the R-CHOP + placebo Arm will receive R-CHOP (Rituximab-375 mg/m2 i.v., Cyclophosphamide-750 mg/m2 i.v., Doxorubicin-50 mg/m2 i.v., Vincristine-1.4 mg/m2 i.v. (2 mg max), and Prednisone-100 mg p.o.), as directed, plus an identical number of tablets as the subjects in the enzastaurin Arm.
Other: R-CHOP + placebo
R-CHOP + placebo
Other Name: Placebo

Primary Outcome Measures :
  1. Overall survival in subjects who possess the DGM1™ biomarker [ Time Frame: 3.5 years ]
    The primary objective of this study is to compare the effect of R-CHOP/enzastaurin versus R-CHOP alone on overall survival in treatment naive, high-risk subjects with DLBCL who possess the DGM1™ biomarker.

Secondary Outcome Measures :
  1. Overall survival in subjects who do not possess the DGM1™ biomarker [ Time Frame: 3.5 years ]
    A secondary objective of this study is to compare the effect of R-CHOP/enzastaurin versus R-CHOP alone on overall survival in treatment naive, high-risk subjects with DLBCL who do not possess the DGM1™ biomarker.

  2. Safety of enzastaurin by assessing incidence of adverse events/serious adverse events, change of vital signs, ECG results, lab results, and physical exam findings from baseline [ Time Frame: 3.5 years ]

    The safety analysis will include the following:

    • Summary of extent of exposure
    • Summary of the number of blood transfusions required
    • Summary of adverse events, serious adverse events, and subjects discontinuing for adverse events rates
    • Summary of laboratory findings and change from baseline
    • Summary of QTc data and change from baseline according to ICH E14
    • Summary of other relevant safety observations
    • Listings of laboratory and non-laboratory adverse events by maximum CTCAE grade and relationship to study drug using CTCAE v4.03

Other Outcome Measures:
  1. Presence of chromaturia as a predictor of efficacy [ Time Frame: 3.5 years ]
    Urine color will be analyzed by the central lab and overall survival will be determined for subjects with reddish discoloration of the urine. Testing may be performed to define the chemical profile of the urine.

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

Inclusion Criteria

  1. Male or female at least 18 years of age and able to provide informed consent.
  2. Histologically-confirmed diagnosis of CD20-positive DLBCL based on the WHO classification (2016); the diagnosis must be confirmed at the enrolling site. Subjects with high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements and high-grade B-cell lymphoma, NOS are eligible.
  3. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
  4. International Prognostic Index (IPI) score of at least 3.
  5. Estimated life expectancy of at least 12 weeks.
  6. Adequate organ function as follows (within 14 days prior to randomization):

    1. Hepatic: total bilirubin ≤1.5 times upper limit of normal (ULN); alanine transaminase (ALT) and aspartate transaminase (AST) ≤1.5 times ULN (<5 times ULN if liver involvement)
    2. Renal: creatinine clearance of >50 mL/min by Cockcroft- Gault equation
    3. Bone marrow: platelets ≥75 x 109/L, absolute neutrophil count (ANC) ≥1.5 x 109/L, hemoglobin ≥10 g/dL. (Platelets ≥50 x 109/L, ANC ≥1.0 x 109/L, hemoglobin ≥8 g/dL permitted if documented bone marrow involvement)
  7. Male or female with reproductive potential, must be willing to use an approved contraceptive method (for example, intrauterine device (IUD), birth control pills, or barrier device) during and for 3 months after discontinuation of study treatment. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to randomization.

    1. Men are considered of reproductive potential unless they have undergone a vasectomy and confirmed sterile by a post-vasectomy semen analysis.
    2. Women are considered of reproductive potential unless they have undergone hysterectomy and/or surgical sterilization (at least 6 weeks following a bilateral oophorectomy, bilateral tubal ligation, or bilateral tubal occlusive procedure that has been confirmed in accordance with the device's label) or achieved postmenopausal status (defined as cessation of regular menses for greater than 12 consecutive months in women at least 45 years of age).
  8. Left ventricular ejection fraction ≥50% by echocardiography or nuclear medicine multi-gated scan.
  9. Must be able to swallow tablets.
  10. Must be able to comply with study protocol procedures.
  11. Willing to consent to have blood stored for possible future biomarker and disease analysis.
  12. Must have available and willing to submit pre-systemic treatment DLBCL tumor biopsy tissue/slides for central pathology review.

Exclusion Criteria

  1. Received treatment with an investigational drug within the last 30 days.
  2. Receiving or has received radiation or any other systemic anticancer treatment for lymphoma (Up to 7 days of corticosteroids are permitted but must be administered after eligibility IPI determination and imaging scans).
  3. History of indolent lymphoma or follicular Grade 3b lymphoma.
  4. Primary mediastinal (thymic) large B-cell lymphoma.
  5. B-cell lymphoma, unclassifiable, with features. intermediate between DLBCL and classical Hodgkin lymphoma.
  6. Burkitt lymphoma.
  7. Pregnancy or breastfeeding.
  8. Known central nervous system (CNS) involvement.
  9. Any significant concomitant disorder based on the discretion of the investigator, including but not limited to active bacterial, fungal, or viral infection, incompatible with participation in the study.
  10. A second primary malignancy (except adequately treated non-melanoma skin cancer); subjects who have had another malignancy in the past, but have been disease-free for more than 5 years, and subjects who have had a localized malignancy treated with curative intent and disease free for more than 2 years are eligible.
  11. Use of a strong inducer or moderate or strong inhibitor of CYP3A4 within 7 days prior to start of study therapy or expected requirement for use on study therapy.
  12. Personal or immediate family history of long QT syndrome, QTc interval >450 msec (males) or >470 msec (females) at screening (recommended that QTc be calculated using Fridericia correction formula, QTcF: see Section 6.2.1), or a history of unexplained syncope.
  13. Use of any medication that can prolong the QT/QTc interval within 7 days prior to start of study therapy or expected requirement for use on study therapy.
  14. History of severe allergic or anaphylactic reaction to monoclonal antibody therapy.
  15. Confirmed diagnosis of progressive multifocal leukoencephalopathy.
  16. Ongoing grade 2 or higher peripheral neuropathy.
  17. Have any of the following cardiac disorders: uncontrolled hypertension, unstable angina, myocardial infarction within 8 weeks of Day1, NYHA Grade 2 or higher congestive heart failure, ventricular arrhythmia requiring medication within 1 year of Day 1, NYHA Grade 2 or higher peripheral vascular disease.
  18. Received a live vaccine within 28 days of study Day 1.
  19. HIV positive.
  20. Evidence of chronic hepatitis C infection as indicated by antibody to HCV with positive HCV-RNA.
  21. Evidence of chronic hepatitis B infection as indicated by either:

    1. HBsAg+ or
    2. HBcAb+ with HBV-DNA+ (any detectable amount is considered positive)

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 identifier (NCT number): NCT03263026

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Contact: Ron Shazer, MD 1.858.799.1021 ext 709
Contact: Steve Haynes 910-350-2306

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United States, Alabama
Oncology Specialties: Clearview Cancer Institute Recruiting
Huntsville, Alabama, United States, 35805
Contact: Brian Matthews, MD         
United States, Arkansas
Central Arkansas Radiation Therapy Institute Recruiting
Little Rock, Arkansas, United States, 72205
Contact: Kamal Patel, Dr    501-906-3012   
United States, Colorado
Centura Health Corporation Recruiting
Denver, Colorado, United States, 80210
United States, Delaware
Christiana Care Health Services, Inc Recruiting
Newark, Delaware, United States, 19713
Contact: Michael Guarino, Dr   
United States, Illinois
Loyola University Medical Center Not yet recruiting
Maywood, Illinois, United States, 60153
Illinois CancerCare Recruiting
Peoria, Illinois, United States, 61615
Contact: Madhuri Bajaj, PhD         
Orchard Healthcare Research Recruiting
Skokie, Illinois, United States, 60077
Contact: Ira Oliff, Dr.    224-534-7580   
United States, Indiana
Indiana University Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Michael Robertson, MD         
United States, Kentucky
Norton Cancer Institute Oncology Practices - St. Matthews Location Recruiting
Louisville, Kentucky, United States, 40241
Contact: Joseph Maly, MD         
United States, Maryland
Regional Cancer Care Associates, MD Recruiting
Bethesda, Maryland, United States, 20817
Contact: Ralph Boccia, MD         
United States, Minnesota
Minnesota Oncology Hematology Allina Health, Virginia Piper Cancer Institute Recruiting
Minneapolis, Minnesota, United States, 55407
Contact: Michaela Tsai, Dr         
United States, Missouri
Saint Louis University Recruiting
Saint Louis, Missouri, United States, 63104
Contact: Mark Fesler, Dr.   
Mercy Research Recruiting
Springfield, Missouri, United States, 65806
Contact: Bethany Sleckman, PhD         
United States, Nevada
Comprehensive Cancer Centers of Nevada Recruiting
Las Vegas, Nevada, United States, 89169
Contact: Edwin Kingsley, Dr   
United States, New Hampshire
Norris Cotton Cancer Center Dartmouth-Hitchcock Medical Center Recruiting
Lebanon, New Hampshire, United States, 03766
Contact: Frederick Lansigan, Dr   
United States, New Jersey
Summit Medical Group Recruiting
Morristown, New Jersey, United States, 07960
Contact: Benjamin B Freeman         
United States, New Mexico
San Juan Oncology Associates Recruiting
Farmington, New Mexico, United States, 87401
Contact: Sardar Imam, PhD         
United States, New York
New York Medical College Recruiting
Hawthorne, New York, United States, 10595
Contact: DeLong Liu, MD         
Laura & Isaac Perlmutter Cancer Center at NYU Langone Medical Center Recruiting
New York, New York, United States, 10016
Contact: Catherine Diefenbach, MD         
Icahn School of Medicine at Mount Sinai Recruiting
New York, New York, United States, 10029
Contact: Joshua Brody, PhD         
Contact: Monica Toscano    212-824-7302   
United States, North Carolina
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
Wake Forest University Baptist Medical Center Recruiting
Winston-Salem, North Carolina, United States, 27157
United States, Ohio
Hematology & Oncology Associates, Inc. Recruiting
Canton, Ohio, United States, 44708
Contact: Mitchell Haut, Dr   
Mid Ohio Oncology/Hematology Inc. Recruiting
Columbus, Ohio, United States, 43219
Contact: Mark Knapp, Dr   
Tri-County Hematology & Oncology Associates, Inc. Recruiting
Massillon, Ohio, United States, 44646
Contact: Norman Rafique, Dr   
Toledo Clinic Cancer Centers Recruiting
Toledo, Ohio, United States, 43623
Contact: Rex Mowat, MD         
United States, Oregon
Providence Portland Medical Center Recruiting
Portland, Oregon, United States, 97213
Contact: John Godwin, MD         
United States, South Carolina
Gibbs Cancer Center Recruiting
Spartanburg, South Carolina, United States, 29303
United States, South Dakota
Avera Cancer Institute Recruiting
Sioux Falls, South Dakota, United States, 57105
Contact: Kelly McCaul, Dr         
United States, Texas
University of Texas Southwestern Medical Center - Harold C. Simmons Comprehensive Cancer Center Recruiting
Dallas, Texas, United States, 75235
Baylor Scott and White University Medical Center Recruiting
Dallas, Texas, United States, 75246
Contact: Moshe Levy, MD         
Brooke Army Medical Center Recruiting
Fort Sam Houston, Texas, United States, 78234
Contact: Russell Baur, MD         
Oncology Consultants: Memorial City Recruiting
Houston, Texas, United States, 77024
Contact: Julio Peguero, MD         
Baylor College of Medicine (BCM) - Baylor Clinic Recruiting
Houston, Texas, United States, 77030
Contact: Martha Mims, Dr   
United States, Virginia
Hematology-Oncology Associates of Fredericksburg, Inc Recruiting
Fredericksburg, Virginia, United States, 22408
Contact: Matthew Whitehurst, MD         
United States, Washington
Virginia Mason Medical Center Recruiting
Seattle, Washington, United States, 98101
Contact: David Aboulafia, PhD         
Seattle Cancer Center Alliance Recruiting
Seattle, Washington, United States, 98109
United States, Wisconsin
University of Wisconsin Hospital and Clinics Recruiting
Madison, Wisconsin, United States, 53792
Contact: Julie Chang, Dr   
Vince Lombardi Cancer Center (Aurora St. Luke's Medical Center) Recruiting
Milwaukee, Wisconsin, United States, 53215
Beijing Cancer Hospital Recruiting
Beijing, China, 100142
Contact: Jun Zhu, PhD         
Peking University Third Hospital (Hematology Dept) Not yet recruiting
Beijing, China, 100191
JiLin Cancer Hospital(Lymphoma hematology Dept) Not yet recruiting
Changchun, China, 130012
West China Hospital of Sichuan University (Hematology Dept) Not yet recruiting
Chengdu, China, 637400
Second Affiliated Hospital of Dalian Medical University Recruiting
Dalian, China, 116044
Contact: Yang ZHANG, PhD         
Fujian Medical University Union Hospital Not yet recruiting
Fuzhou, China, 350001
GuangDong General Hospital Recruiting
Guangzhou, China, 510080
Contact: Wenyu LI, PhD         
ZheJiang Cancer Hospital ( Lymphoma Dept) Recruiting
Hangzhou, China, 310022
Contact: HaiYan Yang, MD         
Harbin Medical University Cancer Hospital (Oncology Internal) Recruiting
Harbin, China, 150081
Contact: QingYuan Zhang, PhD         
Fudan University Shanghai Cancer Hospital Recruiting
Shanghai, China, 200032
Contact: Junning Cao, PhD         
Fourth Hospital of Hebei Medical University Not yet recruiting
Shijiazhuang, China, 050011
Tianjin Medical University Cancer Institute and Hospital Recruiting
Tianjin, China, 300060
Contact: HuiLai Zhang, PhD         
The First Affiliated Hospital of Medical School of Zhejiang University (Hematology Dept) Recruiting
Zhejiang, China, 310058
Contact: Jie Jing, MD         
HeNan Cancer Hospital (Hematology Dept) Recruiting
Zhengzhou, China, 450003
Contact: YongPing SONG, MD         
The First Affiliated Hospital of ZhengZhou University (Oncology Dept) Recruiting
Zhengzhou, China, 450052
Contact: MingZhi ZHANG, PhD         
Sponsors and Collaborators
Denovo Biopharma LLC
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Study Director: Ron Shazer, MD Denovo Biopharma LLC

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Responsible Party: Denovo Biopharma LLC Identifier: NCT03263026     History of Changes
Other Study ID Numbers: DB102-02
First Posted: August 28, 2017    Key Record Dates
Last Update Posted: April 19, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Denovo Biopharma LLC:
Non-Hodgkin's Lymphoma
Additional relevant MeSH terms:
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Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Anti-Inflammatory Agents
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents, Phytogenic