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M8891 First in Human in Solid Tumors (M8891)

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: NCT03138538
Recruitment Status : Terminated (As part of a portfolio-level management of the company's oncology pipeline, it was decided to stop the next phase of internal development of the MetAP2 (M8891) program to enable realization of other opportunities within the oncology portfolio.)
First Posted : May 3, 2017
Results First Posted : March 11, 2022
Last Update Posted : March 11, 2022
Sponsor:
Collaborator:
Merck KGaA, Darmstadt, Germany
Information provided by (Responsible Party):
EMD Serono ( EMD Serono Research & Development Institute, Inc. )

Brief Summary:
The purpose of this study was to determine the maximum tolerated dose (MTD), safety, tolerability, Pharmacokinetic (PK), pharmacodynamic and clinical activity of M8891 as single agent in participants with advanced solid tumors in Part 1.

Condition or disease Intervention/treatment Phase
Advanced Solid Tumors Metastatic Renal Cell Carcinoma Drug: Part 1: M8891 Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 27 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-label, Phase I Dose Escalation Trial of Methionine Aminopeptidase 2 Inhibitor M8891 in Subjects With Advanced Solid Tumors
Actual Study Start Date : August 8, 2017
Actual Primary Completion Date : September 16, 2020
Actual Study Completion Date : September 16, 2020


Arm Intervention/treatment
Experimental: M8891 7 mg
Participant received M8891 at dose of 7 milligrams (mg) orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study.
Drug: Part 1: M8891
Participants receives M8891 orally once daily at escalated dose levels under fasting condition for consecutive 21-day cycles of continuous treatment until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study.

Experimental: M8891 12 mg
Participant received M8891 at dose of 12 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study.
Drug: Part 1: M8891
Participants receives M8891 orally once daily at escalated dose levels under fasting condition for consecutive 21-day cycles of continuous treatment until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study.

Experimental: M8891 20 mg
Participant received M8891 at dose of 20 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study.
Drug: Part 1: M8891
Participants receives M8891 orally once daily at escalated dose levels under fasting condition for consecutive 21-day cycles of continuous treatment until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study.

Experimental: M8891 35 mg
Participant received M8891 at dose of 35 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study.
Drug: Part 1: M8891
Participants receives M8891 orally once daily at escalated dose levels under fasting condition for consecutive 21-day cycles of continuous treatment until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study.

Experimental: M8891 60 mg
Participant received M8891 at dose of 60 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study.
Drug: Part 1: M8891
Participants receives M8891 orally once daily at escalated dose levels under fasting condition for consecutive 21-day cycles of continuous treatment until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study.

Experimental: M8891 80 mg
Participant received M8891 at dose of 80 mg orally with first dose in Cycle 1 Day 1 and consist of consecutive 21-day cycles of continuous once daily M8891 monotherapy under fasting conditions until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study.
Drug: Part 1: M8891
Participants receives M8891 orally once daily at escalated dose levels under fasting condition for consecutive 21-day cycles of continuous treatment until disease progression, unacceptable toxicity, withdrawal of consent, or any criterion for withdrawal from the study.




Primary Outcome Measures :
  1. Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) Assessed Using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 4.03 [ Time Frame: At the end of Cycle 1 (each Cycle is of 21 days) ]
    A DLT was defined as the occurrence of any of following events that were judged by the study investigator, to be related to the study medication: Grade 4 liver enzyme elevation; Grade 4 neutropenia lasting >5 days or Grade >= 3 neutropenia with fever; Grade 4 thrombocytopenia lasting >5 days or Grade >=3 thrombocytopenia with clinically significant bleeding; Any treatment interruption >7 days or >30% of total dose in Cycle 1 due to AEs not related to the underlying disease or concomitant medication; Grade >=3 non-hematologic toxicity excluding Grade 3 nausea or vomiting lasting <48 hours, and resolves to <= Grade 1 either spontaneously or with medication, Grade 3 fatigue <= 3 days, Grade 3 hypertension in the absence of maximal medical therapy, Grade 3 rash <= 3 days, Grade 3 electrolyte abnormality that lasts <72 hours, is not clinically complicated, and resolves spontaneously or responds to conventional medication and Grade >=3 single lab value increase without clinical correlate.


Secondary Outcome Measures :
  1. Number of Participants With Treatment-Emergent Adverse Events (TEAE) and TEAEs Leading to Death [ Time Frame: Up to 1136 Days ]
    An Adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. TEAEs include both Serious TEAEs and non-serious TEAEs.

  2. Number of Participants With Treatment-Emergent Adverse Events (TEAE) by Severity [ Time Frame: Up to 1136 Days ]
    Severity of adverse events (AE) were assessed by the investigator according to National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) version 4.03 as Grade 1 to Grade 5. Grade 1= Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4= Life-threatening and Grade 5= Death. The number of participants that experienced at least one solicited local TEAE were summarized by grade. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. TEAEs include both Serious TEAEs and non-serious TEAEs. Number of participants with Grade >=3, >=4 and 5 were reported.

  3. Maximum Observed Plasma Concentration (Cmax) of M8891 [ Time Frame: Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days) ]
    Maximum observed plasma concentration (Cmax) was taken directly from the observed concentration-time curve.

  4. Time to Reach Maximum Observed Plasma Concentration (Tmax) of M8891 [ Time Frame: Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days) ]
    The time to reach the maximum observed plasma concentration (tmax) was obtained directly from the concentration versus time curve.

  5. Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of M8891 [ Time Frame: Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days) ]
    The AUC from time zero (= dosing time) to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification (LLOQ), calculated using the mixed log-linear trapezoidal rule (linear up, log down).

  6. Area Under the Concentration-time Curve From Zero Extrapolated to Infinity (AUC0-inf) of M8891 [ Time Frame: Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days) ]
    The AUC from time zero (dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from the determination of the terminal first order (elimination) rate constant (lambda z). AUC0-inf = AUC0-t plus Clast pred/lambda z. Lambda Z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve. Clastpred was the last predicted quantifiable concentration.

  7. Area Under the Plasma Concentration Versus Time Curve Within One Dosing Interval (AUC0-tau) of M8891 [ Time Frame: Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days) ]
    AUC (0-tau) is the area under the plasma concentration time curve within 1 dosing interval. Calculated using the mixed log linear trapezoidal rule (linear up, log down).

  8. Apparent Terminal Half Life (t1/2) of M8891 [ Time Frame: Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days) ]
    Terminal half-life of M8891 in Plasma was calculated as log2/ lambda z. Lambda z was determined from the terminal slope of the log-transformed concentration curve using linear regression on terminal data points of the curve.

  9. Terminal Elimination Rate Constant (Lambda z) of M8891 [ Time Frame: Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days) ]
    Lambda z was determined from the terminal slope of the log-transformed concentration curve using linear regression on terminal data points of the curve.

  10. Apparent Total Body Clearance (CL/f) of M8891 [ Time Frame: Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days) ]
    Apparent total body clearance of drug from plasma following extravascular administration, calculated as dose/AUC0-infinity for M8891. Area under the plasma concentration-time curve from time zero (dosing time) extrapolated to infinity of unchanged drug calculated as AUC0-t + AUCextra. AUCextra represents the extrapolated part of AUC0-infinity calculated by Clastpred/lambda z, where Clastpred is the predicted plasma concentration at the last sampling time point, calculated from the log linear regression line for lambda z determination at which the measured plasma concentration is at or above lower limit of quantification.

  11. Apparent Body Clearance of Drug Following Extravascular Administration At Steady State (CLss/f) of M8891 [ Time Frame: Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days) ]
    The apparent total body clearance of drug at steady state following extravascular administration, taking into account the fraction of dose absorbed. It is calculated as dose/AUCtau for M8891.

  12. Apparent Volume of Distribution During Terminal Phase (VZ/f) of M8891 [ Time Frame: Cycle 1 Pre-dose, 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 (Each cycle is of 21 days) ]
    Apparent volume of distribution during the terminal phase following extravascular administration for M8891 was calculated. Vz/f = Dose/(AUC0-infinity multiply by Lambda z) following single dose. The AUC from time zero (dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda z determination. AUC(0- inf)=AUC0-t plus Clastpred/lambda z where Clastpred was last predicted concentration. Lambda Z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve.

  13. Accumulation Ratios of AUC (Racc AUC) of M8891 [ Time Frame: Pre-dose and at 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 of Cycle 1 (each cycle is 21 days) ]
    Racc (AUC) is defined as the accumulation factor to assess the increase in exposure until steady state is reached. Accumulation ratio for AUC was calculated as AUC, after dosing on Day 15 divided by AUC, after dosing on Day 1 of Cycle 1.

  14. Accumulation Ratio of Cmax (Racc Cmax) of M8891 [ Time Frame: Pre-dose and at 1, 2, 3, 4, 5, 6, 8, 12, 24 hours post-dose on Day 1 and 15 of Cycle 1 (each cycle is 21 days) ]
    Accumulation ratio of Cmax was calculated as Cmax, after dosing on Day 15 divided by Cmax, after dosing on Day 1 of Cycle 1.

  15. Number of Participants With Best Overall Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria [ Time Frame: Up to 1136 Days ]
    BOR was determined according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) as assessed by investigators. BOR is defined as the best response of any of the complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from the date of randomization until disease progression. CR: Disappearance of all evidence of target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 millimeter (mm). PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD) defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SLD while on study. PD is defined as at least a 20 percent (%) increase in the SLD of target lesion, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.

  16. Number of Participants With Clinical Benefit [ Time Frame: Up to 1136 Days ]
    Clinical benefit defined as Complete Response (CR), Partial Response (PR) or Stable Disease (SD) for >= 12 weeks. Clinical benefit was assessed according to RECIST Version 1.1. CR: defined as disappearance of all target and all non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 millimeter (mm). PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. SD: defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest SLD while on study. PD is defined as at least a 20 percent (%) increase in the SLD of target lesion, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.

  17. Progression-Free Survival (PFS) [ Time Frame: Up to 1136 Days ]
    Progression-free survival (PFS) defined as the time from first study drug administration to either first observation of progressive disease (PD) (as assessed by Investigators according to RECIST v1.1) or occurrence of death due to any cause, whichever occurs first. Progressive disease (PD) defined as at least a 20% increase in sum of longest diameter (SLD) of target lesions, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. PFS was measured using Kaplan-Meier (KM) estimates. Here the 20 mg dose level was selected for stratification as the highest dose level equal to or smaller than the median of all dose levels administered to at least 1 participant.

  18. Number of Participants With Change From Baseline in Laboratory Test Abnormalities to Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 [ Time Frame: Up to 1136 Days ]
    The laboratory measurements included hematology, biochemistry, and urinalysis values were graded with National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 toxicity grades (where Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening and Grade 5 = death). Number of participants with change from baseline to grade 3 or higher values for the hematology, biochemistry and urinalysis parameters were reported.

  19. Number of Participants With Clinically Meaningful Changes From Baseline in Vital Signs [ Time Frame: Up to 1136 Days ]
    Vital sign assessments included assessments of heart rate, diastolic blood pressure, systolic blood pressure, weight, respiratory rate and temperature. Clinical relevance was assessed by the investigator. Number of participants who had any clinically meaningful change from baseline in vital signs were reported.

  20. Number of Participants With Clinically Meaningful Changes From Baseline in Electrocardiogram (ECG) Values [ Time Frame: Up to 1136 Days ]
    ECG parameters included rhythm, heart rate (as measured by RR interval), PR interval, QRS duration, QT intervals, and corrected QT(QTc) intervals. Clinical significance was determined by the investigator. Number of participants with clinically meaningful change from baseline in 12-lead ECG were reported.

  21. Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PF) Score of 2 or Higher Than 2 [ Time Frame: Up to 1136 Days ]
    ECOG PS score is widely used by doctors and researchers to assess how a participants' disease is progressing, and is used to assess how the disease affects the daily living abilities of the participant, and determine appropriate treatment and prognosis. The score ranges from Grade 0 to Grade 5, where Grade 0 = Fully active, able to carry on all pre-disease performance without restriction, Grade 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (like light house work, office work), Grade 2 = Ambulatory and capable of all self-care but unable to carry out any work activities, Grade 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours and Grade 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair, Grade 5 = Death. Number of participants with ECOG performance status score of 2 or higher than 2 were reported.

  22. Percentage of Participants With Objective Response [ Time Frame: Up to 1136 Days ]
    Objective response is defined as the percentage of participants with complete response (CR) and partial response (PR). CR is defined as disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions.



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:

  • Participants must be refractory to or intolerant of existing cancer therapy(ies) known to provide clinical benefit.
  • Histologically confirmed advanced solid tumors with no clear curative treatment options available after at least 1 prior systemic anticancer therapy.
  • Tumor accessible for biopsies and agreement to conduct pre-dose and post-dose fresh tumor biopsies.
  • Male or female subjects at least 18 years of age
  • Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1 at Screening
  • Histologic or cytologic evidence/proven of metastatic renal cell carcinoma (mRCC) with clear cell component
  • Part 2A: Participants should have progressed to 1 or more previous lines of systemic anticancer therapy, excluding treatment with cabozantinib
  • Part 2B: Participants should have progressed to 1 or 2 previous lines of systemic anticancer therapy, excluding treatment with cabozantinib. Participants should have failed to only 1 previous TKI for metastatic disease. Adjuvant therapy with sunitinib will be considered as 1 line of therapy for metastatic disease in the case that disease progression occurs during or within 3 months of the completion of the treatment.
  • Other protocol defined inclusion criteria could apply

Exclusion Criteria:

  • ECOG PS >= 2
  • Extensive prior radiotherapy on more than 30% of bone marrow reserves, or prior bone marrow/stem cell transplantation within 5 years of study start.
  • Severe bone marrow, renal or liver impairment.
  • Tumor in contact with, invading or encasing major blood vessels or radiographic evidence of significant cavitary pulmonary lesions
  • Uncontrolled hypertension defined as sustained Blood Pressure (BP) > 150 millimeters of mercury (mm Hg) systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment
  • Participant is pregnant or breastfeeding
  • Part 2A and 2B: Previous use of cabozantinib or a MetAP2 inhibitor, tumor in contact with invading or encasing major blood vessels or radiographic evidence of significant cavitary pulmonary lesions
  • Other protocol defined exclusion criteria could apply

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): NCT03138538


Locations
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United States, Connecticut
Smilow Cancer Hospital - Yale
New Haven, Connecticut, United States, 06510
United States, Indiana
Indiana University Health Hospital
Indianapolis, Indiana, United States, 46202
United States, Maryland
Sidney Kimmel Cancer Center - Johns Hopkins
Baltimore, Maryland, United States, 21205-1911
United States, Michigan
Henry Ford Health System
Detroit, Michigan, United States, 48202
United States, Nebraska
Nebraska Cancer Specialists
Omaha, Nebraska, United States, 68130
United States, Nevada
Comprehensive Cancer Centers of Nevada
Las Vegas, Nevada, United States, 89169
United States, New Jersey
Rutgers Cancer Institute of New Jersey
New Brunswick, New Jersey, United States, 08901
Sponsors and Collaborators
EMD Serono Research & Development Institute, Inc.
Merck KGaA, Darmstadt, Germany
Investigators
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Study Director: Medical Responsible EMD Serono Research & Development Institute, Inc., a business of Merck KGaA, Darmstadt, Germany
  Study Documents (Full-Text)

Documents provided by EMD Serono ( EMD Serono Research & Development Institute, Inc. ):
Study Protocol  [PDF] March 11, 2020
Statistical Analysis Plan  [PDF] April 20, 2018

Additional Information:
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Responsible Party: EMD Serono Research & Development Institute, Inc.
ClinicalTrials.gov Identifier: NCT03138538    
Other Study ID Numbers: MS100015_0019
First Posted: May 3, 2017    Key Record Dates
Results First Posted: March 11, 2022
Last Update Posted: March 11, 2022
Last Verified: December 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Per company policy, following approval of a new product or a new indication for an approved product in both the EU and the US, EMD Serono will share study protocols, anonymized patient level and study level data and redacted clinical study reports from clinical trials in patients with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website https://www.emdgroup.com/en/research/our-approach-to-research-and-development/healthcare/clinical-trials/commitment-responsible-data-sharing.html

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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 EMD Serono ( EMD Serono Research & Development Institute, Inc. ):
Advanced Solid Tumors
Metastatic Renal Cell Carcinoma
M8891
Methionine Aminopeptidase 2 Inhibitor
Additional relevant MeSH terms:
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Carcinoma, Renal Cell
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases