BNC105P in Combination With Everolimus/Following Everolimus For Progressive Metastatic Clear Cell Renal Cell Carcinoma

Phase I/II Study of BNC105P in Combination With Everolimus or Following Everolimus For Progressive Metastatic Clear Cell Renal Cell Carcinoma Following Prior Tyrosine Kinase Inhibitors

The purpose of this study is to determine whether BNC105P in combination with/following everolimus is effective in the treatment of progressive metastatic clear cell renal cell carcinoma following prior tyrosine kinase inhibitors.

Study Overview

• Status: Completed
• Conditions: Renal Cell Carcinoma
• Intervention / Treatment: Drug: Everolimus; Drug: BNC105P

Detailed Description

OUTLINE: This is a multi-center study.

Phase I: Patients will be accrued in the classic 3 patients per dose per cohort design, 21-day cycle

• Dose Level 1 Everolimus 10 mg BNC105P 4.2 mg/m2
• Dose Level 2 Everolimus 10 mg BNC105P 8.4 mg/m2
• Dose Level 3 Everolimus 10 mg BNC105P 12.6 mg/m2
• Dose Level 4 Everolimus 10 mg BNC105P 16 mg/m2

Phase II: Patients will be randomized 1:1 to Arm A or Arm B

Combination Arm A: Everolimus 10 mg + BNC105P MTD (from Phase 1 study) 21 day cycle

Sequential Arm B: Everolimus 10 mg 21 day cycle

• Patients to receive BNC105P monotherapy at 16 mg/m2 following progression or intolerable toxicity on everolimus therapy.

Karnofsky Performance Score (KPS) ≥70 within 7 days prior to registration for protocol therapy.

Life Expectancy: Not specified

Hematopoietic:

• White blood cell count (WBC) > 3.5 K/mm3
• Hemoglobin (Hgb) > 8.5 g/dL
• Platelets > 100 K/mm3
• Absolute neutrophil count (ANC) > 1.5 K/mm3

Hepatic:

• Total Bilirubin < 1.25 x ULN
• Aminotransferase (AST and ALT) < 2.5 x ULN

Renal:

• Serum Creatinine < 2.5 x ULN (upper limit normal)

Cardiovascular:

• No significant cardiovascular events within 6 months (CVA, CAD, peripheral arterial obstruction, arrhythmias, cardiac dysfunction) of registration for protocol therapy
• No history of clinical CHF or LVEF <50% by Echo (or MUGA) within 30 days prior to registration for protocol therapy.

• Study Type: Interventional
• Enrollment (Actual): 154
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Royal Prince Alfred Hospital: Sydney Cancer Centre
    • Randwick, New South Wales, Australia, 2031
      • Prince of Wales Hospital
    • Wahroonga, New South Wales, Australia, 2076
      • Sydney Adventist Hospital Ltd.
  • Queensland
    • Greenslopes, Queensland, Australia, 4120
      • Gallipoli Medical Research Foundation: Greenslopes Private Hospital
    • Herston, Queensland, Australia, 4029
      • Royal Brisbane & Women's Hospital
    • Woolloongabba, Queensland, Australia, 4201
      • Princess Alexandra Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital
    • Kurralta Park, South Australia, Australia, 5037
      • Ashford Cancer Centre
  • Tasmania
    • Launceston, Tasmania, Australia, 7250
      • Gallipoli Medical Research Foundation: Launceston General Hospital
  • Victoria
    • Frankston, Victoria, Australia, 3199
      • Peninsula Oncology Centre
    • Heidelberg, Victoria, Australia, 3084
      • Austin Hospital
    • Melbourne, Victoria, Australia, 3004
      • Alfred Hospital
  • Western Australia
    • Perth, Western Australia, Australia, 6000
      • Royal Perth Hospital
• Singapore
  • Singapore, Singapore, 169610
    • National Cancer Centre Singapore
• United States
  • Alabama
    • Muscle Shoals, Alabama, United States, 35661
      • Northwest Alabama Cancer Center
  • Arkansas
    • Hot Springs, Arkansas, United States, 71913
      • Genesis Cancer Center
  • California
    • Burbank, California, United States, 91505
      • Providence Health System: Roy and Patricia Disney Family Cancer Center
    • Corona, California, United States, 92879
      • Compassionate Cancer Care Medical Group, Inc.
    • Corona, California, United States, 92879
      • Compassionate Cancer Care Medical Group
    • Duarte, California, United States, 91010
      • City of Hope
    • Fountain Valley, California, United States, 92708
      • Robert A. Moss, M.D., FACP, Inc.
    • Fresno, California, United States, 93720
      • California Cancer Associates for Research and Excellence
    • Greenbrae, California, United States, 94904
      • Marin Specialty Care
    • Los Angeles, California, United States, 90017
      • Good Samaritan Hospital
    • Los Angeles, California, United States, 90095
      • UCLA Med - Hematology & Oncology
    • Riverside, California, United States, 92501
      • Compassionate Cancer Care Medical Group
    • Whittier, California, United States, 90603
      • American Institute of Research
  • Colorado
    • Denver, Colorado, United States, 80210
      • Centura Health Research Center
    • Golden, Colorado, United States, 80401
      • Western Oncology & Hematology
  • Florida
    • Brooksville, Florida, United States, 34613
      • Cancer Care Centers of Florida: Brooksville
    • Fort Lauderdale, Florida, United States, 33308
      • Broward Oncology Associates
    • Gainesville, Florida, United States, 32610
      • University of Florida, Shands Cancer Center
    • Jacksonville, Florida, United States, 32256
      • Cancer Specialists of North Florida
    • Miami, Florida, United States, 33136
      • Advanced Pharma CR, LLC
    • New Port Richey, Florida, United States, 34652
      • Cancer Care Centers of Florida
    • Ocala, Florida, United States, 34471
      • Ocala Cancer Institute
    • Rockledge, Florida, United States, 32955
      • Cancer Care Centers of Brevard
  • Georgia
    • Athens, Georgia, United States, 30607
      • Northeast Georgia Cancer Care, LLC
    • Dublin, Georgia, United States, 31021
      • Dublin Hematology & Oncology Care
  • Idaho
    • Post Falls, Idaho, United States, 83854
      • Kootenai Cancer Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University, Robert H. Lurie Comprehensive Cancer Center
    • Galesburg, Illinois, United States, 61401
      • Medical & Surgical Specialists, LLC
    • Skokie, Illinois, United States, 60076
      • Edward H. Kaplan, M.D., & Associates
  • Indiana
    • Evansville, Indiana, United States, 47713
      • Deaconess Clinic
    • Fort Wayne, Indiana, United States, 46815
      • Fort Wayne Oncology & Hematology, Inc
    • Goshen, Indiana, United States, 46527
      • IU Health Goshen
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Melvin and Bren Simon Cancer Center
    • Indianapolis, Indiana, United States, 46219
      • IU Health Central Indiana Cancer Centers
    • Indianapolis, Indiana, United States, 46256
      • Community Regional Cancer Center
    • Lafayette, Indiana, United States, 47905
      • Horizon Oncology Research
    • Muncie, Indiana, United States, 47303
      • IU Health at Ball Memorial Hospital Cancer Center
    • Munster, Indiana, United States, 46321
      • Monroe Medical Associates
    • Newburgh, Indiana, United States, 47630
      • Oncology Hematology Associates of SW Indiana
    • South Bend, Indiana, United States, 46601
      • Northern Indiana Cancer Research Consortium
  • Iowa
    • Sioux City, Iowa, United States, 51101
      • Siouxland Hematology Oncology Associates, LLP, Nylen Cancer Center
  • Kansas
    • Wichita, Kansas, United States, 67214
      • Cancer Center of Kansas
  • Kentucky
    • Hazard, Kentucky, United States, 41701
      • Kentucky Cancer Clinic
    • Paducah, Kentucky, United States, 42001
      • Purchase Cancer Group
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70809
      • Medical Oncology LLC
    • Metairie, Louisiana, United States, 70006
      • Metairie Oncologists
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48106
      • St. Joseph Mercy Hospital
    • Grand Rapids, Michigan, United States, 49546
      • Cancer and Hematology Centers of Western Michigan
    • Wyoming, Michigan, United States, 49519
      • Metro Health Cancer Care
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Montana
    • Bozeman, Montana, United States, 59715
      • Bozeman Deaconness Cancer Center
    • Great Falls, Montana, United States, 59405
      • Sletten Cancer Specialists
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Methodist Cancer Center
  • New Hampshire
    • Manchester, New Hampshire, United States, 03102
      • Dartmouth-Hitchcock Medical Center
  • New Jersey
    • Elizabeth, New Jersey, United States, 07202
      • Trinitas Regional Medical Center
    • Somerville, New Jersey, United States, 08876
      • Somerset Hematology Oncology Associates
  • New Mexico
    • Albuquerque, New Mexico, United States, 87110
      • Presbyterian Medical Group
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico Cancer Center: Albuquerque
  • New York
    • Albany, New York, United States, 12208
      • New York Oncology Hematology, PC
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • Lake Success, New York, United States, 11042
      • NYU Langone Arena Oncology
    • New York, New York, United States, 10029
      • Tisch Cancer Institute at Mount Sinai Medical Center
    • Nyack, New York, United States, 10960
      • Hematology Oncology Associates of Rockland
  • North Carolina
    • Pinehurst, North Carolina, United States, 28374
      • First Health of the Carolinas
  • Ohio
    • Middletown, Ohio, United States, 45042
      • Signal Point Clinical Research Center
    • Wooster, Ohio, United States, 44691
      • Lawrence M. Stallings, M.D.
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73120
      • Mercy Physicians Of Oklahoma
  • Oregon
    • Springfield, Oregon, United States, 97477
      • Willamette Valley Cancer Institute
  • Pennsylvania
    • Danville, Pennsylvania, United States, 17822
      • Geisinger Medical Center
    • Gettysburg, Pennsylvania, United States, 17235
      • Gettysburg Cancer Center
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny Cancer Center
    • State College, Pennsylvania, United States, 16803
      • Mount Nittany Medical Center
    • West Reading, Pennsylvania, United States, 19611
      • Berks Hematology Oncology Associates
  • Rhode Island
    • Cranston, Rhode Island, United States, 02920
      • Hematology and Oncology Associates of Rhode Island
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • MUSC Hollings Cancer Center
    • Hilton Head Island, South Carolina, United States, 29926
      • South Carolina Cancer Specialists
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • The Jones Clinic, PC
  • Texas
    • Austin, Texas, United States, 78758
      • Texas Oncology: Austin North
    • Bedford, Texas, United States, 76022
      • Texas Oncology: Bedford
    • Dallas, Texas, United States, 75246
      • Texas Oncology, PA
    • Fort Worth, Texas, United States, 76104
      • Texas Oncology: Fort Worth
    • Houston, Texas, United States, 77030
      • Methodist Hospital Research Institute
    • Houston, Texas, United States, 77024
      • Texas Oncology: Houston Memorial City
    • Houston, Texas, United States, 77055
      • Houston Cancer Center
    • Lubbock, Texas, United States, 79410
      • Joe Arrington Cancer Research and Treatment Center
    • San Antonio, Texas, United States, 78229
      • CTRC at the UT Health Science Center at San Antonio
  • Virginia
    • Lynchburg, Virginia, United States, 24501
      • Lynchburg Hematology Oncology Clinic, Inc.
  • Washington
    • Bremerton, Washington, United States, 98310
      • Harrison HealthPartners Bremerton Hematology & Oncology
    • Kirkland, Washington, United States, 98034
      • Cascade Cancer Center
    • Seattle, Washington, United States, 98109
      • University of Washington, Seattle Cancer Care Alliance
    • Seattle, Washington, United States, 98109
      • Group Health Medical Centers
    • Spokane, Washington, United States, 99204
      • Rockwood Clinic
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • University of Wisconsin, Clinical Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histological or cytological proof of component (any percent) of clear cell RCC (renal cell carcinoma).
• Metastatic or locally advanced unresectable RCC. NOTE: Prior nephrectomy is not mandatory.
• Progressive disease after 1-2 prior VEGF-directed tyrosine kinase inhibitors (TKIs).
• Measurable disease according to RECIST and obtained by imaging within 30 days prior to registration for protocol therapy.
• Written informed consent and HIPAA authorization for release of personal health information.
• Age > 18 years at the time of consent.
• Females of childbearing potential and males must be willing to use an effective method of contraception (hormonal or barrier method of birth control; abstinence) from the time consent is signed until 4 weeks after treatment discontinuation.
• Females of childbearing potential must have a negative pregnancy test within 7 days prior to registration for protocol therapy.

Exclusion Criteria:

• No active brain metastases. Patients with neurological symptoms must undergo a head CT scan or brain MRI to exclude brain metastasis within 30 days prior to registration on protocol therapy. NOTE: A patient with prior brain metastasis are eligible if they have completed their radiation treatment for brain metastasis ≥30 days prior to registration for protocol therapy, are off steroids, and are asymptomatic.
• No other currently active malignancy.
• No treatment with any investigational agent within 14 days prior to registration for protocol therapy. NOTE: If treated with investigational agent within 14 days prior to registration, AE must be resolved back to baseline.
• Prior cancer treatment must be completed at least 14 days prior to registration for protocol therapy and the patient must have recovered from the acute toxic effects of the regimen. With the exception of Bevacizumab treatment, which must be completed 30 days prior to registration for protocol therapy.
• Prior radiation therapy to < 25% of the bone marrow [see bone marrow radiation chart in the study procedure manual (SPM)] allowed if completed within 30 days prior to registration for protocol therapy.
• Corrected QT interval (QTc) ≤ 450 msec at least 7 days prior to registration for protocol therapy.
• No clinically significant infections as judged by the treating investigator.
• No liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis.
• No collecting duct, medullary or sarcomatoid histology.
• No prior treatment with temsirolimus or everolimus in the phase II component of the study. NOTE: Prior treatment with these agents is permitted in the phase I component of the study.
• No use of full dose, therapeutic anti-coagulation with warfarin or related anti-coagulants or unfractionated or low molecular weight heparins.
• No uncontrolled hypertension (BP >150/100mmHg despite full doses of 1 anti-hypertensive medication).
• No thrombotic event within 6 months (deep vein thrombosis, pulmonary embolism) of registration for protocol therapy.
• No grade 2 or greater peripheral neuropathy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Combination Arm A: Everolimus + BNC105P; Combination Arm A: Everolimus 10 mg, BNC105P MTD (from Phase 1 study) 21 day cycle	Drug: Everolimus; Everolimus 10 mg. Taken orally, every evening, 1 hr before or 2 hrs after meals; Drug: BNC105P; BNC105P, up to 16 mg/m^2
Active Comparator: Sequential Arm B:Everolimus followed by BNC105P Monotherapy; Sequential Arm B: Everolimus 10 mg, 21 day cycle Patients to receive BNC105P monotherapy at 16 mg/m2 following progression or intolerable toxicity on everolimus therapy.	Drug: Everolimus; Everolimus 10 mg. Taken orally, every evening, 1 hr before or 2 hrs after meals; Drug: BNC105P; BNC105P, up to 16 mg/m^2

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase I: Maximum Tolerated Dose of BNC105P in Combination With Everolimus.	Phase I	Until disease progression or unacceptable toxicity, up to 24 cycles or 24 months
Phase I: Toxicities of BNC105P in Combination With Everolimus.	Determine the toxicities of BNC105P in combination with everolimus. Drug-related treatment emergent adverse events by CTCAE grade 2 or greater are reported	Until disease progression or unacceptable toxicity, up to 24 cycles or 24 months
Phase II: 6-month Progression Free Survival (PFS) With the Addition of BNC105P to Everolimus.	Improvement in 6-month PFS with the addition of BNC105P to everolimus. Progression is defined using RECIST criteria as at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase I: Response Rate of BNC105P in Combination With Everolimus.	Number of objective responses per RECIST criteria. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD. Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.	Until disease progression or unacceptable toxicity, up to 24 cycles or 24 months
Geometric Mean Half-life of BNC105 and BNC105P in Combination With Everolimus.	Determine the PK Profile for BN105P in combination with everolimus by calculating the geometric mean half-life of BNC105P	12 months
Phase II: Response Rate With Combination Therapy Compared to Everolimus Alone	Objective response is defined as a confirmed CR or PR per RECIST criteria. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD. Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.	12 months
Phase II: Progression Free Survival (PFS) With BNC105P Alone in Patients After Progressing on Everolimus.	Median time to progression for arm P participants who crossed over to BNC105P monotherapy after progression. Progression is defined per RECIST criteria as at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions	12 months
Phase II: Adverse Events of Everolimus and BNC105P When Administered as a Combination or Sequential Regimen.	Determine adverse events of everolimus and BNC105P when administered as a combination or sequential regimen. Total number of serious and non-serious adverse events for Arm A and Arm B are summarized. Complete adverse event information is supplied in the Adverse Events reporting section.	12 months
Phase II: Overall Survival	Determine overall survival probability, up to a maximum of 5 years from registration for protocol therapy.	60 months
Exploratory Objective: Correlation of PFS With Biomarkers	Exploratory analysis of serum biomarkers were undertaken to generate a potential signature for response. The correlation with 6 month progression free survival P value for four plasma biomarkers is reported.	6 months

Collaborators and Investigators

• Sponsor: Hoosier Cancer Research Network
• Collaborators: Bionomics Limited
• Investigators: Study Chair: Thomas Hutson, D.O., Hoosier Cancer Research Network

Publications and helpful links

General Publications

• Thomas E. Hutson, Long H. Dang, Richard C. Lauer, Alexander Starodub, Ralph J. Hauke, Matt D. Galsky, Kathryn A. Bylow, Theodore Logan, Charles Lance Cowey, David C. Bibby, Gabriel Kremmidiotis, Elizabeth E. Doolin, Tina C. Lavranos, Guru Sonpavde, Noah M. Hahn, Christopher Sweeney, John Sarantopoulos. Phase I results of a phase I/II trial of BNC105P with everolimus in metastatic renal cell carcinoma (mRCC) patients previously treated with VEGFR tyrosine kinase inhibitors. J Clin Oncol 30, 2012 (suppl; abstr 4603) http://www.asco.org/ASCOv2/Meetings/Abstracts&vmview=abst_detail_view&confID=114&abstractID=91911
• John Sarantopoulos, Long H. Dang, Richard C. Lauer, Alexander Starodub, Ralph J. Hauke, Matt D. Galsky, Kathryn A. Bylow, Charles Lance Cowey, David C. Bibby, Gabriel Kremmidiotis, Elizabeth E. Doolin, Tina C. Lavranos, Jose Luis Iglesias, Guru Sonpavde, Theodore Logan, Noah M. Hahn, Christopher Sweeney, Thomas E. Hutson. A phase I/II trial of BNC105P with everolimus in metastatic renal cell carcinoma (mRCC) patients: Updated phase I results of the Disruptor-1 trial. J Clin Oncol 31, 2013 (suppl; abstr 4563. http://abstracts2.asco.org/AbstView_132_107981.html
• Pal S, Azad A, Bhatia S, Drabkin H, Costello B, Sarantopoulos J, Kanesvaran R, Lauer R, Starodub A, Hauke R, Sweeney CJ, Hahn NM, Sonpavde G, Richey S, Breen T, Kremmidiotis G, Leske A, Doolin E, Bibby DC, Simpson J, Iglesias J, Hutson T. A Phase I/II Trial of BNC105P with Everolimus in Metastatic Renal Cell Carcinoma. Clin Cancer Res. 2015 Aug 1;21(15):3420-7. doi: 10.1158/1078-0432.CCR-14-3370. Epub 2015 Mar 18.
• Yang ES, Nassar AH, Adib E, Jegede OA, Alaiwi SA, Manna DLD, Braun DA, Zarei M, Du H, Pal SK, Naik G, Sonpavde GP. Gene Expression Signature Correlates with Outcomes in Metastatic Renal Cell Carcinoma Patients Treated with Everolimus Alone or with a Vascular Disrupting Agent. Mol Cancer Ther. 2021 Aug;20(8):1454-1461. doi: 10.1158/1535-7163.MCT-20-1091. Epub 2021 Jun 9.

Helpful Links

• Hoosier Cancer Research Network Homepage

Study record dates

Study Major Dates

• Study Start: January 1, 2010
• Primary Completion (Actual): December 1, 2016
• Study Completion (Actual): December 1, 2016

Study Registration Dates

• First Submitted: December 15, 2009
• First Submitted That Met QC Criteria: December 15, 2009
• First Posted (Estimate): December 17, 2009

Study Record Updates

• Last Update Posted (Actual): July 11, 2022
• Last Update Submitted That Met QC Criteria: July 7, 2022
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: Metastatic Kidney Cancer; BNC105P
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Kidney Neoplasms; Carcinoma, Renal Cell; Carcinoma; Physiological Effects of Drugs; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Everolimus
• Other Study ID Numbers: HOG GU09-145