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Panobinostat and Everolimus in Treating Patients With Metastatic or Unresectable Renal Cell Cancer That Does Not Respond to Treatment With Sunitinib Malate or Sorafenib Tosylate

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ClinicalTrials.gov Identifier: NCT01582009
Recruitment Status : Terminated (pts off study, PI left institute)
First Posted : April 20, 2012
Results First Posted : May 17, 2017
Last Update Posted : June 14, 2017
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Novartis
Information provided by (Responsible Party):
Roswell Park Cancer Institute

Tracking Information
First Submitted Date  ICMJE July 15, 2010
First Posted Date  ICMJE April 20, 2012
Results First Submitted Date  ICMJE April 7, 2017
Results First Posted Date  ICMJE May 17, 2017
Last Update Posted Date June 14, 2017
Study Start Date  ICMJE March 2010
Actual Primary Completion Date October 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 17, 2017)
  • Progression-free Survival (PFS) [ Time Frame: The time from registration to documentation of disease progression up to 3 years ]
    6 month PFS survival rate. Calculated as the total number of failures (deaths or progression) divided by the total follow-up or exposure time of patients on study. Assessed using Kaplan Meier and Proportional Hazards.
  • Number of Participants With Clinical Response [ Time Frame: The time from registration up to 3 years ]
    Number of participants with clinical response. Response will be evaluated in this study using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors ver 1.0 Committee [JNCI 92(3):205-216, 2000]. Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are used in the RECIST ver. 1.0 criteria.
Original Primary Outcome Measures  ICMJE
 (submitted: April 19, 2012)
Progression-free survival (PFS) event rate [ Time Frame: The time from registration to documentation of disease progression up to 3 years ]
Calculated as the total number of failures (deaths or progression) divided by the total follow-up or exposure time of patients on study.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 17, 2017)
  • Number of Participants With an Adverse Event. [ Time Frame: The time from registration up to 3 years ]
    Number of participants with an adverse event. Please refer to the adverse event reporting for more detail.
  • Median Progression Free Survival [ Time Frame: The time from registration up to 3 years ]
    Median progression free survival. Assessed using Kaplan Meier and Proportional Hazards.
  • 6-month Overall Survival Rate [ Time Frame: The time from registration up to 3 years ]
    6-month overall survival rate
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Panobinostat and Everolimus in Treating Patients With Metastatic or Unresectable Renal Cell Cancer That Does Not Respond to Treatment With Sunitinib Malate or Sorafenib Tosylate
Official Title  ICMJE A Phase I/II Study of the HDAC Inhibitor LBH-589 in Combination With the mTOR Inhibitor Everolimus (RAD001) in Metastatic Renal Cell Carcinoma
Brief Summary

RATIONALE: Panobinostat and everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth or by blocking blood flow to the tumor.

PURPOSE: This phase I/II trial is studying the side effects and best dose of giving panobinostat together with everolimus and to see how well they work in treating patients with metastatic or unresectable renal cell cancer that does not respond to treatment with sunitinib malate or sorafenib tosylate

Detailed Description

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability and determine the recommended dosing for the combination of LBH589 and Everolimus in patients with metastatic renal cell carcinoma. (Phase I) II. To assess the preliminary evidence of tumor response in patients treated with LBH589 and Everolimus. (Phase I) III. To evaluate the effect of LBH589 and Everolimus on the progression-free survival event rate. (Phase II) IV. To determine the clinical response rate of LBH589 and Everolimus in patients with metastatic renal cell carcinoma. (Phase II)

SECONDARY OBJECTIVES:

I. To determine the toxicity of the combination of LBH589 and Everolimus in patients with metastatic renal cell carcinoma. (Phase II) II. To evaluate the effect of LBH589 and Everolimus on time-to-tumor-progression (TTP), disease-free survival and overall survival. (Phase II) III. To assess the pharmacodynamic effects of LBH589 and Everolimus in peripheral blood mononuclear cells (PBMNC) and tumor that are accessible before and after treatment, if available. (Phase II) IV. To evaluate the modulation of tumor metabolism and blood in patients treated with LBH589 and Everolimus by FDG and 015 water PET/CT scan. (Phase II)

OUTLINE: This is a dose-escalation study of panobinostat and everolimus, followed by a phase II study.

Patients receive oral panobinostat once daily on days 1, 3, 4, 8, 10, and 12 and oral everolimus once daily on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed for at least 4 weeks.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Clear Cell Renal Cell Carcinoma
  • Recurrent Renal Cell Cancer
  • Stage III Renal Cell Cancer
  • Stage IV Renal Cell Cancer
Intervention  ICMJE
  • Drug: panobinostat
    Given orally
    Other Names:
    • Faridak
    • HDAC inhibitor LBH589
    • histone deacetylase inhibitor LBH589
    • LBH589
  • Drug: everolimus
    Given orally
    Other Names:
    • 42-O-(2-hydroxy)ethyl rapamycin
    • Afinitor
    • RAD001
  • Other: laboratory biomarker analysis
    Correlative studies
  • Other: pharmacological study
    Correlative studies
    Other Name: pharmacological studies
  • Other: liquid chromatography
    Correlative studies
    Other Name: LC
  • Other: mass spectrometry
    Correlative studies
  • Other: enzyme-linked immunosorbent assay
    Correlative studies
    Other Name: ELISA
  • Other: immunohistochemistry staining method
    Correlative studies
    Other Name: immunohistochemistry
Study Arms  ICMJE Experimental: Arm I: Oral Panobinostat and Oral Everolimus
Patients receive oral panobinostat once daily on days 1, 3, 4, 8, 10, and 12 and oral everolimus once daily on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
Interventions:
  • Drug: panobinostat
  • Drug: everolimus
  • Other: laboratory biomarker analysis
  • Other: pharmacological study
  • Other: liquid chromatography
  • Other: mass spectrometry
  • Other: enzyme-linked immunosorbent assay
  • Other: immunohistochemistry staining method
Publications * Wood A, George S, Adra N, Chintala S, Damayanti N, Pili R. Phase I study of the mTOR inhibitor everolimus in combination with the histone deacetylase inhibitor panobinostat in patients with advanced clear cell renal cell carcinoma. Invest New Drugs. 2020 Aug;38(4):1108-1116. doi: 10.1007/s10637-019-00864-7. Epub 2019 Oct 25.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: October 8, 2015)
26
Original Estimated Enrollment  ICMJE
 (submitted: April 19, 2012)
48
Actual Study Completion Date  ICMJE December 2015
Actual Primary Completion Date October 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients must have histologically confirmed metastatic or unresectable renal cell carcinoma
  • Predominant clear cell component is required
  • Patients must have metastatic disease which has progressed on or within 6 months of stopping treatment with VEGFR receptor tyrosine kinase inhibitors
  • Previous therapy with bevacizumab, interleukin 2, or interferon alpha is also permitted
  • Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed
  • Serum albumin >= 3g/dL
  • AST/SGOT and ALT/SGPT =< 2.5 x upper limit of normal (ULN)
  • Serum bilirubin =< 1.5 x ULN
  • Serum creatinine =< 1.5 x ULN or 24-hour creatinine clearance >= 50 ml/min
  • Serum potassium >= LLN
  • Serum phosphorous >= LLN
  • Serum total calcium (corrected for serum albumin) or serum ionized calcium >= LLN
  • Serum magnesium >= LLN
  • TSH and free T4 within normal limits (WNL); patients may be on thyroid hormone replacement
  • ANC >= 1.5 x 10^9/L
  • Platelets >= 100 x 10^9/L
  • Hb > 9 g/dL
  • INR < 1.3 (or < 3 on anticoagulants)
  • Fasting serum cholesterol =< 300 mg/dL OR =< 7.75 mmol/L AND fasting triglycerides =< 2.5 x ULN (in case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication
  • Baseline MUGA or ECHO must demonstrate LVEF >= the lower limit of the institutional normal
  • ECOG Performance Status of =< 2

Exclusion Criteria:

  • Pure papillary and chromophobe renal cell carcinoma, collecting duct tumors and transitional cell carcinoma are not eligible
  • Prior treatment with a pan-HDAC or mTOR inhibitor
  • Patients currently receiving anticancer therapies or who have received anticancer therapies within 4 weeks of the start of study drug (including chemotherapy, radiation therapy, antibody based therapy, etc.)
  • Patients who have had a major surgery of significant traumatic injury within 4 weeks of start of study drug and who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or patients that may require major surgery during the course of the study
  • Prior treatment with any investigational drug within the preceding 4 weeks
  • Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent; topical or inhaled corticosteroids are allowed
  • Patients should not receive immunization with attenuated live vaccines within one weeks of study entry or during study period; close contact with those who have received attenuated live vaccines should be avoided during treatment with everolimus (Examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and TY2a typhoid vaccines)
  • Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases
  • Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin
  • Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:
  • 1) Symptomatic congestive heart failure of New York Heart Association Class III or 4
  • 2) Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease
  • 3) Concomitant use of drugs with a risk of causing torsades de pointes
  • 4) Severely impaired lung functions as defined as spirometry and DLCO that is 50% of the normal predicted value and/or O2 saturation that is 88% or less at rest on room air
  • 5) Uncontrolled diabetes as defined by fasting serum glucose > 1.5 x ULN; optimal glycemic control should be achieved before starting trial therapy
  • 6) Active (acute or chronic) or uncontrolled severe infections
  • 7) Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis; a detailed assessment of Hepatitis B/C medical history and risk factors must be done at screening for all patients; HBV DNA and HCV RNA PCR testing are required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior HBV/HCV infection
  • A known HIV seropositivity
  • Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)
  • Patients with an active, bleeding diathesis
  • Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods; adequate contraception must be used throughout the trial and for 8 weeks after the last dose of study drug by both sexes
  • Adults of reproductive potential who are not using effective birth control methods; if barrier contraceptive are being used, these must be continued throughout this trial by both sexes; hormonal contraceptives are not acceptable as a sole method of contraception
  • Women of childbearing potential must have a negative urine or serum pregnancy test within 14 days prior to administration of everolimus
  • Patients who have received prior treatment with an mTOR inhibitor (sirolimus, temsirolimus, everolimus)
  • Patients with a known hypersensitivity to everolimus (everolimus) or other rapamycins (sirolimus, temsirolimus) or to its excipients
  • History of noncompliance to medical regimens
  • Male patient whose sexual partner(s) are WOCBP who are not willing to use adequate contraception, during the study and for 8 weeks after the end of treatment
  • Patients unwilling to or unable to comply with the protocol
  • Patients currently receiving strong or moderate CYP3A4 inhibitors or inducers; patients should not begin study drugs until at least 72 hours after the last dose (or longer, as indicated) of the inhibitor or inducer
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01582009
Other Study ID Numbers  ICMJE I146308
NCI-2009-01599 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Roswell Park Cancer Institute
Study Sponsor  ICMJE Roswell Park Cancer Institute
Collaborators  ICMJE
  • National Cancer Institute (NCI)
  • Novartis
Investigators  ICMJE
Principal Investigator: Saby George, MD Roswell Park Cancer Institute
PRS Account Roswell Park Cancer Institute
Verification Date May 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP