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Clear Cell Renal Cell CarcinomaPhase 1/2NCT01582009

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

A Phase 1/2 study testing panobinostat, everolimus and laboratory biomarker analysis in people with Clear Cell Renal Cell Carcinoma and Recurrent Renal Cell Cancer, run by Roswell Park Cancer Institute at 2 sites in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
panobinostat, everolimus and laboratory biomarker analysis
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
26 participants
Where
2 sitesUnited States
Study dates
Mar 2010to Dec 2015
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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

Who cannot join

  • 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
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  • 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

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • Roswell Park Cancer Institute

    Buffalo, New York, 14263

  • University of Rochester Medical Center

    Rochester, New York, 14642

Other trials in United States

About this study

Official title: A Phase I/II Study of the HDAC Inhibitor LBH-589 in Combination With the mTOR Inhibitor Everolimus (RAD001) in Metastatic Renal Cell Carcinoma

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

Read the detailed description

PRIMARY OBJECTIVES:

  1. 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:

  1. 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.

Being tested
panobinostat, everolimus, laboratory biomarker analysis, pharmacological study, liquid chromatography
Medical subject headings
Carcinoma, Renal Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • panobinostatDrug

    Also called Faridak, HDAC inhibitor LBH589, histone deacetylase inhibitor LBH589, LBH589

    Given orally

  • everolimusDrug

    Also called 42-O-(2-hydroxy)ethyl rapamycin, Afinitor, RAD001

    Given orally

  • laboratory biomarker analysisOther

    Correlative studies

  • pharmacological studyOther

    Also called pharmacological studies

    Correlative studies

  • liquid chromatographyOther

    Also called LC

    Correlative studies

  • mass spectrometryOther

    Correlative studies

  • enzyme-linked immunosorbent assayOther

    Also called ELISA

    Correlative studies

  • immunohistochemistry staining methodOther

    Also called immunohistochemistry

    Correlative studies

Study groups in NCT01582009
Study groupRoleWhat they receive
Arm I: Oral Panobinostat and Oral EverolimusExperimentalPatients 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.
Receives: 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

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Progression-free Survival (PFS)

    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.

    Measured: The time from registration to documentation of disease progression up to 3 years

  2. Number of Participants With Clinical Response

    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.

    Measured: The time from registration up to 3 years

Secondary outcomes (3)

  1. Number of Participants With an Adverse Event.

    Number of participants with an adverse event. Please refer to the adverse event reporting for more detail.

    Measured: The time from registration up to 3 years

  2. Median Progression Free Survival

    Median progression free survival. Assessed using Kaplan Meier and Proportional Hazards.

    Measured: The time from registration up to 3 years

  3. 6-month Overall Survival Rate

    6-month overall survival rate

    Measured: The time from registration up to 3 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 Apr 2012 (estimated)
  2. Study startMar 2010
  3. Primary completionOct 2015
  4. Study completionDec 2015

Why it stopped: pts off study, PI left institute

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
26 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01582009
Sponsor's protocol ID
I146308
Other IDs
NCI-2009-01599
Status last verified
Aug 2022
First submitted
15 Jul 2010
Last updated
15 Aug 2022
Data monitoring committee
Yes

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.

    PubMed 31654285

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing panobinostat, everolimus and laboratory biomarker analysis in people with Clear Cell Renal Cell Carcinoma and Recurrent Renal Cell Cancer, run by Roswell Park Cancer Institute at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 21 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 15 Aug 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 17 May 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Progression-free Survival (PFS) (time frame: The time from registration to documentation of disease progression up to 3 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01582009, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Aug 2022.

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