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Onalespib and CDKI AT7519 in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery

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ClinicalTrials.gov Identifier: NCT02503709
Recruitment Status : Recruiting
First Posted : July 21, 2015
Last Update Posted : April 10, 2018
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase I trial studies the side effects and best dose of onalespib and CDKI AT7519 in treating patients with solid tumors that have spread from the primary site (place where they started) to other places in the body (metastatic) or cannot be removed by surgery. Onalespib and CDKI AT7519 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or disease Intervention/treatment Phase
Advanced Malignant Solid Neoplasm Metastatic Malignant Solid Neoplasm Unresectable Solid Neoplasm Drug: CDKI AT7519 Other: Laboratory Biomarker Analysis Drug: Onalespib Other: Pharmacological Study Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To establish the safety, tolerability, and the maximum tolerated dose of the combination of onalespib and AT7519M (CDKI AT7519).

SECONDARY OBJECTIVES:

I. To determine the pharmacokinetics of the combination of onalespib and AT7519M.

II. To assess the pharmacodynamic effect of the combination of onalespib and AT7519M on HSP70 expression and modulation of HSP90 client proteins in peripheral blood mononuclear cells (PBMCs) and plasma.

III. To observe and record anti-tumor activity.

OUTLINE: This is a dose-escalation study.

Patients receive onalespib intravenously (IV) over 1 hour on days 1 and 4 (course 0 only). Patients then receive onalespib IV over 1 hour and CDKI AT7519 IV over 1 hour on days 1, 4, 8, and 11 (course 1 and subsequent courses thereafter). Courses repeat every 21 days (7 days for course 0 only) in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 37 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Trial of the Combination of the Heat Shock Protein-90 (HSP90) Inhibitor Onalespib (AT13387) and the Cyclin-Dependent Kinase (CDK) Inhibitor AT7519M in Patients With Advanced Solid Tumors
Actual Study Start Date : April 8, 2016
Estimated Primary Completion Date : June 30, 2018

Arm Intervention/treatment
Experimental: Treatment (onalespib, CDKI AT7519)
Patients receive onalespib IV over 1 hour on days 1 and 4 (course 0 only). Patients then receive onalespib IV over 1 hour and CDKI AT7519 IV over 1 hour on days 1, 4, 8, and 11 (course 1 and subsequent courses thereafter). Courses repeat every 21 days (7 days for course 0 only) in the absence of disease progression or unacceptable toxicity.
Drug: CDKI AT7519
Given IV
Other Names:
  • AT7519
  • AT7519M
  • CDK inhibitor AT7519M
  • Cyclin-Dependent Kinase Inhibitor AT7519M

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Onalespib
Given IV
Other Names:
  • AT 13387
  • AT-13387
  • AT13387

Other: Pharmacological Study
Correlative studies




Primary Outcome Measures :
  1. Incidence of adverse events of onalespib and CDKI AT7519 [ Time Frame: Up to 30 days after the last dose of study drug ]
    Scored using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

  2. Tolerability of onalespib and CDKI AT7519 [ Time Frame: Up to 30 days after the last dose of study drug ]
    Assessed using the NCI CTCAE version 5.0.

  3. Maximum tolerated dose of onalespib and CDKI AT7519 [ Time Frame: 21 days ]
    Defined as =< 1 out of 6 patients experiencing dose limiting toxicity.


Secondary Outcome Measures :
  1. Pharmacokinetic parameters of onalespib and CDKI AT7519 [ Time Frame: Before infusion, at 30 and 59 minutes of infusion, and at 1.5, 2, 4, 6, 8, and 24 hours at end of infusion on day 1 of course 0 and days 1 and 11 of course 1 ]
    Individual patient plasma concentration-time curves will be analyzed by noncompartmental methods using routines supplied in the WinNonlin Professional Version 4.0.1 software package. Pharmacokinetic parameters and variables will be calculated according to standard equations. Mean values of the pharmacokinetic parameters will be statistically compared using the paired two-tailed t-test of the log-transformed data.

  2. Pharmacodynamic (PD) parameters of onalespib and CDKI AT7519 [ Time Frame: Prior to onalespib administration during course 0, 2-4 hours after completion of onalespib on day 4 of course 0, and 2-4 hours after completion of CDKI AT7519 on day 11 of course 1 ]
    PD effect of the combination of onalespib and CDKI AT7519 on Hsp70 expression and modulation of Hsp90 client proteins in peripheral blood mononuclear cells (PBMCs) will be assessed. All PD evaluations and comparisons will be done with exploratory intent, using primarily descriptive and non-parametric techniques.

  3. Antitumor activity of the combination [ Time Frame: Up to 30 days after the last dose of study drug ]
    Measured by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v.1.1).



Information from the National Library of Medicine

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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:

  • Patients must have histologically confirmed solid tumor that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective
  • Patients must have evaluable disease or disease measurable per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; measurable disease is defined as at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) with conventional techniques or as >= 10 mm (>= 1 cm) with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
  • There are no limits on prior lines of therapy; however, patients must have recovered to eligibility levels from prior toxicity or adverse events as a result of previous treatment prior to entering the study (except alopecia)
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-1
  • Life expectancy of greater than 3 months
  • Absolute neutrophil count >= 1,500/microliters
  • Platelets >= 100,000/microliters
  • Total bilirubin =< 1.5 X institutional upper limit of normal
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal
  • Creatinine < 1 X institutional upper limit of normal OR creatinine clearance >= 50 mL/min determined by Cockcroft-Gault formula
  • Creatine phosphokinase =< institutional upper limit of normal
  • Women of childbearing potential and male patients with partners of childbearing potential must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry, for the duration of study participation, and for 2 months after completion of study; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; women of childbearing potential enrolling on study must have a negative pregnancy test within 72 hours of enrollment in order to be eligible; breastfeeding should be discontinued while the mother is treated with onalespib and AT7519M
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Patients who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study; patients who have had prior onalespib or AT7519M as a monotherapy will not be excluded
  • Patients who are receiving any other investigational agents
  • Patients with known brain metastases or carcinomatous meningitis are excluded from this clinical trial, with the exception of patients with brain metastatic disease that has previously been treated and remained stable on MRI >= 2 months after treatment, without steroids or anti-epileptic medications; these patients may be enrolled at the discretion of the principal investigator
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to onalespib or AT7519M
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements; additionally, patients with other co-morbid disease or metabolic dysfunction that would render the subject at high risk for treatment complications may be excluded at the discretion of the principal investigator in the interest of patient safety
  • Pregnant women are excluded from this study
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy known to interact with CYP isoenzymes are ineligible; in addition, HIV patients with CD4 count < 200 cells/uL are ineligible; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
  • Consistent corrected QT (QTc) > 450 msec for men and > 470 msec for women by Fridericia formula, on 3 separate electrocardiograms (ECGs); patients with a history of long QTc syndrome or personal or family history of ventricular arrhythmias will be excluded
  • Patients with pre-existing retinal disease on ophthalmologic exam will be excluded
  • Patients with left ventricular ejection fraction < 50% on echocardiogram or multigated acquisition scan will be excluded
  • Patients with grade >= 2 peripheral neuropathy will not be permitted on study

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): NCT02503709


Locations
United States, District of Columbia
MedStar Georgetown University Hospital Recruiting
Washington, District of Columbia, United States, 20007
Contact: Stephen V. Liu    202-444-2223      
Principal Investigator: Stephen V. Liu         
United States, Maryland
National Cancer Institute Developmental Therapeutics Clinic Recruiting
Bethesda, Maryland, United States, 20892
Contact: A P. Chen    800-411-1222      
Principal Investigator: A P. Chen         
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: A P. Chen    800-411-1222      
Principal Investigator: A P. Chen         
United States, Massachusetts
Massachusetts General Hospital Cancer Center Recruiting
Boston, Massachusetts, United States, 02114
Contact: Khanh T. Do    877-442-3324      
Principal Investigator: Khanh T. Do         
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Khanh T. Do    877-442-3324      
Principal Investigator: Khanh T. Do         
United States, Ohio
Ohio State University Comprehensive Cancer Center Recruiting
Columbus, Ohio, United States, 43210
Contact: John L. Hays    800-293-5066    Jamesline@osumc.edu   
Principal Investigator: John L. Hays         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Khanh Do Dana-Farber - Harvard Cancer Center LAO

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02503709     History of Changes
Other Study ID Numbers: NCI-2015-01098
NCI-2015-01098 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
P9899
L9899
UK11143
16-711
9899 ( Other Identifier: Dana-Farber - Harvard Cancer Center LAO )
9899 ( Other Identifier: CTEP )
UM1CA186709 ( U.S. NIH Grant/Contract )
ZIABC011078 ( U.S. NIH Grant/Contract )
First Posted: July 21, 2015    Key Record Dates
Last Update Posted: April 10, 2018
Last Verified: March 2018

Additional relevant MeSH terms:
Neoplasms
Cyclin-Dependent Kinase Inhibitor Proteins
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action