Clinical Trials /

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

NCT02503709

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: NCI-2015-01098
  • SECONDARY ID: NCI-2015-01098
  • SECONDARY ID: P9899
  • SECONDARY ID: L9899
  • SECONDARY ID: UK11143
  • SECONDARY ID: 16-711
  • SECONDARY ID: 9899
  • SECONDARY ID: 9899
  • SECONDARY ID: UM1CA186709
  • SECONDARY ID: ZIABC011078
  • NCT ID: NCT02503709

Conditions

  • Advanced Malignant Solid Neoplasm
  • Metastatic Malignant Solid Neoplasm
  • Unresectable Solid Neoplasm

Interventions

DrugSynonymsArms
CDK Inhibitor AT7519AT7519, AT7519M, CDK inhibitor AT7519M, Cyclin-Dependent Kinase Inhibitor AT7519MTreatment (onalespib, CDKI AT7519)
OnalespibAT 13387, AT-13387, AT13387Treatment (onalespib, CDKI AT7519)

Purpose

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.

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), plasma, and tumor biopsies.

      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 (cycle 0 only).
      Patients then receive onalespib IV over 1 hour and CDKI AT7519 IV over 1 hour on days 1, 4,
      8, and 11 (cycle 1 and subsequent cycles thereafter). Cycles 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (onalespib, CDKI AT7519)ExperimentalPatients receive onalespib IV over 1 hour on days 1 and 4 (cycle 0 only). Patients then receive onalespib IV over 1 hour and CDKI AT7519 IV over 1 hour on days 1, 4, 8, and 11 (cycle 1 and subsequent cycles thereafter). Cycles repeat every 21 days (7 days for course 0 only) in the absence of disease progression or unacceptable toxicity.
  • CDK Inhibitor AT7519
  • Onalespib

Eligibility 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

          -  The effects of onalespib and AT7519M on the developing human fetus are unknown; for
             this reason, 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; because there is an unknown but potential risk to
             nursing infants secondary to treatment of the mother with onalespib and AT7519M,
             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

          -  The effects of onalespib and AT7519M on the developing human fetus are unknown; for
             this reason, 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 due
             to potential eye toxicities known to be associated with onalespib

          -  Patients with left ventricular ejection fraction < 50% on echocardiogram or multigated
             acquisition scan will be excluded based on known cardiotoxicities associated with
             onalespib

          -  Patients with grade >= 2 peripheral neuropathy will not be permitted on study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events of onalespib and CDKI AT7519
Time Frame:Up to 30 days after the last dose of study drug
Safety Issue:
Description:Scored using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Secondary Outcome Measures

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

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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