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