- Some people have cancers that don t respond to standard treatments. In these cases,
doctors may try to use drugs to slow the growth of the cancer.
- To test the safety and efficacy of the drug combination of ganetespib and ziv-aflibercept.
- Adults age 18 and over with advanced cancer of the colon, lung, urinary tract, and
- Participants will be screened with medical history, blood tests, and scans to measure
- Participants will have one or two eye exams, with dilating eye drops.
- Participants will get the study drugs at the clinic as an infusion in a vein.
Ganetespib will be given once a week on the same day for 3 weeks in a row, followed by
a 1-week rest period. Ziv-aflibercept will be given once every other week. The drugs
will be given in 28-day cycles.
- Participants may have a small piece of their tumor collected once or twice. This is
done using a small needle during computed tomography (CT), magnetic resonance imaging
(MRI), or ultrasound scan.
- Participants will have their blood pressure checked at each visit. They will check it
at home every day of the study.
- Participants may have one or more whole-body PET scans with 89Zr-panitumumab. A small
amount of a radioactive chemical will be injected through a tube in an arm.
Participants will lie on a bed that slides in and out of the donut-shaped PET scanner.
They will have small amounts of blood drawn.
- Participants may stay in the study as long as they are tolerating the drugs and their
tumor is not getting worse.
- Ganetespib is a non-geldamycin synthetic inhibitor of Hsp90 that has demonstrated
activity against multiple cancer cell lines and tumor xenografts in preclinical models.
Inhibiting the Hsp90 chaperone complex results in the recruitment of ubiquitin ligases,
polyubiquination, and proteosomal degradation of Hsp90 client proteins, including
transcription factors and proteins involved in angiogenesis (VEGF, VEGFR, HIF-1,
STAT-3); growth factor independence (RAF, EGFR,Her2, IGFR); resistance to anti-growth
signals (CDK4); tissue invasion and metastases (MET, MMP2); and avoidance of apoptosis
(AKT, RIP, Survivin, Bcl-2).
- HIF-1 activation has been implicated in mediating resistance to anti-angiogenic
therapy; recent evidence implicates a greater role for Hsp90 in direct modulation of
- Combining Hsp90 inhibition with ganetespib and anti-angiogenic therapy with
Ziv-Aflibercept, a soluble fusion protein with high binding affinity for VEGF-A,
VEGF-B, and PIGF, presents a rational novel strategy for improving upon and overcoming
resistance to anti-angiogenic therapy
- To establish the safety, tolerability, and maximum tolerated dose (MTD) of the combination
of ganetespib and Ziv-Aflibercept in patients with refractory gastrointestinal carcinomas,
non-squamous non-small cell lung carcinomas, urothelial carcinomas, and sarcomas
- To assess modulation of HIF1 as a pharmacodynamic marker of therapy with the
combination of ganetespib and Ziv-Aflibercept
- To assess modulation of EGFR expression using 89Zr-labeled, EGFR-targeting antibody
panitumumab PET/CT imaging of tumor lesions prior to and following treatment with study
- Adult patients with histologically confirmed metastatic gastrointestinal carcinomas,
non-squamous non-small cell lung carcinomas, urothelial carcinomas, and sarcomas with
disease progression after at least one line of standard therapy
- Participants in the expansion phase must demonstrate EGFR expression on archival tumor
samples and have disease amenable to biopsy with willingness to undergo pre- and
- No major surgery within 4 weeks prior to study enrollment, no radiation or chemotherapy
within 3 weeks prior to enrollment; patients must have recovered from toxicities of
prior therapies to at least eligibility levels prior to enrollment.
- Ganetespib will be administered intravenously weekly on days 1, 8, and 15 of a 28-day
cycle. Ziv-Aflibercept will be administered intravenously every 2 weeks, on days 1 and
15, during a 28-day cycle.
- The escalation portion of the trial will follow a standard 3+3 design, whereby patients
are dose-escalated in cohorts of 3 until dose-limiting toxicity is observed.
- Once the MTD is established, 10 additional patients will be enrolled to the expansion
phase, at the MTD, and tumor biopsies will be obtained to assess pharmacodynamic
endpoints. During cycle 1 of the expansion phase, ganetespib will be administered
intravenously weekly, on days 8 and 15 with omission of day 1 treatment to accommodate
a baseline biopsy pre-ganetespib but after administration of Ziv-Aflibercept. For all
subsequent cycles, ganetespib will be administered days 1, 8, and 15. Ziv-Aflibercept
will still be administered intravenously every 2 weeks, on days 1 and 15, of a 28-day
- PET/CT imaging with 89Zr-labeled panitumumab will be performed to evaluate tumor
distribution prior to and following treatment with study agents.
- INCLUSION CRITERIA:
Patients must have histologically confirmed recurrent or metastatic gastrointestinal
carcinomas, non-squamous non-small cell lung carcinomas, urothelial carcinomas, and
sarcomas with disease progression after at least one line of standard therapy. Disease
should have progressed following all treatments known to prolong survival, unless a given
treatment is contraindicated.
- Patients with colorectal carcinoma must have progressed through at least two lines of
standard chemotherapy in the metastatic setting.
- Patients with non-small cell lung cancer with known sensitizing EGFR mutation and/or
ALK rearrangement should have received prior erlotinib and/or crizotinib,
- Patients with urothelial carcinoma will have progressed on prior platinum-based
therapy or for which platinum-based therapy is contraindicated.
- Patients enrolled on the expansion phase of the protocol must demonstrate EGFR
expression by immunohistochemistry on archival tumor samples prior to undergoing (89)
Zr-panitumumab PET/CT scans.
Age greater than or equal to 18 years of age.
ECOG performance status < 2.
Life expectancy > 3 months.
Patients must have normal organ and marrow function as defined below:
absolute neutrophil count greater than or equal to 1,500/mcL
platelets greater than or equal to 100,000/mcL
total bilirubin less than or equal to 1.5 times institutional upper limit of normal
AST(SGOT)/ALT(SGPT) less than or equal to 3 times institutional upper limit of normal
creatinine less than or equal to 1.2 times institutional upper limit of normal
creatinine clearance greater than or equal to 60 mL/min/1.73 m2 for patients with
creatinine levels above institutional normal
urine protein/creatinine < 1 mg/mg
INR < 1.5
Cardiac function within institutional normal limits on echocardiogram.
Patients must have blood pressure no greater than 140 mmHg (systolic blood pressure) and
90 mmHg (diastolic blood pressure) for eligibility. Initiation or adjustment of
antihypertensive medications is permitted prior to study entry provided that the average
of three blood pressure measurements at enrollment visit is less than 140/90 mmHg.
The effects of ganetespib on the developing human fetus are unknown. For this reason and
because anti-angiogenic agents similar to ziv-aflibercept are known to be teratogenic,
women of child-bearing potential and men must agree to use two forms of contraception
(hormonal or barrier method of birth control; abstinence; sterilization) prior to study
entry, for the duration of study participation, and for 3 months after completing study
treatment. 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. Men treated or enrolled on this protocol must also agree to use two forms of
contraception prior to the study, for the duration of study participation, and for 3
months after completion of administration of both ganetespib and ziv-aflibercept.
Ability to understand and the willingness to sign a written informed consent document.
During the escalation phase of the protocol, patients may have evaluable or measurable
disease. During the expansion phase of the protocol, patients must have 1) measurable
disease, 2) disease amenable to biopsy and 3) willingness to undergo pre- and
Patients who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered
from adverse events due to agents administered more than 3 weeks earlier.
Patients who are receiving any other investigational agents.
Patients with known active brain metastases or carcinomatous meningitis are excluded from
this clinical trial. Patients whose brain metastatic disease status has remained stable
for greater than or equal to 4 weeks following treatment of brain metastases are eligible
to participate at the discretion of the principal investigator.
Uncontrolled intercurrent illness including, but not limited to, ongoing or active
untreated infection, or psychiatric illness/social situations that would limit compliance
with study requirements.
Patients with known serious cardiac illness or medical conditions, including but not
- Clinically unstable cardiac disease, including unstable atrial fibrillation,
symptomatic bradycardia, unstable congestive heart failure, unstable angina or
history of myocardial infarct within 6 months prior to enrollment, or indwelling
- Ventricular tachycardia or a supraventricular tachycardia that requires treatment
with antiarrhythmic agents
- Second- or third-degree atrioventricular block unless treated with a permanent
- Complete left bundle branch block
- History of long QT syndrome or a family member with this condition
No major surgery within 4 weeks prior to enrollment or history of gastrointestinal
bleeding within 3 months prior to enrollment. No signs or symptoms of active bleeding or
nonhealing ulcer will be permitted at study entry. Patients with central pulmonary tumors
with evidence of bronchial invasion, or presenting with hemoptysis will be excluded.
QTc > 470 msec on electrocardiogram (by Bazett s; average of triplicate recordings at
the discretion of the PI) will exclude patients from entry on study. Medications that are
known to cause QTc interval prolongation are prohibited for patients entering on trial.
Patients for whom a given medication that may cause QTc interval prolongation cannot be
discontinued, may be eligible at the discretion of the study PI, provided QTc interval
criteria is met at enrollment. A comprehensive list of agents with the potential to cause
QTc prolongation can be found in Appendix C and at http://crediblemeds.org.
Pregnant women and women who are breastfeeding are excluded from this study because the
effects of the study drugs on the developing fetus are unknown.
HIV-positive patients on combination antiretroviral therapy are ineligible because of the
potential for pharmacokinetic interactions with ganetespib and zivaflibercept. In
addition, these patients are at increased risk of lethal infections when treated with
marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving
combination antiretroviral therapy when indicated.
Substrates of CYP3A4 or CYP2C19
Preliminary results of a clinical drug-drug interaction study, examining the effect of
ganetespib on the pharmacokinetics of the CYP2C19-sensitive probe omeprazole,show a modest
(20%) increase in omeprazole exposure when coadministered with ganetespib. In vitro data
implies expectation of greater interaction with CYP2C19substrates than with CYP3A4
substrates. Caution is advised when sensitive narrow therapeutic range CYP3A4 or CYP2C19
substrates are concomitantly administered.
Inhibitors of P-Glycoprotein Efflux Transporters
Concomitant medications that are strong inhibitors of P-glycoprotein efflux transporters
should be used with caution during the study; examples of these medications include
ritonavir, cyclosporine, verapamil, erythromycin, ketoconazole, itraconazole, quinidine,
Concurrent anticoagulation will be permitted providing the patient is receiving a stable
dose of anticoagulants before study entry. Patients receiving anticoagulants will be
eligible for this trial. Evidence of clinically significant bleeding diathesis or
underlying coagulopathy (e.g., INR > 1.5 without vitamin K antagonist therapy) will not
Minimum Eligible Age: 18 Years
Maximum Eligible Age: N/A
Eligible Gender: Both