Patient case: 61-year-old male with Ampullary carcinoma. Genetic variant: KRAS. Other conditions: None.

Clinical trial: Ganetespib and Ziv-Aflibercept in Refractory Gastrointestinal Carcinomas, Non-Squamous Non-Small Cell Lung Carcinomas, Urothelial Carcinomas, and Sarcomas

Summary: Background:
  - 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.
  Objectives:
  - To test the safety and efficacy of the drug combination of ganetespib and ziv-aflibercept.
  Eligibility:
  - Adults age 18 and over with advanced cancer of the colon, lung, urinary tract, and sarcomas.
  Design:
  -  Participants will be screened with medical history, blood tests, and scans to measure their tumors.
  -  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.

Detailed description: BACKGROUND:
  -  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 VEGF signaling.
  -  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
  PRIMARY OBJECTIVE:
  - 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
  SECONDARY OBJECTIVE:
  -  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 drugs
  ELIGIBILITY:
  -  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 post-treatment biopsies
  -  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.
  STUDY DESIGN:
  -  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 cycle.
  -  PET/CT imaging with 89Zr-labeled panitumumab will be performed to evaluate tumor distribution prior to and following treatment with study agents.

Eligibility: -  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, respectively.
  -  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
  OR
  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 post-treatment biopsies.
  EXCLUSION CRITERIA:
  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
  limited to:
  -  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 temporary pacemaker
  -  Ventricular tachycardia or a supraventricular tachycardia that requires treatment with antiarrhythmic agents
  -  Second- or third-degree atrioventricular block unless treated with a permanent pacemaker
  -  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, and elacridar.
  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 be permitted.

Relevance to patient case: not relevant