Ganetespib and Ziv-Aflibercept in Refractory Gastrointestinal Carcinomas, Non-Squamous Non-Small Cell Lung Carcinomas, Urothelial Carcinomas, and Sarcomas
Condition: Neoplasms
MeSH terms: Carcinoma; Sarcoma; Carcinoma, Transitional Cell; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Intervention: Ziv-Aflibercept; Ganetespib
Intervention description: Ziv-aflibercept is a soluble fusion protein with high binding affinity for vascular endothelial growth factor A (VEGF-A), vascular endothelial growth factor B (VEGF-B), and placenta growth factor (PIGF) and thus confers anti-angiogenic activity; Ganetespib is a non-geldamycin synthetic inhibitor of Hsp90 with activity against multiple cancer cell lines and tumor xenografts in preclinical models.
Intervention MeSH terms: Aflibercept
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 5.0
Sex: All
Minimum age: 18 Years
Maximum age: 120 Years
Healthy volunteers: No
Keywords: Urothelial Carcinomas; Non-Squamous Non-Small Cell Lung Carcinomas; Refractory Gastrointestinal Carcinomas; Hsp90 Inhibitor; 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 positron emission tomography (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.
    

Eligibility criteria:

        -  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 epidermal growth
             factor receptor (EGFR) mutation and/or anaplastic lymphoma receptor tyrosine kinase
             (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 positron emission tomography (PET)/computed tomography (CT) scans.

        Age greater than or equal to 18 years of age.

        Eastern Cooperative Oncology Group (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

          -  Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase SGOT)/alanine
             aminotransferase (ALT)(serum glutamic pyruvic transaminase 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 m^2 for patients with
             creatinine levels above institutional normal

          -  urine protein/creatinine < 1 mg/mg

          -  International Normalized Ratio (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 Q wave, T wave (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.

        Corrected QT interval (QTc) > 470 msec on electrocardiogram (by Bazett's; average of
        triplicate recordings at the discretion of the principal investigator (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.

        Human immunodeficiency virus (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 cytochrome P450 3A4 (CYP3A4) or cytochrome P450 2C19 (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 CYP2C19 substrates 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.