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

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ClinicalTrials.gov Identifier: NCT02192541
Recruitment Status : Terminated (Drug supplier suspended further clinical development of Ganetespib)
First Posted : July 17, 2014
Results First Posted : January 30, 2018
Last Update Posted : March 29, 2018
Sponsor:
Information provided by (Responsible Party):
Alice Chen, M.D., National Institutes of Health Clinical Center (CC)

Brief 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.

Condition or disease Intervention/treatment Phase
Neoplasms Drug: Ziv-Aflibercept Drug: Ganetespib Phase 1

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 5 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study of Ganetespib and Ziv-Aflibercept in Patients With Advanced Gastrointestinal Carcinomas, Non-Squamous Non-Small Cell Lung Carcinomas, Urothelial Carcinomas, and Sarcomas
Actual Study Start Date : December 2, 2014
Actual Primary Completion Date : February 25, 2016
Actual Study Completion Date : February 25, 2016


Arm Intervention/treatment
Experimental: Ganetespib and Ziv-Aflibercept
Ganetespib was administered intravenously, over 1 hour, weekly, on days 1, 8, and 15 of each 28-day cycle. Ziv-aflibercept was administered intravenously, over 1 hour, every 2 weeks, on days 1 and 15 of each 28-day cycle. Ganetespib was started at a dose level of 100 mg/m^2 + ziv-aflibercept at 3 mg/kg or 4 mg/kg.
Drug: Ziv-Aflibercept
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
Other Names:
  • ZALTRAP
  • VEGF-TRAP

Drug: Ganetespib
Ganetespib is a non-geldamycin synthetic inhibitor of Hsp90 with activity against multiple cancer cell lines and tumor xenografts in preclinical models.
Other Name: STA-9090




Primary Outcome Measures :
  1. Number of Participants With Serious and Non-serious Adverse Events Regardless of Attribution Assessed by the Common Terminology Criteria in Adverse Events (CTCAE) v4.0 [ Time Frame: Date treatment consent signed to date off study, approximately 12 months and 44 days ]
    Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

  2. Number of Participants With Grade 2 or Greater Adverse Events Possibly, Probably, or Definitely Related to Administration of the Study Drugs [ Time Frame: Date treatment consent signed to date off study, approximately 12 months and 44 days ]
    Adverse Events were graded according to Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. Grade refers to the severity of the Adverse Event. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to adverse event (AE). AEs were considered possibly attributable to both study drugs, except where otherwise noted. Star (*) symbol indicates that the AE is possibly related to Ziv-aflibercept and unlikely to be related to Ganetespib.

  3. Maximum Tolerated Dose (MTD) of the Combination of Ganetespib and Ziv-aflibercept [ Time Frame: Cycle one (28 days) ]
    MTD is defined as the dose level at which no more than 1 of 6 patients experience a dose limiting toxicity (DLT) during the first cycle of the treatment, and the dose level below that at which at least 2 (of <6) patients have a DLT as a result of the drug. Determination of DLT is based on the first cycle of treatment.


Secondary Outcome Measures :
  1. Modulation of Hypoxia-Inducible Factor 1 (HIF-1) Alpha [ Time Frame: Cycle 2, Day 7 ]
    To determine whether the combination of ganetespib and ziv-aflibercept modulated intratumoral Hypoxia-inducible factor 1 (HIF-1)-alpha expression, tumor biopsies were to be analyzed for change in HIF-1-alpha expression by immunofluorescence assay (IFA). Paired pre-and post-combination treatment samples were to be compared for qualitative changes in levels of HIF-1- alpha expression. Cores were to be normalized against the percentage of tumor within the sample.

  2. Modulation of Epidermal Growth Factor Receptor (EGFR) Expression [ Time Frame: Cycle 1 Day 16 ]
    To evaluate for tumor distribution of EGFR, patients were to undergo 89Zr-immuno-positron emission tomography (PET) imaging with 89Zr-labeled EGFR-targeting panitumumab antibody evaluate modulation of EGFR client protein prior to and after treatment with the combination of ganetespib and ziv-aflibercept. Panitumumab is a fully human monoclonal antibody that targets EGFR and competes with endogenous ligands to block stimulation of EGFR. 89z-immuno-PET imaging with panitumumab as a targeting ligand allows for quantification of EGFR within tumors.

  3. Number of Participants According to Best Response Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) [ Time Frame: Baseline and every 2 months up to 5 months ]
    Radiologic response assessments by computed tomography (CT) scans were performed at baseline and every two cycles to evaluate tumor response based on the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Per Response Evaluation Criteria In Solid Tumors Criteria for target lesions: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for a Partial Response nor sufficient increase to qualify for Progressive Disease (PD); PD, 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Complete Response (CR), Disappearance of all target lesions.

  4. Number of Cycles on Treatment [ Time Frame: up to 5 months ]
    The number of 28-day treatment cycles (ganetespib on days 1, 8, and 15; ziv-aflibercept on days 1 and 15) administered to each evaluable patient. Number represents treatment cycles that were started; not all cycles were completed.


Other Outcome Measures:
  1. Number of Participants Who Had a Dose Limiting Toxicity (DLT) [ Time Frame: Cycle one (28 days) ]
    A DLT is defined as an adverse event that is related (possibly, probably, or definitely) to administration of study drugs during cycle one and is a Grade ≥ 3 non-hematological toxicity. Grade ≥3 non-hematological toxicity felt to be related to study medications are: Grade 3 diarrhea if it is refractory to treatment; Grade 3 nausea and vomiting if it is refractory to anti-emetic therapy and unable to be corrected; rise in creatinine to Grade 3, not corrected to Grade 1 or less within 48 hours with intravenous (IV) fluids; Any Grade 4 corrected QT interval (QTc) prolongation; Grade 4 neutropenia ≥5 days or febrile neutropenia,...).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 120 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02192541


Locations
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United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Alice P Chen, M.D. National Cancer Institute (NCI)
  Study Documents (Full-Text)

Documents provided by Alice Chen, M.D., National Institutes of Health Clinical Center (CC):
Informed Consent Form  [PDF] February 3, 2016


Additional Information:
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Alice Chen, M.D., Principal Investigator, National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier: NCT02192541     History of Changes
Other Study ID Numbers: 140150
14-C-0150
First Posted: July 17, 2014    Key Record Dates
Results First Posted: January 30, 2018
Last Update Posted: March 29, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Alice Chen, M.D., National Institutes of Health Clinical Center (CC):
Urothelial Carcinomas
Non-Squamous Non-Small Cell Lung Carcinomas
Refractory Gastrointestinal Carcinomas
Hsp90 Inhibitor
Sarcomas
Additional relevant MeSH terms:
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Carcinoma
Sarcoma
Carcinoma, Transitional Cell
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Connective and Soft Tissue
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms