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

Phase 1

Terminated

Conditions: Neoplasms

Interventions: Drug: Ziv-Aflibercept
Drug: Ganetespib

Registration Number: NCT02192541

Lead Sponsor: National Cancer Institute (NCI)

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.

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 vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGFR), hypoxia-inducible factor 1 (HIF-1), signal transducers and activators of transcription protein 3 (STAT-3); growth factor independence rapidly accelerated fibrosarcoma (RAF), epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (Her2), insulin-like growth factor 1 receptor (IGFR); resistance to anti-growth signals cyclin-dependent kinase 4 (CDK4); tissue invasion and metastases mesenchymal-epithelial transition factor (MET), matrix metalloproteinase-2 (MMP2); and avoidance of apoptosis protein kinase B (AKT), rat insulin promoter (RIP), Survivin, B cell lymphoma (Bcl-2).

* HIF-1-alpha 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 vascular endothelial growth factor A (VEGF-A), vascular endothelial growth factor B (VEGF-B), and placenta growth factor (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 HIF-1-alpha as a pharmacodynamic marker of therapy with the combination of ganetespib and Ziv-Aflibercept

* To assess modulation of epidermal growth factor receptor (EGFR) expression using 89Zr-labeled, EGFR-targeting antibody panitumumab positron emission tomography (PET)/computed tomography (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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 5

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Ganetespib and Ziv-Aflibercept	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.
Ganetespib and Ziv-Aflibercept	Ganetespib	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.

Primary Outcome Measures

Name	Time	Method
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	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.
Number of Participants With Grade 2 or Greater Adverse Events Possibly, Probably, or Definitely Related to Administration of the Study Drugs	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.
Maximum Tolerated Dose (MTD) of the Combination of Ganetespib and Ziv-aflibercept	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

Name	Time	Method
Modulation of Hypoxia-Inducible Factor 1 (HIF-1) Alpha	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.
Modulation of Epidermal Growth Factor Receptor (EGFR) Expression	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.
Number of Participants According to Best Response Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1)	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.
Number of Cycles on Treatment	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.