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

NCT02192541 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: 14015014-C-0150
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

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.

Conditions

Neoplasms

Keywords

Urothelial Carcinomas; Non-Squamous Non-Small Cell Lung Carcinomas; Refractory Gastrointestinal Carcinomas; Hsp90 Inhibitor; Sarcomas

Outcome Measures

Primary Outcomes (3)

• 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

  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.

  Date treatment consent signed to date off study, approximately 12 months and 44 days

• Number of Participants With Grade 2 or Greater Adverse Events Possibly, Probably, or Definitely Related to Administration of the Study Drugs

  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.

  Date treatment consent signed to date off study, approximately 12 months and 44 days

• Maximum Tolerated Dose (MTD) of the Combination of Ganetespib and Ziv-aflibercept

  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.

  Cycle one (28 days)

Secondary Outcomes (4)

• Modulation of Hypoxia-Inducible Factor 1 (HIF-1) Alpha

  Cycle 2, Day 7

• Modulation of Epidermal Growth Factor Receptor (EGFR) Expression

  Cycle 1 Day 16

• 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

• Number of Cycles on Treatment

  up to 5 months

Other Outcomes (1)

• Number of Participants Who Had a Dose Limiting Toxicity (DLT)

  Cycle one (28 days)

Study Arms (1)

Ganetespib and Ziv-Aflibercept

EXPERIMENTAL

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; Drug: Ganetespib

Interventions

Ziv-Aflibercept DRUG

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

Also known as: ZALTRAP, VEGF-TRAP

Ganetespib and Ziv-Aflibercept

Ganetespib DRUG

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

Also known as: STA-9090

Ganetespib and Ziv-Aflibercept

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• creatinine clearance greater than or equal to 60 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011 Mar 4;144(5):646-74. doi: 10.1016/j.cell.2011.02.013.

  PMID: 21376230 BACKGROUND

• Bottsford-Miller JN, Coleman RL, Sood AK. Resistance and escape from antiangiogenesis therapy: clinical implications and future strategies. J Clin Oncol. 2012 Nov 10;30(32):4026-34. doi: 10.1200/JCO.2012.41.9242. Epub 2012 Sep 24.

  PMID: 23008289 BACKGROUND

• Stravopodis DJ, Margaritis LH, Voutsinas GE. Drug-mediated targeted disruption of multiple protein activities through functional inhibition of the Hsp90 chaperone complex. Curr Med Chem. 2007;14(29):3122-38. doi: 10.2174/092986707782793925.

  PMID: 18220746 BACKGROUND

• Meehan R, Kummar S, Do K, O'Sullivan Coyne G, Juwara L, Zlott J, Rubinstein L, Doroshow JH, Chen AP. A Phase I Study of Ganetespib and Ziv-Aflibercept in Patients with Advanced Carcinomas and Sarcomas. Oncologist. 2018 Nov;23(11):1269-e125. doi: 10.1634/theoncologist.2018-0203. Epub 2018 May 31.

  PMID: 29853657 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Neoplasms; Sarcoma

Interventions

aflibercept; STA 9090

Condition Hierarchy (Ancestors)

Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type

Results Point of Contact

• Title: Alice P. Chen, M.D.
• Organization: National Cancer Institute

chenali@mail.nih.gov

(240) 781-3320

Study Officials

• Alice P Chen, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: July 15, 2014
• First Posted: July 17, 2014
• Study Start: December 2, 2014
• Primary Completion: February 25, 2016
• Study Completion: February 25, 2016
• Last Updated: March 29, 2018
• Results First Posted: January 30, 2018

Record last verified: 2018-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)