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A Two-Dimensional Dose-Finding Study of Ixazomib in Combination With Gemcitabine and Doxorubicin, Followed by a Phase II Extension to Assess the Efficacy of This Combination in Metastatic, Surgically Unresectable Urothelial Cancer

Information source: M.D. Anderson Cancer Center
ClinicalTrials.gov processed this data on August 20, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Bladder Cancer

Intervention: Ixazomib (Drug); Gemcitabine (Drug); Doxorubicin (Drug)

Phase: Phase 1/Phase 2

Status: Recruiting

Sponsored by: M.D. Anderson Cancer Center

Official(s) and/or principal investigator(s):
Arlene Siefker-Radtke, MD, Principal Investigator, Affiliation: M.D. Anderson Cancer Center

Overall contact:
Arlene Siefker-Radtke, MD, Phone: 713-792-2830

Summary

This clinical research study is made up of 2 phases. The goal of Phase 1 of this study is to learn the highest tolerated dose of the combination of ixazomib, gemcitabine, and doxorubicin that can be given to patients with urothelial cancer. The goal of Phase 2 of this study is to learn if the combination of ixazomib, gemcitabine, and doxorubicin can help to control urothelial cancer. The safety of the drug combinations will be studied in both phases.

Clinical Details

Official title: A Phase I Two-Dimensional Dose-Finding Study of Ixazomib in Combination With Gemcitabine and Doxorubicin, Followed by a Phase II Extension to Assess the Efficacy of This Combination in Metastatic, Surgically Unresectable Urothelial Cancer

Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Maximum Tolerated Doses (MTDs) for Combination of Ixazomib and Gemcitabine/Doxorubicin

Secondary outcome: Objective Response

Detailed description: Study Groups: If you are found to be eligible to take part in this study, you will be assigned to a study group based on when you join this study. Up to 6 groups of up to 4 participants will be enrolled in Phase 1 of the study, and up to 33 participants will be enrolled in Phase 2. If you are enrolled in Phase 1, the combination dose of ixazomib, gemcitabine, and doxorubicin you receive will depend on when you join this study. The first group of participants will receive the lowest combination dose level. Each new group will receive a higher dose of the drug combination than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of the drug combination is found. If you are enrolled in Phase 2, you will receive the drug combination at the highest dose that was tolerated in Phase 1. Study Drug Administration: On Day 1 of every 14-day cycle, you will take ixazomib 1 time by mouth, receive gemcitabine by vein over about 90 minutes, and receive doxorubicin by vein over 15-30 minutes. Gemcitabine and doxorubicin may be given through a catheter. A catheter is a sterile flexible tube that will be placed into a large vein while you are under anesthesia. Your doctor will explain this procedure to you in more detail, and you will be required to sign a separate consent form. You should not chew, break, or open the capsules of ixazomib. If the capsules break, be careful not to spread their dust while cleaning it up. The product may be harmful to breathe in, swallow, or touch. Gloves and protective clothing should be worn during cleanup and return of broken capsules and powder to minimize skin contact. The area should be ventilated and the site washed with soap and water after material pick-up is complete. The material should be disposed of as hazardous medical waste in compliance with federal, state, and local regulations. In case of contact with the powder (such as from a broken capsule), skin should be washed right away with soap and large amounts of water for at least 15 minutes. In case of contact with the eyes, large amounts of water should be used to flush the eyes for at least 15 minutes. Call the study staff right away if this happens. Study Visits: On Day 1 of each cycle:

- You will have a physical exam.

- Blood (about 3-4 tablespoons) will be drawn for routine tests.

- Every 3 cycles starting with Cycle 4 (Cycles 4, 7, 10, and so on), you will also have

an x-ray and CT scans or MRIs to check the status of the disease. On Day 8 of Cycles 1 and 2, blood (about 3-4 tablespoons) will be drawn for routine tests. If the disease gets worse, you will have either an ECHO or MUGA scan to check your heart function. At any time that the doctor thinks it is needed, you will have a bone scan to check the status of the disease. Length of Treatment: You may continue receiving the study drugs for as long as the doctor thinks it is in your best interest. You may no longer be able to take the study drugs if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions. This is an investigational study. Ixazomib is not FDA approved or commercially available for the treatment of urothelial cancer. Gemcitabine and doxorubicin are FDA approved and commercially available for several other types of cancer. Their use in combination with ixazomib in urothelial cancer is investigational. The study doctor can explain how the study drugs are designed to work. Up to 57 participants will be enrolled in this study. All will take part at MD Anderson.

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria: 1. All patients must have histologic demonstration of metastatic or locally unresectable transitional cell carcinoma of the urothelium. Minor components (<50% overall) of variant such as glandular or squamous differentiation, or evolution to more aggressive phenotypes such as sarcomatoid or small cell change are acceptable. The PI, Dr. Siefker-Radtke, will serve as the final arbiter of eligibility. 2. All patients must have measurable or evaluable disease. In general, liver and lung lesions should be at least 1 cm, and patients with node-only disease should have lesions of >/= 1. 5 cm in greatest dimension. Patients with disease confined to bone may be eligible if a measurable lytic defect is present or a serum marker is elevated (>4 x ULN). The Principal Investigator is the final arbiter in questions related to measurability. Patients with a three-dimensional mass or pelvic sidewall fixation on bladder examination under anesthesia are considered to have measurable disease. 3. Patients must have had at least one prior therapy to be eligible for either phase I or II, unless they are either not candidates for or refuse cisplatin-based therapy. 4. Phase I: Patients are eligible with any number of prior regimens regardless of what those regimens contained (i. e. prior Bortezomib or combination gemcitabine and adriamycin is acceptable). 5. Phase II: patients are eligible if their previous chemotherapy regimen did not contain bortezomib, carfilzomib, or other known proteasome inhibitor or a combination of gemcitabine >/= 800 mg/m^2 plus adriamycin >/= 30 mg/m^2. Patients who receive sequential or alternating therapy as part of front-line treatment will be counted as having one prior regimen. Patients who have failed prior neoadjuvant chemotherapy will be eligible for this trial. 6. If prior history of ischemic heart disease or exposure to 200 mg/m^2 of doxorubicin, patients must have a measured ejection fraction (either by MUGA, ECHO, stress test, or ventriculography) of at least 45%. 7. Have preserved hepatic function as shown by alanine aminotransferase (ALT) and AST (SGOT) levels /= Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical examination during the screening period. 5. Total bilirubin >/= 1. 5 x the upper limit of the normal range (ULN). 6. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent. 7. Female subject is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotropin (beta-hCG) pregnancy test (Unless there is reasonable certainty that beta-hCG is coming from the tumor). Pregnancy testing is not required for post-menopausal or surgically sterilized women. 8. Participation in other clinical trials with investigational agents not included in this trial, within 30 days of the start of this trial and throughout the duration of this trial. 9. Patients with significant atherosclerotic disease, as defined by: a) Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure (See Appendix 5) uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.; b) Symptomatic congestive heart failure.; c) Claudication limiting activity and ; d) History of cerebrovascular events within the last year (including TIA).; e) Unstable angina. 10. Patients with known active brain metastases. [Subjects with previously treated brain metastases are eligible provided they are stable (defined as without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment) and neurologic symptoms have returned to baseline.] 11. Radiotherapy within 28 days before enrollment. If the involved field is small, 14 days will be considered a sufficient interval between treatment and administration of the therapy. 12. Diagnosed or treated for another malignancy within 2 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with pathologically confirmed completely resected prostate cancer no higher than stage pT2a and no biochemical relapse, or pT2c tumors involving less than 5% of the prostate and no biochemical relapse, nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection. 13. Systemic treatment, within 14 days before the first dose of ixazomib, with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort. 14. Failure to have fully recovered (ie, /= Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical examination during the screening period.

Locations and Contacts

Arlene Siefker-Radtke, MD, Phone: 713-792-2830

University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States; Recruiting
Additional Information

University of Texas MD Anderson Cancer Center Website

Starting date: July 2015
Last updated: July 6, 2015

Page last updated: August 20, 2015

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