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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

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ClinicalTrials.gov Identifier: NCT02420847
Recruitment Status : Active, not recruiting
First Posted : April 20, 2015
Last Update Posted : July 20, 2018
Sponsor:
Collaborator:
Millennium Pharmaceuticals, Inc.
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief 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.

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.


Condition or disease Intervention/treatment Phase
Bladder Cancer Drug: Ixazomib Drug: Gemcitabine Drug: Doxorubicin Phase 1 Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 50 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : July 3, 2015
Estimated Primary Completion Date : July 2021
Estimated Study Completion Date : July 2022


Arm Intervention/treatment
Experimental: Ixazomib + Gemcitabine + Doxorubicin

Phase I

Starting dose of Ixazomib 4.0 mg by mouth on Day 1 of every 14-day cycle. Starting dose of Gemcitabine 10 mg/m2/min by vein on Day 1 of each 14 day cycle.

Starting dose of Doxorubicin 33 mg/m2 by vein on Day 1 of each 14 day cycle.

Phase II Starting doses of Ixazomib, Gemcitabine, and Doxorubicin is maximum tolerated dose (MTD) from Phase I.

Drug: Ixazomib

Phase I Starting Dose of Ixazomib: 4.0 mg by mouth on Day 1 of every 14-day cycle.

Phase II Starting Dose of Ixazomib: MTD from Phase I.


Drug: Gemcitabine

Phase I Starting Dose of Gemcitabine: 10 mg/m2/min by vein on Day 1 of each 14 day cycle.

Phase II Starting Dose of Gemcitabine: MTD from Phase I.

Other Names:
  • Gemcitabine hydrochloride
  • Gemzar

Drug: Doxorubicin

Phase I Starting Dose of Doxorubicin: 33 mg/m2 by vein on Day 1 of each 14 day cycle.

Phase II Starting Dose of Doxorubicin: MTD from Phase I.

Other Names:
  • Doxorubicin hydrochloride
  • Adriamycin PFS
  • Rubex
  • Adriamycin RDF
  • Adriamycin




Primary Outcome Measures :
  1. Maximum Tolerated Doses (MTDs) for Combination of Ixazomib and Gemcitabine/Doxorubicin [ Time Frame: 14 days ]
    Maximum tolerated doses (MTDs) identified for the combination therapy of Ixazomib and Gemcitabine/Doxorubicin (i.e. dose pairs that have an acceptable target toxicity rate of 30%). Gemcitabine and Doxorubicin are given together thus considered as one combination-dose in the study design. NCI-CTCAE v4.0 criteria used for assessment of toxicity.


Secondary Outcome Measures :
  1. Objective Response [ Time Frame: 6 weeks ]
    Complete response defined as resolution of all cancer related symptoms, normalization of tumor markers, and disappearance of radiographic evidence of disease. Partial response defined as a ≥ 50% decrease in disease volume with no evidence of progression in any site. Overall patient success (Major Response) requires ≥ 90% reduction of tumor volume that is sustained, with no evidence of progression after initial response. In addition, all cancer-related symptoms must be resolved. Progressive disease defined as a ≥ 25% increase in tumor volume from baseline.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. All patients must have histologic demonstration of metastatic or locally unresectable transitional cell carcinoma of the urothelium. Variant histology is allowed as long as there is an urothelial component present. The PI 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 </= 3 x the upper limit of normal.
  8. ECOG performance status (PS) </= 2. Patients with a PS of 3 are eligible if the performance status is due to their malignancy, and not a co-morbid medical condition (ex: perineal pain impacting their ability to sit or ambulate, etc.)
  9. Male or Female patients 18 years or older who: a) Are postmenopausal for at least 1 year before the screening visit, OR; b) Are surgically sterile, OR; c) If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of study drug, OR ; d) Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.); Male patients, even if surgically sterilized (ie, status post-vasectomy), must agree to one of the following: e) Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR;
  10. (Cont. #9) f) Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)
  11. Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.

Exclusion Criteria:

  1. Platelet count of < 100 x 10^9/L. Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days before study enrollment.
  2. An absolute neutrophil count of < 1.0 x 10^9/L.
  3. A calculated creatinine clearance of < 30 mL/min using Cockcroft Gault or measured by 24 hour urine
  4. Patient has >/= 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 1 toxicity) from the reversible effects of prior chemotherapy.
  15. Major surgery within 14 days before enrollment. The PI will serve as the final arbiter as to what constitutes major surgery.
  16. Infection requiring current intravenous antibiotic therapy. The PI will serve as the final arbiter regarding eligibility.
  17. Ongoing or active systemic infection with the following: known active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive.
  18. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
  19. Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib including difficulty swallowing. Patients who have had cystectomy with conduit, neobladder, or pouch using a portion of their terminal ileum are allowed if, the patient is stable without clinically significant metabolic disturbances OR stoma- and/or anastomosis-related complications OR post-surgical gut abnormalities that would compromise drug absorption.
  20. Patient has >/= Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical examination during the screening period.

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): NCT02420847


Locations
United States, Texas
University of Texas MD Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
Millennium Pharmaceuticals, Inc.
Investigators
Principal Investigator: Arlene Siefker-Radtke, MD M.D. Anderson Cancer Center

Additional Information:
Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT02420847     History of Changes
Other Study ID Numbers: 2014-0661
NCI-2015-00682 ( Other Identifier: NCI CTRP )
First Posted: April 20, 2015    Key Record Dates
Last Update Posted: July 20, 2018
Last Verified: July 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by M.D. Anderson Cancer Center:
Bladder cancer
Urothelial cancer
Transitional cell carcinoma of the urothelium
Metastatic
Locally unresectable
Ixazomib
Gemcitabine
Gemcitabine hydrochloride
Gemzar
Doxorubicin
Doxorubicin hydrochloride
Adriamycin PFS
Adriamycin RDF
Adriamycin
Rubex

Additional relevant MeSH terms:
Urinary Bladder Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Urinary Bladder Diseases
Urologic Diseases
Gemcitabine
Doxorubicin
Ixazomib
Liposomal doxorubicin
Glycine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Protease Inhibitors
Glycine Agents
Neurotransmitter Agents