A Phase I/II Trial of AEZS-108 in Urothelial Cancer Patients Who Failed Platinum-chemotherapy

Study Overview
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Brief Summary
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The purpose of this study is to determine the appropriate dose of AEZS-108 to treat patients with a tumor of the urinary system.

Detailed Description
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AEZS-108 is an investigational drug, combining luteinizing hormone-releasing hormone (LHRH), an hormone and doxorubicin (a drug approved to treat different types of cancer). Some tumors, such as those found in the urinary system (also called urothelial carcinomas), have LHRH hormone receptors to which the LHRH hormone part of AEZS-108 is attracted. AEZS-108 is expected to work by accumulating mostly on the surface of cancer cells that have LHRH hormone receptors and by delivering doxorubicin more directly into the cells to kill them. This would allow the use doxorubicin at lower doses and thus would cause less toxicity. In the first part of the study, the appropriate dose of AEZS-108 will be determined based on its side effects. The best dose will be the highest one without severe side effects. In the second part of the study, this best dose of AEZS-108 will be given to determine its efficacy to stop the tumor from progressing.

Official Title
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A Phase I/II Trial of AEZS-108 in Locally Advanced Unresectable or Metastatic Luteinizing Hormone-releasing Hormone(LHRH) Positive Urothelial Carcinoma Patients Who Failed Platinum Based Chemotherapy

Conditions
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Urothelial Carcinoma

Intervention / Treatment
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* Drug: AEZS-108
* Drug: AEZS-108 at MTD


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed locally advanced or metastatic urothelial carcinoma Expression of LHRH receptors confirmed by immunohistochemistry on archival cancer tissue Measurable disease on radiological studies Patients with Locally advanced unresectable or metastatic urothelial carcinoma Documented progression on at least one prior chemotherapy regimen which must have incorporated platinum based therapy Left ventricular ejection fraction (EF) > 50% Eastern cooperative oncology group (ECOG) status of 0, 1 or 2 Adequate bone marrow, renal and hepatic function Exclusion Criteria: Prior treatment with or allergy to any components of AEZS-108 Active second malignancies other than non-melanoma skin cancers Ongoing use of an LHRH agonist (or antagonist) Presence of an active infection or fever > 38.5 C, parenchymal brain metastases or uncontrolled intercurrent illness Prior exposure to anthracyclines or anthracenediones including doxorubicin, daunorubicin, and mitoxantrone Patients who received radiotherapy within 4 weeks of entry Major surgery within the last 4 weeks and minor surgery in last 7 days

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Phase 1 : conventional 3+3 design. Phase 2: Simon's two-stage design will be utilized. In Stage I, 22 patients will be treated with the dose determined in Phase I. The study will be terminated for futility if no more than 2 patients out of the 22 patients in Stage I are responders. If 3 or more responders are observed, an additional 18 patients will be enrolled. If at least 8 out of the 40 patients are responders, the treatment will be considered worthy of further development.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 - Cohort 1<br>Determination of maximum tolerated dose (MTD) and recommended parenteral administration dosing for AEZS-108 in 4 sequential cohorts of patients (3-6 patients/cohort). Patients will be enrolled in cohorts of 3 at a specified AEZS-108 dose beginning with 160mg/m^2. Enrollment will be suspended until all members of a cohort have been observed for dose limiting toxicities (DLT) for a period of 3 weeks (1 cycle of AEZS-108) from initial treatment with AEZS-108. Dose escalation will proceed within each cohort according to a specific scheme where DLT is defined. | Drug: AEZS-108<br>* 128, 160, 210 or 267 mg/m2, 2-hour intravenous (IV) infusion, Day 1 of 21-day cycles , until toxicity or progression, up to 6 cycles<br>* Other names: D-81858;|
| Experimental: Phase 1 - Cohort 2<br>Determination of maximum tolerated dose (MTD) and recommended parenteral administration dosing for AEZS-108 in 4 sequential cohorts of patients (3-6 patients/cohort). | Drug: AEZS-108 at MTD<br>* 2-hour IV infusion, Day 1 of 21-day cycles , until toxicity or progression, up to 6 cycles<br>* Other names: D-81858;|
| Experimental: Phase 1 - Cohort 3<br>Determination of maximum tolerated dose (MTD) and recommended parenteral administration dosing for AEZS-108 in 4 sequential cohorts of patients (3-6 patients/cohort). | Drug: AEZS-108<br>* 128, 160, 210 or 267 mg/m2, 2-hour intravenous (IV) infusion, Day 1 of 21-day cycles , until toxicity or progression, up to 6 cycles<br>* Other names: D-81858;|
| Experimental: Phase 1 - Cohort 4<br>Determination of maximum tolerated dose (MTD) and recommended parenteral administration dosing for AEZS-108 in 4 sequential cohorts of patients (3-6 patients/cohort). | Drug: AEZS-108<br>* 128, 160, 210 or 267 mg/m2, 2-hour intravenous (IV) infusion, Day 1 of 21-day cycles , until toxicity or progression, up to 6 cycles<br>* Other names: D-81858;|
| Experimental: Phase 2<br>AEZS-108 at MTD to determine efficacy in up to 40 patients. | Drug: AEZS-108<br>* 128, 160, 210 or 267 mg/m2, 2-hour intravenous (IV) infusion, Day 1 of 21-day cycles , until toxicity or progression, up to 6 cycles<br>* Other names: D-81858;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) | Toxicity per Common Terminology Criteria for Adverse Events (CTCAE). | Day 1 of each 21-day cycle | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective tumor response | Response evaluation criteria in solid tumors (RECIST) criteria. | Within 5 days of cycle 4, then every 3 cycles | 
| Progression-free survival (PFS) | Time elapsed from the start of treatment to the date of documented progression or death, whichever comes first. | last cycle | 
| Pharmacokinetics (PK) | To evaluate PK parameters of a single dose AEZS-108 and explore whether the PK parameters are associated with cardiac effects as measured by electrocardiography. | cycle 1 | 
| Overall survival | Time elapsed from the start of treatment until death. | last cycle | 
| Circulating tumor cell (CTC) levels | To quantify tumor cells and attempt to correlate their presence and response to the outcomes of this study. | last cycle | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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bladder cancer, ureter cancer, renal pelvis cancer, urethra