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

Phase 1

Terminated

Brief Summary: 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: 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.

Recruitment & Eligibility

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

Arm && Interventions

Group	Intervention	Description
Phase 1 - Cohort 3	AEZS-108	Determination of maximum tolerated dose (MTD) and recommended parenteral administration dosing for AEZS-108 in 4 sequential cohorts of patients (3-6 patients/cohort).
Phase 1 - Cohort 4	AEZS-108	Determination of maximum tolerated dose (MTD) and recommended parenteral administration dosing for AEZS-108 in 4 sequential cohorts of patients (3-6 patients/cohort).
Phase 1 - Cohort 2	AEZS-108 at MTD	Determination of maximum tolerated dose (MTD) and recommended parenteral administration dosing for AEZS-108 in 4 sequential cohorts of patients (3-6 patients/cohort).
Phase 2	AEZS-108	AEZS-108 at MTD to determine efficacy in up to 40 patients.
Phase 1 - Cohort 1	AEZS-108	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.

Primary Outcome Measures

Name	Time	Method
Maximum tolerated dose (MTD)	Day 1 of each 21-day cycle	Toxicity per Common Terminology Criteria for Adverse Events (CTCAE).

Secondary Outcome Measures

Name	Time	Method
Progression-free survival (PFS)	last cycle	Time elapsed from the start of treatment to the date of documented progression or death, whichever comes first.
Overall survival	last cycle	Time elapsed from the start of treatment until death.
Objective tumor response	Within 5 days of cycle 4, then every 3 cycles	Response evaluation criteria in solid tumors (RECIST) criteria.
Pharmacokinetics (PK)	cycle 1	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.
Circulating tumor cell (CTC) levels	last cycle	To quantify tumor cells and attempt to correlate their presence and response to the outcomes of this study.

Locations (2): University of Miami Miller School of Medicine
🇺🇸
Miami, Florida, United States
Univerity of Pennsylvania
🇺🇸
Philadelphia, Pennsylvania, United States