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

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

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

Study Overview

• Status: Terminated
• Conditions: Urothelial Carcinoma
• Intervention / Treatment: Drug: AEZS-108; Drug: AEZS-108 at MTD

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.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami Miller School of Medicine
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Univerity of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1 - Cohort 1; 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; 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; Other Names: ZEN-008; AN-152; D-81858
Experimental: Phase 1 - Cohort 2; 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; 2-hour IV infusion, Day 1 of 21-day cycles , until toxicity or progression, up to 6 cycles; Other Names: ZEN-008; AN-152; D-81858
Experimental: Phase 1 - Cohort 3; 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; 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; Other Names: ZEN-008; AN-152; D-81858
Experimental: Phase 1 - Cohort 4; 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; 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; Other Names: ZEN-008; AN-152; D-81858
Experimental: Phase 2; AEZS-108 at MTD to determine efficacy in up to 40 patients.	Drug: AEZS-108; 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; Other Names: ZEN-008; AN-152; D-81858

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: AEterna Zentaris
• Collaborators: University of Miami; University of Miami Sylvester Comprehensive Cancer Center; Miami VA Healthcare System
• Investigators: Principal Investigator: Gustavo Fernandez, MD, University of Miami

Study record dates

Study Major Dates

• Study Start: November 1, 2010
• Primary Completion (Actual): November 1, 2014
• Study Completion (Actual): November 1, 2014

Study Registration Dates

• First Submitted: November 2, 2010
• First Submitted That Met QC Criteria: November 2, 2010
• First Posted (Estimate): November 4, 2010

Study Record Updates

• Last Update Posted (Actual): March 15, 2018
• Last Update Submitted That Met QC Criteria: March 13, 2018
• Last Verified: March 1, 2013

More Information

Terms related to this study

• Keywords: bladder cancer; renal pelvis cancer; urethra; ureter cancer
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Carcinoma; Carcinoma, Transitional Cell; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Doxorubicin
• Other Study ID Numbers: AEZS-108-046; EProst # 20091095 (Other Identifier: Sylvester Comprehensive Cancer Center)