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

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ClinicalTrials.gov Identifier: NCT01234519
Recruitment Status : Terminated (Poor recruitment)
First Posted : November 4, 2010
Last Update Posted : March 15, 2018
Sponsor:
Collaborators:
University of Miami
Miami VA Healthcare System
University of Miami Sylvester Comprehensive Cancer Center
Information provided by (Responsible Party):
AEterna Zentaris

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.

Condition or disease Intervention/treatment Phase
Urothelial Carcinoma Drug: AEZS-108 Drug: AEZS-108 at MTD Phase 1 Phase 2

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  (Clinical Trial)
Actual Enrollment : 12 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention 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)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : November 2010
Actual Primary Completion Date : November 2014
Actual Study Completion Date : November 2014

Resource links provided by the National Library of Medicine

U.S. FDA Resources

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



Primary Outcome Measures :
  1. Maximum tolerated dose (MTD) [ Time Frame: Day 1 of each 21-day cycle ]
    Toxicity per Common Terminology Criteria for Adverse Events (CTCAE).


Secondary Outcome Measures :
  1. Objective tumor response [ Time Frame: Within 5 days of cycle 4, then every 3 cycles ]
    Response evaluation criteria in solid tumors (RECIST) criteria.

  2. Progression-free survival (PFS) [ Time Frame: last cycle ]
    Time elapsed from the start of treatment to the date of documented progression or death, whichever comes first.

  3. Pharmacokinetics (PK) [ Time Frame: 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.

  4. Overall survival [ Time Frame: last cycle ]
    Time elapsed from the start of treatment until death.

  5. Circulating tumor cell (CTC) levels [ Time Frame: last cycle ]
    To quantify tumor cells and attempt to correlate their presence and response to the outcomes of this study.



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

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

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): NCT01234519


Locations
United States, Florida
University of Miami Miller School of Medicine
Miami, Florida, United States, 33136
United States, Pennsylvania
Univerity of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
Sponsors and Collaborators
AEterna Zentaris
University of Miami
Miami VA Healthcare System
University of Miami Sylvester Comprehensive Cancer Center
Investigators
Principal Investigator: Gustavo Fernandez, MD University of Miami

Responsible Party: AEterna Zentaris
ClinicalTrials.gov Identifier: NCT01234519     History of Changes
Other Study ID Numbers: AEZS-108-046
EProst # 20091095 ( Other Identifier: Sylvester Comprehensive Cancer Center )
First Posted: November 4, 2010    Key Record Dates
Last Update Posted: March 15, 2018
Last Verified: March 2013

Keywords provided by AEterna Zentaris:
ureter cancer
renal pelvis cancer
bladder cancer
urethra

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Transitional Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Prolactin Release-Inhibiting Factors
Doxorubicin
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antibiotics, Antineoplastic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action