Clofarabine Therapy in Locally Advanced or Metastatic Urothelial Carcinoma

Official title

Clofarabine Therapy in Patients With Locally Advanced or Metastatic Urothelial Carcinoma: a Phase 1/2 Dose-Escalation Study

Overview

This phase 1/2 study will evaluate the maximum tolerated dose, efficacy, and safety of clofarabine in patients with advanced or metastatic urothelial cancer.

Detailed description

Clofarabine is an antimetabolite chemotherapeutic agent used as a subsequent line of treatment in pediatric patients with leukemia. In preclinical studies, it showed promising results, surpassing the effectiveness of the current standard of care. The study aims to define the maximum tolerated dose of clofarabine in patients with metastatic or locally advanced urothelial carcinoma. It also seeks to characterize the pharmacokinetics of clofarabine and assess the efficacy, safety, and tolerability of the treatment. The study population consists of patients with histologically confirmed urothelial carcinoma and radiologically documented metastatic or unresectable locally advanced disease, who have already received standard-of-care treatment. The study will be performed using a dose-escalation regimen.

Interventions

• Drug Clofarabine
  Patients receive i.v. clofarabine in a dose-escalation regimen

Primary outcome measures

• Determining the maximum tolerated dose (MTD) [Time frame: From the start of study drug administration through the first 28 days of dosing (Cycle 1), based on the observed incidence of dose-limiting toxicity (DLT) and evaluation of maximum tolerated dose (MTD)]

Secondary outcome measures (7)

• Objective response rate (ORR) [Time frame: From the date of study treatment start until the date of the best documented objective response (for a maximum duration of 36 months).]
• Duration of response (DOR) [Time frame: From the date of the first documented objective response of PR or CR, whichever is noted earlier, to disease progression or death (for a maximum duration of 36 months).]
• Progression-free survival (PFS) [Time frame: From the date of study treatment start until the date of the first observed progression or date of death due to any cause, if death occurs before progression is documented (for a maximum duration of 36 months).]
• Overall survival (OS) [Time frame: From the date of study treatment start until the date of death due to any cause (for a maximum duration of 36 months).]
• Safety and tolerability endpoints [Time frame: Day 1 up to 90 days after last dose of study drug.]
• Area under the concentration-time curve (AUC) [Time frame: Day 1 up to the date of the last dose of study drug.]
• Maximum serum concentration (Cmax) of Clofarabine [Time frame: Day 1 up to the date of the last dose of study drug.]

Eligibility criteria

Inclusion criteria

• Patients with histologically or cytologically confirmed urothelial carcinoma, radiologically documented metastatic or unresectable locally advanced disease
• Patients who have already received standard treatment and did not benefit from it, or patients who have refused standard therapy
• Age ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Absolute neutrophil count (ANC) greater than or equal to 1500.
• White blood cell (WBC) count greater than 3.0.
• Platelets greater than or equal to 100.
• Hemoglobin greater than 9.0 g/dL.
• Adequate hepatobiliary function as indicated by the following laboratory values: Total bilirubin ≤ 1.5 x upper limit of normal (ULN); Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN
• Adequate renal function as indicated by the following laboratory values: Serum creatinine ≤ 1.0 mg/dL; if serum creatinine > 1.0 mg/dL, then the estimated glomerular filtration rate (GFR) must be > 60 mL/min/1.73 m\^2 as calculated by the Modification of Diet in Renal Disease (MDRD) equation
• Adequate cardiac function (NYHA cardiac III-IV excluded)
• Male and female patients must use an effective contraceptive method during the study and for a minimum of 6 months after study treatment
• Female patients of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to enrollment
• Willing and able to provide informed consent

Exclusion criteria

• Received previous treatment with clofarabine
• Current concomitant chemotherapy, radiation therapy, or immunotherapy
• Prior radiation therapy to the pelvis
• Currently participation in other investigational drug studies or having received other investigational drugs within the previous 30 days
• Have any other severe concurrent disease, or have a history of serious organ dysfunction or disease involving the heart, kidney, liver, or other organ system that may place the patient at undue risk to undergo treatment. In particular: a) New York Heart Association classification stage II, III, or IV congestive heart failure; b) Coronary artery disease or arteriosclerotic cardiovascular disease (angina, myocardial infraction) within 3 months of first dose of study drug; c) Any other primary cardiac disease that, in the opinion of the investigator, increases the risk of ventricular arrhythmia.
• Patients with a systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).
• Any medical condition that requires chronic use of oral high-dose corticosteroids (in excess of 1 mg/kg/day) (low-dose corticosteroid for pre-medication purposes are allowed).
• Any significant concurrent disease, illness, or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results
• Diagnosis of another malignancy, unless the patient has been disease-free for at least 5 years following the completion of curative intent therapy with the following exceptions: Patients with treated non-melanoma skin cancer, in-situ carcinoma or cervical intraepithelial neoplasia regardless of disease-free duration are eligible for this study if definitive treatment for the condition has been completed; Patients with organ-confined prostate cancer with no evidence of recurrent or progressive disease based on PSA value are eligible for this study if hormonal therapy has been initiated or a radical prostatectomy has been performed
• Had currently active gastrointestinal disease, or prior surgery that might affect the ability of the participants to absorb oral Clofarabine.
• Had prior treatment with a known nephrotoxic drug within 2 weeks of the first dose of study drug, unless the participants had a calculated GFR >30 at 2 time points no <7 days apart during the 2- week period prior to the first dose of study drug.
• Positive human immunodeficiency virus (HIV) test.
• Female patients who are pregnant/breastfeeding.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Austria · 1 center

• Department of Urology, Medical University of Vienna — Vienna

Publications

• Foss FM, Parker T. A Phase I Dose-Escalation Study of Clofarabine in Patients with Relapsed or Refractory Low-Grade or Intermediate-Grade B-Cell or T-Cell Lymphoma. Oncologist. 2018 Apr;23(4):397-e30. doi: 10.1634/theoncologist.2017-0658. Epub 2018 Feb 7. PMID 29438091
• Kantarjian HM, Erba HP, Claxton D, Arellano M, Lyons RM, Kovascovics T, Gabrilove J, Craig M, Douer D, Maris M, Petersdorf S, Shami PJ, Yeager AM, Eckert S, Abichandani R, Faderl S. Phase II study of clofarabine monotherapy in previously untreated older adults with acute myeloid leukemia and unfavorable prognostic factors. J Clin Oncol. 2010 Feb 1;28(4):549-55. doi: 10.1200/JCO.2009.23.3130. Epub PMID 20026805
• Kantarjian HM, Gandhi V, Kozuch P, Faderl S, Giles F, Cortes J, O'Brien S, Ibrahim N, Khuri F, Du M, Rios MB, Jeha S, McLaughlin P, Plunkett W, Keating M. Phase I clinical and pharmacology study of clofarabine in patients with solid and hematologic cancers. J Clin Oncol. 2003 Mar 15;21(6):1167-73. doi: 10.1200/JCO.2003.04.031. PMID 12637486
• Zhenchuk A, Lotfi K, Juliusson G, Albertioni F. Mechanisms of anti-cancer action and pharmacology of clofarabine. Biochem Pharmacol. 2009 Dec 1;78(11):1351-9. doi: 10.1016/j.bcp.2009.06.094. Epub 2009 Jul 1. PMID 19576186
• Gutmann M, Ertl IE, Herek P, Vician P, Pirker C, Nossing C, Brettner R, Lemberger U, Grausenburger R, Batlogg K, Baumfried O, Prantl I, Singh N, Laukhtina E, Oszwald A, Wasinger G, Comperat E, Berger W, Shariat SF, Englinger B. Clofarabine Has a Superior Therapeutic Window as compared to Gemcitabine in Preclinical Bladder Cancer Models. Eur Urol Oncol. 2024 Dec;7(6):1166-1170. doi: 10.1016/j.euo.2 PMID 38755094
• Ertl IE, Lemberger U, Ilijazi D, Hassler MR, Bruchbacher A, Brettner R, Kronabitter H, Gutmann M, Vician P, Zeitler G, Koren A, Lardeau CH, Mohr T, Haitel A, Comperat E, Oszwald A, Wasinger G, Clozel T, Elemento O, Kubicek S, Berger W, Shariat SF. Molecular and Pharmacological Bladder Cancer Therapy Screening: Discovery of Clofarabine as a Highly Active Compound. Eur Urol. 2022 Sep;82(3):261-270. PMID 35393162

Identifiers

NCT: NCT07034053 · CLOFARABINE_UC

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗