Cytochrome P450 Inhibition to Decrease Dosage of Dasatinib for Chronic Myelogenous Leukemia

Cytochrome P450 Inhibition With Ketoconazole to Decrease Dosage and Costs of Dasatinib for Chronic Myelogenous Leukemia

This phase 2 single-arm study aims to demonstrate the efficacy of strong cytochrome inhibition with ketoconazole to reduce dasatinib dosage for adults with chronic myelogenous leukemia. Researchers will describe response rates and adverse events.

Study Overview

• Status: Recruiting
• Conditions: Chronic Myeloid Leukemia, Chronic Phase
• Intervention / Treatment: Drug: Dasatinib Pill; Drug: Ketoconazole Pill

Detailed Description

Dasatinib is a second-generation tyrosine kinase inhibitor that is metabolized by the cytochrome P450. Dasatinib has shown efficacy in patients with chronic myelogenous leukemia. Standard-dose dasatinib is 50mg-140mg/day orally, continuously. However, when combined with a strong CYP3A4 inhibitor, a dose reduction of 75% is warranted.

This phase 2 single-arm study aims to demonstrate the efficacy of strong cytochrome inhibition with ketoconazole to reduce the dosage and costs of dasatinib for adults with chronic myelogenous leukemia. Researchers will describe cytogenetic and molecular response rates at 3, 6, and 12 months and adverse events (i.e., pleural effusion) associated with this strategy.

• Study Type: Interventional
• Enrollment (Anticipated): 15
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Fernando De la Garza Salazar, MD; Phone Number: (52) 811 080 2131; Email: fernandodelagarza@gmail.com

Study Locations

• Mexico
  • Nuevo Leon
    • Monterrey, Nuevo Leon, Mexico, 64630
      • Recruiting
      • Hospital Universitario Dr. Jose Eleuterio González
      • Contact: Dr Fernando De la Garza Salazar, MD; Phone Number: 8442322102; Email: fernandodelagarza@gmail.com
      • Contact: Fernando De la Garza Salazar, MD; Phone Number: 8442322102

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:

1. Age >18 years
2. Chronic myeloid leukemia in chronic phase according to the World Health Organization 2016
3. Eastern Cooperative Oncology Group (ECOG) 0-2

Exclusion Criteria:

1. Chronic heart disease (NYHA III-IV)
2. Bleeding disorders not attributed to the hematological malignancy
3. Pregnancy
4. Lactation
5. Chronic myeloid leukemia in blast phase
6. Organic dysfunction (Marshall score ≥2)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dasatinib and ketoconazole; Patients will receive dasatinib at a dose of 25mg orally daily for one year and ketoconazole 200mg orally two times per day for one year.	Drug: Dasatinib Pill; Patients will receive half pill of dasatinib 50mg (25mg/day, orally) for one year; Other Names: Sprycel; Drug: Ketoconazole Pill; Patients will receive ketoconazole 200mg two times a day, orally, for one year.; Other Names: Nizoral

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The rate of Complete Cytogenetic Response	B-cell antigen receptor(BCR)/Tyrosine-protein kinase-ABL1(ABL1) IS <=1% at 6 months	Up to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The rate of Molecular Response (MR4)	Log reduction in BCR/ABL of 4	Up to 6 months
The rate of Molecular Response (MR4.5)	Log reduction in BCR/ABL of 4.5	Up to 6 months
The rate of sustained Molecular Response (MR4.5)	Log reduction in BCR/ABL of 4.5	Up to 12 months
The proportion of non hematological side effects	Proportion of patients that presented non hematological side effects to the intervention	Up to 12 months
The rate of Complete Cytogenetic Response	BCR/ABL IS <=1% at 12 months	Up to 12 months

Collaborators and Investigators

• Sponsor: Hospital Universitario Dr. Jose E. Gonzalez
• Collaborators: Fernando De la Garza Salazar

Publications and helpful links

General Publications

• Hochhaus A, Saussele S, Rosti G, Mahon FX, Janssen JJWM, Hjorth-Hansen H, Richter J, Buske C; ESMO Guidelines Committee. Chronic myeloid leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017 Jul 1;28(suppl_4):iv41-iv51. doi: 10.1093/annonc/mdx219. Erratum in: Ann Oncol. 2018 Oct 1;29(Suppl 4):iv261. Ann Oncol. 2018 Oct;29 Suppl 4:iv261.
• Johnson FM, Agrawal S, Burris H, Rosen L, Dhillon N, Hong D, Blackwood-Chirchir A, Luo FR, Sy O, Kaul S, Chiappori AA. Phase 1 pharmacokinetic and drug-interaction study of dasatinib in patients with advanced solid tumors. Cancer. 2010 Mar 15;116(6):1582-91. doi: 10.1002/cncr.24927.
• Naqvi K, Jabbour E, Skinner J, Anderson K, Dellasala S, Yilmaz M, Ferrajoli A, Bose P, Thompson P, Alvarado Y, Jain N, Takahashi K, Burger J, Estrov Z, Borthakur G, Pemmaraju N, Paul S, Cortes J, Kantarjian HM. Long-term follow-up of lower dose dasatinib (50 mg daily) as frontline therapy in newly diagnosed chronic-phase chronic myeloid leukemia. Cancer. 2020 Jan 1;126(1):67-75. doi: 10.1002/cncr.32504. Epub 2019 Sep 25.

Study record dates

Study Major Dates

• Study Start (Anticipated): November 1, 2024
• Primary Completion (Anticipated): November 1, 2024
• Study Completion (Anticipated): November 1, 2024

Study Registration Dates

• First Submitted: November 16, 2022
• First Submitted That Met QC Criteria: November 25, 2022
• First Posted (Estimate): December 6, 2022

Study Record Updates

• Last Update Posted (Estimate): December 6, 2022
• Last Update Submitted That Met QC Criteria: November 25, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Protein Kinase Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Ketoconazole; Dasatinib
• Other Study ID Numbers: HE22-00031

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No