Imatinib for Pain in Sickle Cell Anemia (IMPACT)

IMatinib for PAin in Chronic Treatment of Sickle Cell Anemia (IMPACT SCA): A Pilot Study of Imatinib in Patients With Sickle Cell Anemia and Recurrent Vaso-occlusive Pain

In this protocol, the investigators propose to evaluate the biochemical effects of imatinib on sickle red blood cells (RBCs). Patients will be administered imatinib mesylate orally following the guidelines previously established for use of imatinib in other disorders. The biochemical effects of imatinib on sickle RBCs will be examined, including changes in their levels of band 3 tyrosine phosphorylation and the abundances of RBC-derived microparticles in their blood. In addition, the patients will be monitored for symptoms of sickle cell disease (SCD). The investigators expect band 3 tyrosine phosphorylation to decrease dramatically in patients treated with imatinib. The investigators also anticipate a reduction in the numbers of RBC-derived microparticles in circulation (quantitated by assaying the number of glycophorin A positive microparticles in peripheral blood samples by flow cytometry. Most importantly, the investigators expect to see a reduction in the frequency of vaso-occlusive crises, and possibly acute chest syndrome and utilization of opioids. The study duration is planned as 6 months in order to provide adequate time for potential change in the primary endpoints (e.g. percent irreversibly sickled cells).

Study Overview

• Status: Recruiting
• Conditions: Sickle Cell Disease
• Intervention / Treatment: Drug: Imatinib Mesylate

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Seethal Jacob, MD; Phone Number: 317-944-8784; Email: seejacob@iu.edu

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Recruiting
      • Riley Hospital for Children at IU Health
      • Contact: Anne Bubnick; Phone Number: 317-948-0101; Email: abubnick@iu.edu
      • Principal Investigator: Seethal Jacob, MD
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Recruiting
      • Cincinnati Children's Hospital
      • Contact: Charles Quinn, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 25 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Age: patients must be ≥18 years of age and ≤25 years of age at the time of study entry.
2. Diagnosis: Patients must have documented diagnosis of sickle cell disease (Hemoglobin SS Disease or S-Beta 0 Thalassemia) by either high pressure liquid chromatography (HPLC) or Hemoglobin Electrophoresis
3. Disease status: Patients must have at least 2 documented episodes of vaso-occlusive pain in the prior year as defined by an acute episode of pain lasting greater than 24 hours, with no medically determined cause other than a vaso-occlusive event that resulted in treatment with oral or parenteral opiates or with a parenteral nonsteroidal anti-inflammatory drug.
4. Performance Level: Karnofsky ≥80 for patients >10 years of age and Lansky ≥80 for patients ≤10 years of age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.

5. Organ function requirements:

   a. Adequate bone marrow function defined as i. Peripheral absolute neutrophil count (ANC) ≥1000/µL ii. Platelet count ≥100,000/ µL (transfusion independent) b. Adequate renal function defined as i. Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥70 mL/min/1.73 m2 or ii. A serum creatinine based on age/gender c. Adequate Liver Function Defined As: i. Total bilirubin (sum of conjugated + unconjugated) ≤1.5 times upper limit of normal (ULN) for age, and ii. serum glutamate pyruvate transaminase (SGPT or ALT) <2.5 upper limit of normal. For the purpose of this study, the ULN for SGPT is 45 U/L iii. Serum albumin ≥2 g/dL d. Adequate cardiac function defined as: i. Shortening fraction or ejection fraction greater than the institutional norm, and ii. Corrected QT interval ≤450 msec

6. Informed Consent: All patients and/or their parents or legal guardians must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.

Exclusion Criteria:

1. Chronic transfusion protocol.

   a. Patients currently on a chronic transfusion protocol are not eligible

2. Hydroxyurea Intolerance

   a. Patients who are ineligible for hydroxyurea due to persistent marrow suppression (e.g. thrombocytopenia, neutropenia)

3. Pregnancy or Breast-Feeding

   a. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method.

4. Concomitant Medications

   1. Investigational Drugs: Patients who are currently receiving another investigational drug.
   2. Anti-cancer agents: Patients who are currently receiving other anti-cancer agents.
   3. The following CYP3A4 inducers are prohibited 14 days before the start of imatinib and during the study with imatinib: rifampin, rifabutin, carbamazepine, Phenobarbital, phenytoin, St. John's wort, efavirenz, and tipranavir.
   4. The following CYP3A4 inhibitors are prohibited 7 days before the start of imatinib and during the study with imatinib: azole antifungals (itraconazole, ketoconazole); clarithromycin, erythromycin, diltiazem, verapamil, HIV protease inhibitors (indinavir, saquinavir, ritonavir, atazanavir, nelfainavir); delavirdine.
5. Patients who have an uncontrolled infection.
6. Prior use of Imatinib: Patients who have previously received imatinib are not eligible for study.
7. Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study.
8. Patient is < 5 years free of a malignancy. Existence of any other malignant disease is not allowed.
9. Patient with Grade III/IV cardiac problems as defined by the New York Heart Association Criteria. (i.e., congestive heart failure, myocardial infarction within 6 months of study).
10. Patients with a history of QT prolongation, need for concomitant use of anti-arrhythmics or other agents known to prolong QT interval, or electrolyte derangement that cannot be corrected to within normal limits prior to initiation of study drug.
11. Patients with a family history of sudden cardiac death.
12. Patient has a severe and/or uncontrolled medical disease other than sickle cell disease (i.e., uncontrolled diabetes, chronic renal disease, or active uncontrolled infection).
13. Patient has known chronic liver disease (i.e., chronic active hepatitis, and cirrhosis).
14. Patient has a known diagnosis of human immunodeficiency virus (HIV) infection.
15. Patient had a major surgery within 2 weeks prior to study entry.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• 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: Imatinib Intervention	Drug: Imatinib Mesylate; The starting dose for subjects will be 340 mg/m2/day with a maximum dose of 600 mg daily. Patients will receive Imatinib orally once daily for 6 months.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in Biochemical Effects - Band 3 Phosphorylation	Percent change in Band 3 Phosphorylation tested in red blood cells	change from baseline Band 3 Phosphorylation at 7 months
Changes in Biochemical Effects - Microparticle Release	Percent change in Microparticle Release tested in red blood cells	change from baseline micro particle release at 7 months
Change in Functional RBC analysis	Percent Irreversibly Sickled Cells by ektacytometry and Percent altered susceptibility to sickling by OxygenScan	change from baseline functional RBC at 7 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vaso-occlusive Crisis (VOC)	Defined as an acute episode of pain lasting greater than 24 hours, with no medically determined cause other than a vaso-occlusive event that resulted in treatment with oral or parenteral opiate agents and/or parenteral nonsteroidal anti-inflammatory agents. Measured by pain scale (1-10) or Wong-Baker Faces scale based on age:	monthly over 7 months
Acute Chest Syndrome (ACS)	Defined as respiratory distress (hypoxia, shortness of breath, chest pain, tachypnea) with evidence of an infiltrate on chest x-ray Measured with clinical evaluation.	monthly over 7 months
Opioid Use	Defined as both oral and parenteral opioid use Oral use will be documented in pain diary by patient/guardian and reviewed at each visit.	monthly over 7 months
Hospitalizations	Defined as an emergency room or clinic visit resulting in an inpatient admission or observation for a sickle cell-related event (e.g. vaso-occlusive pain, acute chest syndrome, etc).	monthly over 7 months
Assessment toxicities of imatinib in patients with sickle cell anemia (SCA)	Clinical evaluation	monthly over 7 months

Collaborators and Investigators

• Sponsor: Indiana University
• Collaborators: Children's Hospital Medical Center, Cincinnati; Purdue University

Study record dates

Study Major Dates

• Study Start (Actual): February 26, 2020
• Primary Completion (Anticipated): September 1, 2025
• Study Completion (Anticipated): September 1, 2025

Study Registration Dates

• First Submitted: June 16, 2019
• First Submitted That Met QC Criteria: June 24, 2019
• First Posted (Actual): June 25, 2019

Study Record Updates

• Last Update Posted (Actual): May 19, 2023
• Last Update Submitted That Met QC Criteria: May 17, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Sickle Cell; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Imatinib Mesylate
• Other Study ID Numbers: IMPACT SCA

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: Yes
• Studies a U.S. FDA-regulated device product: No