A Phase 3 Study for the Efficacy and Safety of Radotinib in CP-CML Patients With Resistance/Intolerance to Previous TKIs

Study Description

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Brief Summary:

In a multicenter, single-arm, open-label and Phase III Radotinib clinical study, chronic phase Ph+ chronic myeloid leukemia patients with resistance or Intolerance to previous TKIs therapy including Imatinib will be recruited. In this phase 3 study, 195 subjects are expected to be enrolled in a single arm with the administration of Radotinib 400mg twice daily, which includes 20% of dropout rate.

Condition or disease	Intervention/treatment	Phase
Leukemia, Myeloid, Chronic Phase	Drug: Radotinib	Phase 3

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	195 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase 3 Multi-center, Single-arm, Open-label Study for the Efficacy and Safety of Radotinib in Chronic Phase Chronic Myeloid Leukemia Patients With Resistance or Intolerance to Previous TKIs Therapy Including Imatinib
Actual Study Start Date :	June 25, 2018
Estimated Primary Completion Date :	March 15, 2020
Estimated Study Completion Date :	April 1, 2022

Arms and Interventions

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Arm

Intervention/treatment

Experimental: Radotinib; Enrolled subjects will continue to administer radotinib 400mg twice daily (800mg/day) orally every 12 hours at regular dosing hours for 12 months. Dose modification is allowed if the subject cannot comply with the protocol-defined dosing schedule due to hematologic or non-hematologic toxicities and toxicities resolve within 28 days (within 42 days for hematologic toxicities). For radotinib, maximum 2 dose reductions will be allowed by stage to 600mg and to 400mg.

Drug: Radotinib; Brand name/manufacturer: Supect Cap./IL-YANG PHARM. Co., Ltd.; Active ingredient: radotinib HCl 106.8mg (100mg as radotinib) or HCl 213.6mg (200mg as radotinib); Appearance and formulation: hard capsule with a light blue cap and a body containing pale yellow powder; Storage conditions: Store in an airtight light proof container at room temperature.; Other Name: SUPECT

Outcome Measures

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Primary Outcome Measures :

1. Major Cytogenetic Response (MCyR) [ Time Frame: at month 6 ]
   MCyR is defined as 0~35% CCyR+PCyR based on ≥20 metaphase myelocytes. Chromosome test results from <20 metaphase myelocytes will be excluded from the analysis.

Secondary Outcome Measures :

1. Cytogenetic Response (CCyR) [ Time Frame: at month 12/24, by month 24 ]
   CCyR is defined as complete loss of Ph chromosome based on ≥20 metaphase myelocytes. Chromosome test results from <20 metaphase myelocytes will be excluded from the analysis.
2. Major molecular response [ Time Frame: at month 12/24, by month 24 ]
   MMR is defined as a ≥3-log reduction in BCR-ABL1 transcript level from the standardized reference or BCR-ABL1/ABL % of ≤0.1% according to the international reference when the level of BCR-ABL1 gene was measured by RQ-PCR, a standardized quantitative genetic method.
3. Overall Survival(OS) [ Time Frame: by month 24 ]
   OS is defined as the duration from the first day of Radotinib administration to the day of death for certain causes.
4. Progression Free Survival (PFS) [ Time Frame: by month 24 ]
   PFS is defined as the duration from the first day of Radotinib administration to the earliest day of disease progression or death for certain causes.

Other Outcome Measures:

1. BCR-ABL1 point mutation [ Time Frame: up to month 24 ]
   Incidence rate of BCR-ABL1 point mutations that are newly found during the course of radotinib treatment
2. correlation between the concentration of radotinib in blood and the response (efficacy and safety) [ Time Frame: up to month 24 ]
   To measure the concentration of radotinib in blood
3. Incidence of Radotinib-Adverse Events [ Time Frame: up to month 24 ]
   Toxicities will be evaluated in all subjects treated with radotinib.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

1. Male or female patients aged 18 years old
2. Chronic Phase Ph+ Chronic Myeloid Leukemia patients who failed the previous therapy (with resistance or intolerance to the previous therapy) including Imatinib
3. ECOG scale 0, 1 or 2

4. Chronic phase is defined as all of the following conditions that subjects meet.

   • Blast in peripheral blood and bone marrow <15%
   • The sum of blast and promyelocyte in peripheral blood and bone marrow <30%
   • Basophil in peripheral blood <20%
   • Platelets count ≥100 × 10^9/L (≥ 100,000/mm3)
   • No evidence of involvement of extramedullary leukemia other than enlargements of liver and spleen

5. Patients who have adequate organ functions as defined below:

   • Total bilirubin < 1.5 × upper limit of normal (ULN)
   • SGOT and SGPT < 2.5× ULN
   • Creatinine < 1.5 × ULN
   • Serum amylase and lipase ≤ 1.5 × ULN
   • Alkaline Phosphatase ≤ 2.5 × ULN (only if not related to the tumor)
6. Women of childbearing potential should have a negative serum or urine pregnancy test within 14 days of the enrollment.
7. Patients providing written informed consent form before the study related screening procedures.

Exclusion Criteria:

1. Patients who have been diagonised accelerated phase and blast crisis CML in previous therapy if only once.
2. Patients with MCyR at the time of screening

3. Any below impaired cardiac function:

   • LVEF <45% or < lower bound of normal limit of study site (whichever higher), confirmed by echocardiogram at the site
   • Patients who cannot have QT intervals measured according to ECG
   • Complete left bundle branch block
   • Patients with cardiac pacemakers
   • Patients with congenital long QT syndrome or the family history of known long QT syndrome
   • History of, or presence of symptomatic ventricular or atrial tachyarrhythmias
   • Clinically significant resting bradycardia (< 50 bpm)

   • The mean QTcF >450msec following three consecutive ECG tests at baseline

     : Screening test will be performed again for QTcF after the adjustment of electrolyte if QTcF >450msec and the electrolyte is not within the normal range.

   • Medical history of clinically confirmed myocardial infarction
   • Medical history of unstable angina (within last 12 months)
   • Other clinically significant cardiac disease (e.g. congestive heart failure, or uncontrolled hypertension)
4. Patients with T315I point mutations
5. Patients with central nervous system involvement as cytopathologically confirmed (in the absence of symptoms, no need to perform lumbar puncture before the entry of the clinical study)
6. Severe or uncontrolled chronic disease (that is, uncontrolled diabetes, active or uncontrolled infections)
7. Significant medical history of congenital or acquired bleeding disorders that are not related to leukemia
8. Patients who previously received radiotherapy to at least 25% of the bodies with high portion of bone marrow
9. Patients who received the major surgery within 4 weeks before the initiation of the IP administration or who failed to recover from the surgery that was performed before then.
10. Patients who participated in other clinical study and are receiving any other IP.
11. Patients who cannot give consent to the clinical study.
12. Patients currently receiving treatment with a strong CYP3A4 inhibitors (e.g. erythromycin, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, mibefradil) or CYP3A4 inducers (e.g. dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbitol, St. John's Wort) and that can neither stop the administration of these drugs before the start of the IP administration nor switch to other drugs. List of these drugs is provided in the Appendix 2.
13. Patients who are currently receiving treatment with a medication that has the potential to prolong QT intervals and can neither stop the administration of the drugs before the start of the IP administration nor switch to other drugs (list of medications that have the potential to prolong QT interval is provided in the Appendix 3.) If subjects need to start such drug treatments during the study, they should contact the sponsor, IL-YANG PHARM. Co., Ltd.
14. Gastrointestinal disorder or gastrointestinal disease that may result in a significant change in the absorption of the investigational product(e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, enterocolectomy, or GI bypass surgery)
15. Medical history of acute or chronic pancreatitis within the past one year
16. Acute or chronic liver, pancreas, or severe kidney disease that are not associated with the disease

17. Women patients that meet the following conditions should be excluded from the clinical study.

    • Pregnancy
    • Breastfeeding
    • Pregnancy confirmed at screening pregnancy test
    • Women of childbearing potential who is unwilling to use an appropriate method of contraception during the study (a postmenopausal woman will be considered of non-childbearing potential if they have seen amenorrhea for at least 12 months or longer.).
18. Male patients who are unwilling to use proper method of contraception during the study

Contacts and Locations

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Contacts

Contact: Hye Lin Park	+82.70.7165.7316	hlpark@ilyang.co.kr
Contact: Da Won Park	+82.70.7165.7317	dwpark@ilyang.co.kr

Locations

Korea, Republic of
The catholic university of Korea, Seoul ST. Marry's Hospital	Recruiting
Seoul, Korea, Republic of, 06591
Contact: Dong-Wook Kim, MD

Sponsors and Collaborators

Il-Yang Pharm. Co., Ltd.

Investigators

Principal Investigator:	Dong Wook Kim	the Catholic University of Korea's St. Mary's Hospital

More Information

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Responsible Party:	Il-Yang Pharm. Co., Ltd.
ClinicalTrials.gov Identifier:	NCT03459534 History of Changes
Other Study ID Numbers:	RT51KRI03
First Posted:	March 9, 2018
Last Update Posted:	July 24, 2018
Last Verified:	February 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Undecided

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

Additional relevant MeSH terms:

Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase; Neoplasms by Histologic Type	Neoplasms; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases