Study of Nilotinib as First Line Treatment in Philadelphia Chromosome Positive(Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP)

A Phase II Multi-center, Open-label, Non-randomized Study of Nilotinib as First Line Treatment in Adult Patients With Newly Diagnosed Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP)

The study was a local multicentric, open-label, non-randomized phase II study of nilotinib as a first line treatment in adult patients with newly-diagnosed Philadelphia chromosome-positive (Ph+) and chronic phase myeloid leukemia (CML-CP).

Study Overview

• Status: Completed
• Conditions: Chronic Myelogenous Leukemia
• Intervention / Treatment: Drug: Nilotinib

Detailed Description

This was a multicenter, open-label, single-arm, phase 2 study of nilotinib as a frontline treatment for patients with Ph+ CMLCP. All patients received oral nilotinib 300 mg twice daily for a planned treatment duration of 24 months or until early discontinuation.

The primary efficacy end point was the cumulative rate of Major Molecular Response (MMR) in all participants by 12 months. Secondary efficacy end points included the rate of Complete Cytogenic Response (CCyR) at 6 and 12 months; cumulative rates of MMR up to 24 months; time to and durability of MMR; and cumulative rate of Complete Haematologic Response (CHR) by 12 months.

Patient evaluations, including hematologic assessments, were conducted every 15 days during the first 3 months, monthly until month 12, and then every 3 months until the end of the study (24 months). All efficacy analyses were performed in the intent-to treat population.

• Study Type: Interventional
• Enrollment (Actual): 112
• Phase: Phase 2

Contacts and Locations

Study Locations

• Turkey
  • Adana, Turkey, 01330
    • Novartis Investigative Site
  • Ankara, Turkey, 06100
    • Novartis Investigative Site
  • Bursa, Turkey, 16059
    • Novartis Investigative Site
  • Diyarbakir, Turkey, 21000
    • Novartis Investigative Site
  • Gaziantep, Turkey, 27310
    • Novartis Investigative Site
  • Istanbul, Turkey, 34093
    • Novartis Investigative Site
  • Izmir, Turkey, 35040
    • Novartis Investigative Site
  • Izmir, Turkey, 35340
    • Novartis Investigative Site
  • Okmeydani, Turkey, 34370
    • Novartis Investigative Site
  • Talas / Kayseri, Turkey, 38039
    • Novartis Investigative Site
  • Trabzon, Turkey, 61080
    • Novartis Investigative Site
  • Meselik
    • Eskisehir, Meselik, Turkey, 26480
      • Novartis Investigative Site
  • TUR
    • Istanbul, TUR, Turkey, 34098
      • Novartis Investigative Site

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:

• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
• First cytogenetic diagnosis of CML-CP with cytogenetic confirmation of Philadelphia chromosome of (9;22) translocations within 6 months. Standard conventional cytogenetic analysis must be performed.
• Previously untreated for CML, except for hydroxyurea and/or anagrelide (except imatinib treatment for max. 31 days long)
• Adequate end organ function with following laboratory criteria: total bilirubin < 1.5 x upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x upper limit of normal (ULN); creatinine < 1.5 x upper limit of normal (ULN); serum amylase and lipase ≤ 1.5 x upper limit of normal (ULN); alkaline phosphatase ≤ 2.5 x upper limit of normal (ULN) unless considered tumor related
• Serum potassium, magnesium, and phosphorus levels are equal or above the lower limit of normal prior to the first dose of study medication

Exclusion Criteria:

• Treatment with tyrosine kinase inhibitor(s) prior to study (in emergent cases where the patient requires disease management while awaiting study start, commercial supplies of imatinib at any dose may be prescribed to the patient but for no longer than 31 days in duration)
• Known cytopathologically confirmed Central Nervous System CNS infiltration
• Impaired cardiac function
• Severe or uncontrolled medical conditions (i.e. uncontrolled diabetes, active or uncontrolled infection)
• Acute or chronic liver, pancreatic or severe renal disease considered unrelated to disease
• Patients with another primary malignancy except if the other primary malignancy is neither currently clinically significant or requiring active intervention
• History of significant congenital or acquired bleeding disorder unrelated to cancer
• Previous radiotherapy to ≥25% of the bone marrow
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery)
• Use of therapeutic coumarin derivatives (i.e. warfarin, acenocoumarol, phenprocoumon)
• Patients actively receiving therapy with strong Cytochrome P450 3A4 isoenzyme (CYP3A4) inhibitors (e.g, erythromycin, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, mibefradil)
• Patients actively receiving therapy with medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug

Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Nilotinib; administered orally at a dose of 300 mg twice daily for 24 months	Drug: Nilotinib; administered orally at a dose of 300 mg twice daily for 24 months; Other Names: Tasigna, AMN107

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Achieved Major Molecular Response (MMR) During the First 12 Months	Major Molecular Response (MMR) was defined as BCR-ABL1^IS ≤0.1%, on the International Scale [BCR-ABL1IS]) by 12 months. BCR is the Breakpoint Cluster Region gene / BCR gene product and ABL is the Abelson proto-oncogene. BCR-ABL is the Fusion gene from BCR and ABL/Protein product from BCR-ABL. Participants who withdrew prematurely or those who failed to provide data for the study for other reasons were designated as premature withdrawal or inevaluable, respectively, and were included in the ITT analysis as non-responders.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Achieved Major Molecular Response (MMR) up to 24 Months	Major Molecular Response (MMR) was defined as BCR-ABL1^IS ≤0.1%, on the International Scale [BCR-ABL1IS]) by 12 months. BCR is the Breakpoint Cluster Region gene / BCR gene product and ABL is the Abelson proto-oncogene. BCR-ABL is the Fusion gene from BCR and ABL/Protein product from BCR-ABL. Participants who withdrew prematurely or those who failed to provide data for the study for other reasons were designated as premature withdrawal or inevaluable, respectively, and were included in the ITT analysis as non-responders.	3, 6, 9, 15, 18, 21 and 24 months
Percentage of Participants With Complete Cytogenetic Response (CCyR) at Month 6 and 12	CCyR rate is identified as the rate of patients who had 0% of Ph+ metaphase.	Month 6 and 12
Percentage of Participants With Complete Hematologic Response (CHR) at Month 3, 6, 9, 12, 18 and 24	A confirmed complete hematological response (CHR) is defined when all of the following criteria are achieved: WBC <10 x 109/L, thrombocyte <450 x 109/L, myelocyte + metamyelocyte <%5 in blood, no sign of blast and promyelocyte in blood, basophil <%5, and no sign of extramedullary involvement.	Month 3, 6, 9, 12, 18 and 24
Time to Major Molecular Response (MMR)	Time to MMR is defined as the time period from the date of first dose intake until the first documented MMR.	24 months
Duration of Major Molecular Response (MMR)	MMR duration is defined as the time from the date of first documented MMR to the first time of the lost MMR, progression or death.	24 months

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Saydam G, Haznedaroglu IC, Kaynar L, Yavuz AS, Ali R, Guvenc B, Akay OM, Baslar Z, Ozbek U, Sonmez M, Aydin D, Pehlivan M, Undar B, Dagdas S, Ayyildiz O, Akin G, Dag IM, Ilhan O. Frontline nilotinib treatment in Turkish patients with Philadelphia chromosome-positive chronic Myeloid Leukemia in chronic phase: updated results with 2 years of follow-up. Hematology. 2018 Dec;23(10):771-777. doi: 10.1080/10245332.2018.1498167. Epub 2018 Jul 11.
• Saydam G, Haznedaroglu IC, Kaynar L, Yavuz AS, Ali R, Guvenc B, Akay OM, Baslar Z, Ozbek U, Sonmez M, Aydin D, Pehlivan M, Undar B, Dagdas S, Ayyildiz O, Akkaynak DZ, Akin G, Ilhan O. Outcomes with frontline nilotinib treatment in Turkish patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase. Hematology. 2018 Feb 27:1-7. doi: 10.1080/10245332.2018.1444919. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 25, 2011
• Primary Completion (ACTUAL): August 1, 2019
• Study Completion (ACTUAL): August 1, 2019

Study Registration Dates

• First Submitted: January 4, 2011
• First Submitted That Met QC Criteria: January 10, 2011
• First Posted (ESTIMATE): January 11, 2011

Study Record Updates

• Last Update Posted (ACTUAL): September 1, 2020
• Last Update Submitted That Met QC Criteria: August 18, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: newly diagnosed; Chronic Myelogenous Leukemia; First line treatment; CML-CP; major molecular response; Philadelphia chromosome positive; Ph+; Social risk
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Chromosome Aberrations; Translocation, Genetic; Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Philadelphia Chromosome
• Other Study ID Numbers: CAMN107ETR02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

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