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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01274351
• Collaborator: (none)
• Enrollment: 112
• Locations: 13
• Arm: 1
• Actual Duration (Months): 102.2
• Patients Per Site: 8.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Chronic Myelogenous Leukemia	Drug: Nilotinib	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 112 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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)
• Actual Study Start Date: Jan 25, 2011
• Actual Primary Completion Date: Aug 1, 2019
• Actual Study Completion Date: Aug 1, 2019

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Who Achieved Major Molecular Response (MMR) During the First 12 Months [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.

Secondary Outcome Measures

1. Percentage of Participants Who Achieved Major Molecular Response (MMR) up to 24 Months [3, 6, 9, 15, 18, 21 and 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.

2. Percentage of Participants With Complete Cytogenetic Response (CCyR) at Month 6 and 12 [Month 6 and 12]

   CCyR rate is identified as the rate of patients who had 0% of Ph+ metaphase.

3. Percentage of Participants With Complete Hematologic Response (CHR) at Month 3, 6, 9, 12, 18 and 24 [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.

4. Time to Major Molecular Response (MMR) [24 months]

   Time to MMR is defined as the time period from the date of first dose intake until the first documented MMR.

5. Duration of Major Molecular Response (MMR) [24 months]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Eskisehir	Meselik	Turkey	26480
2	Novartis Investigative Site	Istanbul	TUR	Turkey	34098
3	Novartis Investigative Site	Adana		Turkey	01330
4	Novartis Investigative Site	Ankara		Turkey	06100
5	Novartis Investigative Site	Bursa		Turkey	16059
6	Novartis Investigative Site	Diyarbakir		Turkey	21000
7	Novartis Investigative Site	Gaziantep		Turkey	27310
8	Novartis Investigative Site	Istanbul		Turkey	34093
9	Novartis Investigative Site	Izmir		Turkey	35040
10	Novartis Investigative Site	Izmir		Turkey	35340
11	Novartis Investigative Site	Okmeydani		Turkey	34370
12	Novartis Investigative Site	Talas / Kayseri		Turkey	38039
13	Novartis Investigative Site	Trabzon		Turkey	61080

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - May 20, 2012
• Statistical Analysis Plan - Mar 14, 2014

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01274351
• Other Study ID Numbers: CAMN107ETR02
• First Posted: Jan 11, 2011
• Last Update Posted: Sep 1, 2020
• Last Verified: Aug 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: First line treatment; newly diagnosed; Philadelphia chromosome positive; Chronic Myelogenous Leukemia; Ph+; CML-CP; major molecular response; Social risk
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Philadelphia Chromosome

Study Results

Participant Flow

Recruitment Details	A total of 112 participants were enrolled into the study from the 15 sites in Turkey.
Pre-assignment Detail	This was an open-label study with one treatment arm. The study did not involve a reference treatment.

Arm/Group Title	Nilotinib
Arm/Group Description	administered orally at a dose of 300 mg twice daily for 24 months
Period Title: Overall Study
STARTED	112
COMPLETED	92
NOT COMPLETED	20

Baseline Characteristics

Arm/Group Title	Nilotinib
Arm/Group Description	administered orally at a dose of 300 mg twice daily for 24 months
Overall Participants	112
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	47
Sex: Female, Male (Count of Participants)
Female	49 43.8%
Male	63 56.3%
Race and Ethnicity Not Collected (Count of Participants)

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Who Achieved Major Molecular Response (MMR) During the First 12 Months
Description	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.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) analysis set

Arm/Group Title	Nilotinib
Arm/Group Description	administered orally at a dose of 300 mg twice daily for 24 months
Measure Participants	112
Count of Participants [Participants]	74 66.1%

2. Secondary Outcome

Title	Percentage of Participants Who Achieved Major Molecular Response (MMR) up to 24 Months
Description	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.
Time Frame	3, 6, 9, 15, 18, 21 and 24 months

Outcome Measure Data

Analysis Population Description

ITT analysis set

Arm/Group Title	Nilotinib
Arm/Group Description	administered orally at a dose of 300 mg twice daily for 24 months
Measure Participants	112
3 months	28 25%
6 months	57 50.9%
9 months	67 59.8%
15 months	84 75%
18 months	92 82.1%
21 months	93 83%
24 months	93 83%

3. Secondary Outcome

Title	Percentage of Participants With Complete Cytogenetic Response (CCyR) at Month 6 and 12
Description	CCyR rate is identified as the rate of patients who had 0% of Ph+ metaphase.
Time Frame	Month 6 and 12

Outcome Measure Data

Analysis Population Description

ITT analysis set included only the participants who had measurements i.e. excluding drop outs.

Arm/Group Title	Nilotinib
Arm/Group Description	administered orally at a dose of 300 mg twice daily for 24 months
Measure Participants	112
Month 6	89 79.5%
Month 12	84 75%

4. Secondary Outcome

Title	Percentage of Participants With Complete Hematologic Response (CHR) at Month 3, 6, 9, 12, 18 and 24
Description	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.
Time Frame	Month 3, 6, 9, 12, 18 and 24

Outcome Measure Data

Analysis Population Description

ITT analysis set included only the participants who had measurements i.e. excluding drop outs.

Arm/Group Title	Nilotinib
Arm/Group Description	administered orally at a dose of 300 mg twice daily for 24 months
Measure Participants	112
Month 3	104 92.9%
Month 6	102 91.1%
Month 9	100 89.3%
Month 12	96 85.7%
Month 18	93 83%
Month 24	92 82.1%

5. Secondary Outcome

Title	Time to Major Molecular Response (MMR)
Description	Time to MMR is defined as the time period from the date of first dose intake until the first documented MMR.
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

ITT analysis set. Only participants with a MMR were included in the analysis

Arm/Group Title	Nilotinib
Arm/Group Description	administered orally at a dose of 300 mg twice daily for 24 months
Measure Participants	93
Mean (Standard Deviation) [days]	252.38 (153.22)

6. Secondary Outcome

Title	Duration of Major Molecular Response (MMR)
Description	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.
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

ITT analysis set. Only participants with a MMR and subsequent loss of MMR were included in the analysis

Arm/Group Title	Nilotinib
Arm/Group Description	administered orally at a dose of 300 mg twice daily for 24 months
Measure Participants	12
Mean (Standard Deviation) [days]	91 (4.22)

Adverse Events

Time Frame	Adverse events were collected from the start of the treatment to end of the treatment i.e 24 months.
Arm/Group Title	Nilotinib
Arm/Group Description	administered orally at a dose of 300 mg twice daily for 24 months
All Cause Mortality
	Nilotinib
	Affected / at Risk (%)	# Events
Total	2/112 (1.8%)
Serious Adverse Events
	Nilotinib
	Affected / at Risk (%)	# Events
Total	43/112 (38.4%)
Blood and lymphatic system disorders
Acute leukaemia	1/112 (0.9%)
Neutropenia	2/112 (1.8%)
Thrombocytopenia	4/112 (3.6%)
Cardiac disorders
Chest Pain	3/112 (2.7%)
Acute myocardial infarction	2/112 (1.8%)
Angina unstable	1/112 (0.9%)
Bradycardia	1/112 (0.9%)
Myocardial ischaemia	1/112 (0.9%)
Paroxysmal arrhythmia	1/112 (0.9%)
Eye disorders
Conjunctivitis allergic	1/112 (0.9%)
Gastrointestinal disorders
Abdominal pain	2/112 (1.8%)
Oral disorder	1/112 (0.9%)
Pancreatitis acute	1/112 (0.9%)
General disorders
Asthenia	1/112 (0.9%)
Pyrexia	1/112 (0.9%)
Hepatobiliary disorders
Hepatitis toxic	1/112 (0.9%)
Immune system disorders
Hypersensitivity	1/112 (0.9%)
Infections and infestations
Periorbital cellulitis	1/112 (0.9%)
Investigations
Alanine aminotransferase increased	1/112 (0.9%)
Arteriogram coronary	3/112 (2.7%)
Lipase increased	2/112 (1.8%)
Weight decreased	1/112 (0.9%)
Musculoskeletal and connective tissue disorders
Lumbar vertebral fracture	1/112 (0.9%)
Pain in extremity	1/112 (0.9%)
Upper limb fracture	1/112 (0.9%)
Nervous system disorders
Brain neoplasm	1/112 (0.9%)
Pregnancy, puerperium and perinatal conditions
Pregnancy	1/112 (0.9%)
Skin and subcutaneous tissue disorders
Alopecia	1/112 (0.9%)
Pruritus	1/112 (0.9%)
Rash	1/112 (0.9%)
Surgical and medical procedures
Skin neoplasm excision	1/112 (0.9%)
Uterine dilation and curettage	1/112 (0.9%)
Other (Not Including Serious) Adverse Events
	Nilotinib
	Affected / at Risk (%)	# Events
Total	90/112 (80.4%)
Blood and lymphatic system disorders
Leukopenia	10/112 (8.9%)
Thrombocytopenia	19/112 (17%)
Gastrointestinal disorders
Abdominal pain upper	6/112 (5.4%)
Constipation	7/112 (6.3%)
Hepatobiliary disorders
Hyperbilirubinaemia	17/112 (15.2%)
Hypercholesterolaemia	11/112 (9.8%)
Investigations
Alanine aminotransferase increased	12/112 (10.7%)
Amylase increased	7/112 (6.3%)
Blood alkaline phosphatase increased	10/112 (8.9%)
Blood phosphorus decreased	7/112 (6.3%)
Blood triglycerides increased	11/112 (9.8%)
Haemoglobin decreased	7/112 (6.3%)
Lipase increased	9/112 (8%)
Musculoskeletal and connective tissue disorders
Myalgia	7/112 (6.3%)
Pain in extremity	7/112 (6.3%)
Respiratory, thoracic and mediastinal disorders
Influenza	13/112 (11.6%)
Upper respiratory tract infection	8/112 (7.1%)
Skin and subcutaneous tissue disorders
Alopecia	6/112 (5.4%)
Pruritus	16/112 (14.3%)
Rash	13/112 (11.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.