DECLINE: An Open-label, Randomised Multicenter Phase 3b Study to Determine the Confirmed Rate of Molecular Response ≥ 4 Log (MR4) at Two Years

• Sponsor: Prof. Dr. Nikolas von Bubnoff (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02174445
• Collaborator: Novartis (Industry)
• Enrollment: 14
• Locations: 18
• Arms: 2
• Actual Duration (Months): 67
• Patients Per Site: 0.8
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This is an open-label, multicenter, randomised phase 3b clinical trial of Imatinib 400 to 800 mg daily versus Nilotinib 300 mg two times daily in chronic phase CML patients with confirmed MMR without MR4.5

Condition or Disease	Intervention/Treatment	Phase
Chronic Myeloid Leukemia	Drug: Imatinib; Drug: Nilotinib	Phase 3

Detailed Description

This is an open-label, multicenter, randomised phase 3b clinical trial of Imatinib 400 to 800 mg daily versus Nilotinib 300 mg two times daily in chronic phase CML patients with confirmed MMR without MR4.5 (after having received Imatinib 400 to 800 mg daily for at least 18 months) to determine the proportion of patients with confirmed MR4 after two years. Patients in treatment arm A (Imatinib) who do not achieve confirmed MR4 2 years after randomisation will be offered cross-over from Imatinib 400 to 800 mg daily to Nilotinib 300 mg twice daily. One hundred thirty-two (132) patients will be included and randomised 1:1 to each treatment arm.

The study will be stratified by duration of Imatinib treatment before screen-ing (≤36 months / >36 months) as well as by the level of response at inclusion (MMR / MR4).

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Imatinib Continuation Versus Nilotinib 300 mg Twice Daily in Patients With Chronic Myeloid Leukemia (CML) in Chronic Phase and Major Molecular Re-sponse (MMR) Without Molecular Response ≥ 4.5 Log (MR4.5) Receiving Imatinib at a Dose of 400 to 800 mg Daily. An Open-label, Randomised Multicenter Phase 3b Study to Determine the Confirmed Rate of Molecular Response ≥ 4 Log (MR4) at Two Years
• Actual Study Start Date: Mar 1, 2014
• Actual Primary Completion Date: Dec 1, 2018
• Actual Study Completion Date: Oct 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Imatinib Imatinib 400-800mg, daily, maximum 6 years	Drug: Imatinib; Imatinib, 400 to 800 mg p.o., daily; Other Names: Glivec
Active Comparator: Nilotinib Nilotinib, 300mg, twice daily, maximum 6 years	Drug: Nilotinib; 300mg p.o., twice-daily; Other Names: Tasigna

Outcome Measures

Primary Outcome Measures

1. Proportion of patients with confirmed MR4 after two years of study treatment [2 years]

   Proportion of patients with confirmed MR4 at two years of study treatment in both treatment arms. Confirmed MR4 at two years is defined as either BCR-ABL ≤ 0.01% IS at 21 and 24 months or BCR-ABL ≤ 0.01% IS at 24 months and confirmation within six weeks

Eligibility Criteria

Criteria

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

Inclusion criteria:

1. Signed written informed consent

2. Male or female patients aged >=18 years (without upper limit of age)

3. ECOG performance status of 0 to 2

4. CML in chronic phase, with chronic phase defined as blasts < 15% in blood and/or bone marrow and peripheral blood basophils < 20% and platelets ≥ 100 G/L

5. Pretreatment with Imatinib with a treatment duration of at least 18 months at a dosage of 400 to 800 mg daily

6. Major molecular response (MMR) without molecular response ≥ 4.5 log (MR4.5), i.e. BCR-ABL>0.0032% and ≤0.1% IS confirmed by central la-boratory at screening will be required for randomisation

7. Patients must have a serum Creatinine of ≤ 1.5 x ULN, SGOT ≤ 1.5 x ULN, total bilirubin ≤ 1.5 x ULN (except known M. Gilbert), and Lipase ≤ 1.5 x ULN

8. Women of child-bearing potential defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months, must have a negative serum pregnancy test during screening period. Male and fe-male patients of reproductive potential must agree to employ highly ef-fective methods of birth control throughout the study and for up to 3 months following discontinuation of study drug. Appropriate methods are e.g. a highly effective method of first choice, i.e. a method with a low failure rate (less than 1% per year) like sexual abstinence, com-bined oral contraceptives, implants, injectable, some Intra Uterine Devices (IUDs), vasectomized partner, in combination with a method of second choice like condom, diaphragm, or cup pessary with spermicidal foam/gel/film/cream/suppository.

Exclusion Criteria:

1. Any previous treatment for CML other than Hydroxyurea, Imatinib or Interferon alpha

2. Evidence of features of accelerated or blast phase at any time

3. Previous loss of hematologic or cytogenetic response

4. Concomitant medications known to be strong inducers or inhibitors of P450 Isoenzyme CYP3A4

5. Finding of a secondary BCR-ABL resistance mutation at any time

6. History of intolerance to Imatinib that required treatment interruption longer than 4 weeks (cumulative) or dose reductions to less than 400 mg daily for longer than 4 weeks (cumulative) during the last 12 months before informed consent

7. Patients who had prior allogeneic, syngeneic, or autologous bone mar-row transplant or stem cell transplant

8. Patients unwilling to or unable to comply with the planned therapeutic intervention or to comply with the study treatment visits including blood sample collection within the protocol

9. History of pancreatitis, chronic inflammatory diseases or autoimmune diseases

10. Patients who underwent solid organ transplantation

11. Impaired cardiac function, including any of the following:

• History of or presence of complete left bundle branch block, right bundle branch block plus left anterior hemi block, bifascicular block in screening ECG

• Use of a cardiac pacemaker

• ST depression of > 1mm in 2 or more leads and/or T wave inver-sions in 2 or more contiguous leads in screening ECG

• Congenital Long QT Syndrome

• QTc> 450 msec in the screening ECG

• QT prolonging concomitant medication

• History of or presence of significant ventricular or atrial tachy-arrhythmia in screening ECG

• History of or presence of clinically significant resting bradycardia (< 50 beats per minute)

• Myocardial infarction within 12 months prior to informed consent

• Unstable angina diagnosed or treated during the past 12 months before informed consent

• Other clinically significant heart disease (e.g., congestive heart fail-ure, uncontrolled hypertension, history of labile hypertension)

1. Known HIV and/or hepatitis B or C infection (testing is not mandatory)

2. Other malignancies within the past 3 years before informed consent except for adequately treated carcinoma of the cervix and basal or squamous cell carcinoma of the skin

3. Women who are pregnant or breast feeding

4. Male/female patients of reproductive potential unwilling to practice a highly effective method of birth control

5. History of noncompliance to medical regimens

6. Treatment with another investigational product during this study or during the last 30 days prior to informed consent

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Universitätsklinikum Aachen	Aachen		Germany	52074
2	Praxis Dr. Bruder / Dr. Heinrich / Prof. Bangerter	Augsburg		Germany	86150
3	Universitätsklinikum Bonn	Bonn		Germany	53105
4	Gemeinschaftspraxis	Dresden		Germany	01307
5	Praxis Dr. Hauch	Erfurt		Germany	99084
6	Internistische Schwerpunktpraxis Erlangen oncosearch	Erlangen		Germany	91052
7	Praxis für Hämatologie/Onkologie Dres. Rudolph, Sengpiel, von Verschuer	Essen		Germany	45136
8	University Medical Center	Freiburg		Germany	79106
9	Universitätsklinikum Hamburg-Eppendorf	Hamburg		Germany	20246
10	Universitätsklinikum Jena	Jena		Germany	07747
11	Universitätsklinik Köln	Köln		Germany	50937
12	Gemeinschaftspraxis Hämatologie/Onkologie	Magdeburg		Germany	39104
13	Klinikum Mannheim GmbH Universitätsklinikum	Mannheim		Germany	68167
14	Überörtliche Gemeinschaftspraxis Hämato-Onkologie Pasing/Fürstenfeldbruck	Munich		Germany	81241
15	Klinikum rechts der Isar, Technische Universität München	München		Germany	81675
16	Onkologische Praxis Oldenburg	Oldenburg		Germany	26121
17	Medizinische Statistik Saarbrücken, GbR	Saarbrucken		Germany	66113
18	Universitätsklinikum Ulm	Ulm		Germany	89081

Sponsors and Collaborators

• Prof. Dr. Nikolas von Bubnoff
• Novartis

Investigators

• Principal Investigator: Nikolas von Bubnoff, Professor, University Hospital Freiburg

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Prof. Dr. Nikolas von Bubnoff, Mr., University Hospital Freiburg
• ClinicalTrials.gov Identifier: NCT02174445
• Other Study ID Numbers: CAMN107ADE18T; 2013-000077-68; DRKS00006285
• First Posted: Jun 25, 2014
• Last Update Posted: Dec 2, 2019
• Last Verified: Nov 1, 2019

• Keywords provided by Prof. Dr. Nikolas von Bubnoff, Mr., University Hospital Freiburg: Patients with CML in chronic phase; Imatinib; Nilotinib
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Imatinib Mesylate

Study Results

No Results Posted as of Dec 2, 2019