Study to Assess Efficacy and Safety of Nilotinib 300mg Twice Daily in Patients With Philadelphia Positive Chronic Myeloid Leukaemia (CML) in Chronic Phase Who Are Intolerant to Prior Tyrosine Kinase Inhibitors.

NCT02108951 | Terminated Phase 3 Results DMC FDA Drug

• 1 other identifier: CAMN107AAU04
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 14

Brief Summary

The purpose of this Australian study was to assess the efficacy and safety of nilotinib 300mg twice daily in patients with chronic myeloid leukemia chronic phase who were intolerant but responsive to 1st line treatment with imatinib or dasatinib. Eligible patients have been previously treated with imatinib or dasatinib for at least 3 months and are experiencing non-hematologic toxicity whilst having documented responses that meet PBS authority for 1st line treatment of CML without current MR4.5.

Conditions

Philidelphia Positive Chronic Myeloid Leukaemia

Keywords

CML; Ph-CML; leukaemia; leukemia; chronic myeloid leukemia; chronic myeloid leukaemia; TKI intolerance; tyrosine kinase inhibitor; tyrosine kinase inhibitor intolerance

Outcome Measures

Primary Outcomes (5)

• Deep Molecular Response (MR4.5) Rate: Percentage of Patients Who Have Achieved a 4.5-log Reduction in BCR-ABL Level Within 24 Month

  Deep Molecular Response (MR4.5) rate is defined as the percentage of patients who have achieved a 4.5 -log reduction in Breakpoint cluster region - Abelson murine leukemia (BCR-ABL) levels. BCR-ABL levels are measured in patients by real-time quantitative polymerase chain reaction (RQ-PCR) testing of peripheral blood by the 24 months following the commencement of nilotinib therapy. MR4.5 corresponds to a BCR-ABL ratio 0.0032% international scale (IS) using RQ-PCR. If a post-baseline value for BCR-ABL is \< 0.1 X the baseline value, the patient were classified as achieving a 1 log reduction in BCR-ABL.

  Baseline, 96 weeks (24 months)

• Molecular Response (MR4.0) Rate: Percentage of Patients Who Have Achieved a 4.0-log Reduction in BCR-ABL Level Within 12 Months and 24 Months

  Molecular Response (MR4.0) rate is defined as the percentage of patients who have achieved a 4-log reduction in BCR-ABL levels at 12 months and 24 months following the commencement of nilotinib therapy. Breakpoint cluster region - Abelson murine leukemia (BCR-ABL) levels are measured in patients by real-time quantitative polymerase chain reaction (RQ-PCR) testing of peripheral blood by the 24 months following the commencement of nilotinib therapy. MR4.0 corresponds to a BCR-ABL ratio 0.01% international scale (IS) using RQ-PCR. If a post-baseline value for BCR-ABL is \< 0.1 X the baseline value, the patients were classified as achieving a 1 log reduction in BCR-ABL.

  Baseline, 48 weeks (12 months), 96 weeks (24 months)

• Major Molecular Response (MMR) Rate: Percentage of Patients Who Have Achieved a 3 Log Reduction in BCR-ABL Levels Within 12 Months and 24 Months

  Major Molecular Response (MMR) rate is defined as the percentage of patients who have achieved a 3 log reduction in BCR-ABL levels at 12 months and at 24 months following the commencement of nilotinib therapy. Breakpoint cluster region - Abelson murine leukemia (BCR-ABL) levels are measured in patients by real-time quantitative polymerase chain reaction (RQ-PCR) testing of peripheral blood at the 12 and 24 months following the commencement of nilotinib therapy. MMR corresponds to a BCR-ABL ratio 0.1% international scale (IS) using RQ-PCR. If a post-baseline value for BCR-ABL is \< 0.1 \* the baseline Value, the patient will be classified as achieving a 1 log drop.

  Baseline, 48 weeks (12 months), 96 weeks (24 months)

• Duration of Prior TKI Therapy for Patients Based on MR4.5 Achievement Status Within 24 Months

  Breakpoint cluster region - Abelson murine leukemia (BCR-ABL) levels are measured in patients by real-time quantitative polymerase chain reaction (RQ-PCR) testing of peripheral blood by the 24 months following the commencement of nilotinib therapy. Deep molecular response (MR4.5) rate was defined as the percentage of patients who have achieved a 4.5-log reduction (MR4.5) in BCR-ABL levels during the 24 months following the commencement of nilotinib therapy. MR4.5 corresponds to a BCR-ABL ratio 0.0032% IS using RQ-PCR. If a post-baseline value for BCR-ABL is \< 0.1 X the baseline value, the patient were classified as achieving a 1 log reduction in BCR-ABL.

  Baseline, 96 weeks (24 months)

• Number of Patients With MR4.5 Response by Baseline BCR-ABL Response Level Within 24 Months

  Deep Molecular Response (MR4.5) rate is defined as the percentage of patients who have achieved a 4.5 -log reduction in Breakpoint cluster region - Abelson murine leukemia (BCR-ABL) levels. BCR-ABL levels are measured in patients by real-time quantitative polymerase chain reaction (RQ-PCR) testing of peripheral blood by the 24 months following the commencement of nilotinib therapy. MR4.5 corresponds to a BCR-ABL ratio 0.0032% international scale (IS) using RQ-PCR. If a post-baseline value for BCR-ABL is \< 0.1 X the baseline value, the patient were classified as achieving a 1 log reduction in BCR-ABL.

  Baseline, 96 weeks (24 months)

Secondary Outcomes (9)

• Kinetics of Molecular Response: Percentage of Patients With no Response Based on BCR-ABL Over Time After the Switch to Nilotinib

  Baseline, week 4, 8, 12, 24, 36, 48, 60, 72, 84, 96

• Kinetics of Molecular Response: Percentage of Patients With MMR Based on BCR-ABL Over Time After the Switch to Nilotinib

  Baseline, week 4, 8, 12, 24, 36, 48, 60, 72 and 96

• Kinetics of Molecular Response: Percentage of Patients With MR4.0 Based on BCR-ABL Over Time After the Switch to Nilotinib

  Baseline, week 4, 8, 12, 24, 36, 48, 60, 72, 84, 96

• Kinetics of Molecular Response: Percentage of Patients With MR4.5 Based on BCR-ABL Over Time After the Switch to Nilotinib

  Baseline, week 4, 8, 12, 24, 36, 48, 60, 72, 84, 96

• Kaplan-Meier Estimates of Time to Deep Molecular Response (MR4.5)

  96 weeks (24 months)

Study Arms (1)

Nilotinib

EXPERIMENTAL

Nilotinib was administered orally at 300 mg BD at approximately 12 hour intervals which had to be taken without food. The capsules were to be swallowed whole with water and no food should have been consumed for at least 2 hours before and at least 1 hour after the dose was taken. Prior to the first dose of nilotinib, patients were required to have an imatinib or dasatinib washout period of at least 3 days. Therapy with nilotinib was to be continued for up to 24 months while on study.

Drug: Nilotinib

Interventions

Nilotinib DRUG

Nilotinib 150mg hard gelatin capsules taken orally

Also known as: AMN107

Nilotinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent prior to screening procedures
• Eastern Cooperative Oncology Grou (ECOG) Performance Status of 0, 1, or 2.
• Patient with diagnosis of Ph+ CML-CP associated with BCR-ABL quantifiable by RQ-PCR (IS).
• Patient has received a minimum of 3 months of imatinib or dasatinib treatment (any dose) since initial diagnosis with a documented response.
• Patient is eligible for Pharmaceutical Benefits Scheme (PBS) reimbursed 1st line TKI treatment.
• Patient has experienced non-hematological Adverse Events (AE(s)) of any grade, which persisted for at least 1 month despite supportive care or recurred at any grade at least once. Patients who, at the Investigator's discretion, require immediate discontinuation due to the severity of the adverse event are also eligible.
• No other current or planned anti-leukemia therapies.
• Adequate organ function.
• Potassium, Magnesium and Total Calcium above Lower limit of normal.
• life expectancy of more than 12 months in the absence of any intervention

You may not qualify if:

• Prior treatment with nilotinib.
• Prior Accelerated Phase (AP), Blast Crisis (BC) or allogeneic-transplant (unless the patient received an autologous transplant and was in Chrionic Phase (CP) prior to transplant and never in AP or BC).
• Patient has documented Molecular Response (MR) 4.5 at the time of study entry
• Patients with atypical BCR-ABL transcript not quantifiable by standard RQ-PCR.
• Known impaired cardiac function.
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug.
• Pregnant or breast feeding (lactating) women.
• Women of child-bearing potential unwilling or unable to use highly effective contraception.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (14)

Novartis Investigative Site

Canberra, Australian Capital Territory, 2605, Australia

Location

Novartis Investigative Site

Kingswood, New South Wales, 2747, Australia

Location

Novartis Investigative Site

Kogarah, New South Wales, 2217, Australia

Location

Novartis Investigative Site

Liverpool, New South Wales, 2170, Australia

Location

Novartis Investigative Site

St Leonards, New South Wales, 2065, Australia

Location

Novartis Investigative Site

Douglas, Queensland, 4810, Australia

Location

Novartis Investigative Site

Nambour, Queensland, 4560, Australia

Location

Novartis Investigative Site

South Brisbane, Queensland, 4101, Australia

Location

Novartis Investigative Site

Adelaide, South Australia, 5000, Australia

Location

Novartis Investigative Site

Fitzroy, Victoria, 3065, Australia

Location

Novartis Investigative Site

Geelong, Victoria, 3220, Australia

Location

Novartis Investigative Site

Melbourne, Victoria, 3000, Australia

Location

Novartis Investigative Site

Murdoch, Western Australia, 6150, Australia

Location

Novartis Investigative Site

Nedlands, Western Australia, 6009, Australia

Location

MeSH Terms

Conditions

Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Interventions

nilotinib

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Myeloid; Myeloproliferative Disorders; Bone Marrow Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Limitations and Caveats

The study was planned to enroll 130 patients. Study got terminated with 20 patients because of slow recruitment. Therefore, due to small sample size, the results cannot be considered clinical significant.

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 7, 2014
• First Posted: April 9, 2014
• Study Start: July 7, 2014
• Primary Completion: August 10, 2016
• Study Completion: August 10, 2016
• Last Updated: October 27, 2017
• Results First Posted: October 27, 2017

Record last verified: 2017-09

Locations

AU (14)