The Life After Stopping Tyrosine Kinase Inhibitors Study (The LAST Study)

• ClinicalTrials.gov Identifier: NCT02269267
• Recruitment Status: Completed
• First Posted: October 21, 2014
• Results First Posted: March 1, 2023
• Last Update Posted: March 3, 2023
• Sponsor: Medical College of Wisconsin
• Collaborators: University of Chicago; University of California, San Francisco; University of Utah; Dana-Farber Cancer Institute; Emory University; Barbara Ann Karmanos Cancer Institute; Duke Cancer Institute; Fred Hutchinson Cancer Center; Memorial Sloan Kettering Cancer Center; Weill Medical College of Cornell University; H. Lee Moffitt Cancer Center and Research Institute
• Information provided by (Responsible Party): Ehab L Atallah, Medical College of Wisconsin

Study Description

Brief Summary:

This is a non-randomized, prospective, single-group longitudinal study. The purpose of this study is to improve the decision making process used by physicians and patients when they are considering stopping their Tyrosine Kinase Inhibitor (TKI) medication.

Condition or disease	Intervention/treatment	Phase
Leukemia, Myeloid, Chronic	Drug: Imatinib (Stopping their TKI); Drug: Dasatinib (Stopping their TKI); Drug: Nilotinib (Stopping their TKI); Drug: Bosutinib (Stopping their TKI)	Phase 2

Detailed Description:

This is a non-randomized, prospective, single-group longitudinal study. The overall objective is to improve decision making for TKI discontinuation in eligible chronic myelogenous leukemia (CML) patients. Patients with CML on treatment with imatinib, dasatinib, nilotinib, or bosutinib and are in confirmed deep molecular response will stop their TKI. Confirmed deep (> 4 log reduction) molecular response (>MR4) defined as p210 (bcr-abl) fusion protein (BCR-ABL) < 0.01%, for at least two years. The study will closely monitor patients using standard real-time Quantitative Polymerase Chain Reaction (RQ-PCR) testing for molecular recurrence, testing them monthly for six months, then every other month until 24 months, and then quarterly until 36 months. Concurrently, the study will assess a wide range of patient-reported outcomes (PROs) before stopping TKIs and after discontinuation in conjunction with Polymerase Chain Reaction (PCR) testing, though at fewer time points, utilizing online and/or phone questionnaires. Patients who have molecular CML recurrence based on RQ-PCR will restart imatinib, dasatinib, nilotinib, or bosutinib and will continue to be monitored for disease status and health status until the end of the study.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 173 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: The Life After Stopping Tyrosine Kinase Inhibitors Study (The LAST Study)
• Actual Study Start Date: December 18, 2014
• Actual Primary Completion Date: April 6, 2021
• Actual Study Completion Date: April 6, 2022

Arms and Interventions

Arm

Intervention/treatment

Discontinuation of TKI medication; Patients with CML on treatment with imatinib, dasatinib, nilotinib, or bosutinib and are in confirmed deep molecular response will stop their TKI. Confirmed deep (> 4 log reduction) molecular response (>MR4) defined as p210 (bcr-abl) fusion protein (BCR-ABL) < 0.01%, for at least two years.

Drug: Imatinib (Stopping their TKI); Patients with CML on treatment with imatinib and are in confirmed deep molecular response will stop their TKI. Confirmed deep (> 4 log reduction) molecular response (>MR4) defined as p210 (bcr-abl) fusion protein (BCR-ABL) < 0.01%, for at least two years. Concurrently, the study will assess a wide range of PROs before stopping TKIs and after discontinuation in conjunction with PCR testing, though at fewer time points, utilizing online and/or phone questionnaires.; Other Name: Gleevec; Drug: Dasatinib (Stopping their TKI); Patients with CML on treatment with dasatinib and are in confirmed deep molecular response will stop their TKI. Confirmed deep (> 4 log reduction) molecular response (>MR4) defined as p210 (bcr-abl) fusion protein (BCR-ABL) < 0.01%, for at least two years. Concurrently, the study will assess a wide range of PROs before stopping TKIs and after discontinuation in conjunction with PCR testing, though at fewer time points, utilizing online and/or phone questionnaires.; Other Name: Sprycel; Drug: Nilotinib (Stopping their TKI); Patients with CML on treatment with nilotinib and are in confirmed deep molecular response will stop their TKI. Confirmed deep (> 4 log reduction) molecular response (>MR4) defined as p210 (bcr-abl) fusion protein (BCR-ABL) < 0.01%, for at least two years. Concurrently, the study will assess a wide range of PROs before stopping TKIs and after discontinuation in conjunction with PCR testing, though at fewer time points, utilizing online and/or phone questionnaires.; Other Name: Tasigna; Drug: Bosutinib (Stopping their TKI); Patients with CML on treatment with bosutinib and are in confirmed deep molecular response will stop their TKI. Confirmed deep (> 4 log reduction) molecular response (>MR4) defined as p210 (bcr-abl) fusion protein (BCR-ABL) < 0.01%, for at least two years. Concurrently, the study will assess a wide range of PROs before stopping TKIs and after discontinuation in conjunction with PCR testing, though at fewer time points, utilizing online and/or phone questionnaires.; Other Name: BOSULIF

Outcome Measures

Primary Outcome Measures :

1. Number of Patients With Chronic Myeloid Leukemia (CML) Who Develop Molecular Recurrence After Discontinuing TKIs. [ Time Frame: 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 27, 30, 33, 36 months ]
   The number of patients who develop molecular recurrence after discontinuing TKIs. This will be reported as the number of new occurrences from the end of the prior time frame.
2. Patient-reported Health Status Related to Fatigue of Patients at Baseline (Before Stopping Tyrosine Kinase Inhibitors (TKIs) [ Time Frame: Baseline ]
   Patient-reported health status of fatigue using the Patient-Reported Outcomes Measurement Information System (PROMIS) scales. The research team used five questions. The responses are in a Likert -style scale numbered one to five -- 1 (not at all) and 5 (very much). PROMIS scales use a T-score metric for interpretation of results. The mean score for a relevant reference population (United States general population in this case) is 50 and 10 is the standard deviation of that population. T-score range is 20 to 80. Thus, a score of 40 is one standard deviation lower than the reference population mean and a score of 60 is one standard deviation higher than the reference population mean. Higher scores for this scale are indicative of worse symptoms.
3. Patient-reported Health Status Related to Fatigue of Patients at 6 Months (After Stopping Tyrosine Kinase Inhibitors (TKIs) [ Time Frame: Six months ]
   Patient-reported health status of fatigue using the Patient-Reported Outcomes Measurement Information System (PROMIS) scales. The research team used five questions. The responses are in a Likert -style scale numbered one to five -- 1 (not at all) and 5 (very much). PROMIS scales use a T-score metric for interpretation of results. The mean score for a relevant reference population (United States general population in this case) is 50 and 10 is the standard deviation of that population. T-score range is 20 to 80. Thus, a score of 40 is one standard deviation lower than the reference population mean and a score of 60 is one standard deviation higher than the reference population mean. Higher scores for this scale are indicative of worse symptoms.
4. Patient-reported Health Status Related to Diarrhea of Patients at Baseline (Before Stopping Tyrosine Kinase Inhibitors (TKIs) [ Time Frame: Baseline ]
   Patient-reported health status of diarrhea using the Patient-Reported Outcomes Measurement Information System (PROMIS) scales. There are two unrelated questions. Question no. 1 focuses on loose or watery stool and asks how many days the subject experienced this. O is no days and 4 is six to seven days. Question no. 2 asks if the subject often feels the need to empty the bowel right away. Responses are 0 (never) to 4 (more than once a day). Responses are a Likert -style scale numbered one to five -- 1 (not at all) and 5 (very much). PROMIS scales use a T-score metric interpret results. The mean score for a relevant reference population (United States general population) is 50 and 10 is the standard deviation of the population. T-score range is 20 to 80. A score of 40 is one standard deviation lower than the reference population mean and 60 is one standard deviation higher than the reference population mean. Higher scores indicate worse symptoms.
5. Patient-reported Health Status Related to Diarrhea of Patients at 6 Months (After Stopping Tyrosine Kinase Inhibitors (TKIs) [ Time Frame: Six months ]
   Patient-reported health status of diarrhea using the Patient-Reported Outcomes Measurement Information System (PROMIS) scales. There are two unrelated questions. Question no. 1 focuses on loose or watery stool and asks how many days the subject experienced this. O is no days and 4 is six to seven days. Question no. 2 asks if the subject often feels the need to empty the bowel right away. Responses are 0 (never) to 4 (more than once a day). Responses are a Likert -style scale numbered one to five -- 1 (not at all) and 5 (very much). PROMIS scales use a T-score metric interpret results. The mean score for a relevant reference population (United States general population) is 50 and 10 is the standard deviation of the population. T-score range is 20 to 80. A score of 40 is one standard deviation lower than the reference population mean and 60 is one standard deviation higher than the reference population mean. Higher scores indicate worse symptoms.
6. Patient-reported Health Status Related to Sleep Status of Patients at Baseline (Before Stopping Tyrosine Kinase Inhibitors (TKIs) [ Time Frame: Baseline ]
   Patient-reported health status of sleep using the Patient-Reported Outcomes Measurement Information System (PROMIS) scales. There are four questions. The responses are in a Likert Scale numbered one to five. All questions are regarding the quality of sleep. The answers are one (not at all) to 5 (very much). PROMIS scales use a T-score metric interpret results. The mean score for a relevant reference population (United States general population) is 50 and 10 is the standard deviation of the population. T-score range is 20 to 80. A score of 40 is one standard deviation lower than the reference population mean and 60 is one standard deviation higher than the reference population mean. Higher scores indicate worse symptoms.
7. Patient-reported Health Status Related to Sleep Status of Patients at 6 Months (After Stopping Tyrosine Kinase Inhibitors (TKIs) [ Time Frame: Six months ]
   Patient-reported health status of sleep using the Patient-Reported Outcomes Measurement Information System (PROMIS) scales. There are four questions. The responses are in a Likert Scale numbered one to five. All questions are regarding the quality of sleep. The answers are one (not at all) to 5 (very much). PROMIS scales use a T-score metric interpret results. The mean score for a relevant reference population (United States general population) is 50 and 10 is the standard deviation of the population. T-score range is 20 to 80. A score of 40 is one standard deviation lower than the reference population mean and 60 is one standard deviation higher than the reference population mean. Higher scores indicate worse symptoms.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

1. Age 18 or older at time of study entry
2. Willing and able to give informed consent
3. Diagnosed with CML in chronic phase and have either the b3a2 (e14a2) or b2a2 (e13a2) variants that give rise to the p210 BCR-ABL protein
4. Currently taking imatinib, dasatinib, nilotinib or bosutinib
5. Patient has been on TKI therapy for at least 3 years
6. Documented BCR-ABL <0.01% (>MR4 i.e. >4 log reduction) or undetectable BCR-ABL by PCR for at least 2 years according to the patient's local lab
7. Documented BCR-ABL <0.01% (>MR4 i.e. >4 log reduction) or undetectable BCR-ABL at least 3 times prior to screening according to the patient's local lab
8. Two (2) Screening PCRs have been completed and both results are < 0.01% (>MR4 i.e > 4 log reduction) by central lab
9. Has been on any number of TKIs, but has not been resistant to any TKI (changes made for intolerance are allowed)
10. Patient has been compliant with therapy per treating physician

Exclusion Criteria:

1. Prior hematopoietic stem cell transplantation
2. Poor compliance with taking TKI
3. Unable to comply with lab appointments schedule and PRO assessments
4. Life expectancy less than 36 months
5. Patients who have been resistant to previous TKI therapy are not eligible
6. Pregnant or lactating women

Contacts and Locations

Locations

United States, California

Helen Diller Family Comprehensive Cancer Center University of California

San Francisco, California, United States, 94143

United States, Florida

Moffit Cancer Center

Tampa, Florida, United States, 33612

United States, Georgia

Winship Cancer Institute of Emory University

Atlanta, Georgia, United States, 30322

United States, Illinois

The University of Chicago

Chicago, Illinois, United States, 60637

The University of Chicago Medicine Comprehensive Cancer Center at Silver Cross

New Lenox, Illinois, United States, 60451

United States, Massachusetts

Beth Israel Deaconess Medical Center (Satellite site of Dana Farber)

Boston, Massachusetts, United States, 02215

Dana Farber Cancer Institute

Boston, Massachusetts, United States, 02215

United States, Michigan

Karmanos Cancer Institute of Wayne State University

Detroit, Michigan, United States, 48201

United States, New York

Roswell Park Cancer Institute

Buffalo, New York, United States, 14263

Weill Medical College of Cornell University

New York, New York, United States, 10021

Memorial Sloan Kettering Cancer Center

New York, New York, United States, 10065

United States, North Carolina

Duke University Medical Center

Durham, North Carolina, United States, 27710

United States, Texas

MD Anderson Cancer Center

Houston, Texas, United States, 77054

United States, Utah

University of Utah Huntsman Cancer Institute

Salt Lake City, Utah, United States, 84132-2408

United States, Washington

Fred Hutchinson Cancer Research Center

Seattle, Washington, United States, 98109-1024

United States, Wisconsin

Froedtert Hospital & Medical College of Wisconsin

Milwaukee, Wisconsin, United States, 53226

Sponsors and Collaborators

Medical College of Wisconsin

University of Chicago

University of California, San Francisco

University of Utah

Dana-Farber Cancer Institute

Emory University

Barbara Ann Karmanos Cancer Institute

Duke Cancer Institute

Fred Hutchinson Cancer Center

Memorial Sloan Kettering Cancer Center

Weill Medical College of Cornell University

H. Lee Moffitt Cancer Center and Research Institute

Investigators

• Principal Investigator: Ehab Atallah, MD; Medical College of Wisconsin
• Principal Investigator: Kathryn Flynn, PhD; Medical College of Wisconsin

  Study Documents (Full-Text)

Documents provided by Ehab L Atallah, Medical College of Wisconsin:

Study Protocol and Statistical Analysis Plan  [PDF] January 23, 2017

More Information

Publications of Results:

Atallah E, Schiffer CA, Weinfurt KP, Zhang MJ, Radich JP, Oehler VG, Pinilla-Ibarz J, Deininger MWN, Lin L, Larson RA, Mauro MJ, Moore JO, Ritchie EK, Shah NP, Silver RT, Wadleigh M, Cortes J, Thompson J, Guhl J, Horowitz MM, Flynn KE. Design and rationale for the life after stopping tyrosine kinase inhibitors (LAST) study, a prospective, single-group longitudinal study in patients with chronic myeloid leukemia. BMC Cancer. 2018 Apr 2;18(1):359. doi: 10.1186/s12885-018-4273-1.

Atallah E, Schiffer CA, Radich JP, Weinfurt KP, Zhang MJ, Pinilla-Ibarz J, Kota V, Larson RA, Moore JO, Mauro MJ, Deininger MWN, Thompson JE, Oehler VG, Wadleigh M, Shah NP, Ritchie EK, Silver RT, Cortes J, Lin L, Visotcky A, Baim A, Harrell J, Helton B, Horowitz M, Flynn KE. Assessment of Outcomes After Stopping Tyrosine Kinase Inhibitors Among Patients With Chronic Myeloid Leukemia: A Nonrandomized Clinical Trial. JAMA Oncol. 2021 Jan 1;7(1):42-50. doi: 10.1001/jamaoncol.2020.5774.

• Responsible Party: Ehab L Atallah, Professor (Principal Investigator), Medical College of Wisconsin
• ClinicalTrials.gov Identifier: NCT02269267
• Other Study ID Numbers: PRO00023447
• First Posted: October 21, 2014
• Results First Posted: March 1, 2023
• Last Update Posted: March 3, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:

Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia; Neoplasms by Histologic Type; Neoplasms; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Imatinib Mesylate; Dasatinib; Tin Fluorides; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Cariostatic Agents; Protective Agents; Physiological Effects of Drugs