DASFREE: Open-Label Study Evaluating Dasatinib Therapy Discontinuation in Patients With Chronic Phase Chronic Myeloid Leukemia With Stable Complete Molecular Response

• Sponsor: Bristol-Myers Squibb (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01850004
• Collaborator: ICON plc (Industry), PPD (Industry), Molecular MD (Other), European Organisation for Research and Treatment of Cancer - EORTC (Other), MultiPharma (Other), Steering Committee (Other)
• Enrollment: 84
• Locations: 28
• Arm: 1
• Actual Duration (Months): 92.5
• Patients Per Site: 3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The study purpose is to test the hypothesis that Chronic Phase Chronic Myeloid Leukemia (CP-CML) patients with stable Complete Molecular Response (CMR) who discontinue Dasatinib treatment are able to maintain a sustained remission in the long-term, with undetectable or minimally detectable BCR-ABL residual disease.

Condition or Disease	Intervention/Treatment	Phase
Chronic Phase Chronic Myeloid Leukemia	Drug: Dasatinib	Phase 2

Detailed Description

Primary Purpose: Protocol designed to evaluate remission of disease after treatment discontinuation. Treatment re-started if relapse occurs

Study Design

• Study Type: Interventional
• Actual Enrollment: 84 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: Open-Label Single Arm Phase 2 Study Evaluating Dasatinib Therapy Discontinuation In Patients With Chronic Phase Chronic Myeloid Leukemia (CP-CML) With Stable Complete Molecular Response (CMR) DASFREE
• Actual Study Start Date: Jan 22, 2014
• Actual Primary Completion Date: Sep 20, 2017
• Actual Study Completion Date: Oct 8, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dasatinib Dasatinib 50, 80, 100, 140, 180 mg tablets by mouth, once daily, up to 60 months	Drug: Dasatinib; Other Names: Sprycel

Outcome Measures

Primary Outcome Measures

1. Major Molecular Response (MMR) Rate [At 12 months after Dasatinib discontinuation (assessed up to approximately June 4, 2018)]

   Major Molecular Response (MMR) rate at 12 months is the percentage of participants who maintain MMR (BCR-ABL transcripts < 0.1% on the International Scale [IS]) at 12 months after Dasatinib discontinuation without restarting Dasatinib

Secondary Outcome Measures

1. Event-free Survival (EFS) Rate After Dasatinib Discontinuation [At 12 months]

   EFS was defined as the time from the date of dasatinib treatment discontinuation to the date of loss of MMR.

2. Relapse-free Survival (RFS) After Dasatinib Discontinuation [At 6,12,18, 24 months and every 6 months thereafter up to 5 years]

   Relapse is defined as any of the following events while a subject is on study: the loss of MMR, loss of Complete Cytogenetic Response (CCyR), loss of Complete Hematologic Response (CHR) or progression to advanced/blastic phase. RFS is defined as the time from Dasatinib treatment discontinuation to the date of relapse. Subjects who did not relapse were censored on the date of their last molecular assessment.

3. Progression Free Survival (PFS) Rate [From Dasatinib treatment discontinuation up to 5 years]

   Progression is defined as Transformation to Accelerated Phase or Blast Crisis (AP/BC) Accelerated Phase (AP) Blasts in PB or BM 15-29%; Blast + promyelocytes >= 30% with blasts < 30% or ACA in Ph+ cells (clonal progression), or basophils in blood >= 20%,or platelets < 100 x 109 /L unrelated to therapy Blastic Phase or Crisis (BP/BC) Blasts in PB or BM >= 30%, or extramedullary blast cell involvement (with the exception of spleen and liver)

Eligibility Criteria

Criteria

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

For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com

Inclusion Criteria

• Signed Written Informed Consent

• Target Population

1. Men and women diagnosed with CP-CML, on treatment with dasatinib for a minimum of 2 years at the time of enrollment and in dasatinib-induced complete molecular remission ongoing for at least 1 year prior to study entry.

2. Patients are eligible if they have been in stable dasatinib induced CMR for a minimum of nine months, documented by at least three assessments, conducted 2 - 6.5 months apart, at a local lab.

3. Subjects who have received dasatinib beyond first or second line treatment and meet other enrollment criteria are eligible for the study provided prior Tyrosine-kinase inhibitors (TKI) were discontinued due to intolerance or lack efficacy, although only one instance of lack of efficacy to TKI is allowed.

4. Eastern Co-Operative Group (ECOG) Performance Status (PS) of 0-1

• Age and Reproductive Status

1. Men and women, ages ≥18

2. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within 24 hours prior to the restart of study drug

3. Women must not be breastfeeding

4. WOCBP must agree to follow instructions for method(s) of contraception at the restart of treatment with study drug (dasatinib) and for the duration treatment plus 30 days (duration of ovulatory cycle) for a total of 30 days post-treatment completion

5. Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for 90 days after study entry (withdrawal of dasatinib), at restart of study drug (dasatinib) and for the duration of treatment with study drug (dasatinib) plus 90 days (duration of sperm turnover) for a total of 90 days post-treatment completion

Exclusion Criteria:

• Target Disease Exceptions

1. Patients who have not achieved a 1-log reduction in BCR-ABL transcript levels compared with baseline as determined by local standards or > 10% IS [International Standard]) documented at 3.0-6.5 months since the initial start of dasatinib therapy.

2. Patients who have previously undergone hematopoietic stem cell transplantation (SCT) or who are scheduled for SCT

3. Previous diagnosis of CML accelerated phase or blast crisis

• Medical History and Concurrent Diseases

1. Prior or concurrent malignancy, except the following:

• Curatively treated basal cell or squamous cell skin cancer

• Cervical carcinoma in situ

• Adequately treated Stage I or II cancer from which the subject is currently in complete remission

• Any other cancer from which the subject has been disease free for 3 years

1. A serious uncontrolled medical disorder or active infection that would impair the ability of the subject to receive protocol therapy in case re-initiation of dasatinib is needed.

2. Uncontrolled or significant cardiovascular disease

3. Subjects with prior history of pericardial effusion or pleural effusion that required thoracentesis are excluded. Subjects with prior history of pericardial or pleural effusion that was clinically manageable and a maintained CMR for ≥ 1 year on a stable dose of dasatinib are allowed.

4. History of significant bleeding disorder unrelated to CML

• Allergies and Adverse Drug Reaction

1. Subjects with known hypersensitivity to excipients of Dasatinib tablets

• Sex and Reproductive Status

1. Patients who are pregnant or breastfeeding or likely to become pregnant

2. Men whose partner is unwilling or unable to avoid pregnancy

• Other Exclusion Criteria

1. Patients with a history of non-compliance to CML treatment and monitoring requirements

2. Prisoners or subjects who are involuntarily incarcerated

• Additional Criteria for Patients Eligible to Restart Dasatinib

• Any patient who has lost MMR and is eligible for re-starting dasatinib therapy must not have developed a condition that precludes dasatinib use.

Other protocol defined inclusion/exclusion criteria could apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope National Medical Center	Duarte	California	United States	91010
2	UCLA Clinical and Translational Research Center (CTRC)	Los Angeles	California	United States	90095
3	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California	United States	94143
4	Northwestern University, Feinberg School of Medicine	Chicago	Illinois	United States	60611
5	John Theurer Cancer Center, Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
6	Herbert Irving Comprehensive Cancer Center-Columbia University Medical Center	New York	New York	United States	10032
7	Texas Oncology-Baylor Charles A. Sammons Cancer Center	Dallas	Texas	United States	75246
8	MD Anderson Cancer Center Clinic	Houston	Texas	United States	77030-4000
9	Local Institution	Toronto	Ontario	Canada	M5G 2M9
10	Local Institution	Paris		France	75010
11	Local Institution	Pessac		France	33604
12	Local Institution	Pierre Benite Cedex		France	69495
13	Local Institution	Vandoeuvre-les-Nancy Cedex		France	54511
14	Local Institution	Aachen		Germany	D-52074
15	Local Institution	Berlin		Germany	13353
16	Local Institution	Mannheim		Germany	68167
17	Local Institution	Rostock		Germany	18057
18	Local Institution	Ulm		Germany	89081
19	Local Institution	Catania		Italy	95123
20	Local Institution	Firenze		Italy	50134
21	Local Institution	Napoli		Italy	80131
22	Local Institution	Orbassano		Italy	10043
23	Local Institution	Roma		Italy	00144
24	Local Institution	Rome		Italy	00161
25	Local Institution	Las Palmas de Gran Canaria		Spain	35010
26	Local Institution	Madrid		Spain	28034
27	Local Institution	Malaga		Spain	29010
28	Local Institution	Oviedo		Spain	33011

Sponsors and Collaborators

• Bristol-Myers Squibb
• ICON plc
• PPD
• Molecular MD
• European Organisation for Research and Treatment of Cancer - EORTC
• MultiPharma
• Steering Committee

Investigators

• Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Study Documents (Full-Text)

• Study Protocol - Jul 24, 2017
• Statistical Analysis Plan - Jul 13, 2018

More Information

Additional Information:

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting
• Investigator Inquiry Form
• FDA Safety Alerts and Recalls

Publications

None provided.

• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT01850004
• Other Study ID Numbers: CA180-406; 2012-001421-27
• First Posted: May 9, 2013
• Last Update Posted: Dec 16, 2021
• Last Verified: Dec 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase; Dasatinib

Study Results

Participant Flow

Arm/Group Title	Total
Arm/Group Description	Off treatment and On treatment after restarting Dasatinib
Period Title: Overall Study
STARTED	84
COMPLETED	76
NOT COMPLETED	8

Baseline Characteristics

Arm/Group Title	Total
Arm/Group Description	Off-treatment and On-treatment after restarting Dasatinib
Overall Participants	84
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	52.6 (14.57)
Sex: Female, Male (Count of Participants)
Female	37 44%
Male	47 56%
Race/Ethnicity, Customized (Count of Participants)
White	75 89.3%
Black/African American	3 3.6%
Asian	1 1.2%
Other	5 6%

Outcome Measures

1. Primary Outcome

Title	Major Molecular Response (MMR) Rate
Description	Major Molecular Response (MMR) rate at 12 months is the percentage of participants who maintain MMR (BCR-ABL transcripts < 0.1% on the International Scale [IS]) at 12 months after Dasatinib discontinuation without restarting Dasatinib
Time Frame	At 12 months after Dasatinib discontinuation (assessed up to approximately June 4, 2018)

Outcome Measure Data

Analysis Population Description

All evaluable participants

Arm/Group Title	Total
Arm/Group Description	All evaluable participants
Measure Participants	84
Number (95% Confidence Interval) [Percentage of Participants]	47.6 56.7%

2. Secondary Outcome

Title	Event-free Survival (EFS) Rate After Dasatinib Discontinuation
Description	EFS was defined as the time from the date of dasatinib treatment discontinuation to the date of loss of MMR.
Time Frame	At 12 months

Outcome Measure Data

Analysis Population Description

All evaluable participants

Arm/Group Title	Total
Arm/Group Description	All evaluable participants
Measure Participants	84
Number (95% Confidence Interval) [Percentage of participants]	48.7 58%

3. Secondary Outcome

Title	Relapse-free Survival (RFS) After Dasatinib Discontinuation
Description	Relapse is defined as any of the following events while a subject is on study: the loss of MMR, loss of Complete Cytogenetic Response (CCyR), loss of Complete Hematologic Response (CHR) or progression to advanced/blastic phase. RFS is defined as the time from Dasatinib treatment discontinuation to the date of relapse. Subjects who did not relapse were censored on the date of their last molecular assessment.
Time Frame	At 6,12,18, 24 months and every 6 months thereafter up to 5 years

Outcome Measure Data

Analysis Population Description

All evaluable participants

Arm/Group Title	Total
Arm/Group Description	All Evaluable Subjects
Measure Participants	84
At 6 Months	61.9 73.7%
At 12 Months	48.7 58%
At 18 Months	47.5 56.5%
At 24 months	46.0 54.8%
At 30 months	46.0 54.8%
At 36 months	46.0 54.8%
At 42 months	46.0 54.8%

4. Secondary Outcome

Title	Progression Free Survival (PFS) Rate
Description	Progression is defined as Transformation to Accelerated Phase or Blast Crisis (AP/BC) Accelerated Phase (AP) Blasts in PB or BM 15-29%; Blast + promyelocytes >= 30% with blasts < 30% or ACA in Ph+ cells (clonal progression), or basophils in blood >= 20%,or platelets < 100 x 109 /L unrelated to therapy Blastic Phase or Crisis (BP/BC) Blasts in PB or BM >= 30%, or extramedullary blast cell involvement (with the exception of spleen and liver)
Time Frame	From Dasatinib treatment discontinuation up to 5 years

Outcome Measure Data

Analysis Population Description

All evaluable participants

Arm/Group Title	Total
Arm/Group Description	All evaluable participants
Measure Participants	84
At 6 months	100.0 119%
At 12 months	100.0 119%
At 18 months	100.0 119%
At 24 months	100.0 119%
At 30 months	100.0 119%
At 36 months	100.0 119%
At 42 months	100.0 119%

Adverse Events

Time Frame	5 years from date of enrollment
Arm/Group Title	Dasatinib
Arm/Group Description	All evaluable participants
All Cause Mortality
	Dasatinib
	Affected / at Risk (%)	# Events
Total	0/84 (0%)
Serious Adverse Events
	Dasatinib
	Affected / at Risk (%)	# Events
Total	5/45 (11.1%)
Blood and lymphatic system disorders
Lymphadenopathy	1/45 (2.2%)
Gastrointestinal disorders
Abdominal pain	1/45 (2.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	1/45 (2.2%)
Metastases to peritoneum	1/45 (2.2%)
Prostate cancer	1/45 (2.2%)
Other (Not Including Serious) Adverse Events
	Dasatinib
	Affected / at Risk (%)	# Events
Total	16/45 (35.6%)
Blood and lymphatic system disorders
Neutropenia	3/45 (6.7%)
Gastrointestinal disorders
Diarrhoea	4/45 (8.9%)
General disorders
Asthenia	5/45 (11.1%)
Fatigue	6/45 (13.3%)
Infections and infestations
Nasopharyngitis	5/45 (11.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	4/45 (8.9%)
Myalgia	4/45 (8.9%)
Nervous system disorders
Dizziness	3/45 (6.7%)
Headache	4/45 (8.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.