Phase 2 Dasatinib Combo With Smoothened (SMO) Antagonist (BMS-833923)

• Sponsor: Bristol-Myers Squibb (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01357655
• Collaborator: (none)
• Enrollment: 70
• Locations: 24
• Arms: 2
• Duration (Months): 52
• Patients Per Site: 2.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of the study is to compare response rates in newly diagnosed Chronic Phase (CP) CML subjects treated with dasatinib plus BMS-833923 versus dasatinib alone.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: Dasatinib; Drug: BMS-833923	Phase 2

Detailed Description

1. Design:

Study Design and Duration as current described are no longer applicable since enrollment was prematurely concluded due to a decision by the sponsor. Subjects currently enrolled in the trial will continue to receive dasatinib alone at a starting dose of 100 mg QD for:

1. a maximum of 5 years after entry into the study

2. until progression by Investigators determination/judgment

3. intolerance to Dasatinib

4. the study is terminated due to safety concerns or

5. other administrative reasons as communicated by the sponsor

6. Research Hypothesis :

The research hypothesis and primary objective of this study as originally designed are no longer applicable as subjects enrolment has been terminated due to administrative reasons by the sponsor. The objective of the altered design of this study is to describe the safety profile and tolerability of dasatinib

Study Design

• Study Type: Interventional
• Actual Enrollment: 70 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Randomized, Multicenter Phase 2 Trial of Dasatinib (SPRYCEL®) vs. Dasatinib Plus Smoothened Antagonist (BMS-833923) in the Treatment of Subjects With Newly Diagnosed Chronic Phase Philadelphia Chromosome Positive Chronic Myeloid Leukemia (CML).
• Study Start Date: Sep 1, 2011
• Actual Primary Completion Date: Jan 1, 2016
• Actual Study Completion Date: Jan 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm 1: Dasatinib	Drug: Dasatinib; Tablets, Oral, 100 mg, Once daily, approximately 5 years depending on response; Other Names: Sprycel®
Experimental: Arm2: Dasatinib + BMS-833923 Dasatinib for 1 year followed by dasatinib plus BMS-833923 for 2 years followed by dasatinib alone for approximately 2 years; depending on response	Drug: Dasatinib; Tablets, Oral, 100 mg, Once daily, approximately 5 years depending on response; Other Names: Sprycel® ; Drug: BMS-833923; Capsules, Oral, dose to be determined, Once daily, approximately 2 years depending on response

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Major Molecular Response [Baseline up to 12 months]

   Major molecular response (MMR) was assessed using BCR-ABL transcript levels measured by real-time quantitative polymerase chain reaction (qPCR). MMR was defined as a ratio BCR-ABL/ABL ≤0.1% on the international scale (ie, at least 3 log reduction from a standardized baseline value). Number of participants with MMR by timepoint are cumulative.

Secondary Outcome Measures

1. Complete Molecular Response at Any Time [Baseline to End of study (approximately 48 months)]

2. Progression-free Survival, Measured by the Time From Start of Treatment to Progression or Death [Baseline to End of study (approximately 48 months)]

3. Event-free Survival, Measured by the Time From Start of Treatment to Progression, Death or Treatment Discontinuation [Baseline to End of study (approximately 48 months)]

4. Transformation-free Survival Measured by the Time From Start of Treatment to Criteria for Accelerated or Blast Phase CML Are Met and Death [Baseline to End of study (approximately 48 months)]

5. Number of Participants Experiencing Serious Adverse Events (SAE), Drug-Related Adverse Event (AE), AE Leading to Discontinuation, and Death [From date of first dose of study treatment up to the date of the last dose plus 30 days (approximately 49 months)]

   AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Drug-related=having certain, probable, possible, or missing relationship to study drug.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Subjects ≥ 18 years of age who have signed informed consent

• Philadelphia positive Chronic Myeloid Leukemia (CML) in chronic phase

• Previously untreated chronic phase CML, except for Anagrelide or Hydroxyurea.

• Eastern Co-Operative Group (ECOG) Performance Status (PS) Score 0 - 2

Exclusion Criteria:

• Known Abl-kinase T315I or T315A mutation

• Serious or uncontrolled medical disorder (including infection or cardiovascular disease) or dementia or other serious psychiatric condition

• Prior chemotherapy.

• Women who are pregnant or breastfeeding or Women of Child Bearing Potential (WOCBP) who are unwilling or unable to use an acceptable method to avoid pregnancy during the entire study period.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	John Theurer Cancer Center	Hackensack	New Jersey	United States	07601
2	Tennessee Oncology Pllc	Nashville	Tennessee	United States	37203
3	Huntsman Cancer Institute	Salt Lake City	Utah	United States	84112
4	Local Institution	San Miguel De Tucuman	Tucuman	Argentina	4000
5	Local Institution	Antwerpen		Belgium	2060
6	Local Institution	Brugge		Belgium	B-8000
7	Local Institution	Edmonton	Alberta	Canada	T6G 1Z2
8	Local Institution	Helsinki		Finland	00290
9	Local Institution	Nantes	Cedex	France	44000
10	Local Institution	Bordeaux		France	33076
11	Local Institution	Le Chesnay		France	78150
12	Local Institution	Lille		France	59037
13	Local Institution	Paris Cedex 10		France	75475
14	Local Institution	Strasbourg Cedex		France	67091
15	Local Institution	Toulouse Cedex 09		France	31059
16	Local Institution	Chorzow		Poland	41-500
17	Local Institution	Gdansk		Poland	80-952
18	Local Institution	Krakow		Poland	30-510
19	Local Institution	Lodz		Poland	93-513
20	Local Institution	Wroc#aw		Poland	50-367
21	Local Institution	Madrid		Spain	28006
22	Local Institution	Madrid		Spain	28034
23	Local Institution	Oviedo		Spain	33006
24	Local Institution	Pamplona		Spain	31008

Sponsors and Collaborators

• Bristol-Myers Squibb

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• BMS clinical trial educational resource

Publications

None provided.

• Responsible Party: Bristol-Myers Squibb
• ClinicalTrials.gov Identifier: NCT01357655
• Other Study ID Numbers: CA180-363; 2011-000083-10
• First Posted: May 23, 2011
• Last Update Posted: Mar 14, 2017
• Last Verified: Jan 1, 2017

• Keywords provided by Bristol-Myers Squibb: Myelogenous; Chronic; BCR-ABL Positive
• Additional relevant MeSH terms: Leukemia; Dasatinib

Study Results

Participant Flow

Pre-assignment Detail	70 participants were enrolled, 66 were treated. Reasons for non-treatment include 1 adverse event and 3 no longer met study criteria. Participants enrolled were only treated with Dasatinib. The Dasatinib + SMO antagonist (BMS-833923) arm did not have participants because the recommended phase 2 dose of the SMO antagonist had not been determined.

Arm/Group Title	Dasatinib	Dasatinib + SMO Antagonist (BMS-833923)
Arm/Group Description	Dasatinib: Tablets, Oral, 100 mg, were given once daily for approximately 1 year before the study was terminated.	No participants were randomized to this arm because no recommended phase 2 dose of the SMO antagonist could be determined (in a separate trial). Dasatinib for 1 year followed by dasatinib plus SMO antagonist (BMS-833923) for 2 years followed by dasatinib alone for approximately 2 years; depending on response Dasatinib: Tablets, Oral, 100 mg, Once daily BMS-833923: Capsules, Oral, dose to be determined, Once daily, approximately 2 years depending on response
Period Title: Overall Study
STARTED	66	0
COMPLETED	0	0
NOT COMPLETED	66	0

Baseline Characteristics

Arm/Group Title	Dasatinib	Dasatinib + SMO Antagonist (BMS-833923)	Total
Arm/Group Description	Dasatinib: Tablets, Oral, 100 mg, were given once daily for approximately 1 year before the study was terminated.	No participants were randomized to this arm because no recommended phase 2 dose of the SMO antagonist could be determined (in a separate trial). Dasatinib for 1 year followed by dasatinib plus SMO antagonist (BMS-833923) for 2 years followed by dasatinib alone for approximately 2 years; depending on response Dasatinib: Tablets, Oral, 100 mg, Once daily BMS-833923: Capsules, Oral, dose to be determined, Once daily, approximately 2 years depending on response	Total of all reporting groups
Overall Participants	66	0	66
Age, Customized (Count of Participants)
<=18 years	0 0%	0 NaN	0 0%
Between 18 and 64 years	54 81.8%	0 NaN	54 81.8%
>=65 years	12 18.2%	0 NaN	12 18.2%
Sex: Female, Male (Count of Participants)
Female	27 40.9%	0 NaN	27 40.9%
Male	39 59.1%	0 NaN	39 59.1%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Major Molecular Response
Description	Major molecular response (MMR) was assessed using BCR-ABL transcript levels measured by real-time quantitative polymerase chain reaction (qPCR). MMR was defined as a ratio BCR-ABL/ABL ≤0.1% on the international scale (ie, at least 3 log reduction from a standardized baseline value). Number of participants with MMR by timepoint are cumulative.
Time Frame	Baseline up to 12 months

Outcome Measure Data

Analysis Population Description

Efficacy Sample: all treated participants with at least one assessment on treatment. Participants enrolled in this trial could not be randomized to the Dasatinib + SMO antagonist arm because no recommended phase 2 dose of the SMO antagonist could be determined (in a separate trial).

Arm/Group Title	Dasatinib	Dasatinib + SMO Antagonist (BMS-833923)
Arm/Group Description	Dasatinib: Tablets, Oral, 100 mg, were given once daily for approximately 1 year before the study was terminated.	No participants were randomized to this arm because no recommended phase 2 dose of the SMO antagonist could be determined (in a separate trial). Dasatinib for 1 year followed by dasatinib plus SMO antagonist (BMS-833923) for 2 years followed by dasatinib alone for approximately 2 years; depending on response Dasatinib: Tablets, Oral, 100 mg, Once daily BMS-833923: Capsules, Oral, dose to be determined, Once daily, approximately 2 years depending on response
Measure Participants	64	0
Baseline	1 1.5%	0 NaN
3 Months	9 13.6%	0 NaN
6 Months	30 45.5%	0 NaN
12 Months	34 51.5%	0 NaN

2. Secondary Outcome

Title	Complete Molecular Response at Any Time
Time Frame	Baseline to End of study (approximately 48 months)

Outcome Measure Data

Analysis Population Description

The study was terminated prior to data collection for this endpoint.

Arm/Group Title	Dasatinib	Dasatinib + SMO Antagonist (BMS-833923)
Arm/Group Description	Dasatinib: Tablets, Oral, 100 mg, were given once daily for approximately 1 year before the study was terminated.	No participants were randomized to this arm because no recommended phase 2 dose of the SMO antagonist could be determined (in a separate trial). Dasatinib for 1 year followed by dasatinib plus SMO antagonist (BMS-833923) for 2 years followed by dasatinib alone for approximately 2 years; depending on response Dasatinib: Tablets, Oral, 100 mg, Once daily BMS-833923: Capsules, Oral, dose to be determined, Once daily, approximately 2 years depending on response
Measure Participants	0	0

3. Secondary Outcome

Title	Progression-free Survival, Measured by the Time From Start of Treatment to Progression or Death
Time Frame	Baseline to End of study (approximately 48 months)

Outcome Measure Data

Analysis Population Description

The study was terminated prior to data collection for this endpoint.

Arm/Group Title	Dasatinib	Dasatinib + SMO Antagonist (BMS-833923)
Arm/Group Description	Dasatinib: Tablets, Oral, 100 mg, were given once daily for approximately 1 year before the study was terminated.	No participants were randomized to this arm because no recommended phase 2 dose of the SMO antagonist could be determined (in a separate trial). Dasatinib for 1 year followed by dasatinib plus SMO antagonist (BMS-833923) for 2 years followed by dasatinib alone for approximately 2 years; depending on response Dasatinib: Tablets, Oral, 100 mg, Once daily BMS-833923: Capsules, Oral, dose to be determined, Once daily, approximately 2 years depending on response
Measure Participants	0	0

4. Secondary Outcome

Title	Event-free Survival, Measured by the Time From Start of Treatment to Progression, Death or Treatment Discontinuation
Time Frame	Baseline to End of study (approximately 48 months)

Outcome Measure Data

Analysis Population Description

The study was terminated prior to data collection for this endpoint.

Arm/Group Title	Dasatinib	Dasatinib + SMO Antagonist (BMS-833923)
Arm/Group Description	Dasatinib: Tablets, Oral, 100 mg, were given once daily for approximately 1 year before the study was terminated.	No participants were randomized to this arm because no recommended phase 2 dose of the SMO antagonist could be determined (in a separate trial). Dasatinib for 1 year followed by dasatinib plus SMO antagonist (BMS-833923) for 2 years followed by dasatinib alone for approximately 2 years; depending on response Dasatinib: Tablets, Oral, 100 mg, Once daily BMS-833923: Capsules, Oral, dose to be determined, Once daily, approximately 2 years depending on response
Measure Participants	0	0

5. Secondary Outcome

Title	Transformation-free Survival Measured by the Time From Start of Treatment to Criteria for Accelerated or Blast Phase CML Are Met and Death
Time Frame	Baseline to End of study (approximately 48 months)

Outcome Measure Data

Analysis Population Description

The study was terminated prior to data collection for this endpoint.

Arm/Group Title	Dasatinib	Dasatinib + SMO Antagonist (BMS-833923)
Arm/Group Description	Dasatinib: Tablets, Oral, 100 mg, were given once daily for approximately 1 year before the study was terminated.	No participants were randomized to this arm because no recommended phase 2 dose of the SMO antagonist could be determined (in a separate trial). Dasatinib for 1 year followed by dasatinib plus SMO antagonist (BMS-833923) for 2 years followed by dasatinib alone for approximately 2 years; depending on response Dasatinib: Tablets, Oral, 100 mg, Once daily BMS-833923: Capsules, Oral, dose to be determined, Once daily, approximately 2 years depending on response
Measure Participants	0	0

6. Secondary Outcome

Title	Number of Participants Experiencing Serious Adverse Events (SAE), Drug-Related Adverse Event (AE), AE Leading to Discontinuation, and Death
Description	AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Drug-related=having certain, probable, possible, or missing relationship to study drug.
Time Frame	From date of first dose of study treatment up to the date of the last dose plus 30 days (approximately 49 months)

Outcome Measure Data

Analysis Population Description

All Treated Participants; Participants enrolled in this trial could not be randomized to the Dasatinib + SMO antagonist arm because no recommended phase 2 dose of the SMO antagonist could be determined (in a separate trial).

Arm/Group Title	Dasatinib	Dasatinib + SMO Antagonist (BMS-833923)
Arm/Group Description	Dasatinib: Tablets, Oral, 100 mg, were given once daily for approximately 1 year before the study was terminated.	No participants were randomized to this arm because no recommended phase 2 dose of the SMO antagonist could be determined (in a separate trial). Dasatinib for 1 year followed by dasatinib plus SMO antagonist (BMS-833923) for 2 years followed by dasatinib alone for approximately 2 years; depending on response Dasatinib: Tablets, Oral, 100 mg, Once daily BMS-833923: Capsules, Oral, dose to be determined, Once daily, approximately 2 years depending on response
Measure Participants	66	0
SAE	18 27.3%
Drug-Related AE	56 84.8%
Death	2 3%
AE Leading to Discontinuation	14 21.2%

Adverse Events

Time Frame	From date of first dose of study treatment up to the date of the last dose plus 30 days (approximately 49 months)
Adverse Event Reporting Description	All Treated Participants Study Initiated: September 14, 2011 Study Completion: January 26, 2016
Arm/Group Title	Dasatinib
Arm/Group Description	Dasatinib: Tablets, Oral, 100 mg, Once daily, approximately 1 year
All Cause Mortality
	Dasatinib
	Affected / at Risk (%)	# Events
Total	2/66 (3%)
Serious Adverse Events
	Dasatinib
	Affected / at Risk (%)	# Events
Total	18/66 (27.3%)
Blood and lymphatic system disorders
Anaemia	2/66 (3%)
Thrombocytopenia	1/66 (1.5%)
Cardiac disorders
Cardiac failure chronic	1/66 (1.5%)
Myocardial ischaemia	1/66 (1.5%)
Cardiac failure	1/66 (1.5%)
Atrial fibrillation	1/66 (1.5%)
Cardiac tamponade	1/66 (1.5%)
Eye disorders
Amaurosis fugax	1/66 (1.5%)
Gastrointestinal disorders
Small intestinal obstruction	1/66 (1.5%)
Colitis	2/66 (3%)
Volvulus	1/66 (1.5%)
Apical granuloma	1/66 (1.5%)
Inguinal hernia	1/66 (1.5%)
Gastritis	1/66 (1.5%)
General disorders
Death	1/66 (1.5%)
Hepatobiliary disorders
Cholecystitis acute	2/66 (3%)
Immune system disorders
Hypersensitivity	1/66 (1.5%)
Infections and infestations
Vaginal abscess	1/66 (1.5%)
Pneumonia	4/66 (6.1%)
Urosepsis	1/66 (1.5%)
Liver abscess	1/66 (1.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Ovarian neoplasm	1/66 (1.5%)
Prostate cancer	1/66 (1.5%)
Renal cancer	1/66 (1.5%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	5/66 (7.6%)
Other (Not Including Serious) Adverse Events
	Dasatinib
	Affected / at Risk (%)	# Events
Total	60/66 (90.9%)
Blood and lymphatic system disorders
Anaemia	20/66 (30.3%)
Leukopenia	8/66 (12.1%)
Thrombocytopenia	17/66 (25.8%)
Neutropenia	14/66 (21.2%)
Gastrointestinal disorders
Vomiting	13/66 (19.7%)
Constipation	4/66 (6.1%)
Diarrhoea	18/66 (27.3%)
Abdominal pain	5/66 (7.6%)
Abdominal pain upper	4/66 (6.1%)
Nausea	14/66 (21.2%)
General disorders
Chest pain	6/66 (9.1%)
Fatigue	8/66 (12.1%)
Pyrexia	10/66 (15.2%)
Peripheral swelling	4/66 (6.1%)
Asthenia	13/66 (19.7%)
Infections and infestations
Nasopharyngitis	5/66 (7.6%)
Pharyngitis	4/66 (6.1%)
Sinusitis	4/66 (6.1%)
Gastroenteritis	6/66 (9.1%)
Upper respiratory tract infection	8/66 (12.1%)
Investigations
Aspartate aminotransferase increased	4/66 (6.1%)
Weight increased	4/66 (6.1%)
Metabolism and nutrition disorders
Hypercholesterolaemia	4/66 (6.1%)
Hypophosphataemia	4/66 (6.1%)
Hypocalcaemia	5/66 (7.6%)
Musculoskeletal and connective tissue disorders
Muscle spasms	6/66 (9.1%)
Pain in extremity	6/66 (9.1%)
Arthralgia	7/66 (10.6%)
Back pain	5/66 (7.6%)
Nervous system disorders
Headache	27/66 (40.9%)
Psychiatric disorders
Anxiety	4/66 (6.1%)
Insomnia	6/66 (9.1%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	7/66 (10.6%)
Pleural effusion	9/66 (13.6%)
Epistaxis	4/66 (6.1%)
Cough	12/66 (18.2%)
Dyspnoea	10/66 (15.2%)
Dyspnoea exertional	4/66 (6.1%)
Skin and subcutaneous tissue disorders
Rash	11/66 (16.7%)
Acne	4/66 (6.1%)
Vascular disorders
Hypertension	7/66 (10.6%)

Limitations/Caveats

No recommended phase 2 dose of the SMO antagonist was determined (in a separate trial). It was decided to discontinue enrollment and end this trial early. The decision was not made due to any new safety signals for dasatinib or the SMO antagonist.

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.