Imatinib Mesylate and Interferon Alfa in Treating Patients With Chronic Myelogenous Leukemia

• Sponsor: OHSU Knight Cancer Institute (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00015847
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 25
• Locations: 2
• Duration (Months): 121
• Patients Per Site: 12.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

RATIONALE: Imatinib mesylate and interferon alfa may interfere with the growth of the cancer cells. Combining imatinib mesylate with interferon alfa may kill more cancer cells.

PURPOSE: Phase II trial to study the effectiveness of combining imatinib mesylate with interferon alfa in treating patients who have chronic myelogenous leukemia.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Biological: recombinant interferon alfa; Drug: imatinib mesylate	Phase 2

Detailed Description

OBJECTIVES:

• Determine the maximum tolerated dose of interferon alfa administered with imatinib mesylate in patients with chronic phase chronic myelogenous leukemia. (Phase I closed to accrual as of 7/9/03.)

• Determine the safety and tolerability of this regimen in this patient population.

• Determine the complete, major, and minor cytogenetic response rates and complete hematologic response rate in patients after 6 and 12 months of treatment with this regimen.

• Determine the molecular response (reverse transcriptase-polymerase chain reaction for bcr-abl) rate in patients who have a complete cytogenetic response after 6 and 12 months of treatment with this regimen.

• Determine the pharmacokinetics of this regimen in these patients.

OUTLINE: This is a dose-escalation, multicenter study.

• Phase I (closed to accrual as of 7/9/03): Patients receive oral imatinib mesylate once daily beginning on day 1 and interferon alfa (IFN-A) subcutaneously once daily or 3 times weekly beginning on day 14. Courses repeat every 35 days for up to 1 year in the absence of disease progression or unacceptable toxicity. After completion of 1 year of therapy, patients may receive additional therapy, provided that the patient is benefiting from imatinib mesylate. IFN-A is discontinued in patients who achieve a molecular remission that is confirmed on 2 successive bone marrow samples. Imatinib mesylate is discontinued in patients who achieve and maintain a molecular remission for 2 years.

Sequential dose escalation of IFN-A is followed by sequential dose escalation of imatinib mesylate. Cohorts of 3-6 patients receive escalating doses of IFN-A and then imatinib mesylate until the maximum tolerated dose (MTD) of the combination is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity.

• Phase II: Patients receive imatinib mesylate and IFN-A as in phase I at the established MTD.

Patients are followed for 30 days.

PROJECTED ACCRUAL: Approximately 3-15 patients will be accrued for the phase I portion of this study. (Phase I closed to accrual as of 7/9/03.) A total of 40 patients will be accrued for the phase II portion of the study within 3-4 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Dose-Finding Study to Determine the Safety, Tolerability, and Anti-Leukemic Effects of STI571 (NSC 716051) in Combination With Interferon-alpha in Patients With Chronic Myelogenous Leukemia in Chronic Phase
• Study Start Date: Apr 1, 2001
• Actual Primary Completion Date: May 1, 2011
• Actual Study Completion Date: May 1, 2011

Outcome Measures

Primary Outcome Measures

1. Complete Cytogenetic Response at 6 and 12 Months (Phase II) [At 6 and 12 months during phase II]

   Cytogenetic response in terms of the percentage of Ph chromosome positive metaphases in bone marrow is defined as follows: Complete* (0% Ph-positive cells) Partial* (1-34%) Minor (35-95%) None (96-100%).

2. Minor Cytogenetic Response at 6 and 12 Months (Phase II) [At 6 and 12 months during phase II]

3. Complete Hematologic Response at 6 and 12 Months (Phase II) [At 6 and 12 months during phase II]

4. Molecular Response in Patients With Complete Cytogenetic Response at 6 and 12 Months (Phase II) [At 6 and 12 months during phase II]

5. Treatment-related Toxicity (i.e., Grade 3 or 4 Nonhematologic Toxicity) as Measured by NCI CTCAE v3.0 (Phase I) [12 Months]

   1=mild, 2=moderate, 3=severe, 4=life threatening/disabling, 5=death

6. Major Cytogenetic Response After 6 and 12 Months of Treatment. [6 and 12 months after treatment]

   Cytogenetic response in terms of the percentage of Ph chromosome positive metaphases in bone marrow is defined as follows: Complete* (0% Ph-positive cells) Partial* (1-34%) Minor (35-95%) None (96-100%). *Major cytogenetic response includes complete and partial cytogenetic response.

Eligibility Criteria

Criteria

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

DISEASE CHARACTERISTICS:

• Cytogenetically confirmed chronic myelogenous leukemia (CML)

• Less than 15% blasts in peripheral blood or bone marrow

• Less than 30% blasts and promyelocytes in peripheral blood or bone marrow

• Less than 20% basophils in blood or bone marrow

• Platelet count at least 100,000/mm^3

• No leukemia beyond bone marrow, blood, liver, or spleen

• No chloroma

• Phase I (closed to accrual as of 7/9/03):

• Philadelphia (Ph) chromosome-positive CML in chronic phase

• Phase II:

• Newly diagnosed Ph chromosome-positive CML in chronic phase

• Initial diagnosis within 6 months of study

• No prior therapy for CML except hydroxyurea and/or anagrelide hydrochloride

• Phase I (closed to accrual as of 7/9/03) and II:

• No identified sibling donors where allogeneic stem cell transplantation is elected as first-line therapy

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• ECOG 0-2

Life expectancy:

• Not specified

Hematopoietic:

• See Disease Characteristics

Hepatic:

• Bilirubin no greater than 1.5 times upper limit of normal (ULN)

• AST or ALT no greater than 2 times ULN

Renal:

• Creatinine no greater than 1.5 times ULN

Cardiovascular:

• No New York Heart Association class III or IV heart disease

Other:

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use 2 methods of effective barrier contraception during and for at least 3 months after study participation

• No other serious uncontrolled medical condition

• No autoimmune disease

• No prior noncompliance to medical regimens or potential unreliability

• No prior grade 3 or greater non-hematologic toxicity due to prior interferon (phase I [closed to accrual as of 7/9/03])

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• See Disease Characteristics

• No prior bone marrow or peripheral blood stem cell transplantation

• At least 2 weeks since prior interferon alfa (phase I [closed to accrual as of 7/9/03])

Chemotherapy:

• See Disease Characteristics

• At least 6 weeks since prior busulfan (phase I [closed to accrual as of 7/9/03] )

• At least 2 weeks since prior cytarabine (phase I [closed to accrual as of 7/9/03])

• No concurrent chemotherapy

• Concurrent hydroxyurea allowed during the first 3 months of study

Endocrine therapy:

• Not specified

Radiotherapy:

• Not specified

Surgery:

• Not specified

Other:

• At least 4 weeks since prior investigational agents other than imatinib mesylate (phase I [closed to accrual as of 7/9/03])

• No concurrent grapefruit juice

• Concurrent anagrelide hydrochloride allowed during the first 3 months of study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Robert H. Lurie Comprehensive Cancer Center at Northwestern University	Chicago	Illinois	United States	60611
2	OHSU Knight Cancer Institute	Portland	Oregon	United States	97239

Sponsors and Collaborators

• OHSU Knight Cancer Institute
• National Cancer Institute (NCI)

Investigators

• Study Chair: Brian J. Druker, MD, OHSU Knight Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: OHSU Knight Cancer Institute
• ClinicalTrials.gov Identifier: NCT00015847
• Other Study ID Numbers: CDR0000068443; OHSU-6263; OHSU-409; NCI-2794; OHSU-HEM-00072-LX
• First Posted: Jan 27, 2003
• Last Update Posted: Aug 20, 2012
• Last Verified: Jun 1, 2012

• Keywords provided by OHSU Knight Cancer Institute: relapsing chronic myelogenous leukemia; chronic phase chronic myelogenous leukemia; Philadelphia chromosome positive chronic myelogenous leukemia
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Interferons; Interferon-alpha; Imatinib Mesylate

Study Results

Participant Flow

Arm/Group Title	Imatinib Mesylate
Arm/Group Description	Once daily oral administration of STI571 (imatinib mesylate) at a dose of 400 mg or 600mg for 12 months.
Period Title: Overall Study
STARTED	25
COMPLETED	25
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Imatinib Mesylate
Arm/Group Description	Once daily oral administration of STI571 (imatinib mesylate) at a dose of 400 mg or 600mg for 12 months.
Overall Participants	25
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	23 92%
>=65 years	2 8%
Sex: Female, Male (Count of Participants)
Female	10 40%
Male	15 60%
Region of Enrollment (participants) [Number]
United States	25 100%

Outcome Measures

1. Primary Outcome

Title	Complete Cytogenetic Response at 6 and 12 Months (Phase II)
Description	Cytogenetic response in terms of the percentage of Ph chromosome positive metaphases in bone marrow is defined as follows: Complete* (0% Ph-positive cells) Partial* (1-34%) Minor (35-95%) None (96-100%).
Time Frame	At 6 and 12 months during phase II

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Imatinib Mesylate
Arm/Group Description	Once daily oral administration of STI571 (imatinib mesylate) at a dose of 400 mg or 600mg for 12 months.
Measure Participants	25
Number [Participants]	13 52%

2. Primary Outcome

Title	Minor Cytogenetic Response at 6 and 12 Months (Phase II)
Time Frame	At 6 and 12 months during phase II

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Primary Outcome

Title	Complete Hematologic Response at 6 and 12 Months (Phase II)
Time Frame	At 6 and 12 months during phase II

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Primary Outcome

Title	Molecular Response in Patients With Complete Cytogenetic Response at 6 and 12 Months (Phase II)
Time Frame	At 6 and 12 months during phase II

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Primary Outcome

Title	Treatment-related Toxicity (i.e., Grade 3 or 4 Nonhematologic Toxicity) as Measured by NCI CTCAE v3.0 (Phase I)
Description	1=mild, 2=moderate, 3=severe, 4=life threatening/disabling, 5=death
Time Frame	12 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Imatinib Mesylate
Arm/Group Description	Once daily oral administration of STI571 (imatinib mesylate) at a dose of 400 mg or 600mg for 12 months.
Measure Participants	25
Number [Participants]	8 32%

6. Primary Outcome

Title	Major Cytogenetic Response After 6 and 12 Months of Treatment.
Description	Cytogenetic response in terms of the percentage of Ph chromosome positive metaphases in bone marrow is defined as follows: Complete* (0% Ph-positive cells) Partial* (1-34%) Minor (35-95%) None (96-100%). *Major cytogenetic response includes complete and partial cytogenetic response.
Time Frame	6 and 12 months after treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Imatinib Mesylate
Arm/Group Description	Once daily oral administration of STI571 (imatinib mesylate) at a dose of 400 mg or 600mg for 12 months.
Measure Participants	25
Number [Participants]	18 72%

Adverse Events

Arm/Group Title	Imatinib Mesylate
Arm/Group Description	Once daily oral administration of STI571 (imatinib mesylate) at a dose of 400 mg or 600mg for 12 months.
All Cause Mortality
	Imatinib Mesylate
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Imatinib Mesylate
	Affected / at Risk (%)	# Events
Total	8/25 (32%)
Gastrointestinal disorders
Diarrhea	1/25 (4%)	4
General disorders
Fatigue	1/25 (4%)	6
Hepatobiliary disorders
Elevated Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT)	3/25 (12%)	6
Infections and infestations
Infection	1/25 (4%)	1
Musculoskeletal and connective tissue disorders
Bone Pain	1/25 (4%)	3
Skin and subcutaneous tissue disorders
Rash	1/25 (4%)	3
Other (Not Including Serious) Adverse Events
	Imatinib Mesylate
	Affected / at Risk (%)	# Events
Total	15/25 (60%)
General disorders
Chills	2/25 (8%)
Headache	2/25 (8%)
Musculoskeletal and connective tissue disorders
Myalgia	3/25 (12%)
Muscle Cramps	2/25 (8%)
Gout	2/25 (8%)
Psychiatric disorders
Depression	2/25 (8%)
Skin and subcutaneous tissue disorders
Pruritis	2/25 (8%)

Limitations/Caveats

Early termination; 12 month follow-up was not carried out.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.