Gemcitabine and Mitoxantrone in Treating Patients With Relapsed Acute Myeloid Leukemia

• Sponsor: The Cleveland Clinic (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00268242
• Collaborator: National Cancer Institute (NCI) (NIH), Duke University (Other)
• Enrollment: 24
• Locations: 2
• Arm: 1
• Duration (Months): 65.9
• Patients Per Site: 12
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as gemcitabine and mitoxantrone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells.

PURPOSE: This phase II trial is studying how well giving gemcitabine together with mitoxantrone works in treating patients with relapsed acute myeloid leukemia.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: Gemcitabine Hydrochloride; Drug: Mitoxantrone Hydrochloride	Phase 2

Detailed Description

OBJECTIVES:

Primary

• Determine the complete response (CR) rate (CR and incomplete blood count recovery (CRi)) of patients with acute myeloid leukemia in first relapse treated with gemcitabine hydrochloride and mitoxantrone hydrochloride.

Secondary

• Evaluate disease free and overall survival of patients with acute myeloid leukemia in first relapse treated with this particular chemotherapy regimen.

• Assess hematologic and non-hematologic toxicity associated with this regimen.

• Assess laboratory correlates of drug resistance in patients with relapsed acute myeloid leukemia.

• Assess the percentage of patients receiving subsequent bone marrow transplantation.

OUTLINE: This is an open-label, multicenter study.

Patients receive gemcitabine hydrochloride IV over 12 hours on day 1 and mitoxantrone hydrochloride IV over 30-60 minutes on days 1, 2, and 3. After completion of a single course of therapy, patients who achieve a complete response may receive 1 additional course of therapy at the discretion of the treating physician.

After completion of study treatment, patients are followed periodically for survival.

PROJECTED ACCRUAL: A total of 40 patients will be accrued for this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Gemcitabine/ Mitoxantrone in Patients With Acute Myeloid Leukemia in First Relapse
• Study Start Date: Jan 1, 2006
• Actual Primary Completion Date: Aug 1, 2010
• Actual Study Completion Date: Jul 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Gemcitabine + Mitoxantrone Gemcitabine Hydrochloride as administered as a continuous intravenous infusion (I.V.) at 10mg/m^2/minute for 12 hours, starting on Day 1. Mitoxantrone Hydrochloride was given at a dose of 12mg/m^2/day I.V. on days 1, 2, and 3.	Drug: Gemcitabine Hydrochloride; 10 mg/m2/ min IV for 12 hours; Other Names: Gemcitabine ; Drug: Mitoxantrone Hydrochloride; 12 mg/m2/day IV (administer over 30-60 minutes) on Day 1, 2 and 3; Other Names: Mitoxantrone

Outcome Measures

Primary Outcome Measures

1. Complete Response Rate [4 Weeks]

   Assumptions/ hypothesis: A Complete Response (CR) rate of 30% or less is unacceptable, and 50% or more is promising. A two-stage design will be used. Initially, 18 patients will be enrolled. If 5 or fewer achieve CR, the study will be stopped. Otherwise, an additional 22 patients will be accrued. Accrual was not halted while follow-up of the first 18 evaluable patients was under way. Therefore, 24 patients were enrolled. Four weeks is anticipated for observation for response. Only 5 patients (21%) achieved a CR and therefore, the study was terminated. Since response was assessed using the International Working Group criteria, a complete response was determined by Morphologic complete remission: A CR designation requires that the patient achieve the morphologic leukemia-free state and have an absolute neutrophil count of more than 1,000/μL and platelets of ≥ 100,000/μL, a cytogenic CR and a morphologic CR with incomplete blood count recovery (CRi).

2. Duration of the First Complete Response [After a CR is achieved, patients are followed at 3 month intervals for disease progression and survival. If a patient has disease progression after achieving a CR, survival will be captured at 6 month intervals, typically for up to 5 years.]

Secondary Outcome Measures

1. Disease-free and Overall Survival [After a CR is achieved, patients are followed at 3 month intervals for disease progression and survival. If a patient has disease progression after achieving a CR, survival will be captured at 6 month intervals, typically for up to 5 years.]

2. Laboratory Correlates: Immunohistochemistry [Baseline]

   Percentage of patients who had a moderate-strong (2-3+) expression of multidrug resistance (MDR) genes by immunohistochemistry. Multidrug resistance gene 1 (MDR1) Equilibrative nucleoside transporter 2(SLC29A2)

3. White Blood Cell Count at Time of Relapse [After a CR is achieved, patient will be followed at 3 month intervals for disease progression, typically for up to 5 years.]

4. Percentage of Patients Making it to Bone Marrow Transplant. [After completion of protocol therapy]

   Assessing the number of patients who were able to have protocol treatment and have a bone marrow transplant after treatment.

Eligibility Criteria

Criteria

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

DISEASE CHARACTERISTICS:

• Bone marrow examination or peripheral blood analysis confirming active acute myeloid leukemia by WHO criteria

• No M3 acute myeloid leukemia

• Not a candidate for allogenic bone marrow transplantation

• Patient must be in first relapse after having received induction chemotherapy

• Received 1 or 2 courses with remission lasting at least 1 month

• Patients with chloromas or leukemia cutis are eligible

• No evidence of leptomeningeal involvement

PATIENT CHARACTERISTICS:

• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2

• Liver enzymes (total bilirubin, aspartate aminotransferase (AST) and ALT) ≤ 2.5 times the upper limits of normal

• Liver enzymes ≥ 2.5 are acceptable if physician documents that it is secondary to the disease

• Serum creatinine ≤ 3 mg/dL

• No poorly controlled medical conditions that would seriously complicate compliance with this study

• No other active primary malignancy other than carcinoma in situ of the cervix or basal cell carcinoma of the skin

• No New York Heart Association grade III or IV cardiac problems, defined as congestive heart failure or myocardial infarction within 6 months prior to start of study

• Pregnant or nursing women are ineligible

• Negative pregnancy test

• Fertile patients must use effective contraception during and for 3 months after study participation

• No documented history of human immunodeficiency virus (HIV) infection

• No history of chronic liver disease

• Ejection fraction ≥ 45%

• No significant history of non-compliance to medical regimens or inability to give reliable informed consent

PRIOR CONCURRENT THERAPY:

• Previous treatment related toxicities should be resolved to grade 1 or better

• No other investigational agents within 14 days prior to the start of study

• No chemotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to start of study

• No major surgery within 2 weeks prior to start of study

• At least two weeks must have elapsed since the conclusion of radiation therapy and the start of gemcitabine hydrochloride, provided the acute effects of radiation treatment have been resolved

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Duke Comprehensive Cancer Center	Durham	North Carolina	United States	27710
2	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio	United States	44195

Sponsors and Collaborators

• The Cleveland Clinic
• National Cancer Institute (NCI)
• Duke University

Investigators

• Study Chair: Anjali Advani, MD, The Cleveland Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: The Cleveland Clinic
• ClinicalTrials.gov Identifier: NCT00268242
• Other Study ID Numbers: CASE-CCF-7725; P30CA043703; CASE-CCF-7725
• First Posted: Dec 22, 2005
• Last Update Posted: Feb 22, 2018
• Last Verified: Aug 1, 2015

• Keywords provided by The Cleveland Clinic: adult acute myeloid leukemia with 11q23 (MLL) abnormalities; adult acute myeloid leukemia with inv(16)(p13;q22); adult acute myeloid leukemia with t(16;16)(p13;q22); adult acute myeloid leukemia with t(8;21)(q22;q22); recurrent adult acute myeloid leukemia; adult acute minimally differentiated myeloid leukemia (M0); adult acute myeloblastic leukemia without maturation (M1); adult acute myeloblastic leukemia with maturation (M2); adult acute myelomonocytic leukemia (M4); adult acute monoblastic leukemia (M5a); adult acute monocytic leukemia (M5b); adult erythroleukemia (M6a); adult pure erythroid leukemia (M6b); adult acute megakaryoblastic leukemia (M7)
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Gemcitabine; Mitoxantrone

Study Results

Participant Flow

Recruitment Details	Patients were treated at the Cleveland Clinic or Duke University Medical Center during the years 2005-2008.
Pre-assignment Detail	If </= 5 of the initial 18 patients enrolled achieved a CR, the study would be stopped. Accrual was not halted while follow-up of the first 18 evaluable patients was under way. Therefore, 24 patients were enrolled. Only 5 patients (21%) achieved a CR and therefore, the study was terminated.

Arm/Group Title	Gemcitabine + Mitoxantrone
Arm/Group Description	Gemcitabine Hydrochloride as administered as a continuous intravenous infusion (I.V.) at 10mg/m^2/minute for 12 hours, starting on Day 1. Mitoxantrone Hydrochloride was given at a dose of 12mg/m^2/day I.V. on days 1, 2, and 3. Gemcitabine Hydrochloride: 10 mg/m2/ min IV for 12 hours Mitoxantrone Hydrochloride: 12 mg/m2/day IV (administer over 30-60 minutes) on Day 1, 2 and 3
Period Title: Overall Study
STARTED	24
COMPLETED	23
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Gemcitabine + Mitoxantrone
Arm/Group Description	Gemcitabine Hydrochloride as administered as a continuous intravenous infusion (I.V.) at 10mg/m^2/minute for 12 hours, starting on Day 1. Mitoxantrone Hydrochloride was given at a dose of 12mg/m^2/day I.V. on days 1, 2, and 3. Gemcitabine Hydrochloride: 10 mg/m2/ min IV for 12 hours Mitoxantrone Hydrochloride: 12 mg/m2/day IV (administer over 30-60 minutes) on Day 1, 2 and 3
Overall Participants	24
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	51
Sex: Female, Male (Count of Participants)
Female	10 41.7%
Male	14 58.3%
Region of Enrollment (participants) [Number]
United States	24 100%

Outcome Measures

1. Primary Outcome

Title	Complete Response Rate
Description	Assumptions/ hypothesis: A Complete Response (CR) rate of 30% or less is unacceptable, and 50% or more is promising. A two-stage design will be used. Initially, 18 patients will be enrolled. If 5 or fewer achieve CR, the study will be stopped. Otherwise, an additional 22 patients will be accrued. Accrual was not halted while follow-up of the first 18 evaluable patients was under way. Therefore, 24 patients were enrolled. Four weeks is anticipated for observation for response. Only 5 patients (21%) achieved a CR and therefore, the study was terminated. Since response was assessed using the International Working Group criteria, a complete response was determined by Morphologic complete remission: A CR designation requires that the patient achieve the morphologic leukemia-free state and have an absolute neutrophil count of more than 1,000/μL and platelets of ≥ 100,000/μL, a cytogenic CR and a morphologic CR with incomplete blood count recovery (CRi).
Time Frame	4 Weeks

Outcome Measure Data

Analysis Population Description

A total of 5 patients (21%) achieved a complete response.

Arm/Group Title	Gemcitabine + Mitoxantrone
Arm/Group Description	Gemcitabine Hydrochloride as administered as a continuous intravenous infusion (I.V.) at 10mg/m^2/minute for 12 hours, starting on Day 1. Mitoxantrone Hydrochloride was given at a dose of 12mg/m^2/day I.V. on days 1, 2, and 3. Gemcitabine Hydrochloride: 10 mg/m2/ min IV for 12 hours Mitoxantrone Hydrochloride: 12 mg/m2/day IV (administer over 30-60 minutes) on Day 1, 2 and 3
Measure Participants	24
Number [participants]	5 20.8%

2. Secondary Outcome

Title	Disease-free and Overall Survival
Time Frame	After a CR is achieved, patients are followed at 3 month intervals for disease progression and survival. If a patient has disease progression after achieving a CR, survival will be captured at 6 month intervals, typically for up to 5 years.

Outcome Measure Data

Analysis Population Description

1 patient died on day 1 of protocol therapy (secondary to complications from AML).

Arm/Group Title	Gemcitabine + Mitoxantrone
Arm/Group Description	Gemcitabine Hydrochloride as administered as a continuous intravenous infusion (I.V.) at 10mg/m^2/minute for 12 hours, starting on Day 1. Mitoxantrone Hydrochloride was given at a dose of 12mg/m^2/day I.V. on days 1, 2, and 3. Gemcitabine Hydrochloride: 10 mg/m2/ min IV for 12 hours Mitoxantrone Hydrochloride: 12 mg/m2/day IV (administer over 30-60 minutes) on Day 1, 2 and 3
Measure Participants	24
Patients dead >30 days post-tx, no relapse	1 4.2%
Patients alive with no evidence of disease relapse	4 16.7%
Patient death on Day 1 of Protocol Therapy	1 4.2%
Patients dead >30 days post-tx, after relapse	18 75%

3. Secondary Outcome

Title	Laboratory Correlates: Immunohistochemistry
Description	Percentage of patients who had a moderate-strong (2-3+) expression of multidrug resistance (MDR) genes by immunohistochemistry. Multidrug resistance gene 1 (MDR1) Equilibrative nucleoside transporter 2(SLC29A2)
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

23 of 24 patients had available blocks for Immunohistochemical (IHC) analysis; Participants with the SLC29A2 Gene Expression (n=22)

Arm/Group Title	Gemcitabine + Mitoxantrone
Arm/Group Description	Gemcitabine Hydrochloride as administered as a continuous intravenous infusion (I.V.) at 10mg/m^2/minute for 12 hours, starting on Day 1. Mitoxantrone Hydrochloride was given at a dose of 12mg/m^2/day I.V. on days 1, 2, and 3. Gemcitabine Hydrochloride: 10 mg/m2/ min IV for 12 hours Mitoxantrone Hydrochloride: 12 mg/m2/day IV (administer over 30-60 minutes) on Day 1, 2 and 3
Measure Participants	23
Participants with GSTP1 Gene Expression	70 291.7%
Participants with SLC29A2 Gene Expression	55 229.2%
Participants with MRP1 Gene Expression	43 179.2%
Participants with LRP1 Gene Expression	35 145.8%
Participants with MDR1 Gene Expression	22 91.7%

4. Secondary Outcome

Title	White Blood Cell Count at Time of Relapse
Time Frame	After a CR is achieved, patient will be followed at 3 month intervals for disease progression, typically for up to 5 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Gemcitabine + Mitoxantrone
Arm/Group Description	Gemcitabine Hydrochloride as administered as a continuous intravenous infusion (I.V.) at 10mg/m^2/minute for 12 hours, starting on Day 1. Mitoxantrone Hydrochloride was given at a dose of 12mg/m^2/day I.V. on days 1, 2, and 3. Gemcitabine Hydrochloride: 10 mg/m2/ min IV for 12 hours Mitoxantrone Hydrochloride: 12 mg/m2/day IV (administer over 30-60 minutes) on Day 1, 2 and 3
Measure Participants	24
Median (Full Range) [cells per microliter]	3450

5. Primary Outcome

Title	Duration of the First Complete Response
Time Frame	After a CR is achieved, patients are followed at 3 month intervals for disease progression and survival. If a patient has disease progression after achieving a CR, survival will be captured at 6 month intervals, typically for up to 5 years.

Outcome Measure Data

Analysis Population Description

Only 5 patients had a complete response, therefore on 5 patients were analyzed for this measure.

Arm/Group Title	Gemcitabine + Mitoxantrone
Arm/Group Description	Gemcitabine Hydrochloride as administered as a continuous intravenous infusion (I.V.) at 10mg/m^2/minute for 12 hours, starting on Day 1. Mitoxantrone Hydrochloride was given at a dose of 12mg/m^2/day I.V. on days 1, 2, and 3. Gemcitabine Hydrochloride: 10 mg/m2/ min IV for 12 hours Mitoxantrone Hydrochloride: 12 mg/m2/day IV (administer over 30-60 minutes) on Day 1, 2 and 3
Measure Participants	5
Median (Full Range) [months]	7.3

6. Secondary Outcome

Title	Percentage of Patients Making it to Bone Marrow Transplant.
Description	Assessing the number of patients who were able to have protocol treatment and have a bone marrow transplant after treatment.
Time Frame	After completion of protocol therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Gemcitabine + Mitoxantrone
Arm/Group Description	Gemcitabine Hydrochloride as administered as a continuous intravenous infusion (I.V.) at 10mg/m^2/minute for 12 hours, starting on Day 1. Mitoxantrone Hydrochloride was given at a dose of 12mg/m^2/day I.V. on days 1, 2, and 3. Gemcitabine Hydrochloride: 10 mg/m2/ min IV for 12 hours Mitoxantrone Hydrochloride: 12 mg/m2/day IV (administer over 30-60 minutes) on Day 1, 2 and 3
Measure Participants	24
Number [percentage of Patients completed a BMT]	8

Adverse Events

Adverse Event Reporting Description	All Adverse Event (AE) / Serious Adverse Event (SAE) data grades were included together in data reporting; there was no differentiation between AEs and SAEs and no unexpected toxicities were seen. Since all grades were reported together, they are being listed as Serious for that reason.
Arm/Group Title	Gemcitabine + Mitoxantrone
Arm/Group Description	Gemcitabine Hydrochloride as administered as a continuous intravenous infusion (I.V.) at 10mg/m^2/minute for 12 hours, starting on Day 1. Mitoxantrone Hydrochloride was given at a dose of 12mg/m^2/day I.V. on days 1, 2, and 3. Gemcitabine Hydrochloride: 10 mg/m2/ min IV for 12 hours Mitoxantrone Hydrochloride: 12 mg/m2/day IV (administer over 30-60 minutes) on Day 1, 2 and 3
All Cause Mortality
	Gemcitabine + Mitoxantrone
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Gemcitabine + Mitoxantrone
	Affected / at Risk (%)	# Events
Total	24/24 (100%)
Gastrointestinal disorders
Nausea	16/24 (66.7%)
Mucositis	14/24 (58.3%)
Diarrhea	14/24 (58.3%)
Abdominal Pain	9/24 (37.5%)
General disorders
Pain	16/24 (66.7%)
Infections and infestations
Fever or Infection	20/24 (83.3%)
Musculoskeletal and connective tissue disorders
Fatigue	12/24 (50%)
Skin and subcutaneous tissue disorders
Rash	19/24 (79.2%)
Other (Not Including Serious) Adverse Events
	Gemcitabine + Mitoxantrone
	Affected / at Risk (%)	# Events
Total	0/24 (0%)

Limitations/Caveats

If </= 5 of 1st 18 pts had a CR, study would stop (otherwise, another 22 pts would be accrued). Study would stop if >4 of 1st 10 or 10 of 1st 25 pts had unacceptable toxicity per protocol & Common Toxicity Criteria for Adverse Effects (CTCAE) v3.0

More Information

Certain Agreements

Principal Investigators are NOT 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.