Phase II Study of Fludarabine and Mitoxantrone, Followed by GM-CSF(Granulocyte-macrophage Colony-stimulating Factor) and Rituximab
Study Details
Study Description
Brief Summary
Patients with a low-grade, or indolent (slow-growing) form of non-Hodgkin's lymphoma (NHL) in which the usual survival is between 7-10 years are being asked to take part in this study. Although normally-used combinations of chemotherapy will cause NHL to disappear in 30-40% of patients (called complete response or complete remission), almost all will have their disease return.
In this study, researchers tested a combination of anti-cancer agents, fludarabine, rituximab and GM-CSF with mitoxantrone or cyclophosphamide to see if a better and more long-lasting response can be achieved. All of the medications are approved by the Food and Drug
Administration (FDA) and are available on the market. The agents we will use are:
-
Mitoxantrone and fludarabine and cyclophosphamide and fludarabine are combinations of chemotherapy drugs that have been successfully used to treat NHL/CLL (Chronic lymphocytic leukemia) that has returned after treatment and are comparable options for treatment.
-
Rituximab, a monoclonal antibody that kills cancer cells by binding the CD20 antigen found on the surface of B-cells, commonly used along with chemotherapy drugs to improve response rates in lymphoma treatment.
-
GM-CSF (granulocyte-macrophage colony stimulating factor, also called sargramostim, GM, or Leukine), a growth factor which stimulates the development of new ("stem") cells. GM-CSF encourages stem cells to divide, specialize, and become active. It is not a normal part of treatment for NHL.
Using GM-CSF in NHL treatment is the experimental part of this study. The main purpose of this study is to see if giving GM-CSF along with a standard anti-cancer treatment will work better to reduce cancer, and to look at side effects of the treatment.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
Patients with a low-grade, or indolent (slow-growing) form of non-Hodgkin's lymphoma (NHL) in which the usual survival is between 7-10 years are being asked to take part in this study. Although normally-used combinations of chemotherapy will cause NHL to disappear in 30-40% of patients (called complete response or complete remission), almost all will have their disease return.
When NHL is diagnosed, an abundance of white blood cells called B-lymphocytes (or B-cells) are found in the body. Almost all B-cells have a special protein on the surface called a CD20 antigen. Some anti-cancer drugs, called monoclonal antibodies, target cancer cells by binding, or "locking up", specific antigens found on their surfaces, which kills the cancer cells.
In this study, researchers will test a combination of anti-cancer agents to see if a better and more long-lasting response can be achieved. All of the medications are approved by the Food and Drug Administration (FDA) and are available on the market. The agents we will use are:
-Mitoxantrone and fludarabine, a combination of chemotherapy drugs that has been successfully used to treat NHL that has returned after treatment.
OR
-
Cyclophosphamide and fludarabine, a combination of chemotherapy drugs that has been successfully used to treat NHL that has returned after treatment.
-
Rituximab, a monoclonal antibody that kills cancer cells by binding the CD20 antigen found on the surface of B-cells, commonly used along with chemotherapy drugs to improve response rates in lymphoma treatment.
-
GM-CSF (granulocyte-macrophage colony stimulating factor, also called sargramostim, GM, or Leukine), a growth factor which stimulates the development of new (stem) cells. GM-CSF encourages stem cells to divide, specialize, and become active. It is not a normal part of treatment for NHL.
Using GM-CSF in NHL treatment is the experimental part of this study. In studies done in the laboratory, GM-CSF caused an increase in the number of antigens, such as CD20, on the surface of B-cells. If more antigens are present, it may be easier to target cells that express CD20 or other antigens. Monoclonal antibodies (such as rituximab) might then be able to more effectively bind the antigens and kill the cancer cells.
The main purpose of this study is to see if giving GM-CSF along with a standard anti-cancer treatment will work better to reduce cancer, and to look at side effects of the treatment.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Fludarabine and Mitoxantrome followed by GM-CSF and Rituximab Initial patients (n=9) received fludarabine (25 mg/m2 IV) and mitoxantrone (10 mg/m2 IV)with sequential administration of GM-CSF (500 mcg subcutaneously) on days 6 and 7 and rituximab (375 mg/m2) on day 8. After a change in the protocol, all additional patients (n=6) received fludarabine (25 mg/m2 IV) and cyclophosphamide (250 mg/m2 IV)with sequential administration of GM-CSF (500 mcg subcutaneously) on days 6 and 7 and rituximab (375 mg/m2) on day 8. All patients received dditional doses of GM-CSF (days +8 through +14) were given for patients to reduce variability in neutropenic management. |
Drug: Mitoxantrone/Cyclophosphamide, Fludarabine, Rituximab and GM-CSF
Initial patients (n=9) received fludarabine (25 mg/m^2 intravenously) and mitoxantrone (10 mg/m^2 intravenously)with sequential administration of GM-CSF(Granulocyte-macrophage colony stimulating factor) (500 µcg subcutaneously) on days 6 and 7 and rituximab (375 mg/m^2) on day 8.
After a change in the protocol, all additional patients (n=6) received fludarabine (25 mg/m^2 intravenously) and cyclophosphamide (250 mg/m^2 intravenously)with sequential administration of GM-CSF (500 µcg subcutaneously) on days 6 and 7 and rituximab (375 mg/m^2) on day 8. All patients received additional doses of GM-CSF (days +8 through +14) were given for patients to reduce variability in neutropenic management.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Number of Patients's Who Had Complete Response and Partial Response to the Treatment of Fludarabine and Cyclophosphamide Followed by GM-CSF and Rituximab. [6 months]
Complete Response (CR): Disappearance of all clinical evidence of active tumor for a minimum of eight weeks and absence of any symptoms related to the tumor. Partial Response (PR):50% decrease in the sum of the product diameters of all lesions that persist for at least four weeks. No lesion can increase in size and no new lesion can appear during this period. Stable disease (SD):A tumor that is neither growing nor shrinking.No new tumors have developed
Eligibility Criteria
Criteria
Inclusion Criteria:
- To qualify for this study, the patient must have relapsed, refractory or previously untreated low-grade (indolent) non-Hodgkin lymphoma of the following subtypes: Follicular center cell lymphoma grade 1, lymphoplasmacytoid lymphoma, small lymphocytic lymphoma, splenic marginal-zone types lymphoma, monocytoid B-cell lymphoma and extranodal mucosa-associated lymphoid tissue (MALT) lymphomas. Final eligibility will be determined by the health professionals conducting this clinical trial.
Exclusion Criteria:
- Patients who have received prior treatment with purine analogs will be excluded from this study. Also, patients whose diagnostic/histologic subtype cannot be confirmed by our institution will not be able to participate in this study. Final eligibility will be determined by the health professionals conducting this clinical trial.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Emory University Winship Cancer Institute | Atlanta | Georgia | United States | 30322 |
Sponsors and Collaborators
- Emory University
- Bayer
Investigators
- Principal Investigator: Christopher Flowers, MD, Emory University Winship Cancer Institute
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 1048-2001
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Fludarabine and Cyclophosphamide With Sequential Administratio |
|---|---|
| Arm/Group Description | Patients will receive fludarabine and cyclophosphamide with sequential administration of GM-CSF on days 6 and 7 and rituximab on day 8. |
| Period Title: Overall Study | |
| STARTED | 15 |
| COMPLETED | 15 |
| NOT COMPLETED | 0 |
Baseline Characteristics
| Arm/Group Title | Fludarabine and Cyclophosphamide With Sequential Administratio |
|---|---|
| Arm/Group Description | Patients will receive fludarabine and cyclophosphamide with sequential administration of GM-CSF on days 6 and 7 and rituximab on day 8. |
| Overall Participants | 15 |
| Age (Count of Participants) | |
| <=18 years |
0
0%
|
| Between 18 and 65 years |
9
60%
|
| >=65 years |
6
40%
|
| Age (years) [Median (Full Range) ] | |
| Median (Full Range) [years] |
62
|
| Sex: Female, Male (Count of Participants) | |
| Female |
4
26.7%
|
| Male |
11
73.3%
|
| Region of Enrollment (participants) [Number] | |
| United States |
15
100%
|
| Diagnosis Type (Number) [Number] | |
| Low Grade Non Hodgkin's Lymphoma(NHL) |
7
46.7%
|
| Chronic Lymphocytic Leukemia (CLL) |
8
53.3%
|
Outcome Measures
| Title | Number of Patients's Who Had Complete Response and Partial Response to the Treatment of Fludarabine and Cyclophosphamide Followed by GM-CSF and Rituximab. |
|---|---|
| Description | Complete Response (CR): Disappearance of all clinical evidence of active tumor for a minimum of eight weeks and absence of any symptoms related to the tumor. Partial Response (PR):50% decrease in the sum of the product diameters of all lesions that persist for at least four weeks. No lesion can increase in size and no new lesion can appear during this period. Stable disease (SD):A tumor that is neither growing nor shrinking.No new tumors have developed |
| Time Frame | 6 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Chronic Lymphocytic Leukemia | Non Hodgkin Lymphoma |
|---|---|---|
| Arm/Group Description | Chronic Lymphocytic Leukemia (CLL) is a condition characterized by an accumulation of abnormal lymphocytes in the blood and the bone marrow. These lymphocytes do not perform their functions as normal ones would and interfere with the production of other blood cells necessary for the normal functioning of the blood, leading to a host of complications like deficiency of the immune system, coagulation problems, swollen lymph nodes, and many other conditions. Fludarabine-based combination provide effective treatment for patients with low-grade NHL and CLL with high complete response rates that are improved with the addition of Rituximab. | Non-Hodgkin's lymphoma, also called non-Hodgkin lymphoma, is cancer that originates in your lymphatic system, the disease-fighting network spread throughout your body. In non-Hodgkin's lymphoma, tumors develop from lymphocytes - a type of white blood cell. Fludarabine-based combination provide effective treatment for patients with low-grade NHL and CLL with high complete response rates that are improved with the addition of Rituximab. |
| Measure Participants | 8 | 7 |
| Complete Response |
4
26.7%
|
5
NaN
|
| Partial Response |
2
13.3%
|
2
NaN
|
| Stable Disease |
1
6.7%
|
0
NaN
|
Adverse Events
| Time Frame | ||
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Fludarabine and Cyclophosphamide With Sequential Administratio | |
| Arm/Group Description | Patients will receive fludarabine and cyclophosphamide with sequential administration of GM-CSF on days 6 and 7 and rituximab on day 8. | |
All Cause Mortality |
||
| Fludarabine and Cyclophosphamide With Sequential Administratio | ||
| Affected / at Risk (%) | # Events | |
| Total | / (NaN) | |
Serious Adverse Events |
||
| Fludarabine and Cyclophosphamide With Sequential Administratio | ||
| Affected / at Risk (%) | # Events | |
| Total | 0/15 (0%) | |
Other (Not Including Serious) Adverse Events |
||
| Fludarabine and Cyclophosphamide With Sequential Administratio | ||
| Affected / at Risk (%) | # Events | |
| Total | 15/15 (100%) | |
| Blood and lymphatic system disorders | ||
| Neutropenia | 10/15 (66.7%) | |
| Thrombocytopenia | 7/15 (46.7%) | |
| Anemia | 9/15 (60%) | |
| Hypoprotinemia | 1/15 (6.7%) | |
| Endocrine disorders | ||
| Hyperglycemia | 4/15 (26.7%) | |
| Gastrointestinal disorders | ||
| Nausea | 9/15 (60%) | |
| Vomiting | 3/15 (20%) | |
| Diarrhea | 1/15 (6.7%) | |
| Constipation | 5/15 (33.3%) | |
| Muscositis | 3/15 (20%) | |
| General disorders | ||
| Fatigue | 7/15 (46.7%) | |
| Fever | 3/15 (20%) | |
| Night Sweats | 4/15 (26.7%) | |
| Pain | 12/15 (80%) | |
| Weight Loss | 2/15 (13.3%) | |
| Loss of Appetite | 4/15 (26.7%) | |
| Anxiety | 2/15 (13.3%) | |
| Malaise | 2/15 (13.3%) | |
| Musculoskeletal and connective tissue disorders | ||
| Arthritis | 2/15 (13.3%) | |
| Myalgia | 2/15 (13.3%) | |
| Renal and urinary disorders | ||
| Hyperkalemia | 1/15 (6.7%) | |
| Polyuria | 2/15 (13.3%) | |
| Skin and subcutaneous tissue disorders | ||
| Infusion reaction | 4/15 (26.7%) | |
Limitations/Caveats
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.
Results Point of Contact
| Name/Title | Dr. Christopher Flowers |
|---|---|
| Organization | Emory University |
| Phone | 404-778-3942 |
| crflowe@emory.edu |
- 1048-2001