A Phase 1/2 interventional study of Oxaliplatin and Fludarabine in Richter's Transformation and Leukemia, sponsored by M.D. Anderson Cancer Center. Completed at 1 site in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2013-11-26.
Sponsored by M.D. Anderson Cancer Center · Phase 1/2, Interventional, and Treatment
The goal of this clinical research study is to find the highest tolerable dose of fludarabine and cytarabine that can be given in combination with oxaliplatin and rituximab in the treatment of chronic lymphocytic leukemia (CLL), prolymphocytic leukemia, or Richter's transformation. Once the highest tolerable dose for this drug combination is found, the next goal of the study will be to find out if this combination therapy is effective in shrinking or slowing the growth of these diseases.
Cytarabine is designed to insert itself into DNA (the genetic material of cells) and stop the DNA from repairing itself.
Oxaliplatin is designed to kill cancer cells by damaging their DNA.
Fludarabine is designed to make cancer cells less able to repair damaged DNA. This may increase the likelihood of the cells dying.
Rituximab is designed to attach to lymphoma cells, which may cause them to die.
During the Phase I portion of the study, researchers will be testing different doses of the study drug combination. Oxaliplatin and rituximab will be given at the same dose level. However, fludarabine and cytarabine will be given daily for 2 days to the first 3 participants, daily for 3 days to the next 3 participants, and daily for 4 days to the next 3 participants. Although the plan is to treat 3, up to 6 participants may be treated in each of these groups.
If participants who receive the fludarabine and cytarabine for 2 or 3 days do not experience intolerable side effects, after the second cycle they may receive the next higher dose (an additional day of fludarabine and cytarabine) for the following cycles.
Once the highest tolerated dose of fludarabine and cytarabine given in combination with oxaliplatin and rituximab is found, the next group of participants entering the study will take part in the Phase II portion of the study. Participants in the Phase II portion will receive the study drugs at the highest tolerated dose found in the Phase I portion of the study. The goal of this part of the study is to look at how effective the drug combination is in treating patients with Richter's syndrome, prolymphocytic leukemia, and aggressive, relapsed, or refractory CLL. The same dose levels for all 4 drugs will be used throughout the Phase II portion of the study, unless intolerable side effects occur. In that case, the dose may be lowered or the treatment may be stopped.
You may remain on study for up to 6 cycles. You will be taken off-study early if the disease gets worse or intolerable side effects occur.
Once you are no longer receiving treatment, you will have an end-of-treatment visit. At this visit, you will have a physical exam and blood (about 1 teaspoon) will be drawn for routine tests.
If you achieve remission, after your last cycle is complete, you will have blood drawn (about 2 teaspoons each) every 3 months for routine tests. These tests will continue for as long as you are in remission.
This is an investigational study. Fludarabine, cytarabine, oxaliplatin, and rituximab are all FDA approved and commercially available. The use of these drugs together is investigational. Up to 102 patients will take part in this multicenter study. Up to 90 will be enrolled at The University of Texas (UT) MD Anderson Cancer Center.
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This study's enrollment of 92 is above the median of 38 across 4,247 interventional studies indexed under Leukemia.
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Exclusion Criteria:
Oxaliplatin starting dose 30 mg/m\^2/day over 2 hours on days 1-4 before Fludarabine. Fludarabine 30 mg/m\^2 daily intravenous (IV) over 30 minutes on days 2-3, 2-4, or 2-5 until maximum tolerated dose reached. Cytarabine 500 mg/m\^2 daily IV, 2-hour infusion starting 4 hours after first fludarabine dose started, on days 2-3, 2-4, or 2-5, until maximum tolerated dose (MTD) reached. Rituximab 375 mg/m\^2 IV on day 3, course 1 (on day 1, subsequent courses). Pegfilgrastim 6 mg subcutaneously once per chemotherapy cycle, approximately 24 hours after last dose of chemotherapy.
Drug: Oxaliplatin · Drug: Fludarabine · Drug: Cytarabine · Drug: Rituximab · Drug: Pegfilgrastim
Oxaliplatin 25 mg/m\^2 IV per day MTD on days 1-4 before Fludarabine. Fludarabine 30 mg/m\^2 daily IV over 30 minutes on days 2-4. Cytarabine 500 mg/m\^2 daily IV, 2-hour infusion starting 4 hours after fludarabine dose started, on days 2-4. Rituximab 375 mg/m\^2 IV on day 3, course 1 (on day 1, subsequent courses). Pegfilgrastim 6 mg subcutaneously once per chemotherapy cycle, approximately 24 hours after last dose of chemotherapy.
Drug: Oxaliplatin · Drug: Fludarabine · Drug: Cytarabine · Drug: Rituximab · Drug: Pegfilgrastim
Oxaliplatin 30 mg/m\^2/day, over approximately 2 hours, before fludarabine is started, on days 1-4.
Fludarabine 30 mg/m\^2 daily IV, over approximately 30 minutes, on days 2-3, 2-4, or 2-5 until maximum tolerated dose is reached.
Also known as: Fludara
Cytarabine 500 mg/m\^2 daily IV, 2-hour infusion starting 4 hours after first fludarabine dose is started, on days 2-3, 2-4, or 2-5, until maximum tolerated dose is reached.
Also known as: Cytosar, Ara-C
Rituximab 375 mg/m\^2 IV on day 3, course 1 (on day 1, subsequent courses).
Also known as: Rituxan
6 mg subcutaneously once per chemotherapy cycle, approximately 24 hours after last dose of chemotherapy
Also known as: Neulasta
Maximum Total Tolerated Dose (MTD) of Daily Combination Fludarabine 30 mg/m^2 and Cytarabine 500 mg/m^2 Among 3 Dose Levels (Dose Level 1: 2 Days, Dose Level 2: 3 Days or Dose Level 3: 4 Days)
Maximum dose levels for Phase I determined among three possible dose levels of Fludarabine and Cytarabine in combination with fixed doses of Oxaliplatin and Rituximab. Fludarabine and Cytarabine Dose Level 1: Days 2-3 (2 Days); Dose Level 2: Days 2-4 (3 Days); and Dose 3: Days 2-5 (4 Days). MTD is dose level at which less than 2/3 or 2/6 participants experience dose limiting toxicities (DLTs). The number of days of fludarabine and cytarabine administration increased simultaneously. Participants received a subsequent cycle of treatment with 1 additional day of fludarabine and cytarabine treatment no less than 4 weeks from the initiation of the previous cycle if no drug-related grade 3 or 4 non-hematologic life-threatening adverse events, and drug-related non-hematologic toxicity resolved to baseline or \< grade 2. A maximum of 6 cycles were administered.
Time frame: Up to 36 weeks (6 cycles each 4-6 weeks)
Overall Response: Number of Participants With Complete Remission, Nodular Partial Remission, and Partial Remission
Overall Response includes Complete remission (CR), nodular partial remission (nPR), and partial remission (PR) in high-risk, previously untreated participants with Chronic Lymphocytic Leukemia treated with CFAR using National Cancer Institute - Working Group response criteria. CR defined as zero nodes, Liver/spleen not palpable, zero symptoms, polymorphonuclear leukocyte (PMN)\>1,500/uL, Platelets \>100,000uL, Hemoglobin (untransfused) \>11.0g/dL, Lymphocytes \<4,000/uL and Bone Marrow Aspirate biopsy \<30% lymphocytes with no lymphocyte infiltrate; PR defined as nodes \>/= 50% decrease,Liver/spleen \>/= 50% decrease, symptoms not applicable, PMN \>1,500/uL or \>50% improvement from baseline, Platelets 100,000uL or \>/=50% decrease improvement from baseline, Hemoglobin (untransfused) \>11.0g/dL or \>50% improvement from baseline, Lymphocytes \>50% decrease and Bone Marrow Aspirate biopsy Not Applicable for PR; with nPR defined same as PR but with \<30% lymphocytes with residual disease on biopsy.
Time frame: Up to 36 weeks (6 cycles each 4-6 weeks)
Recruitment Period 5/31/2007- 2/1/2012; All participants were registered at The University of Texas MD Anderson Cancer Center.
| Milestone | OFAR (Phase I) | OFAR (Phase II) |
|---|---|---|
| Started | 12 | 78 |
| Completed | 12 | 78 |
| Not completed | 0 | 0 |
Overall Response includes Complete remission (CR), nodular partial remission (nPR), and partial remission (PR) in high-risk, previously untreated participants with Chronic Lymphocytic Leukemia treated with CFAR using National Cancer Institute - Working Group response criteria. CR defined as zero nodes, Liver/spleen not palpable, zero symptoms, polymorphonuclear leukocyte (PMN)\>1,500/uL, Platelets \>100,000uL, Hemoglobin (untransfused) \>11.0g/dL, Lymphocytes \<4,000/uL and Bone Marrow Aspirate biopsy \<30% lymphocytes with no lymphocyte infiltrate; PR defined as nodes \>/= 50% decrease,Liver/spleen \>/= 50% decrease, symptoms not applicable, PMN \>1,500/uL or \>50% improvement from baseline, Platelets 100,000uL or \>/=50% decrease improvement from baseline, Hemoglobin (untransfused) \>11.0g/dL or \>50% improvement from baseline, Lymphocytes \>50% decrease and Bone Marrow Aspirate biopsy Not Applicable for PR; with nPR defined same as PR but with \<30% lymphocytes with residual disease on biopsy.
| participants | OFAR MTD (Phase II) |
|---|---|
| Complete Remission | 3 |
| Partial Remission | 27 |
| Nodular Partial Remission | 9 |
Maximum dose levels for Phase I determined among three possible dose levels of Fludarabine and Cytarabine in combination with fixed doses of Oxaliplatin and Rituximab. Fludarabine and Cytarabine Dose Level 1: Days 2-3 (2 Days); Dose Level 2: Days 2-4 (3 Days); and Dose 3: Days 2-5 (4 Days). MTD is dose level at which less than 2/3 or 2/6 participants experience dose limiting toxicities (DLTs). The number of days of fludarabine and cytarabine administration increased simultaneously. Participants received a subsequent cycle of treatment with 1 additional day of fludarabine and cytarabine treatment no less than 4 weeks from the initiation of the previous cycle if no drug-related grade 3 or 4 non-hematologic life-threatening adverse events, and drug-related non-hematologic toxicity resolved to baseline or \< grade 2. A maximum of 6 cycles were administered.
| mg/m^2 | OFAR (Phase I) |
|---|---|
| Fludarabine MTD (Total 3 Day Dose) | 90 |
| Cytarabine MTD (Total 3 Day Dose) | 1500 |
Collected over Adverse event collection from Day 1 of first cycle of therapy through sixth cycle then follow-up (every three to six months following first year) until off study. Enrollment started May 2007 and completion including follow up was January 2011.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| OFAR (Phase I) | — | 8/12 (66.7%) | 8/12 (66.7%) |
| OFAR MTD (Phase II) | — | 15/78 (19.2%) | 71/78 (91%) |
| Event | OFAR (Phase I) | OFAR MTD (Phase II) |
|---|---|---|
| Neutropenic FeverInfections and infestations | 3/12 | 0/78 |
| InfectionInfections and infestations | 2/12 | 3/78 |
| DiarrheaGastrointestinal disorders | 2/12 | 1/78 |
| DehydrationGastrointestinal disorders | 1/12 | 3/78 |
| DeathGeneral disorders | 1/12 | 5/78 |
| DyspneaGeneral disorders | 1/12 | 1/78 |
| HyponatremiaMetabolism and nutrition disorders | 1/12 | 0/78 |
| Pleural EffusionRespiratory, thoracic and mediastinal disorders | 1/12 | 0/78 |
| Immune Hemolytic AnemiaBlood and lymphatic system disorders | 1/12 | 0/78 |
| Secondary MalignancyNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 0/12 | 2/78 |
| Event | OFAR (Phase I) | OFAR MTD (Phase II) |
|---|---|---|
| ThrombocytopeniaBlood and lymphatic system disorders | 6/12 | 58/78 |
| NeutropeniaBlood and lymphatic system disorders | 8/12 | 57/78 |
| AnemiaBlood and lymphatic system disorders | 4/12 | 35/78 |
| InfectionInfections and infestations | 0/12 | 23/78 |
| NeuropathyNervous system disorders | 3/12 | 5/78 |
| Nausea/VomitingGastrointestinal disorders | 3/12 | 14/78 |
| FatigueGeneral disorders | 2/12 | 19/78 |
| ConstipationGastrointestinal disorders | 2/12 | 4/78 |
| AnorexiaGastrointestinal disorders | 2/12 | 4/78 |
| MucositisGastrointestinal disorders | 2/12 | 5/78 |
| Age Continuous(Years) | OFAR (Phase I) | OFAR MTD (Phase II) | Total |
|---|---|---|---|
| Median | 65 (46 to 76) | 63 (40 to 81) | 63 (40 to 81) |
| Sex: Female, Male(Participants) | OFAR (Phase I) | OFAR MTD (Phase II) | Total |
|---|---|---|---|
| Female | 3 | 20 | 23 |
| Male | 9 | 58 | 67 |
| Region of Enrollment(participants) | OFAR (Phase I) | OFAR MTD (Phase II) | Total |
|---|---|---|---|
| United States | 12 | 78 | 90 |
This study is completed, as verified in Nov 2013. You cannot join it, but the record below documents what was studied.
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M.D. Anderson Cancer Center