A Phase 2/3 interventional study of Rituxan, Cyclophosphamide, Vincristine, Prednisone and Higher Dose of Rituximab in Immune Thrombocytopenic Purpura, sponsored by Weill Medical College of Cornell University. Completed at 1 site in United States. Open to participants aged 12 Years to 100 Years. Per ClinicalTrials.gov, last updated 2019-01-09.
Sponsored by Weill Medical College of Cornell University · Phase 2/3, Interventional, and Treatment
This study is designed to compare the efficacy and safety of higher doses of Rituxan with a regimen combining standard doses of Rituxan + CVP in patients with chronic ITP who did not respond to or relapsed after standard doses of Rituxan. Patients eligible for this protocol will be stratified into two subgroups according to their initial response to Rituxan.
The rationale for using chemotherapy in combination with Rituximab:
Since Rituximab is an anti-B cell therapy, in order to improve the rate of durable responses beyond the 32% (18 of 57) seen with Rituximab alone, it seems appropriate to combine it with a therapy that would also target T cells and/or macrophages. Our plan is therefore to combine Rituximab with a standard chemotherapy (CHOP)-like regimen as previously successfully tested in patients with follicular or diffuse large-B-cell lymphomas 13-15. The "CHOP" chemotherapy regimen is a combination of cyclophosphamide, doxorubicin, vincristine and prednisone (or prednisolone) that has been considered the "gold standard" for treating lymphomas for more than 20 years.
This combination of medications was used in a Hodgkin's patient with refractory ITP and became the template for developing the use of cyclophosphamide, vincristine, and prednisone for ITP as initially reported in 1993. Since reports on doxorubicin efficacy by itself in ITP are only anecdotal 16 and this drug has a potential cardiac toxicity, a CVP regimen (namely a combination of cyclophosphamide + vincristine and prednisone) should be similar in efficacy to CHOP in patients with ITP and have less toxicity. Indeed, the efficacy of such a chemotherapy12 as well as pulses cyclophosphamide therapy alone11 have already been reported in patients with refractory ITP.
Since attempts to increase the efficacy of CHOP by increasing the doses or adding other cytotoxic drugs have failed, a new therapeutic strategy combining CHOP with Rituxan has been successfully developed in the last few years in various types of B-cell lymphomas 13-15. In elderly patients with diffuse large-B-cell lymphoma, the addition of Rituxan to standard CHOP chemotherapy significantly reduced the risk of treatment failure and deaths without increasing toxicity 13. Moreover, in autoimmune disorders, there are few preliminary data suggesting that Rituxan and cyclophopshamide given in combination could be effective and relatively safe in patients with active rheumatoid arthritis 17.
Therefore, the rationale for combining Rituxan with a CHOP-like regimen in ITP is threefold:
Both Rituxan and CHOP or IV cyclophosphamide have efficacy in ITP The treatments have different mechanisms of action. They have minimally-overlapping toxicities.
The rationale for using higher doses of Rituxan in patients who had no response, or relapsed, to the drug at the standard dose:
The standard dose of Rituxan is arbitrary in that one dose of Rituxan has been used in the great majority of the clinical trials and virtually all patients since the FDA approval of Rituxan in 1997: 375 mg/m2 weekly x 4 weeks. To date, because Rituxan is a monoclonal antibody rather than a chemotherapeutic agent, it was recognized that a true maximum tolerated dose (MTD) might not be achieved. Among other factors that could influence the tolerance of higher doses of Rituxan are the rate of CD20 surface expression and the serum level of the antibody11. Limited trials of higher doses have been pursued in CLL18 (up to 2,250 mg/m2 per dose), but not in other types of lymphoma or in autoimmune diseases. In CLL, mild to severe toxicity was exclusively observed with the first dose (375 mg/m2) while toxicity on subsequent higher doses was minimal. In ITP, some of the few patients that have been retreated responded better to the second dose of rituximab than to the initial treatment (although the opposite is also true). Full depletion of the marrow and especially the lymph nodes is not achieved by the current dose regimen and B cells return in substantial number to the peripheral blood within 3-6 months in patients with ITP treated at the conventional dose. We therefore anticipate that in ITP patients who relapsed or did not respond after a previous course of rituximab, doubling the dose could lead to a deeper and more prolonged B cell depletion and to a better increase in the platelet count without enhancing toxicity.
263 studies on the registry are indexed under Purpura; 27 are open to participants now.
This study's enrollment of 17 is below the median of 50 across 171 interventional studies indexed under Purpura.
Browse Purpura studies →Weill Medical College of Cornell University is the lead sponsor of 867 studies on the registry; 160 are open to participants now.
Of its 119 completed or terminated interventional studies of FDA-regulated products, 91 (76%) have results posted.
Counted across the registry records on this site, refreshed daily.
Patients will be eligible to participate in the study if they:
Exclusion Criteria:
Male and female subjects will be ineligible to participate if they:
'Standard Dose of Rituximab administered with C, V, P (CVP)' Interventions: Rituximab will be administered as an IV infusion at the standard dose of 375 mg/m2 for 4 doses at standard rates and use of premedication. The schedule will be to give the first rituximab infusion 5 days (± 3 days) prior to first administration of CVP, and the following 3 infusions will be given on the same day as the 3 cycles of C, V, P. On those days, the IV Cyclophosphamide and Vincristine will be given first so that the administration of fluids with the rituximab can be used as post-cyclophosphamide hydration, Cyclophosphamide dosing will be 750mg/m2 (maximum 2000mg), vincristine 1.4 mg/m2 (up to 1.6 mg), prednisone 100mg po daily for 5 days.
Drug: Rituxan, Cyclophosphamide, Vincristine, Prednisone
In this arm, Rituximab will be administered at a dose of 750 mg/m2 once a week x 4 consecutive weeks (4 infusions in total). We will perform EKG monitor tracings before, during and after Rituxan infusions. This will be a single-lead tracing that will allow us to look at the Q-T interval.
Drug: Higher Dose of Rituximab
'Rituximab, Cyclophosphamide, Vincristine, Prednisone interventions are as follows: Rituximab will be administered as an IV infusion at the standard dose of 375 mg/m2 for 4 doses. However, the schedule of the infusions will be different than the usual one: Rather than administrating the 4 doses once weekly, the first infusion will be given 5 days (± 3 days) prior to the first infusions of C and V and oral P, and the following 3 rituximab infusions will be given on the same day as the 3 cycles of C, V, and P.
Also known as: Rituximab
rituximab 750mg/m2 (twice the standard dose of 375mg/m2) will be given weekly for 4 weeks. Premedication and infusion rate escalation will be exactly the same as for standard dose rituximab. The additional dose will thus run at 400ml/hr.
Efficacy of Higher Double Doses of Rituxan and of Standard Dose of Rituxan + Cyclophosphamide, Vincristine, Prednisone
Outcome measure was determined by comparing the study participants' historical responses to their initial treatment of rituximab at standard dose/regimen without "enhancement" (based on duration of response and type of response) to the participants response to their study treatment responses. Thus each patient was his or her own control although all study treatments included standard dose rituximab treatments (one at double the dose and one with additional treatments).
Time frame: 2 years
Number of Participants With SAEs
How many participants had SAEs among those receiving R-CVP or among those receiving double dose rituximab and did participants in one arm have substantially more SAEs than those in the other arm
Time frame: 2 years
Relative Efficacy of the 2 Groups
The goal is to see if there are major differences between the two arms for each group in term of efficacy and of toxicity both overall and in comparison to the previous responses to rituximab alone. The comparisons are for level of response eg CR (\>100k) vs PR (230-100k) vs NR (\<30k) and for duration of response-----duration of response is controlled by comparison to duration of response from initial rituximab infusions
Time frame: 2 years
| Milestone | Standard Dose of Rituxan Plus CVP (R-CVP) | Double Dose of Rituximab |
|---|---|---|
| Started | 9 | 8 |
| Completed | 9 | 8 |
| Not completed | 0 | 0 |
Outcome measure was determined by comparing the study participants' historical responses to their initial treatment of rituximab at standard dose/regimen without "enhancement" (based on duration of response and type of response) to the participants response to their study treatment responses. Thus each patient was his or her own control although all study treatments included standard dose rituximab treatments (one at double the dose and one with additional treatments).
| Participants | Standard Dose of Rituxan Plus CVP (R-CVP) | Double Dose of Rituximab |
|---|---|---|
| same response as historical rituximab | 8 | 7 |
| Worse Response | 1 | 1 |
| Better Response | 0 | 0 |
How many participants had SAEs among those receiving R-CVP or among those receiving double dose rituximab and did participants in one arm have substantially more SAEs than those in the other arm
| number of patients with SAEs | Rituximab + CVP | Double Dose Rituximab |
|---|---|---|
| Number of Participants With SAEs | 0 | 1 |
The goal is to see if there are major differences between the two arms for each group in term of efficacy and of toxicity both overall and in comparison to the previous responses to rituximab alone. The comparisons are for level of response eg CR (\>100k) vs PR (230-100k) vs NR (\<30k) and for duration of response-----duration of response is controlled by comparison to duration of response from initial rituximab infusions
| number of responders | Rituximab, C, V, P | High Dose Rituximab |
|---|---|---|
| CR | 4 | 4 |
| PR | 1 | 0 |
| response longer than previous response | 0 | 0 |
Collected over collected over 2 years. Non-serious events are listed at a 1% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Rituximab + C, V, P | 0/9 (0%) | 1/9 (11.1%) | 4/9 (44.4%) |
| Double Dose Rituximab | 0/8 (0%) | 0/8 (0%) | 2/8 (25%) |
| Event | Rituximab + C, V, P | Double Dose Rituximab |
|---|---|---|
| Serum SicknessBlood and lymphatic system disorders | 1/9 | 0/8 |
| Event | Rituximab + C, V, P | Double Dose Rituximab |
|---|---|---|
| non-seriousGeneral disorders | 4/9 | 2/8 |
17 patients total treated and analysis is of responding patients for efficacy and SAE for safety
| Age, Customized(years) | Standard Dose of Rituxan Plus CVP (R-CVP) | Double Dose of Rituximab | Total |
|---|---|---|---|
| age continuous | 36 ± 17 | 44 ± 19 | 40 ± 10 |
| Sex/Gender, Customized(Participants) | Standard Dose of Rituxan Plus CVP (R-CVP) | Double Dose of Rituximab | Total |
|---|---|---|---|
| Males entered at Baseline | 4 | 4 | 8 |
| Females entered at baseline | 5 | 4 | 9 |
| Initial response to treatment with standard dose rituximab(Participants) | Standard Dose of Rituxan Plus CVP (R-CVP) | Double Dose of Rituximab | Total |
|---|---|---|---|
| Complete Response (CR) | 4 | 4 | 8 |
| Partial Response (PR) | 1 | 1 | 2 |
| No Response (NR) | 4 | 3 | 7 |
Plan to share: Yes — publication of data in American journal of hematology
This study is completed, as verified in Dec 2018. You cannot join it, but the record below documents what was studied.
Get an email when the registry record changes — status, dates, results — or when someone posts here.
Sign in to followQuestions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.
Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.
Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.
Weill Medical College of Cornell University