Roche trials database

Protocol number:

ML20948

Title of Study:

A multi-centre, single-arm, open-label study to evaluate the efficacy and safety of 1000 mg fixed dose rituximab on days one and fifteen among patients with chronic or relapsing idiopathic thrombocytopenic purpura.

Sponsor:

Hoffmann-La Roche

Company division:

Pharmaceutical

Product name:

rituximab [MabThera/Rituxan]

Generic name:

rituximab

Therapeutic area:

• Idiopathic Thrombocytopenic Purpura

Clinical study summary:

This multi-center, prospective, open label, single-arm study was designed to evaluate the efficacy and safety of MabThera/Rituxan (rituximab) in patients with chronic or relapsing idiopathic thrombocytopenic purpura (ITP). Patients received intravenous doses of 1000 mg MabThera/Rituxan on Day 1 and Day 15 of the treatment period (8 weeks). The follow-up period was from end of Week 8 to Week 52.

Study center(s):

12 centers in Australia

Phase of development:

II

Objectives:

The primary outcome was to determine the overall response rate (ORR) at Week 8 in chronic or relapsing ITP patients administered 1000 mg MabThera/Rituxan on days 1 and 15, as defined by the proportion of patients who achieved a complete response (CR) or partial response (PR) at Week 8.

The secondary outcomes were as follows:

• Time to response (TTR), defined as time from first rituximab infusion to time of onset of minimal response (MR)/PR/CR;
• Complete response, partial response and minimal response rates to MabThera/Rituxan treatment at Week 8;
• Time to complete response;
• Time to partial response;
• Time to minimal response;
• Duration of complete response;
• Duration of partial response;
• Duration of minimal response;
• Time to initiation of new ITP therapy and/or increase in dose of existing ITP therapy, including date on which decision made in relation to splenectomy;
• Therapeutic response (minimal/partial/complete reduction of concomitant ITP therapy) at Week 26 and Week 52;
• B-cell recovery, as determined by CD19+ B cell counts;
• Safety profile of rituximab using National Cancer Institute - Common Terminology Criteria (NCI-CTC) for adverse events (AEs).

Methodology:

Within seven days of screening, patients received an infusion of 1000 mg rituximab on Day 1 followed by a second dose on Day 15. Height, weight, medical history, previous treatments for ITP and a pregnancy test were taken at screening. A full blood count was taken at all visits. Whole blood for polymorphism analysis was taken on Day 1 only. Serum biochemistry was taken at screening, Days 1, 15, 50 and then at Week 52. A physical examination and vital signs were conducted at screening, Days 1, 15, 50, and then during the follow-up period at Weeks 12, 26, 39 and 52. Current or new concomitant treatments were recorded at all visits post screening. Concomitant treatments not related to ITP and AEs were recorded at screening, and all visits during the treatment period. SAEs were recorded at screening, all visits during the treatment period and at Week 12. Serum samples for rituximab level analysis and CD19+ B cell count were assessed on Days 1, 15, 50 then Month 4, Week 26, Month 8, 10 and then at Week 52.

Number of patients (planned/analyzed):

122 patients enrolled and treated

Diagnosis and main criteria for inclusion:

Adult patients, ≥ 18 years of age with refractory, relapsing or chronic idiopathic thrombocytopenic purpura (ITP) with first relapse occurring within 12 months of initial diagnosis and second relapse at any time thereafter.

Test product, dose and mode of administration or test procedure:

Rituximab 1000 mg intravenously on Days 1 and 15

Duration of treatment:

8 weeks

Reference therapy, dose and mode of administration or reference procedure:

N/A

Criteria for evaluation (efficacy, safety):

Efficacy

Primary:

Overall response rate (ORR) defined as the proportion of patients who achieved a confirmed hematological CR or PR at Week 8 (end of treatment phase).

Secondary:

Complete response (CR), partial response (PR), minimal response (MR), time to response, duration of response, time to initiation of new ITP therapy and/or increase in existing dose of ITP therapy, and ORR at Week 12.

Safety: Adverse events graded according to the NCI-CTC, serious AEs (SAEs), infusion reactions, deaths, exposure to study treatment, clinical laboratory tests, and vital signs.

Statistical methods:

Primary: Two-sided 95% confidence interval (CI) for the ORR at 8 weeks calculated using the normal approximation to the binomial distribution.

Secondary: As the primary endpoint

Summary (efficacy, safety, other results):

Efficacy

ORR at Week 8 was 43.5% (95% CI 34.0%, 53.4%) with 47 of the 108 patients in the intent-to-treat replaced (ITTR) population achieving a response (CR or PR). Thus, the ORR was not sufficient to reject the null hypothesis of ORR ≤ 38%. Median time to CR was not determined due to an insufficient number of events. Median time to PR for the ITTR population was 53 days (95% CI 36.0, 152.0), and median time to MR was 22 days (95% CI 8.0, 30.0). Duration of CR was not determined due to insufficient number of events. Median duration of PR was 247 days (95% CI 219.0, not determined [ND]), and median duration of MR was 256 days (95% CI 168.0, ND). Median time to initiation of new ITP therapy was 314 days (95% CI 215.0, ND). At Week 26, 43.5% of patients were considered therapeutic responders, which reduced to 35.2% of patients at Week 52.

Safety

The most common AEs reported were contusion (7%), headache (6%) and fatigue (6%). The majority of AEs reported (151/167) were NCI-CTC grade 1 or 2. Twelve AEs were considered severe and two considered life-threatening (both decreased platelet count). Of the 167 AEs reported, 50 (30%) were considered related to study treatment. Infusion reactions were considered related to study treatment.

Forty (33%) patients reported at least one infusion reaction; the majority (81/86) of which was considered mild or moderate in intensity. Five infusion reactions were considered severe: chest discomfort (2 patients), chest pain, oropharyngeal pain, and dyspnea.

One patient died due to a myocardial infarction, which was not considered related to study treatment. Twelve (10%) patients experienced one or more SAEs. Four SAEs were considered related to study treatment: subdural hematoma; subdural hemorrhage; pneumocystis jiroveci pneumonia; and febrile neutropenia.

No marked findings were observed in any laboratory parameter.

Conclusions:

Whilst the result from the primary efficacy of ORR at 8-weeks was not sufficient to reject the null hypothesis, the observed ORR and durability of response in this study compare favorably with MabThera/Rituxan given over a more frequent schedule. Further investigations are warranted to determine whether the same response can be achieved with single or lower dosing or whether longer more intense dosing, as well as maintenance dosing, might improve ORR and durability of responses.

Date of report:

01.07.2012

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