On-site monitoring

During recruitment of patients monitoring on site is performed according to good clinical practice (GCP) guidelines. The data management will be performed by the Coordination Centre for Clinical Trials (KKS) of the University of Heidelberg.

Ethics, informed consent and safety

The final protocol was approved by the ethics committee of the University of Heidelberg, Medical School (AFmu-085/2007, http://www.klinikum.uni-heidelberg.de) and the Paul-Ehrlich-Institute (PEI-registration number 432/06). This study complies with the Helsinki Declaration in its recent German version, the Medical Association's professional code of conduct, the principles of Good Clinical Practice (GCP) guidelines and the Federal Data Protection Act. The trial will also be carried out in keeping with local legal and regulatory requirements. The medical secrecy and the Federal Data Protection Act will be followed.

Written informed consent is obtained from each patient in oral and written form before inclusion in the trial and the nature, scope, and possible consequences of the trial have been explained by a physician. The investigator will not undertake any measures specifically required only for the clinical trial until valid consent has been obtained.

Study design and endpoints

The MIR study is a prospective phase II study combining systemic Rituximab therapy with involved field irradiation in patients with FL WHO Grad 1 and 2 in Stage I and II.

This trial aims at testing the combination's efficacy and toxicity with an accrual of 85 patients.

Primary endpoint of the study is progression free survival (2 years). Secondary endpoints are complete remission rate after Rituximab monotherapy (week 7) and after complete treatment (week 18), relapse rate, relapse pattern, relapse free survival, overall survival, toxicity and quality of life.

Patient selection

In order to be included in the MIR trial, patients (18 to 75 years) are required to have pathologically documented FL Who grade 1 or 2 in Ann Arbor Stage I or II. The histology has to be confirmed by one of the reference pathologists of the GLSG. Evaluation of CD20 status is compulsory. Maximal tumour diameter is 7 cm. Accrued patients will be expected to demonstrate sufficient compliance, they should also live in relative proximity of the centre of care to ensure adequate follow-up after treatment. In addition, adequate haematological function is essential for inclusion in the trial (leukocytes ≥ 3000 × 10³ /ml, platelets ≥ 100000 × 10 ³ /ml, and haemoglobin ≥ 10 g/dL). Patients are required to use adequate contraception during and at least up to 3 months after treatment. Naturally, written informed consent is obtained prior to commencement of treatment in this trial.

Patients are not eligible with previous irradiation, chemotherapy of immunotherapy. Patients with severe concurrent systemic disease or other malignant disease (apart from cervical carcinoma in-situ, basal cell carcinoma, or unless previously treated and in remission for ≥ 5 years without further treatment) can also not be included in this trial. Furthermore, clinical performance worse than ECOG 2, bulky disease (> 7 cm), splenic involvement, immunodeficiency, viral hepatitis, collagenosis, severe psychiatric illness, hypersensitivity to foreign proteins will prohibit inclusion as will pregnancy or breast feeding.

Statistical Design

The hypothesis states an improvement of the progression free survival after 2 years from 75% to 89% (risk reduction by 40% using Rituximab). 77 patients have to be evaluated to proof the hypthesis with a 95% power using a single arm binomial test. An additional 8 patients have to be recruited for a possible 10% drop-out rate.

Work up

Patients with pathologically documented nodal FL Who grade 1 or 2 in stage I or II receive a complete work-up including, cervical, thoracic, abdominal and pelvic CT scans, bone marrow histology and extensive laboratory testing. An ENT examination is mandatory for supra diaphragmal disease and a kidney function test for abdominal disease. The FLIPI risk score will be calculated for each patient. All in- and exclusion criteria are examined. In the event of patients meeting the required inclusion criteria, information about participation in the study with possible risks and benefits is given to the patients and written informed consent is obtained. In the event of patients declining treatment within the MIR trial, irradiation alone is offered.

Treatment

The treatment lasts over 12 weeks and is divided in 3 sections as illustrated in Figure ​Figure1.1. The first section consists of 4 weekly i.v. infusions of Rituximab (Roche AG, Basel, Switzerland) at a standard dosage of 375 mg/m² given on day 1, 8, 15 and 22. There is a 4 week treatment break thereafter (week 5 - 8) which includes a radiation therapy planning CT of the involved body region in week 7. Response to the Rituximab therapy is also evaluated at this time. Another 4 weekly infusions of Rituximab are administered in week 9-12. At the same time, radiation therapy of the involved lymph node region is applied, a three dimensional radiation planning is compulsory for all patients having abdominal or retroperitoneal disease. Involved field irradiation consists of a dose of 30 Gy in daily fractions of 2 Gy (Monday to Friday). Patients who still show enlarged lymph nodes in week 7 receive additional boost irradiation with a total dose of 40 Gy. Accepted tolerance doses of organs at risk must not be exceeded.

Open in a separate window

Figure 1

Study Schema of the MIR trial (IF = involved-field; f/u = follow up).

Safety and discontinuation of treatment

Toxicities are classified by grade, type, duration, onset, and relationship to study treatment.

Treatment of Rituximab-induced adverse reactions is carried according to recommendations by the provider. All patients will receive anti allergic prophylaxis (paracetamol, clemastin) and when appropriate, corticosteroids. In the case of fever (> 38,5°C), chills, bronchial constriction, hypotension (> 30 mm Hg) it is recommended to discontinue treatment with Rituximab.

Analysis of safety related data is performed with respect to frequency of:

• Serious Adverse Events and Adverse Events stratified by organ-system

• Adverse Events stratified by severity

• Adverse Events stratified by causality.

Patient toxicities will be assessed using the NCI Common Toxicity Criteria (CTC). Toxicity will be evaluated prior to treatment, weekly prior to each course of infusional Rituximab and at follow-up. Unacceptable toxicity is defined as unpredictable, or irreversible Grade 4 toxicity. Decisions regarding Rituximab dose-adjustment will be made using the guidelines below and based on haematological parameters (ANC and platelets) monitored weekly during radiation before each dose of Rituximab.

Whenever necessary, metoclopramide or 5-HT₃-antagonists are used for antiemesis.

Antihistamines such as clemastine are administered prior to Rituximab application.

Trial duration

Patient recruitment is planned to be completed after 24 months. Patients will be monitored for two and a half years after study entry. The total duration of the trial is estimated to be 4 and a half years. Recruitment started in March 2008. As of February 2010, 65 patients have been included in the trial.

Individual exclusion criteria are serious adverse reactions or the patient's voluntary withdrawal from the trial.

Assessment of therapeutic efficiency

CT or MRI of the involved regions are scheduled for week 7 and 18. For screening of the whole body stem, CT or MRI imaging is planned for months 6, 12, 18, 24 and 30 after start of therapy. At all above mentioned follow-up visits, there is also a clinical examination with palpation of all lymph node sites schedulded.

Local response is evaluated in accordance with the Cheson Criteria [30].

• Complete response (CR) is the complete disappearance of all detectable evidence of disease on CT, and all disease-related symptoms, and normalization of biochemical abnormalities, and normal bone marrow biopsy (BMB). Previously involved nodes on CT more than 1.5 cm in their greatest axial diameter must regress to less than 1.5 cm, and previously measured nodes of 1.1-1.5 cm must decrease to less than 1 cm.

• CRu (uncertain) corresponds to CR criteria but with a residual mass more than 1.5 cm in greatest axial diameter that has regressed by more than 75%.

• Partial response (PR) is at least 50% reduction in the sum of the product of the greatest diameters (SPD) of the six largest nodes with no increase in the size of other nodes and no new sites of disease. Splenic and hepatic nodules must regress by at least 50% in the SPD.

• Stable disease (SD) is less than a PR but is not progressive disease. Progressive disease (PD) is more than 50% increase in the sum of the product of the greatest diameters of any previously abnormal node, or appearance of any new lesions during or at the end of therapy.

• Relapsed disease (RD) is the appearance of any new lesion or increase in size of more than 50% of previously involved sites or nodes in patients who achieved CR or CRu.