The amendment concerns an adjustment to the reporting of dose limit toxicity (DLT). The DLTs must be reported during cycles 3 through 6 using the rapid reporting procedure. Furthermore, the labels for Levact® have been modified. For the benefit of our central administration, we kindly request your response to be returned to the Clinical Hematology Secretariat, F4-224.

Amendment 2 On behalf of the Department of Clinical Hematology, you are hereby receiving amendment 2 with attachments of the aforementioned protocol for review at your next meeting. The amendment concerns adjusting the label of lenalidomide (study medication), as the supply will switch to lenalidomide in blister packs. Furthermore, there are some administrative adjustments in the protocol.

Amendment 3 The amendment concerns: A change in the protocol regarding the use of allopurinol before starting treatment (paragraph 9.2.3) and some minor corrections. Additional documents: IB rituximab version 16 IB lenalidomide version 15 Roche contract Addition of a site (Rijnstate Arnhem) Investigator in Enschede changed (Dr. De Groot → Dr. Schaafsma) ABR form: D12 (clarification of reimbursement) explained. Adjustments to the EudraCT form regarding IMP Lenalidomide (PR1, PR4, and PR5): D.2.5. / D.2.5.1 / D.3.3 / D.9.2.1 / D9.2.3 / D.9.2.5.

Amendment 4 The main changes in this amendment are: For the Phase II part of the study, centers in England will also participate (National Cancer Research Institute UK). A change in the inclusion criteria: based on newly available data, patients previously treated with bendamustine may also participate in the study, provided they responded well earlier. The description of the risk management program regarding pregnancy tests due to the use of lenalidomide has been adjusted in the protocol. Update of the investigator’s brochure for study medication Rituximab; new version 17 (July 2012). Update of the investigator’s brochure for study medication Lenalidomide; new version 16. The complete Lenalidomide IB will be sent as soon as it is received. To prevent delays, the protocol and patient information have already been adjusted according to the new safety information received from the manufacturer of this study medication (Celgene). Furthermore, there are some administrative adjustments in the protocol, and based on a review by the National Cancer Research Institute UK, some clarifications have been added. Additionally, changes in the protocol, where applicable, have also been implemented in the patient information.

Amendment 5 Exclusion criteria added: Recent vaccination for yellow fever (within 4 weeks before registration). Update of the section: Guidelines concerning the risk of pregnancy during the use of bendamustine. Male subjects must not father children for six months after treatment. Adjustment in paragraph Special precautions and supportive care: “For patients who are treated with bendamustine, yellow fever vaccination or any vaccination with other live viruses is prohibited at least until one year after the last administration of bendamustine.” Adjustment of inclusion criteria: Use adequate contraception not only during but also after therapy.

Amendment 6 The amendment concerns: Transition from the Phase I part of the study, where the recommended dose level was established, to the Phase II part of the study. The study documents have been adjusted accordingly. An update of the Investigator’s Brochure for Lenalidomide and Rituximab. Expansion of sites participating in the Phase II part of the study: Maasstad Hospital MC Leeuwarden St. Elisabeth Tilburg Admiraal de Ruyter Hospital (locations Vlissingen and Goes) UMC St. Radboud will no longer participate in this research. New independent physicians: VUmc and Groene Hart Gouda.