Amendment 1 was issued to include changes to the inclusion and exclusion criteria and, to the schedule of examinations to optimize the capturing of disease evolution, and the sampling scheme to alleviate the burden on patients (BM, imaging, PK sampling etc.), and to the overall language for further refinement and better clarity.

Amendment 2 was issued to ensure that only patients with measurable C−findings due to mastocytosis were enrolled into the study. Among the Stage I patients enrolled in the study 36% were considered by the SSC to be ineligible for response assessment. To address these issues, systematic collection of the following information was added: history of weight and blood product transfusions, ongoing transfusions, mediator-related symptoms, and antineoplastic therapies since discontinuation of study drug. Changes were made to the response criteria for patients receiving blood transfusions prior to or during study treatment. A patient enrollment approval process by the SSC chair was implemented. Histopathologic response was added as a secondary objective. The definition of the PEP and additional sub-analyses to observe the impact of these were added. In addition, an extension phase was implemented to provide more information on safety and efficacy of midostaurin, and assessment of cardiac function by echocardiogram or MUGA during the study was implemented to allow more frequent monitoring of cardiac function on treatment (previously, assessment of cardiac function was only required at baseline, and further assessments were at the discretion of the investigator). Finally, the recommendation to use prophylactic anti-emetic medication was strengthened to state that anti-emetic medication should be administered to all patients. The type and dose of anti-emetic medication remained at the discretion of the investigator.

Amendment 3 was issued to address the request from the Canadian Health Authorities to add an exclusion criterion of “Patients with heart block of any degree at screening”. The protocol was amended for Canada only.

Amendment 4 was issued to clarify the follow-up for patients who discontinued study treatment in the absence of disease progression (e.g., due to AE). These patients were to be followed for disease status until the time of disease progression, initiation of another antineoplastic therapy, or end of study, whichever was first. Also, the definition of disease progression was updated to comprise a laboratory abnormality not existing at baseline that occurred during study treatment and was attributed to SM. If this new C-Finding demonstrated a worsening > 20% from the value at baseline and was maintained for at least 28 days, this circumstance was defined as disease progression.

Amendment 5 was issued to include language that allowed patients to continue to receive midostaurin in accordance with local regulations.

Amendment 6 was issued to revise the definition of the end of study to allow for an extended collection period of efficacy and safety data for midostaurin in a patient population with ASM or MCL. The end of study definition was revised to occur five years after last patient first treatment, or when all patients had discontinued study treatment, whichever occurred first. This extended period of data collection was reviewed through supplemental annual central adjudication meetings by the SSC. Moreover, patients who continued to benefit from treatment with midostaurin could continue to have access to study treatment. Provision for the use of biomarker samples to support other cytokine evaluations and the assessment of mast cell-associated biomarkers, including somatic cytogenetic and genetic/molecular alterations, was added. The visit evaluation schedule was revised according to the new end-of-study definition, and changes were also made to revise the schedule of examinations after three years of study treatment. Contraceptive requirements were revised to also include oral contraceptives based on the results of Study PKC412A2112, which showed that midostaurin is not a strong CYPA4 inducer. In addition, retrospective collection of the date of diagnosis of SM/ASM/MCL was added to allow comparative assessment of OS data from this study with that from historical data.