New exclusion criterion (#14) and section 11.2.2.8 Gastric protection agents of Concomitant medication added to restrict patient population based on use of medicinal products that increase the pH (reduce acidity) of the upper gastrointestinal tract and define their washout period prior to study treatment starts. Added as Gastric Protection Agents interfere with the solubility and absorption of PQR309 and consequently its bioavailability.

Reduction of starting dose to 60mg Bimiralisib daily, Introduction of intermittent dosing schedules, The inclusion criterion #5 has been modified, from “Maximum one prior system therapy regimen” to “Maximum two prior system therapy regimens excluding high dose chemotherapy at first relapse”. The exclusion criterion #18 has been modified to remove HbA1c as a parameter for exclusion, A treatment delay of >14 days due to AE of hyperglycemia will not automatically lead to withdrawal from the study. Changes made as a response to the observation that the 80 mg daily dosing is not adequately tolerated in the long term in PCNSL. Intermittent schedules: In the initial phase of PQR309 early clinical development, continuous daily administration of PQR309 was evaluated to determine the maximum tolerated dose (MTD) and to establish the safety and pharmacokinetics of continuous administration. It was shown that at a dose of 80 mg per day PQR309 reaches plasma concentrations that were expected to be pharmacologically active based on pre-clinical experiments with most of adverse events (AEs) of CTC AE grade 1 or 2. This dose and regimen was therefore chosen for further evaluation of clinical anticancer activity. However, pre-clinical data with PQR309 suggest that it might not be necessary to inhibit PI3K/mTOR continuously to achieve full efficacy. Therefore, additional intermittent dosing regimens will be explored in this study if continuous daily dosing with 60mg is not adequately tolerated or is inefficacious.

Dose-escalation scheme: The dose-escalation scheme has been changed to reduce the number of patients to 3 per dose level. Three additional patients will only be enrolled if a DLT is seen in the first three patients. Inclusion criterion #5: The term “high dose chemotherapy” has been replaced by the more appropriate term “myeloablative therapy”: Maximum of two prior systemic therapy regimens excluding myeloablative therapy at first relapse Patients who have previously received whole brain radiotherapy (WBRT) may be enrolled if they were free of WBRT-associated symptoms. Consequently, exclusion criterion #3 has been modified as follows: “Patients with persisting symptoms from previous whole brain radiation (WBRT)” Concomitant Medications: The use of concomitant medication has been updated to reflect newly available pre-clinical and clinical data on the drug-drug interaction potential of PQR309. In this context, exclusion criterion #7 and #8 have been removed. A dedicated separate summary-of-changes describing these changes has been provided.