The subject selection / inclusion criteria were updated to ensure adequate contraceptive measures were in place. The dose escalation scheme and corresponding rationale for selection of the starting dose were modified. Reference to the IDSMB was removed. Section concerning handling of patients with hyperglycemia updated. Two clinical sites were added to ensure timely recruitment.

Hospitalization for progressive disease was removed from table 5 (listing of exceptions to SAE definition).

Imaging changed to every 8 weeks instead of every 6 weeks (4 cycles), subsequently every 2 months up to 2 years of treatment and every 6 months afterwards. Inclusion Criteria expanded to require patients to have had at least 2 prior lines of therapy instead of 1, including immune-chemotherapy. An exception was introduced for CLL, reflecting the currently available therapies in this indication. Inclusion and exclusion criteria modified to allow patients with controlled diabetes to be recruited. Exclusion criteria modified to exclude patients with concomitant medications increasing pH and those with previous AEs Grade 3 or higher on PI3K/mTOR inhibitors. Concept of "Dose Levels" was removed; actual doses remained limited to 60 and 80mg qd. The MTD for the continuous treatment schedule defined as 80 mg based on data from clinical trials in patients with solid tumors. The definition of dose limiting toxicity (DLT) was modified for clarity. This version of the protocol was not approved in Germany. As a result, new study PQR309-002A was initiated in Germany and Switzerland.

The definition of dose-limiting toxicity was modified, so that it was based upon AEs "for which a causal connection to bimiralisib cannot be ruled out" as opposed to AEs "possibly, probably or definitely related to the trial drug". This amendment was to accommodate the request from US FDA. This version was only in effect in the US and sites in other countries used the previous version.

Incorporation of intermittent treatment schedules (PQR309 twice weekly) into the protocol. Treatment expanded to not only include q.d. 60mg or 80mg, but also Intermittent Schedule A ("2 days on / 5 days off") and Schedule B ("Mon / Thu") starting with 120mg, increasing with 20mg or 40mg increments. DLT definition expanded with rules for the intermittent dose regimen. Both intermittent regimens were intended to reduce overall exposure compared with continuous dosing. Changes to inclusion criteria: - Specific cut-offs for liver function tests removed. Liver function parameters have to be within the same limits regardless of liver involvement. - Assessment of HbA1c removed. The HbA1c parameter does not reflect a liability for treatment with PQR309. Changes to exclusion criteria: - Expanded to exclude patients who experienced Grade 4 on PI3K/mTOR inhibitors, due to a shift in risk for these patients when being considered for treatment with PQR309. - Expanded with example (chronic active hepatitis). - HbA1c removed. Precautions: Highly effective contraception language added to align with CTFG requirements. Assessments: fasting plasma glucose, height and body weight added.

The dose-escalation scheme was 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. Exclusion criterion 7 clarified to exclude “any major surgery, chemotherapy, immunotherapy or other anticancer therapy within 21 days prior to trial treatment start.” The dose reduction scheme for patients who experience AEs on intermittent dosing schemes was adjusted to clarify that patients may have their dose reduced up to two times. The use of concomitant medication was updated to reflect newly available pre-clinical and clinical data on the drug-drug interactions.