The goal of this study is to characterize the safety, maximum tolerated dose (MTD) and preliminary efficacy profile of IPI-145 given in combination with rituximab, or bendamustine plus rituximab, to subjects with select relapsed/refractory hematologic malignancies.

This trial consists of two parallel arms. For each treatment arm, a 3+3 dose escalation design will be applied in 3-6 subject cohorts until the maximum tolerated dose of IPI-145 when given with rituximab (Arm 1) or in combination with rituximab and bendamustine (Arm 2) is determined. Treatment arm selection will be chosen by the investigator and will depend on the agents previously administered to the subject. Once the MTD has been determined, the arms will move on to a dose expansion phase. During the dose expansion phase, each treatment arm will enroll to population specific cohorts to assess efficacy. All subjects must have had at least one prior anticancer treatment. The dose expansion cohorts are:

Arm 1: Cohort A - CLL: Cohort B - CD20+ NHL

Arm 2: Cohort A - CLL: Cohort B - CD20+ NHL

Inclusion Criteria:

1. Dose Escalation Phase

   Arm 1 and Arm 2: Limited to subjects diagnosed with low grade CD-20 positive B-Cell NHL with at least one prior anticancer treatment.

2. Dose Expansion Phase

   Arm 1 Cohort A: Limited to subjects with CD-20 positive CLL with at least one prior anticancer treatment.

   Arm 1 Cohort B: Limited to subjects with diagnosis of CD-20 positive NHL with at least one prior anticancer treatment.

   Arm 2 Cohort A: Limited to subjects with CD-20 positive CLL with at least one prior anticancer treatment.

   Arm 2 Cohort B: Limited to subjects with diagnosis of CD-20 positive NHL with at least one prior anticancer treatment.

3. Disease status requirement:

   • CLL subjects: symptomatic disease that mandate treatment;
   • Indolent NHL subjects: symptomatic disease requiring treatment according to the clinical judgment of the investigator;
   • Other lymphoma subjects: disease requiring treatment according to the judgment of the investigator.

4. Eastern Cooperative Oncology Group (ECOG) Performance Status score of ≤2.

5. Subject must have measurable disease using the disease-specific response criteria for NHL or CLL

6. Age ≥ 18 years.

7. Subject has recovered from all clinically significant toxicities related to prior antineoplastic therapies with the exception of alopecia and bone marrow and organ functions.

8. Adequate organ system function ≤2 weeks prior to Day 1, defined as follows:

   • Absolute neutrophil count (ANC) ≥1.0 x 109/L unless related to underlying CLL or indolent NHL bone marrow involvement, and then ANC ≥500 x 109/L permitted.
   • Platelets ≥100 x 109/L unless related to underlying CLL or indolent NHL bone marrow involvement, and then platelets ≥75 x 109/L permitted.
   • Subjects receiving IPI-145 plus rituximab with bone marrow involvement may enroll with platelets ≥40 x 109/L.
   • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤1.5 x ULN and total bilirubin ≤1.5 times the upper limit of normal (ULN) (except for subjects with Gilbert's disease)
   • Serum creatinine ≤1.5 x ULN

9. Life expectancy of ≥12 weeks.

10. Women of child-bearing potential (WCBP) must have a negative serum or urine pregnancy test.

11. Ability to understand the nature of this study and give written informed consent.

Exclusion Criteria:

1. Prior allogeneic hematopoietic stem cell transplant (HSCT).

2. Prior autologous transplant or radioimmunotherapy ≤6 months prior to the first dose of trial treatment.

3. Subject has a high grade lymphoma such as Burkitt's, lymphoblastic or small non-cleaved cell lymphomas. Subjects with intermediate grade lymphoma (such as diffuse large B-cell lymphoma) are eligible.

4. Subjects with diffuse B-cell lymphoma must either not be eligible for autologous bone marrow transplant (BMT) or relapsed after autologous BMT.

5. More than three previous cytotoxic chemotherapy regimens for subjects treated on the arm containing bendamustine.

6. Subjects who have had a severe allergic or anaphylactic reaction to any humanized or murine monoclonal antibodies.

7. Chemotherapy, cancer immunosuppressive therapy, growth factors (except erythropoietin), radiation therapy (other than whole brain irradiation [WBI]) surgery or ablative therapy or investigational drugs/devices ≤28 days before first dose of trial treatment.

8. Subjects receiving high doses of corticosteroids must have been tapered to a stable dose at least 7 days before the first dose of trial treatment.

9. Tyrosine kinase inhibitor within 7 days prior to the first dose of trial treatment.

10. Subjects with overt leptomeningeal leukemia or central nervous system (CNS) lymphoma. Subjects must be free of CNS disease for a minimum of 2 months. Subjects with symptoms of CNS disease must have a negative diagnostic lumbar puncture prior to study enrollment.

11. Subjects with a history of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control within the last 6 months.

12. Baseline QTcF >480 ms. Note: This criterion does not apply to subjects with a left bundle branch block.

13. Subjects who have had a venous thromboembolic event requiring anticoagulation and who meet any of the following criteria:

    • Have been on a stable dose of anticoagulation for <1 month.
    • Have had a Grade 2, 3 or 4 hemorrhages in the last 30 days.
    • Are experiencing continued symptoms for their venous thromboembolic event.

14. Subjects with a history of liver disease as a result of alcohol abuse, chronic hepatitis, or other chronic liver disease (other than metastatic disease to the liver).

15. Subjects with positive HBsAg, HBcAb or HCV are excluded.

16. Subjects with a history of tuberculosis within the preceding two years.

17. Prior surgery affecting drug absorption or any gastrointestinal dysfunction that could alter drug absorption.

18. Subjects with a known hypersensitivity to bendamustine or rituximab.

19. Presence of active infection within 72 hours of treatment. Subjects with ongoing use of prophylactic antibiotics are eligible as long as there is no evidence of active infection and the antibiotic is not included on the list of prohibited medications.

20. Known diagnosis of human immunodeficiency virus (HIV).

21. Concurrent administration of medications or foods that are strong or moderate inhibitors or inducers of CYP3A.

22. Women who are pregnant or lactating.

23. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.

24. Concurrent condition that in the investigator's opinion would jeopardize compliance with the protocol or would impart excessive risk associated with study participation that would make it inappropriate for the subject to be enrolled.

25. Inability or unwillingness to comply with study and/or follow-up procedures outlined in the protocol.