Efficacy and Safety Study of Tenalisib (RP6530), a Novel PI3K δ/γ Dual Inhibitor in Patients With Relapsed/Refractory Indolent Non-Hodgkin's Lymphoma (iNHL)

An Open Label, Phase II Study to Evaluate the Efficacy and Safety of Tenalisib (RP6530), a Novel PI3K δ/γ Dual Inhibitor in Adult Patients With Relapsed/Refractory Indolent Non-Hodgkin's Lymphoma (iNHL)

To assess the anti-tumor activity and safety of Tenalisib in patients with relapsed/refractory indolent Non-Hodgkin's Lymphoma (iNHL),

Inclusion Criteria:

1. Patients with histologically confirmed diagnosis of indolent B-cell NHL, with histological subtype limited to:

   1. Follicular lymphoma (FL) G1, G2, or G3a
   2. Marginal zone lymphoma (MZL) (splenic, nodal, or extra-nodal)
   3. Lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM)
   4. Small lymphocytic lymphoma (SLL) with absolute lymphocyte count <5 x10^9/L at the time of diagnosis and at study entry.

2. Relapsed or refractory after ≥ 2 prior lines of therapy (refractory defined as not responding to a standard regimen or progressing within 6 months of the last course of a standard regimen). Patients must have received rituximab and alkylating agents.

3. Patients must have at least one bi-dimensionally measurable lesion (that has not been previously irradiated) with the longest diameter ≥ 1.5 cm.

4. Male or female patients > 18 years of age.

5. ECOG performance status ≤ 2.

6. Life expectancy of at least 3 months.

7. Adequate bone marrow, liver, and renal function as assessed by the following laboratory requirements conducted within 7 days before starting study treatment:

   1. Hemoglobin ≥ 9 g/dl
   2. Absolute neutrophil count (ANC) ≥ 1 x 10^9/L
   3. Platelets ≥50 x 10^9/L (patient without BM involvement) and 30 x 10^9/L (patient with BM involvement)
   4. Total bilirubin ≤1.5 times the upper limit of normal (ULN)
   5. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x ULN if known liver involvement
   6. Creatinine ≤ 1.5 mg/dL OR calculated creatinine clearance ≥ 50 mL/min (as calculated by the Cockcroft-Gault method)

8. Use of an effective means of contraception for female patients of child-bearing potential, and all male partners.

9. Willingness and ability to comply with trial and follow-up procedures, give written informed consent.

Exclusion Criteria:

1. FL grade 3b or transformed disease or CLL

2. Cancer therapy within 3 weeks (21 days) or 5 half-lives (whichever is shorter) prior to C1D1. Corticosteroids (prednisone or equivalent) at a dose of < 20 mg daily are allowed. Corticosteroid should be stabilized for at least 1 week prior to C1D1

3. Auto-SCT within 3 months from C1D1 (patients must not have active graft versus- host disease)

4. History of having received an Allo-SCT

5. Active hepatitis B or C infection

6. Known history of human immunodeficiency virus (HIV) infection

7. Evidence of ongoing severe systemic bacterial, fungal or viral infection

8. Known primary central nervous system lymphoma or any preexisting neurologic manifestations

9. Known history of drug-induced liver injury, alcoholic liver disease, primary biliary cirrhosis, ongoing extrahepatic obstruction caused by stones, cirrhosis of the liver or portal hypertension;

10. Prior exposure to drug that specifically inhibits PI3K

11. Pregnancy or lactation

12. Myeloid growth factors or red blood cells/ platelet transfusion within 14 days prior to C1D1

13. Drug administration within 1 week prior to C1D1

    1. Strong inhibitors or inducers of CYP3A4, CYP2C9, including grapefruit products, herbal supplements and drugs
    2. Substrates of CYP3A4 enzyme with a narrow therapeutic range