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)

Inclusion criteria

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

• Follicular lymphoma (FL) G1, G2, or G3a
• Marginal zone lymphoma (MZL) (splenic, nodal, or extra-nodal)
• Lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM)
• Small lymphocytic lymphoma (SLL) with absolute lymphocyte count <5 x10^9/L at the time of diagnosis and at study entry.
• 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.
• Patients must have at least one bi-dimensionally measurable lesion (that has not been previously irradiated) with the longest diameter ≥ 1.5 cm.
• Male or female patients > 18 years of age.
• ECOG performance status ≤ 2.
• Life expectancy of at least 3 months.
• Adequate bone marrow, liver, and renal function as assessed by the following laboratory requirements conducted within 7 days before starting study treatment:

• Hemoglobin ≥ 9 g/dl
• Absolute neutrophil count (ANC) ≥ 1 x 10^9/L
• Platelets ≥50 x 10^9/L (patient without BM involvement) and 30 x 10^9/L (patient with BM involvement)
• Total bilirubin ≤1.5 times the upper limit of normal (ULN)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x ULN if known liver involvement
• Creatinine ≤ 1.5 mg/dL OR calculated creatinine clearance ≥ 50 mL/min (as calculated by the Cockcroft-Gault method)
• Use of an effective means of contraception for female patients of child-bearing potential, and all male partners.
• Willingness and ability to comply with trial and follow-up procedures, give written informed consent.

Exclusion criteria

• FL grade 3b or transformed disease or CLL
• 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
• Auto-SCT within 3 months from C1D1 (patients must not have active graft versus- host disease)
• History of having received an Allo-SCT
• Active hepatitis B or C infection
• Known history of human immunodeficiency virus (HIV) infection
• Evidence of ongoing severe systemic bacterial, fungal or viral infection
• Known primary central nervous system lymphoma or any preexisting neurologic manifestations
• 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;
• Prior exposure to drug that specifically inhibits PI3K
• Pregnancy or lactation
• Myeloid growth factors or red blood cells/ platelet transfusion within 14 days prior to C1D1
• Drug administration within 1 week prior to C1D1

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