Study Combining SAR245409 With Rituximab or Bendamustine Plus Rituximab in Patients With Indolent Lymphoma, Mantle Cell Lymphoma and Chronic Lymphocytic Leukemia

Study Overview
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Brief Summary
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Primary Objective: - To determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) for SAR245409 when administered in combination with rituximab or bendamustine plus rituximab Secondary Objectives: To determine the safety and tolerability of SAR245409 in combination with rituximab or bendamustine plus rituximab in subjects with indolent Hon-Hodgkin Lymphoma (iNHL) Mantle Cell Lymphoma (MCL) or Chronic Lymphocytic Leukemia (CLL) To determine the pharmacokinetics (PK) of SAR245409, bendamustine and rituximab when used in combination in subjects with iNHL, MCL or CLL To determine the pharmacodynamic (PD) effects of SAR245409 in combination with rituximab or bendamustine plus rituximab in subjects with iNHL, MCL or CLL To determine the antitumor activity of SAR245409 in combination with rituximab or bendamustine plus rituximab in subjects with iNHL, MCL or CLL

Detailed Description
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All subjects will take SAR245409 twice daily. All subjects will receive SAR245409 as long as there is clinical benefit. Combination therapy with SAR245409, bendamustine and rituximab , will be administered over a 28 day cycle for up to 6 to 8 cycles. Subjects receiving the doublet combination , SAR245409 plus rituximab will receive weekly rituximab for 4 - 8 weeks. Monthly Rituximab may be continued beyond 8 weeks.

Official Title
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A Phase 1b, Multicenter, Open-Label, Dose Escalation Study of SAR245409 to Evaluate the Safety, Tolerability and Clinical Activity of SAR245409 in Combination With Rituximab or Bendamustine Plus Rituximab in Patients With Relapsed or Refractory Indolent B-cell Non-Hodgkin Lymphoma, Mantle Cell Lymphoma or Chronic Lymphocytic Leukemia

Conditions
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Indolent Non-Hodgkin Lymphoma, Mantle Cell Lymphoma, Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: SAR245409


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: A confirmed diagnosis of indolent non-Hodgkin lymphoma, mantle cell lymphoma or chronic lymphocytic leukemia Evaluable disease or measurable disease Transfusion independent Able to take oral medication Male and Female subjects > 18 years Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 Women of childbearing potential using adequate contraception Exclusion criteria: Prior therapy with a PI3K, mTOR or dual PI3K/mTOR inhibitor resulting in adverse events necessitating treatment discontinuation Eligible for a hematopoietic stem cell transplant (HSCT) The subject has received investigational or non-investigational cytotoxic chemotherapy (i.e., cyclophosphamide), small molecule cancer therapy (i.e., imatinib), biologic cancer therapies other than rituximab (i.e., alemtuzumab, cytokines, vaccines or other monoclonal antibodies) hormonal therapy, radio- or immuno- conjugates (e.g. ibritumomab tiuxetan, tositumomab) or immunosuppressants to treat malignancy within 4 weeks prior to Cycle 1, Day 1 Radiation therapy within 2 weeks prior to Cycle 1, Day 1 Autologous Hematopoietic Stem Cell Transplant (HSCT) within the past 16 weeks Prior allogeneic HSCT Active central nervous system (CNS) metastases or leptomeningeal involvement Positive Hepatitis B surface antigen (HBsAg) or Hepatitis C Antibody (anti-HCV) Hereditary or acquired immunodeficiency syndrome or human immunodeficiency virus (HIV) infection Active peptic ulcer disease requiring treatment with proton pump inhibitors (e.g. pantoprazole) or Type 2 histamine antagonists (e.g. cimetidine) Diagnosis or treatment for another malignancy within 3 years of enrollment with the exception of complete resection of basal cell or squamous cell carcinoma of the skin, an in situ malignancy or low-risk prostate cancer after curative therapy Inadequate bone marrow function Abnormal liver function Abnormal renal function Abnormal coagulation The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAR245409 + rituximab<br>Subjects will receive oral SAR245409 twice daily continuously and weekly rituximab intravenously | Drug: SAR245409<br>* Pharmaceutical form:capsule Route of administration: oral<br>|
| Experimental: SAR245409 + rituximab + bendamustine (iNHL, MCL)<br>Subjects will receive oral SAR245409 twice daily continuously and monthly bendamustine intravenously. | Drug: SAR245409<br>* Pharmaceutical form:capsule Route of administration: oral<br>|
| Experimental: SAR245409 + rituximab+ bendamustine (CLL)<br>Subjects will receive oral SAR245409 twice daily continuously and monthly bendamustine and rituximab intravenously | Drug: SAR245409<br>* Pharmaceutical form:capsule Route of administration: oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Identification Of Dose-Limiting Toxicity (DLT) and Maximum Tolerated Dose (MTD) |  | 4 weeks to 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with treatment emergent adverse events |  | Time from receiving first dose of SAR245409 until 30 days after the last dose | 
| Pharmacokinetics (Cmax) of SAR245409 |  | up to 2 months | 
| Pharmacokinetics (tmax) of SAR245409 |  | up to 2 months | 
| Pharmacokinetics (AUC0-12h) of SAR245409 |  | up to 2 months | 
| Pharmacokinetics (Ctrough) of SAR245409 |  | up to 2 months | 
| Pharmacokinetics (AUC) of bendamustine |  | up to 2 months | 
| Pharmacokinetics (AUClast) of bendamustine |  | up to 2 months | 
| Pharmacokinetics (Ceoi) of bendamustine |  | up to 2 months | 
| Pharmacokinetics (tmax) of bendamustine |  | up to 2 months | 
| Pharmacokinetics (Cl) of bendamustine |  | up to 2 months | 
| Pharmacokinetics (Vss) of bendamustine |  | up to 2 months | 
| Pharmacokinetics (AUC0-7h) of rituximab |  | up to 2 months | 
| Pharmacokinetics (Ceoi) of rituximab |  | up to 2 months | 
| Pharmacokinetics (tmax) of rituximab |  | up to 2 months | 
| Efficacy as determined by objective response rate (ORR) |  | up to 4 years |