A Phase I/Ib Safety and Efficacy Study of the PI3K-delta Inhibitor TGR-1202 and Ibrutinib in Patients With CLL or MCL

Study Overview
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Brief Summary
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This research study will be evaluating the safety and efficacy of a study drug called TGR-1202 in combination with a known drug ibrutinib, also known as Imbruvica, as a possible treatment for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) or Mantle Cell Lymphoma (MCL) that has come back or that has not responded to standard treatment.

Detailed Description
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This research study is a Phase I and Ib combination clinical trial, which aims to both evaluate the safety of an investigational drug combination and also tries to define the appropriate dose of the investigational drug to evaluate in later clinical trials. Investigational means that the intervention is being studied. It also means that the FDA (U.S. Food and Drug Administration) has not approved TGR-1202 in the United States for use in MCL/CLL/SLL cancers. TGR-1202 is a newly developed drug that may stop cancer cells from growing based on recent laboratory experiments. The results from these experiments suggest this drug may help to kill cancer cells when coupled with ibrutinib. In this research study, the safety and tolerability of TGR-1202 is being investigated to determine the highest dose that can safely be used in combination with ibrutinib. The study is also aimed to evaluate whether TGR-1202 has any effect on tumor growth (nodal response), and to determine the overall repsonse rate and duration of response in patients with CLL/SLL or MCL

Official Title
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A Multi-center Phase I/Ib Study Evaluating the Efficacy and Safety of the Novel PI3k Delta Inhibitor TGR-1202 in Combination With Ibrutinib in Patients With Select B-Cell Malignancies

Conditions
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Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Mantle Cell Lymphoma

Intervention / Treatment
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* Drug: TGR-1202
* Drug: Ibrutinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Leukemia (CLL), or Small Lymphocytic Lymphoma (SLL) Adequate organ system function ( Absolute neutrophil count, Platelets,Bilirubin, Platelets, Aspartate transferase ,Alanine aminotransferase, Creatinine Clearance) Eastern Cooperative Group (ECOG) Performance status ≤ 2 Ability to swallow and retain oral medication Female patients: must have negative serum pregnancy test at study screening/ all male partners must consent to use a medically acceptable method of contraception Willingness and ability to comply with trial and follow-up procedures, and give written informed consent Exclusion Criteria:- Patients receiving cancer therapy (i.e., chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy, surgery and/or tumor embolization) within 3 weeks of Cycle 1/Day 1, Autologous hematologic stem cell transplant within 3 months of study entry. Allogeneic hematologic stem cell transplant within 12 months. Post-allo patients must not have active graft versus-host disease Evidence of active Hepatitis B,Hepatitis C or HIV infection. Active central nervous system involvement by lymphoma Requires treatment with strong CYP3A4/5 inhibitors Severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study QTcF >470 msec (QT interval, Fredericia calculation) Angina not well-controlled by medication Poorly controlled or clinically significant atherosclerotic vascular disease Presence of other active cancers, or history of treatment for invasive cancer within the past 2 years. Require warfarin for anticoagulation Women who are pregnant or lactating

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CLL<br>Dose escalation will occur using a standard 3+3 dose escalation approach, beginning in dose level I with dose cohorts and rules for escalation and de-escalation. Each Cycle = 28 days TGR-1202 (oral): Starting on Day 1 administered daily. Ibrutinib (oral): Starting on Day 1 administered daily. | Drug: TGR-1202<br>* Capsules taken whole daily with water and with food<br>* Other names: Umbralisib;Drug: Ibrutinib<br>* Capsules taken whole with water- Do not consume fish oil, vitamin E, grapefruit, or Seville oranges<br>* Other names: PCI-32765;|
| Experimental: MCL<br>Dose escalation will occur using a standard 3+3 dose escalation approach, beginning in dose level I with dose cohorts and rules for escalation and de-escalation. Each Cycle = 28 days TGR-1202 (oral): Starting on Day 1 administered daily. Ibrutinib (oral): Starting on Day 1 administered daily. | Drug: TGR-1202<br>* Capsules taken whole daily with water and with food<br>* Other names: Umbralisib;Drug: Ibrutinib<br>* Capsules taken whole with water- Do not consume fish oil, vitamin E, grapefruit, or Seville oranges<br>* Other names: PCI-32765;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Who Experienced a Dose Limiting Toxicity (DLT) During Phase I | To assess the safety of TGR1202 in combination with ibrutinib relapsed or refractory CLL or MCL. DLT is based on the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. DLT refers to toxicities experienced at any time during the study treatment, defined as Grade 4 anemia; Grade 4 neutropenia lasting >7 days (while receiving growth factor support); Grade 4 thrombocytopenia lasting > 7 days; Grade ≥3 febrile neutropenia; and Grade ≥3 thrombocytopenia with Grade >2 hemorrhage;Grade ≥ 3 non-hematologic toxicity unresponsive to standard supportive care measure with the exception of asymptomatic Grade ≥3 lab abnormalities that resolve to ≤ Grade 1 or baseline within 7 days;treatment delay of ≥14 days due to unresolved toxicity; and non-hematologic toxicity of Grade 2 (at any time during treatment) that, in the judgment of the Investigators, Study Chair, and the Medical Monitor, is dose-limiting. | Participants were assessed every week or more often as needed during Cycle 1 or more often for up to 28 days to assess Dose-limiting toxicities (DLTs) during Phase I | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008) by Lugano Criteria ( Cheson et al,.24) for MCL | At baseline, End of Cycle 2, End of Cycle 5, End of Cycle 9, End of Cycle 14 and approximately q6 months until C26, then investigator discretion thereafter | 
| Rate of Nodal Response With Lymphocytosis (nPR) |  | 2 years | 
| Rate of Progression Free Survival |  | 2 Years | 
| Duration of Response |  | 2 Years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mantle Cell Lymphoma, Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma