Phase 1b Safety and Efficacy Study of TRU-016

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of TRU-016 in combination with rituximab, in combination with obinutuzumab, in combination with rituximab and idelalisib, or in combination with ibrutinib in patients with CLL; and in combination with bendamustine in patients with PTCL.

Detailed Description
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The study will consist of 8 dose cohorts: Previously untreated patients 20 mg/kg TRU-016 + rituximab. Relapsed patients, 20 mg/kg TRU-016 + rituximab. Previously untreated patients 10 mg/kg TRU-016 + rituximab. Previously untreated patients TRU-016 + obinutuzumab. Relapsed patients, 20 mg/kg TRU-016 + rituximab + idelalisib. Patients with CLL on ibrutinib or another BTK inhibitor for a total of more than 1 year who have not had a complete response (CR) will continue receiving ibrutinib or another BTK inhibitor. Patients with CLL on ibrutinib or another BTK inhibitor with stable disease and in whom the cysteine 481 mutant clone is present at a level >1%, will continue receiving ibrutinib or the alternative BTK inhibitor. Patients with relapsed or refractory PTCL will receive TRU-016 dosed 10 mg/kg for the first dose and then 20 mg/kg weekly for 2 cycles, followed by dosing every other week for an additional 4 cycles (cycle = 28 days) + bendamustine for 2 days every cycle for 6 cycles.

Official Title
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Phase 1b, Open Label Study to Evaluate Safety and Efficacy of TRU-016 in Combination With Rituximab, Obinutuzumab, Rituximab and Idelalisib, or Ibrutinib in Chronic Lymphocytic Leukemia and With Bendamustine in Peripheral T-cell Lymphoma

Conditions
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Chronic Lymphocytic Leukemia, Peripheral T-cell Lymphoma

Intervention / Treatment
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* Biological: 20 mg/kg TRU-016 + Rituximab
* Biological: 10 mg/kg TRU-016 + Rituximab
* Biological: TRU-016 20 mg/kg + Obinutuzumab
* Biological: TRU-016 6-20 mg/kg + idelalisib + rituximab
* Biological: TRU-016 10-20 mg/kg + ibrutinib
* Biological: TRU-016 10-20 mg/kg + bendamustine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of CLL by 2008 IWCLL criteria and with Rai stage intermediate or high risk CLL. Cohort 8 patients must have a diagnosis of PTCL. No prior therapy for CLL for Cohorts 1, 3 and 4. For Cohort 2, 1-3 prior treatments. For Cohort 5, patients must have failed to respond or relapsed after 1 or more treatment regimens. For Cohort 6, patients who have been receiving ibrutinib for at least 12 months, have not had a CR, and in whom no cysteine 481 mutation is detected. For Cohort 7, patients who are receiving ibrutinib with stable disease and now have the cysteine 481 mutant clone present at levels of >1%. For Cohort 8, have refractory or relapsed PTCL after one or more prior therapies. At least one of the following criteria for active disease requiring treatment: progressive splenomegaly and/or lymphadenopathy; anemia or thrombocytopenia due to bone marrow involvement; or progressive lymphocytosis with an increase of >50% over a 2-month period or an unanticipated doubling time of less than 6 months For Cohorts 1, 3 and 4, contraindication to chemotherapy as first-line therapy due to patient age, comorbidity or patient preference Age >/= to 18 years ECOG performance status of </= 2 Life expectancy > 6 months in opinion of Investigator Serum creatinine, total bilirubin, ALT/SGPT </= 2.0 x upper limit of normal ANC >/= 800/mm3, Cohort 8 (PTCL): ANC >/= 1000/mm3 Platelets >/= 30,000/mm3 Exclusion Criteria: For Cohorts 1, 3 and 4 only: Has received treatment with rituximab, alemtuzumab, ofatumumab or any other chemotherapeutic agent for CLL. Cohort 8: Received prior treatment with bendamustine and did not respond during treatment or relapsed less than sex months after completing treatment. Has received an investigational therapy within 30 days of first dose of study drug Previous or concurrent additional malignancy Clinically significant pulmonary dysfunction, active infection, prior allogeneic bone marrow transplant, active autoimmune disease Positive serology for HIV or hepatitis C Hepatitis B surface antigen or hepatitis B core antibody positive Pregnant or breastfeeding Known current drug or alcohol abuse

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 - Previously Untreated CLL<br>20 mg/kg TRU-016 + Rituximab | Biological: 20 mg/kg TRU-016 + Rituximab<br>* TRU-016: 10 mg/kg for first dose, all subsequent doses 20 mg/kg, IV once weekly for 8 weeks followed by 4 monthly doses Rituximab: 375 mg/m2 for first dose, all subsequent doses 500 mg/m2, IV once weekly for 8 weeks followed by 4 monthly doses<br>* Other names: Rituxan;|
| Experimental: Cohort 2 - Relapsed CLL<br>20 mg/kg TRU-016 + Rituximab | Biological: 20 mg/kg TRU-016 + Rituximab<br>* TRU-016: 10 mg/kg for first dose, all subsequent doses 20 mg/kg, IV once weekly for 8 weeks followed by 4 monthly doses Rituximab: 375 mg/m2 for first dose, all subsequent doses 500 mg/m2, IV once weekly for 8 weeks followed by 4 monthly doses<br>* Other names: Rituxan;|
| Experimental: Cohort 3 - Previously Untreated CLL<br>10 mg/kg TRU-016 + Rituximab | Biological: 10 mg/kg TRU-016 + Rituximab<br>* TRU-016: 6 mg/kg for first dose, all subsequent doses 10 mg/kg, IV on Day 1, 8 and 15, followed by 5 monthly doses Rituximab: 375 mg/m2 for first dose, all subsequent doses 500 mg/m2, IV following TRU-016 schedule<br>* Other names: Rituxan;|
| Experimental: Cohort 4 - Previously Untreated CLL<br>20 mg/kg TRU-016 20 + Obinutuzumab | Biological: TRU-016 20 mg/kg + Obinutuzumab<br>* TRU-016: 6 mg/kg on Day 1, 20 mg/kg on Day 8 and 15, then 20 mg/kg once a month for 5 months Obinutuzumab: 100 mg on Day 1, 900 mg on Day 2, 1,000 mg on Day 8 and 15, then 1,000 mg once a month for 5 months<br>* Other names: Gazyva;|
| Experimental: Cohort 5 - Relapse CLL<br>20 mg/kg TRU-016 + idelalisib + rituximab | Biological: TRU-016 6-20 mg/kg + idelalisib + rituximab<br>* TRU-016: 6 mg/kg on Days 15-36 weekly, 10 mg/kg on Days 43 and 50, then 20 mg/kg once a month for 5 months.<br>* Other names: Zydelig, Rituxan;|
| Experimental: Cohort 6 - With CLL on ibrutinib with no complete response<br>20 mg/kg TRU-016 + ibrutinib | Biological: TRU-016 10-20 mg/kg + ibrutinib<br>* TRU-016: Dosed weekly for 8 weeks followed by 4 monthly intravenous (IV) infusions. The first dose will be 10 mg/kg and all subsequent doses will be 20 mg/kg.<br>* Other names: Imbruvica;|
| Experimental: Cohort 7 - With CLL on ibrutinib with stable disease<br>20 mg/kg TRU-016 + ibrutinib | Biological: TRU-016 10-20 mg/kg + ibrutinib<br>* TRU-016: Dosed weekly for 8 weeks followed by 4 monthly intravenous (IV) infusions. The first dose will be 10 mg/kg and all subsequent doses will be 20 mg/kg.<br>* Other names: Imbruvica;|
| Experimental: Cohort 8 - With relapsed or refractory PTCL<br>20 mg/kg TRU-016 + 90 mg/m2 bendamustine | Biological: TRU-016 10-20 mg/kg + bendamustine<br>* TRU-016 dosed 10 mg/kg for the first dose and then 20 mg/kg weekly for 2 cycles, followed by dosing every other week for an additional 4 cycles (cycle = 28 days). Bendamustine (90 mg/m2 on days 2 and 3 of cycle 1 and then days 1 and 2 of cycles 2 to 6) will be infused after completion of TRU-016. If a patient is benefiting with stable disease or better, then TRU-016 may continue to be dosed every 3 weeks after the first 6 cycles; bendamustine will not be dosed beyond 6 cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of adverse events |  | any time point during the study up to 18 months | 
| CLL Cysteine 481 mutation status | The primary endpoint for Cohort 7 is the elimination of the cysteine 481 mutant clone (<1%). | CLL patients in Cohort 7 will be followed for 9 months unless no cysteine 481 mutation is detected. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) |  | any time point during the study up to 18 months | 
| Progression-free survival (PFS) |  | any time point during the study up to 18 months | 
| Overall survival (OS) |  | any time point during the study up to 18 months | 
| Duration of response (DOR) |  | any time point during the study up to 18 months | 
| Resolution of disease-related symptoms | Resolution of disease-related symptoms which are common to the disease include fever, weight loss, night sweats, fatigue, loss of appetite pain, and pruritus; symptoms will be assessed by descriptive statistics and data listings. | any time point during the study up to 18 months | 
| Maximum serum drug concentration (Cmax) |  | any time point during the study up to 12 months | 
| Minimum serum drug concentration (Cmin) |  | any time point during the study up to 12 months | 
| Area under the concentration-time curve (AUC0-t and AUC0-∞) |  | any time point during the study up to 12 months | 
| Systemic clearance (CL) |  | any time point during the study up to 12 months | 
| Volume of distribution (Vd) |  | any time point during the study up to 12 months | 
| Elimination half-life (t1/2) |  | any time point during the study up to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chronic lymphocytic leukemia, CLL, previously untreated chronic lymphocytic leukemia, peripheral T-cell lymphoma, PTCL