Phase 1b Safety and Efficacy Study of TRU-016

Phase 1

Terminated

• Conditions: Chronic Lymphocytic Leukemia; Peripheral T-cell Lymphoma
• Interventions: Biological: 20 mg/kg TRU-016 + Rituximab; Biological: 10 mg/kg TRU-016 + Rituximab; Biological: TRU-016 6-20 mg/kg + idelalisib + rituximab; Biological: TRU-016 10-20 mg/kg + ibrutinib; Biological: TRU-016 20 mg/kg + Obinutuzumab; Biological: TRU-016 10-20 mg/kg + bendamustine

• Registration Number: NCT01644253
• Lead Sponsor: Aptevo Therapeutics

Brief Summary

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

The study will consist of 8 dose cohorts:

1. Previously untreated patients 20 mg/kg TRU-016 + rituximab.

2. Relapsed patients, 20 mg/kg TRU-016 + rituximab.

3. Previously untreated patients 10 mg/kg TRU-016 + rituximab.

4. Previously untreated patients TRU-016 + obinutuzumab.

5. Relapsed patients, 20 mg/kg TRU-016 + rituximab + idelalisib.

6. 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.

7. 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.

8. 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.

Study Timeline

• Study First Submitted: 2012-07-12
• Study First Submitted QC: 2012-07-16
• Study First Posted: 2012-07-19
• Study Start: 2012-09
• Primary Completion: 2020-02-24
• Study Completion: 2021-04-21
• Status Verified: 2021-05
• Last Update Submitted: 2021-05-18
• Last Update Posted: 2021-05-20

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 87

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Cohort 1 - Previously Untreated CLL	20 mg/kg TRU-016 + Rituximab	20 mg/kg TRU-016 + Rituximab
Cohort 3 - Previously Untreated CLL	10 mg/kg TRU-016 + Rituximab	10 mg/kg TRU-016 + Rituximab
Cohort 5 - Relapse CLL	TRU-016 6-20 mg/kg + idelalisib + rituximab	20 mg/kg TRU-016 + idelalisib + rituximab
Cohort 6 - With CLL on ibrutinib with no complete response	TRU-016 10-20 mg/kg + ibrutinib	20 mg/kg TRU-016 + ibrutinib
Cohort 2 - Relapsed CLL	20 mg/kg TRU-016 + Rituximab	20 mg/kg TRU-016 + Rituximab
Cohort 4 - Previously Untreated CLL	TRU-016 20 mg/kg + Obinutuzumab	20 mg/kg TRU-016 20 + Obinutuzumab
Cohort 8 - With relapsed or refractory PTCL	TRU-016 10-20 mg/kg + bendamustine	20 mg/kg TRU-016 + 90 mg/m2 bendamustine
Cohort 7 - With CLL on ibrutinib with stable disease	TRU-016 10-20 mg/kg + ibrutinib	20 mg/kg TRU-016 + ibrutinib

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Overall Response Rate (ORR)	any time point during the study up to 18 months
Duration of response (DOR)	any time point during the study up to 18 months
Area under the concentration-time curve (AUC0-t and AUC0-∞)	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
Overall survival (OS)	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
Systemic clearance (CL)	any time point during the study up to 12 months
Progression-free survival (PFS)	any time point during the study up to 18 months
Resolution of disease-related symptoms	any time point during the study up to 18 months	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.

Trial Locations

Locations (5)

Eastern Regional Medical Center; 🇺🇸 Philadelphia, Pennsylvania, United States

Greenville Health System; 🇺🇸 Greenville, South Carolina, United States

Swedish Cancer Institute,1221 Madison St.; 🇺🇸 Seattle, Washington, United States

Fred Hutchinson Cancer Research Center; 🇺🇸 Seattle, Washington, United States

University of Pittsburgh; 🇺🇸 Pittsburgh, Pennsylvania, United States