Phase 1b Safety and Efficacy Study of TRU-016

• ClinicalTrials.gov Identifier: NCT01644253
• Recruitment Status: Active, not recruiting
• First Posted: July 19, 2012
• Last Update Posted: December 5, 2019
• Sponsor: Aptevo Therapeutics
• Information provided by (Responsible Party): Aptevo Therapeutics

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Chronic Lymphocytic Leukemia; Peripheral T-cell Lymphoma	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	Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 87 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: September 2012
• Estimated Primary Completion Date: October 2020
• Estimated Study Completion Date: December 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort 1 - Previously Untreated CLL; 20 mg/kg TRU-016 + Rituximab	Biological: 20 mg/kg TRU-016 + Rituximab; 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; Other Name: Rituxan
Experimental: Cohort 2 - Relapsed CLL; 20 mg/kg TRU-016 + Rituximab	Biological: 20 mg/kg TRU-016 + Rituximab; 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; Other Name: Rituxan
Experimental: Cohort 3 - Previously Untreated CLL; 10 mg/kg TRU-016 + Rituximab	Biological: 10 mg/kg TRU-016 + Rituximab; 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; Other Name: Rituxan
Experimental: Cohort 4 - Previously Untreated CLL; 20 mg/kg TRU-016 20 + Obinutuzumab	Biological: TRU-016 20 mg/kg + Obinutuzumab; 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; Other Name: Gazyva
Experimental: Cohort 5 - Relapse CLL; 20 mg/kg TRU-016 + idelalisib + rituximab	Biological: TRU-016 6-20 mg/kg + idelalisib + rituximab; 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.; Other Name: Zydelig, Rituxan
Experimental: Cohort 6 - With CLL on ibrutinib with no complete response; 20 mg/kg TRU-016 + ibrutinib	Biological: TRU-016 10-20 mg/kg + ibrutinib; 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.; Other Name: Imbruvica
Experimental: Cohort 7 - With CLL on ibrutinib with stable disease; 20 mg/kg TRU-016 + ibrutinib	Biological: TRU-016 10-20 mg/kg + ibrutinib; 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.; Other Name: Imbruvica
Experimental: Cohort 8 - With relapsed or refractory PTCL; 20 mg/kg TRU-016 + 90 mg/m2 bendamustine	Biological: TRU-016 10-20 mg/kg + bendamustine; 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.

Outcome Measures

Primary Outcome Measures :

1. Incidence and severity of adverse events [ Time Frame: any time point during the study up to 18 months ]
2. CLL Cysteine 481 mutation status [ Time Frame: 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%).

Secondary Outcome Measures :

1. Overall Response Rate (ORR) [ Time Frame: any time point during the study up to 18 months ]
2. Progression-free survival (PFS) [ Time Frame: any time point during the study up to 18 months ]
3. Overall survival (OS) [ Time Frame: any time point during the study up to 18 months ]
4. Duration of response (DOR) [ Time Frame: any time point during the study up to 18 months ]
5. Resolution of disease-related symptoms [ Time Frame: 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.
6. Maximum serum drug concentration (Cmax) [ Time Frame: any time point during the study up to 12 months ]
7. Minimum serum drug concentration (Cmin) [ Time Frame: any time point during the study up to 12 months ]
8. Area under the concentration-time curve (AUC0-t and AUC0-∞) [ Time Frame: any time point during the study up to 12 months ]
9. Systemic clearance (CL) [ Time Frame: any time point during the study up to 12 months ]
10. Volume of distribution (Vd) [ Time Frame: any time point during the study up to 12 months ]
11. Elimination half-life (t1/2) [ Time Frame: any time point during the study up to 12 months ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Georgia

Augusta, Georgia, United States, 30912

United States, Ohio

Columbus, Ohio, United States, 43210

United States, Pennsylvania

Eastern Regional Medical Center

Philadelphia, Pennsylvania, United States, 19124

University of Pittsburgh

Pittsburgh, Pennsylvania, United States, 15232

United States, South Carolina

Greenville Health System

Greenville, South Carolina, United States, 29605

United States, Texas

Houston, Texas, United States, 77030

United States, Washington

Swedish Cancer Institute,1221 Madison St.

Seattle, Washington, United States, 98104

Fred Hutchinson Cancer Research Center

Seattle, Washington, United States, 98109

Sponsors and Collaborators

Aptevo Therapeutics

Investigators

• Study Director: Scott C. Stromatt, M.D.; Aptevo Therapeutics

More Information

• Responsible Party: Aptevo Therapeutics
• ClinicalTrials.gov Identifier: NCT01644253
• Other Study ID Numbers: 16009
• First Posted: July 19, 2012
• Last Update Posted: December 5, 2019
• Last Verified: December 2019

Keywords provided by Aptevo Therapeutics:

chronic lymphocytic leukemia; CLL; previously untreated chronic lymphocytic leukemia; peripheral T-cell lymphoma; PTCL

Additional relevant MeSH terms:

Lymphoma; Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, T-Cell; Lymphoma, T-Cell, Peripheral; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, B-Cell; Lymphoma, Non-Hodgkin; Rituximab; Obinutuzumab; Bendamustine Hydrochloride; Idelalisib; Immunoglobulin G; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors