QUILT-3.002: ALT-803 in Patients With Relapse/Refractory iNHL in Conjunction With Rituximab

Study Overview
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Brief Summary
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This is a Phase I/II, open-label, multi-center, competitive enrollment and dose escalation study of ALT-803 in patients with relapse/refractory indolent B cell non-Hodgkin lymphoma in conjunction with rituximab.

Detailed Description
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The purpose of this study is to evaluate the safety and tolerability, identify the Maximum Tolerated Dose (MTD) or the Minimum Efficacious Dose (MED) and designate a dose level for Phase 2. Also characterize the immunogenicity, pharmacokinetic profile, and biomarker serum levels of ALT-803 in treated patients. The effect of ALT-803 on the peripheral absolute lymphocyte counts and white blood cell counts, the number, phenotype and repertoire of peripheral blood T (total and subsets) and NK cells will be evaluated. In addition, a subset of patients will be evaluated for changes in lymph node immune composition. Anti-tumor responses and survival data will also be collected in this trial.

Official Title
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A Phase 1/2 Study of ALT-803 in Patients With Relapse/Refractory Indolent B Cell Non-Hodgkin Lymphoma in Conjunction With Rituximab

Conditions
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Relapsed/Refractory Indolent B Cell Non-Hodgkin Lymphoma

Intervention / Treatment
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* Biological: Rituximab
* Biological: ALT-803


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed diagnosis of iNHL (Follicular lymphoma grade 1, 2, 3a; marginal zone lymphoma; small lymphocytic lymphoma or lymphoplasmacytic lymphoma) after treatment with at least 1 or more prior rituximab-containing regimens. Anti-CD20 mAb-refractory disease is defined as progressive disease while on rituximab (or another treatment of an anti-CD20 monoclonal antibody) or progression within 6 months of rituximab-containing (or another treatment of an anti-CD20 antibody-containing) therapy. Anti-CD20 mAb-sensitive disease is defined by a response to a prior rituximab-containing (or another treatment of an anti-CD20 monoclonal antibody) regimen, and relapse more than 6 months from the last administration of rituximab-containing (or another treatment of an anti-CD20 antibody-containing) therapy. Measurable disease: At least one lymph node group ≥ 1.5 cm in longest transverse dimension. Patients with cutaneous only disease may be enrolled if they have a clearly measurable skin lesion. Relapsed or Refractory iNHL that has progressed during or following 1 or more prior systemic rituximab-containing (or another treatment of an anti-CD20 antibody-containing) regimens for lymphoma PRIOR/CONCURRENT THERAPY: No anti-lymphoma treatments within 28 days before the start of study treatment. Must have recovered from side effects of prior treatments. PATIENT CHARACTERISTICS: Performance Status • ECOG 0, 1, or 2 Renal Function • Glomerular Filtration Rate (GFR) > 40mL/min or Serum creatinine ≤ 1.5 X ULN Bone Marrow Reserve Platelets ≥30,000/uL Hemoglobin ≥ 8g/dL Absolute Lymphocytes ≥800/uL ANC/AGC ≥750/uL Hepatic Function Total bilirubin ≤ 2.0 X ULN (unless Gilbert's Syndrome or disease infiltration of liver is present) AST, ALT ≤ 3.0 X ULN, or ≤ 5.0 X ULN (if liver lymphoma is present) No positive Hep C serology or active Hep B infection Cardiovascular No congestive heart failure < 6 months No unstable angina pectoris < 6 months No myocardial infarction < 6 months No history of ventricular arrhythmias or severe cardiac dysfunction No history of uncontrollable supraventricular arrhythmias No NYHA Class > II CHF No marked baseline prolongation of QT/QTc interval Pulmonary • Normal clinical assessment of pulmonary function Other Negative serum pregnancy test if female and of childbearing potential Women who are not pregnant or nursing Subjects, both females and males, with reproductive potential must agree to use effective contraceptive measures for the duration of the study No known autoimmune disease other than corrected hypothyroidism No known prior organ allograft or allogeneic transplantation Not HIV positive No active CNS involvement with lymphoma No psychiatric illness/social situation that would limit compliance No other illness that in the opinion of the investigator would exclude the subject from participating in the study Must provide informed consent and HIPPA authorization and agree to comply with all protocol-specified procedures and follow-up evaluations No active systemic infection requiring parenteral antibiotic therapy No disease requiring systemic immunosuppressive therapy (inhaled or topical steroids are allowed). Adrenal replacement steroid doses ≤ 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease. No known histologic transformation from iNHL to DLBCL

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I/II ALT-803 w/rituximab for rel/ref iNHL<br> | Biological: Rituximab<br>* Intravenous infusion; Patients will receive a 4-week induction cycle consisting of Rituximab given on Day 1, 8, 15, 22. Eligible patients will receive a consolidation treatment consisting of Rituximab given on Day 78, 134, 190, 246.<br>* Other names: Rituxin;Biological: ALT-803<br>* Intravenous infusion for cohort 1, 2 and 3; subcutaneous injection for cohort 4, 5, 6 and 7; Patients will receive a 4-week induction cycle consisting of ALT-803 given on Day 2, 8, 15, 22 for patients in cohort 1, 2, 3, 4 and Day 1, 8, 15 and 22 for patients in cohort 5, 6, 7. Eligible patients will receive a consolidation treatment consisting of ALT-803 given on Day 78, 134, 190, 246.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of MTD or MED, Phase II Dose Level Designation | For Phase I Determine the maximum tolerated dose (MTD) level or minimum efficacious dose (MED) and designate the dose level for phase II. | 9 months | 
| Number of treatment related adverse events as a measure of safety | For Phase 1 and 2 Number and severity of treatment related AEs that occur or worsen after the first dose of study treatment will be collected. | 36 months | 
| Overall Response Rate | For Phase 1 and 2 Complete response plus partial response of treated patients | 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | For Phase 1 and 2 Of all treated patients will be assessed at least every three months during years 1 and 2, every 4 months during year 3, and then every 6 months (+/- 2 months) during years 4 and 5 from the start of study treatment, or through the point designated as the end of the study follow up (5 years). | 60 months | 
| Overall Survival | For Phase 1 and 2 Of all treated patients will be assessed at least every three months during years 1 and 2, every 4 months during year 3, and then every 6 months (+/- 2 months) during years 4 and 5 from the start of study treatment, or through the point designated as the end of the study follow up (5 years). | 60 months | 
| Duration of Response | For Phase 1 and 2 Of all treated patients will be assessed at least every three months during years 1 and 2, every 4 months during year 3, and then every 6 months (+/- 2 months) during years 4 and 5 from the start of study treatment, or through the point designated as the end of the study follow up (5 years). | 60 months | 
| Blood Cell Counts | For Phase 1 and 2 Evaluation of the effect of ALT-803 on the peripheral ALC and WBC counts, the number and phenotype of peripheral blood T (total and subsets) and NK cells in treated patients. | 36 months | 
| Levels of specific biomarkers as a predictive measure of efficacy | For Phase 1 and 2 Measures the serum levels of including but not limited to IL-2, IL-4, IL-6, IL-10, IFN-gamma, MCP-1 and TNF-alpha in treated patients. | 36 Months | 
| Immunogenicity | For Phase 1 and 2 Measure the level of anti-ALT-803 neutralizing effects in each patient | 36 Months | 
| Pharmacokinetics as a measure of drug persistence | For Phase 1 and 2 Area under the plasma concentration-time curve from time zero to infinity (AUC) and the half-life of ALT-803 collected from treated patients. | 36 Months | 
| Polymorphism | For Phase 1 and 2 Determine the fcgr3a polymorphism status in each patient to correlate with clinical outcomes. | 36 Months | 
| Mutations | For Phase 1 and 2 Test the recurrent lymphoma mutations in each patient to correlate with clinical outcomes. | 36 Months | 
| Lymph node biopsies | For Phase 1 and 2 Determine the impact of study treatment on the immune cell composition within the tumor microenvironment. | 36 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lymphoma, indolent B Cell, non-Hodgkin Lymphoma, Cancer, Immunotherapy, Relapsed, Refractory, Rituximab, Interleukin-15, Absolute Lymphocyte Count, White Blood Cell, Follicular Lymphoma, Marginal Zone Lymphoma, Small Lymphocytic Lymphoma, Lymphoplasmacytic Lymphoma, anti-CD20