Relapsed/Refractory Indolent B Cell Non-Hodgkin Lymphoma
Conditions
Keywords
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
Brief summary
This is a Phase I/II, open-label, multi-center, competitive enrollment and dose escalation study of N-803 in patients with relapse/refractory indolent B cell non-Hodgkin lymphoma in conjunction with rituximab.
Detailed description
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 N-803 in treated patients. The effect of N-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.
Interventions
BIOLOGICALRituximab
Intravenous infusion 375 mg/m\^2.
BIOLOGICALN-803
Intravenous infusion for Phase 1 cohort 1, 2 and 3; subcutaneous injection for Phase 1 cohort 4, 5, 6 and 7. Phase 2 dosing was based off of the MTD determined in Phase 1.
Sponsors
Altor BioScience
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| MTD or MED of N-803: IV 1, 3, 6 μg/kg, SQ 6, 10, 15, 20 μg/kg | 9 months | Maximum Tolerated Dose level (MTD) is defined as a dose level at which \<2 out of 6 patients experienced Dose Limiting Toxicity (DLT) and that is one level below a dose that was not tolerated. Minimal Efficacious Dose (MED) is defined as a dose level which produces an Absolute Lymphocyte Count (ALC) ≥25,000/μL sustained for 14 days or a total WBC ≥35,000/μL sustained for 14 days among 2/3 or 4/6 of patients. The elevated ALC cannot be attributed to circulating lymphoma cells. Dose levels for N-803 1, 3, 6 μg/kg IV, and 6, 10, 15, 20 μg/kg subcutaneous (SQ) were used to determine the MTD or MED. |
| Number of Participants With Treatment Emergent Adverse Events | 30 days after last dose, up to 40 weeks | Treatment Emergent Adverse Event is defined as any AE that begins or worsens in grade after the start of study treatment until 30 days after the last dose of study treatment or end of study period, whichever is later. |
| Overall Response Rate | 60 months | For Phase 1 and 2, overall response rate (ORR) will be calculated as the ratio of the number of patients who demonstrated response (CR+PR) divided by the number of patients in the Evaluable population. Response and disease progression criteria were defined by the 2007 IHP response assessments for malignant lymphoma. |
Countries
United States
Participant flow
Pre-assignment details
3 subjects from Phase 1 cohort 7 rolled over to the Phase 2 portion of the study. All other participants in Phase 2 only enrolled in the Phase 2 portion of the study.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1 Cohort 1: N-803 - IV 1 ug/kg Rituximab: Intravenous infusion 375 mg/m\^2.
N-803: Intravenous infusion for Phase 1 cohort 1, 2 and 3; subcutaneous injection for Phase 1 cohort 4, 5, 6 and 7. Phase 2 dosing was based off of the MTD determined in Phase 1. | 3 |
| Phase 1 Cohort 2: N-803 - IV 3 ug/kg Rituximab: Intravenous infusion 375 mg/m\^2.
N-803: Intravenous infusion for Phase 1 cohort 1, 2 and 3; subcutaneous injection for Phase 1 cohort 4, 5, 6 and 7. Phase 2 dosing was based off of the MTD determined in Phase 1. | 3 |
| Phase 1 Cohort 3: N-803 - IV 6 ug/kg Rituximab: Intravenous infusion 375 mg/m\^2.
N-803: Intravenous infusion for Phase 1 cohort 1, 2 and 3; subcutaneous injection for Phase 1 cohort 4, 5, 6 and 7. Phase 2 dosing was based off of the MTD determined in Phase 1. | 3 |
| Phase 1 Cohort 4: N-803 - SQ 6 ug/kg Rituximab: Intravenous infusion 375 mg/m\^2.
N-803: Intravenous infusion for Phase 1 cohort 1, 2 and 3; subcutaneous injection for Phase 1 cohort 4, 5, 6 and 7. Phase 2 dosing was based off of the MTD determined in Phase 1. | 3 |
| Phase 1 Cohort 5: N-803 - SQ 10 ug/kg Rituximab: Intravenous infusion 375 mg/m\^2.
N-803: Intravenous infusion for Phase 1 cohort 1, 2 and 3; subcutaneous injection for Phase 1 cohort 4, 5, 6 and 7. Phase 2 dosing was based off of the MTD determined in Phase 1. | 3 |
| Phase 1 Cohort 6: N-803 - SQ 15 ug/kg Rituximab: Intravenous infusion 375 mg/m\^2.
N-803: Intravenous infusion for Phase 1 cohort 1, 2 and 3; subcutaneous injection for Phase 1 cohort 4, 5, 6 and 7. Phase 2 dosing was based off of the MTD determined in Phase 1. | 3 |
| Phase 1 Cohort 7: N-803 - SQ 20 ug/kg Rituximab: Intravenous infusion 375 mg/m\^2.
N-803: Intravenous infusion for Phase 1 cohort 1, 2 and 3; subcutaneous injection for Phase 1 cohort 4, 5, 6 and 7. Phase 2 dosing was based off of the MTD determined in Phase 1. | 3 |
| Phase 2 Cohort 1: Anti-CD20 mAb-sensitive N-803 - SQ 20 ug/kg Rituximab: Intravenous infusion 375 mg/m\^2.
N-803: Intravenous infusion for Phase 1 cohort 1, 2 and 3; subcutaneous injection for Phase 1 cohort 4, 5, 6 and 7. Phase 2 dosing was based off of the MTD determined in Phase 1. | 16 |
| Phase 2 Cohort 2: Anti-CD20 mAb-refractory N-803 - SQ 20 ug/kg Rituximab: Intravenous infusion 375 mg/m\^2.
N-803: Intravenous infusion for Phase 1 cohort 1, 2 and 3; subcutaneous injection for Phase 1 cohort 4, 5, 6 and 7. Phase 2 dosing was based off of the MTD determined in Phase 1. | 9 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Phase 1 | Adverse Event | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Phase 1 | Progressive Disease | 2 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 |
| Phase 2 | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| Phase 2 | Failure to meet continuation criteria | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Phase 2 | Progressive Disease | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 2 |
Baseline characteristics
| Characteristic | Phase 1 Cohort 1: N-803 - IV 1 ug/kg | Phase 1 Cohort 2: N-803 - IV 3 ug/kg | Phase 1 Cohort 3: N-803 - IV 6 ug/kg | Phase 1 Cohort 4: N-803 - SQ 6 ug/kg | Phase 1 Cohort 5: N-803 - SQ 10 ug/kg | Phase 1 Cohort 6: N-803 - SQ 15 ug/kg | Phase 1 Cohort 7: N-803 - SQ 20 ug/kg | Total | Phase 2 Cohort 1: Anti-CD20 mAb-sensitive N-803 - SQ 20 ug/kg | Phase 2 Cohort 2: Anti-CD20 mAb-refractory N-803 - SQ 20 ug/kg |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous Phase 1 | 58.0 years STANDARD_DEVIATION 1 | 64.7 years STANDARD_DEVIATION 7.37 | 69.3 years STANDARD_DEVIATION 8.39 | 60.0 years STANDARD_DEVIATION 4.58 | 65.0 years STANDARD_DEVIATION 10.44 | 68.3 years STANDARD_DEVIATION 10.21 | 62.0 years STANDARD_DEVIATION 3.61 | 63.9 years STANDARD_DEVIATION 7.28 | — | — |
| Age, Continuous Phase 2 | — | — | — | — | — | — | — | 63.0 years STANDARD_DEVIATION 12.48 | 59.5 years STANDARD_DEVIATION 11.39 | 69.1 years STANDARD_DEVIATION 12.54 |
| Patients with relapse/refractory indolent B cell non-Hodgkin lymphoma Phase 1 | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 21 Participants | — | — |
| Patients with relapse/refractory indolent B cell non-Hodgkin lymphoma Phase 2 | — | — | — | — | — | — | — | 25 Participants | 16 Participants | 9 Participants |
| Race (NIH/OMB) Phase 1 American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Phase 1 Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Phase 1 Black or African American | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Phase 1 More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Phase 1 Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Phase 1 Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Phase 1 White | 3 Participants | 3 Participants | 2 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 20 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Phase 2 American Indian or Alaska Native | — | — | — | — | — | — | — | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Phase 2 Asian | — | — | — | — | — | — | — | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Phase 2 Black or African American | — | — | — | — | — | — | — | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Phase 2 More than one race | — | — | — | — | — | — | — | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Phase 2 Native Hawaiian or Other Pacific Islander | — | — | — | — | — | — | — | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Phase 2 Unknown or Not Reported | — | — | — | — | — | — | — | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Phase 2 White | — | — | — | — | — | — | — | 20 Participants | 14 Participants | 6 Participants |
| Sex: Female, Male Phase 1 Female | 2 Participants | 2 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants | 3 Participants | 11 Participants | — | — |
| Sex: Female, Male Phase 1 Male | 1 Participants | 1 Participants | 3 Participants | 3 Participants | 1 Participants | 1 Participants | 0 Participants | 10 Participants | — | — |
| Sex: Female, Male Phase 2 Female | — | — | — | — | — | — | — | 12 Participants | 10 Participants | 2 Participants |
| Sex: Female, Male Phase 2 Male | — | — | — | — | — | — | — | 13 Participants | 6 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 16 | 0 / 9 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 16 / 16 | 9 / 9 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 1 / 3 | 1 / 3 | 0 / 3 | 0 / 3 | 1 / 3 | 3 / 16 | 2 / 9 |
Outcome results
Primary
MTD or MED of N-803: IV 1, 3, 6 μg/kg, SQ 6, 10, 15, 20 μg/kg
Maximum Tolerated Dose level (MTD) is defined as a dose level at which \<2 out of 6 patients experienced Dose Limiting Toxicity (DLT) and that is one level below a dose that was not tolerated. Minimal Efficacious Dose (MED) is defined as a dose level which produces an Absolute Lymphocyte Count (ALC) ≥25,000/μL sustained for 14 days or a total WBC ≥35,000/μL sustained for 14 days among 2/3 or 4/6 of patients. The elevated ALC cannot be attributed to circulating lymphoma cells. Dose levels for N-803 1, 3, 6 μg/kg IV, and 6, 10, 15, 20 μg/kg subcutaneous (SQ) were used to determine the MTD or MED.
Time frame: 9 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 Cohort 7: N-803 - SQ 20 μg/kg | MTD or MED of N-803: IV 1, 3, 6 μg/kg, SQ 6, 10, 15, 20 μg/kg | 20 SQ μg/kg |
Primary
Number of Participants With Treatment Emergent Adverse Events
Treatment Emergent Adverse Event is defined as any AE that begins or worsens in grade after the start of study treatment until 30 days after the last dose of study treatment or end of study period, whichever is later.
Time frame: 30 days after last dose, up to 40 weeks
Population: 3 subjects from Phase 1 cohort 7 rolled over to the Phase 2 portion of the study. All other participants in Phase 2 only enrolled in the Phase 2 portion of the study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1 Cohort 7: N-803 - SQ 20 μg/kg | Number of Participants With Treatment Emergent Adverse Events | Phase 1 | 3 Participants |
| Phase 1 Cohort 2: N-803 - IV 3 ug/kg | Number of Participants With Treatment Emergent Adverse Events | Phase 1 | 3 Participants |
| Phase 1 Cohort 3: N-803 - IV 6 ug/kg | Number of Participants With Treatment Emergent Adverse Events | Phase 1 | 3 Participants |
| Phase 1 Cohort 4: N-803 - SQ 6 ug/kg | Number of Participants With Treatment Emergent Adverse Events | Phase 1 | 3 Participants |
| Phase 1 Cohort 5: N-803 - SQ 10 ug/kg | Number of Participants With Treatment Emergent Adverse Events | Phase 1 | 3 Participants |
| Phase 1 Cohort 6: N-803 - SQ 15 ug/kg | Number of Participants With Treatment Emergent Adverse Events | Phase 1 | 3 Participants |
| Phase 1 Cohort 7: N-803 - SQ 20 ug/kg | Number of Participants With Treatment Emergent Adverse Events | Phase 1 | 3 Participants |
| Phase 2 Cohort 1: Anti-CD20 mAb-sensitive N-803 - SQ 20 ug/kg | Number of Participants With Treatment Emergent Adverse Events | Phase 2 | 16 Participants |
| Phase 2 Cohort 2: Anti-CD20 mAb-refractory N-803 - SQ 20 ug/kg | Number of Participants With Treatment Emergent Adverse Events | Phase 2 | 9 Participants |
Primary
Overall Response Rate
For Phase 1 and 2, overall response rate (ORR) will be calculated as the ratio of the number of patients who demonstrated response (CR+PR) divided by the number of patients in the Evaluable population. Response and disease progression criteria were defined by the 2007 IHP response assessments for malignant lymphoma.
Time frame: 60 months
Population: 3 subjects from Phase 1 cohort 7 rolled over to the Phase 2 portion of the study. All other participants in Phase 2 only enrolled in the Phase 2 portion of the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 Cohort 7: N-803 - SQ 20 μg/kg | Overall Response Rate | Phase 1 | 33 percentage of subjects |
| Phase 1 Cohort 2: N-803 - IV 3 ug/kg | Overall Response Rate | Phase 1 | 33 percentage of subjects |
| Phase 1 Cohort 3: N-803 - IV 6 ug/kg | Overall Response Rate | Phase 1 | 67 percentage of subjects |
| Phase 1 Cohort 4: N-803 - SQ 6 ug/kg | Overall Response Rate | Phase 1 | 33 percentage of subjects |
| Phase 1 Cohort 5: N-803 - SQ 10 ug/kg | Overall Response Rate | Phase 1 | 67 percentage of subjects |
| Phase 1 Cohort 6: N-803 - SQ 15 ug/kg | Overall Response Rate | Phase 1 | 67 percentage of subjects |
| Phase 1 Cohort 7: N-803 - SQ 20 ug/kg | Overall Response Rate | Phase 1 | 100 percentage of subjects |
| Phase 2 Cohort 1: Anti-CD20 mAb-sensitive N-803 - SQ 20 ug/kg | Overall Response Rate | Phase 2 | 80 percentage of subjects |
| Phase 2 Cohort 2: Anti-CD20 mAb-refractory N-803 - SQ 20 ug/kg | Overall Response Rate | Phase 2 | 33 percentage of subjects |