B-cell Lymphoma
Conditions
Keywords
Low Grade B-cell Lymphoma
Brief summary
To assess the safety and tolerability of escalating doses of SD-101 in combination with localized low-dose radiation therapy in adult subjects with untreated low-grade B-cell lymphoma.
Interventions
DRUGSD-101
RADIATIONRadiation therapy
Sponsors
Dynavax Technologies Corporation
Study design
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Biopsy confirmed, untreated, low-grade B-cell lymphoma, including follicular (Grade 1, 2, or 3A) \[Harris, Swerdlow et al. 2008\] or marginal, or CLL/SLL with lymph node involvement. * At least 2 sites of measurable disease per Cheson criteria (must measure at least 1.5 cm in any diameter or 1.0 cm in the shortest diameter if one of the diameters is not ≥ 1.5 cm), one of which must be palpable and easily accessible in a low-risk site (eg, inguinal, axillary, cervical, subcutaneous) for intratumoral injection (denoted as Lesion A in Treatment Cycle 1) and at least one additional untreated lesion that is located outside the radiation field of the treated lesion (Lesion A) and is accessible for an FNA aspirate. * Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1 * Aged 18 years and older * Absolute neutrophil count (ANC) ≥ 1500/mm3 * Platelet count \> 100,000/µL * Serum creatinine (Cr) ≤ 1.5 x upper limit of normal (ULN). * Serum total bilirubin ≤ 1.5 x the ULN. * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN * International normalized ratio or prothrombin time (PT) ≤ 1.5 x ULN unless subject is receiving anticoagulant therapy and the PT or partial thromboplastin time (PTT) must be within the therapeutic range of the intended use of anticoagulants. * Activated PTT (aPTT) ≤ 1.5 x ULN unless subject is receiving anticoagulant therapy, and the PT or PTT is within therapeutic range of intended use of anticoagulants. * Female subjects must have a negative urine or serum pregnancy test within 72 hours prior to taking study medication if of childbearing potential as defined in this protocol. Women of childbearing potential (WOCBP) must be willing to use 2 medically acceptable method of contraceptive from Day 1 through 120 days after the last dose of trial treatment. The 2 medically acceptable birth control methods can be either 2 barrier methods or a barrier method plus a hormonal method to prevent pregnancy. The following are considered adequate barrier methods of contraception: diaphragm, condom (by the partner), cooper intrauterine device, sponge, or spermicide as per local regulations or guidelines. Appropriate hormonal contraceptives will include any registered and marketed contraceptive agent that contains an estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or intramuscular agents). * Ability to understand and sign informed consent form (ICF) and comply with treatment protocol
Exclusion criteria
* Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy (including immune modulators or systemic corticosteroids) within 7 days prior to study enrollment. * Positive for hepatitis B (HBsAg reactive), HCV ribonucleic acid (RNA) qualitative, or human immunodeficiency virus (HIV)( HIV 1/2 antibodies) * Diagnosis of mantle or diffuse large-cell lymphoma, Grade 3B follicular lymphoma \[Harris, Swerdlow et al. 2008\] or gastric mucosa-associated lymphoid tissue (MALT) lymphoma * Clinically significant pleural effusion * Active infection including cytomegalovirus * Pregnant or breast feeding within the projected duration of trial participation through 4 months after the last dose of study treatment. * Autoimmune disease including systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Sjӧgren's syndrome, autoimmune thrombocytopenia, history of uveitis, or other if clinically significant * Lymphoma involvement of the central nervous system * Received any prior therapy for lymphoma * Use of any investigational agent within the last 28 days * Serious, non-healing wound, ulcer, or bone fracture. * If a subject received major surgery, must have recovered adequately from the toxicity and/or complications from the intervention prior to enrollment. * Clinically significant cardiovascular disease (eg, uncontrolled hypertension, myocardial infarction, unstable angina), New York Heart Association (NYHA) Grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication within 1 year prior to Day -1 (Visit 1); Grade II or greater peripheral vascular disease at study entry * Any other significant medical or psychiatric condition, laboratory abnormality, or difficulty complying with protocol requirements that may increase the risk associated with study participation or study drug administration that may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for this study * History of sensitivity to any component of SD-101 * A diagnosis of cancer within the last 3 years prior to enrollment or any known additional malignancy that is progressing or requires active treatment. Exceptions are B-cell lymphoma, basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, and in situ cervical cancer. * Is taking systemic corticosteroids (more than 3 consecutive days) or other immunomodulators or immune suppressive medication
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing Dose-limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD). | Up to Day 36 | — |
| Number of Participants Experiencing Injection-site Reactions (ISRs) | Up to Day 36 | Injection site reaction 1 = Redness, Injection site reaction 2 = Swelling, Injection site reaction 3 = Pain |
| Number of Participants Experiencing Serious Adverse Events (SAEs) | Up to 38 weeks | — |
| Pharmacodynamic Profile - Expression of IFN-responsive Genes (GBP-1, ISG-54, MCP-1, and MxB) | Change from Day 8 to Day 9 | Fold change of IFN-responsive gene expression relative to Day 8 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Preliminary Response - Local (Injected Lesions) | Up to 38 weeks | Subjects with maximum decrease of 50% or greater in sum of products of diameters of lesions. |
| Number of Participants With Preliminary Response - Systemic (Non-injected Lesions) | Up to 38 weeks | Subjects with maximum decrease of 50% or greater in sum of products of diameters of lesions. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 1 mg/mL PART 1
COHORT 1: 1 mg/mL at Days 1, 8, 15, 22, and 29 | 10 |
| 2 mg/mL PART 1
COHORT 2: 2 mg/mL at Days 1, 8, 15, 22, and 29 | 3 |
| 4 mg/mL PART 1
COHORT 3: 4 mg/mL at Days 1, 8, 15, 22, and 29 | 3 |
| 8 mg/mL PART 1
COHORT 4: 8 mg/mL at Days 1, 8, 15, 22, and 29 | 13 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| PART 1: Dose Escalation | Lack of Efficacy | 0 | 2 | 1 | 1 |
| PART 1: Dose Escalation | Other | 1 | 1 | 0 | 0 |
| PART 1: Dose Escalation | Physician Decision | 0 | 0 | 1 | 0 |
| PART 1: Dose Escalation | Study Terminated by Sponsor | 0 | 0 | 1 | 3 |
| PART 2: Dose Expansion | Lack of Efficacy | 1 | 0 | 0 | 1 |
| PART 2: Dose Expansion | Study Terminated by Sponsor | 6 | 0 | 0 | 8 |
Baseline characteristics
| Characteristic | 1 mg/mL | 2 mg/mL | 4 mg/mL | 8 mg/mL | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 1 Participants | 1 Participants | 6 Participants | 11 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 2 Participants | 2 Participants | 7 Participants | 18 Participants |
| Age, Continuous | 56.9 years STANDARD_DEVIATION 13.53 | 56 years STANDARD_DEVIATION 9.54 | 61 years STANDARD_DEVIATION 16.52 | 62.7 years STANDARD_DEVIATION 12.32 | 59.8 years STANDARD_DEVIATION 12.59 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 3 Participants | 3 Participants | 13 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 8 Participants | 3 Participants | 3 Participants | 12 Participants | 26 Participants |
| Region of Enrollment United States | 10 Participants | 3 Participants | 3 Participants | 13 Participants | 29 Participants |
| Sex: Female, Male Female | 4 Participants | 2 Participants | 1 Participants | 6 Participants | 13 Participants |
| Sex: Female, Male Male | 6 Participants | 1 Participants | 2 Participants | 7 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 3 | 0 / 3 | 0 / 13 |
| other Total, other adverse events | 10 / 10 | 3 / 3 | 3 / 3 | 13 / 13 |
| serious Total, serious adverse events | 0 / 10 | 0 / 3 | 1 / 3 | 1 / 13 |
Outcome results
Primary
Number of Participants Experiencing Dose-limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD).
Time frame: Up to Day 36
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1 mg/mL | Number of Participants Experiencing Dose-limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD). | 0 participants |
| 2 mg/mL | Number of Participants Experiencing Dose-limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD). | 0 participants |
| 4 mg/mL | Number of Participants Experiencing Dose-limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD). | 0 participants |
| 8 mg/mL | Number of Participants Experiencing Dose-limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD). | 0 participants |
Comparison: MTD was not observed because no DLTs occurred at the maximum dose tested. Because this is a safety endpoint, a statistical analysis was not conducted.
Primary
Number of Participants Experiencing Injection-site Reactions (ISRs)
Injection site reaction 1 = Redness, Injection site reaction 2 = Swelling, Injection site reaction 3 = Pain
Time frame: Up to Day 36
Population: Safety population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 1 mg/mL | Number of Participants Experiencing Injection-site Reactions (ISRs) | Injection site reaction 3 | 7 Participants |
| 1 mg/mL | Number of Participants Experiencing Injection-site Reactions (ISRs) | Injection site reaction 1 | 4 Participants |
| 1 mg/mL | Number of Participants Experiencing Injection-site Reactions (ISRs) | Injection site reaction 2 | 4 Participants |
| 2 mg/mL | Number of Participants Experiencing Injection-site Reactions (ISRs) | Injection site reaction 1 | 0 Participants |
| 2 mg/mL | Number of Participants Experiencing Injection-site Reactions (ISRs) | Injection site reaction 2 | 1 Participants |
| 2 mg/mL | Number of Participants Experiencing Injection-site Reactions (ISRs) | Injection site reaction 3 | 3 Participants |
| 4 mg/mL | Number of Participants Experiencing Injection-site Reactions (ISRs) | Injection site reaction 3 | 1 Participants |
| 4 mg/mL | Number of Participants Experiencing Injection-site Reactions (ISRs) | Injection site reaction 2 | 2 Participants |
| 4 mg/mL | Number of Participants Experiencing Injection-site Reactions (ISRs) | Injection site reaction 1 | 1 Participants |
| 8 mg/mL | Number of Participants Experiencing Injection-site Reactions (ISRs) | Injection site reaction 3 | 6 Participants |
| 8 mg/mL | Number of Participants Experiencing Injection-site Reactions (ISRs) | Injection site reaction 2 | 2 Participants |
| 8 mg/mL | Number of Participants Experiencing Injection-site Reactions (ISRs) | Injection site reaction 1 | 5 Participants |
Primary
Number of Participants Experiencing Serious Adverse Events (SAEs)
Time frame: Up to 38 weeks
Population: Safety population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 1 mg/mL | Number of Participants Experiencing Serious Adverse Events (SAEs) | Renal and urinary disorders | 0 participants |
| 1 mg/mL | Number of Participants Experiencing Serious Adverse Events (SAEs) | Total # of participants with SAEs | 0 participants |
| 1 mg/mL | Number of Participants Experiencing Serious Adverse Events (SAEs) | Respiratory, thoracic and mediastinal disorders | 0 participants |
| 2 mg/mL | Number of Participants Experiencing Serious Adverse Events (SAEs) | Renal and urinary disorders | 0 participants |
| 2 mg/mL | Number of Participants Experiencing Serious Adverse Events (SAEs) | Total # of participants with SAEs | 0 participants |
| 2 mg/mL | Number of Participants Experiencing Serious Adverse Events (SAEs) | Respiratory, thoracic and mediastinal disorders | 0 participants |
| 4 mg/mL | Number of Participants Experiencing Serious Adverse Events (SAEs) | Respiratory, thoracic and mediastinal disorders | 1 participants |
| 4 mg/mL | Number of Participants Experiencing Serious Adverse Events (SAEs) | Renal and urinary disorders | 0 participants |
| 4 mg/mL | Number of Participants Experiencing Serious Adverse Events (SAEs) | Total # of participants with SAEs | 1 participants |
| 8 mg/mL | Number of Participants Experiencing Serious Adverse Events (SAEs) | Renal and urinary disorders | 1 participants |
| 8 mg/mL | Number of Participants Experiencing Serious Adverse Events (SAEs) | Total # of participants with SAEs | 1 participants |
| 8 mg/mL | Number of Participants Experiencing Serious Adverse Events (SAEs) | Respiratory, thoracic and mediastinal disorders | 0 participants |
Primary
Pharmacodynamic Profile - Expression of IFN-responsive Genes (GBP-1, ISG-54, MCP-1, and MxB)
Fold change of IFN-responsive gene expression relative to Day 8
Time frame: Change from Day 8 to Day 9
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 1 mg/mL | Pharmacodynamic Profile - Expression of IFN-responsive Genes (GBP-1, ISG-54, MCP-1, and MxB) | 7.42 Fold Change | Standard Deviation 4.78 |
| 2 mg/mL | Pharmacodynamic Profile - Expression of IFN-responsive Genes (GBP-1, ISG-54, MCP-1, and MxB) | 8.06 Fold Change | Standard Deviation 2.05 |
| 4 mg/mL | Pharmacodynamic Profile - Expression of IFN-responsive Genes (GBP-1, ISG-54, MCP-1, and MxB) | 9.89 Fold Change | Standard Deviation 0.59 |
| 8 mg/mL | Pharmacodynamic Profile - Expression of IFN-responsive Genes (GBP-1, ISG-54, MCP-1, and MxB) | 7.78 Fold Change | Standard Deviation 7.54 |
Secondary
Number of Participants With Preliminary Response - Local (Injected Lesions)
Subjects with maximum decrease of 50% or greater in sum of products of diameters of lesions.
Time frame: Up to 38 weeks
Population: ITT population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 1 mg/mL | Number of Participants With Preliminary Response - Local (Injected Lesions) | 6 Participants |
| 2 mg/mL | Number of Participants With Preliminary Response - Local (Injected Lesions) | 3 Participants |
| 4 mg/mL | Number of Participants With Preliminary Response - Local (Injected Lesions) | 1 Participants |
| 8 mg/mL | Number of Participants With Preliminary Response - Local (Injected Lesions) | 8 Participants |
Secondary
Number of Participants With Preliminary Response - Systemic (Non-injected Lesions)
Subjects with maximum decrease of 50% or greater in sum of products of diameters of lesions.
Time frame: Up to 38 weeks
Population: ITT population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 1 mg/mL | Number of Participants With Preliminary Response - Systemic (Non-injected Lesions) | 2 Participants |
| 2 mg/mL | Number of Participants With Preliminary Response - Systemic (Non-injected Lesions) | 0 Participants |
| 4 mg/mL | Number of Participants With Preliminary Response - Systemic (Non-injected Lesions) | 0 Participants |
| 8 mg/mL | Number of Participants With Preliminary Response - Systemic (Non-injected Lesions) | 2 Participants |