Refractory Diffuse Large B-Cell Lymphoma, Relapsed, Diffuse Large B-cell Lymphoma
Conditions
Keywords
Radioimmunotherapy, Lu-177, Phase I study, Betalutin, ARC, Antibody Radionuclide Conjugate, HH1, Rituximab, 177Lu-DOTA-HH1, Lilotomab, Lutetium (177Lu)-lilotomab satetraxetan, Additional relevant MeSH terms:, Lymphoma, Lymphoma, Non-Hodgkin, Immune System Diseases, Immunoproliferative Disorders, Diffuse Large B-Cell Lymphoma, Lymphatic Diseases, Lymphoproliferative Disorders, Neoplasms, Neoplasms by Histologic Type, DLBCL, Refractory DLBCL, Relapsed DLBCL
Brief summary
This study is a phase 1, dose finding, open-label study in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). This is a dose escalating study to define the maximum tolerated dose (MTD) of lutetium (177Lu)-lilotomab satetraxetan (Betalutin®) in DLBCL patients who are not eligible for autologous stem cell transplant. The study will also assess safety and tolerability, pharmacokinetics, biodistribution and efficacy.
Interventions
DRUGBetalutin
Dose finding study, starting on 10 MBq/kg b.w. Betalutin® (lutetium (177Lu)-lilotomab satetraxetan), single injection with lilotomab pre-dosing.
Sponsors
Nordic Nanovector
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female aged ≥18 years. 2. Histologically confirmed DLBCL (WHO classification). 3. Received at least one prior line of therapy including immuno-chemotherapy. 4. In first or subsequent relapse, or refractory to the last treatment (defined as less than a complete metabolic response to the last treatment, or disease progression within 6 months from the last treatment). 5. Not suitable for, or declined/unwilling to undergo intensive therapy, including high dose chemotherapy and autologous stem cell transplantation (ASCT). 6. Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy (at least one objectively bi-dimensionally measurable (nodal) lesion (\>1.5 cm in its largest dimension by CT scan). 7. Negative human anti-mouse antibody (HAMA) test. 8. Life expectancy of at least 3 months. 9. Bone marrow tumour infiltration \<25% tumour cells. 10. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2. 11. Normal organ and bone marrow function defined as: 1. Absolute neutrophil count ≥1.5 x 109/L 2. Platelet count ≥150 x 109/L; 3. Haemoglobin ≥9 g/dL 4. Total bilirubin ≤1.5 x upper limit of normal (ULN) (except patients with documented Gilbert's syndrome) 5. Liver enzymes: Aspartate transaminase (AST); Alanine transaminase (ALT) or Alkaline phosphatase (ALP) ≤2.5 x ULN (or ≤5.0 x ULN if liver involvement by primary disease) 6. Adequate renal function as demonstrated by a serum creatinine ≤1.5 mg/dL or a creatinine clearance \>60 mL/min 7. Normal coagulation parameters (elevated international normalized ratio (INR), prothrombin time or activated partial thromboplastin time (APTT) ≤1.3 ULN range acceptable) 12. Women of childbearing potential must: 1. Understand that the study medication may have teratogenic risk 2. Have a negative serum pregnancy test at screening and before Betalutin injection 3. Commit to continued abstinence from heterosexual intercourse (excluding periodic abstinence or the withdrawal method) or begin two acceptable methods of birth control with a Pearl-Index ≤ 1%. without interruption from 4 weeks before starting study drug, throughout study drug therapy and for 12 months after end of study drug therapy, even if she has amenorrhoea. Apart from abstinence, acceptable methods of birth control are: * Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal) * Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable) * Intrauterine device (IUD) * Intrauterine hormone-releasing system (IUS) * Bilateral tubal occlusion * Vasectomised partner 13. Male patients must agree to use condoms during intercourse throughout study drug therapy and the following 12 months. 14. Ability to give written, informed consent prior to any study-specific screening procedures, with the understanding that the consent may be withdrawn by the patient at any time without prejudice. 15. Capable of understanding the protocol requirements, is willing and able to comply with the study protocol procedures, and has signed the informed consent document. 16. A negative Hepatitis B test (HBsAg and anti-HBc) and negative HIV test during screening
Exclusion criteria
1. Prior hematopoietic allogenic stem cell transplantation. 2. Prior autologous stem cell transplantation. 3. Previous total body irradiation. 4. Prior anti-lymphoma therapy (chemotherapy, immunotherapy or other investigational agent), excluding corticosteroids within 4 weeks prior to start of study treatment (i.e. rituximab) (G-CSF or GM-CSF are permitted up to 2 weeks prior to start of study treatment.) 5. Patients who are receiving any other investigational agents. 6. Patients with known or suspected central nervous system involvement of lymphoma. 7. History of a previous treated cancer except for the following: 1. Adequately treated local basal cell or squamous cell carcinoma of the skin 2. Cervical carcinoma in situ 3. Superficial bladder cancer 4. Localized prostate cancer undergoing surveillance or surgery 5. Localised breast cancer treated with surgery and radiotherapy but not including systemic chemotherapy 6. Other adequately treated Stage 1 or 2 cancer currently in complete remission 8. Pregnant or breastfeeding women. 9. Exposure to another CD37 targeting drug. 10. Allergy to X ray contrast agents. 11. A known hypersensitivity to rituximab, HH1, Betalutin or murine proteins or any excipient used in rituximab, lilotomab or Betalutin. 12. Has received a live attenuated vaccine within 30 days prior to enrolling in the study. 13. Evidence of severe or uncontrolled systemic diseases: 1. Uncontrolled infection including evidence of ongoing systemic bacterial, fungal, or viral infection (excluding viral upper respiratory tract infections) at the time of initiation of study treatment 2. Pulmonary conditions e.g. unstable or uncompensated respiratory disease 3. Hepatic, renal neurological or metabolic conditions - which in the opinion of the investigator would compromise the protocol objectives 4. Psychiatric conditions e.g. patients unlikely to comply with the protocol, e.g. mental condition rendering the patient unable to understand the nature, scope, and possible consequences of participating in the study 5. History of erythema multiforme, toxic epidermal necrolysis or Stevens-Johnson syndrome 6. Cardiac conditions, including: * history of acute coronary syndromes (including unstable angina) * class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system; * known uncontrolled arrhythmias (except sinus arrhythmia) in the past 24 weeks.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With DLTs to Determine the MTD | 12 weeks | To determine the MTD of Betalutin that can be administered to DBLCL patients with lilotomab. The MTD was the highest dose at which less than two out of six participants experienced a dose limiting toxicity (DLT) defined as: * Haematologic toxicity: * Grade 4 neutropenia observed for greater than 7 days' duration * Grade 4 thrombocytopenia observed for greater than 7 days' duration * Grade 3 or 4 neutropenia associated with fever (≥38.5°C) of any duration * Grade 3 or 4 thrombocytopenia with bleeding * Thrombocytopenia with any requirement for more than one platelet transfusion before recovering to Grade 1 or less * Grade 4 anaemia, unexplained by underlying disease * Non-haematologic toxicity: * Grade 3 nausea/vomiting/diarrhoea lasting longer than 72 hours despite maximal care or Grade 4 * Any other Grade 3 or 4 non-haematologic toxicities * Any Grade 3 or 4 electrolyte abnormalities that do not resolve to Grade 1 or baseline within 24 hours |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Best Overall Tumour Response | 3 months - 2 years | Efficacy evaluations are measured by tumour response rates using CT and PET/CT imaging with responses classified as described in Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification (Cheson, 2014). The Cheson criteria, 2014 are a combined score taking into consideration, positive or negative scored PET scan, the contrast enhanced CT images and bone marrow biopsies when available. |
| Dosimetry | 3 weeks | Dosimetry will be evaluated by the estimated absorbed radiation dose to target organs. |
Countries
Germany, Italy, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
Participants were screened in the 28 days before receiving rituximab (42 days before receiving lilotomab and Betalutin). Participants were then allocated to one of four treatment cohorts following a 3+3 design. They received rituximab on Day -14, followed by Betalutin and lilotomab on Day 0. Two participants received rituximab but were withdrawn prior to receiving lilotomab and Betalutin and were therefore replaced.
Participants by arm
| Arm | Count |
|---|---|
| 60/10 Betalutin® (lutetium (177Lu)-lilotomab satetraxetan) 10 MBq/kg, single injection with lilotomab 60 mg/m2 pre-dosing on Day 0 following rituximab pre-treatment on Day -14. | 3 |
| 100/10 Betalutin® (lutetium (177Lu)-lilotomab satetraxetan) 10 MBq/kg, single injection with lilotomab 100 mg/m2 pre-dosing on Day 0 following rituximab pre-treatment on Day -14. | 3 |
| 100/15 Betalutin® (lutetium (177Lu)-lilotomab satetraxetan) 15 MBq/kg, single injection with lilotomab 100 mg/m2 pre-dosing on Day 0 following rituximab pre-treatment on Day -14. | 3 |
| 100/20 Betalutin® (lutetium (177Lu)-lilotomab satetraxetan) 20 MBq/kg, single injection with lilotomab 100 mg/m2 pre-dosing on Day 0 following rituximab pre-treatment on Day -14. | 7 |
| Rituximab Only Received rituximab pre-treatment on Day -14. Did not receive Betalutin or lilotomab | 2 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Received Lilotomab and Betalutin | Adverse Event | 0 | 0 | 0 | 1 | 0 |
| Received Lilotomab and Betalutin | Disease progression (including death due to disease progression) | 2 | 0 | 3 | 3 | 0 |
| Received Lilotomab and Betalutin | Lost to Follow-up | 0 | 1 | 0 | 0 | 0 |
| Received Lilotomab and Betalutin | Progressive disease | 1 | 0 | 0 | 0 | 0 |
| Received Lilotomab and Betalutin | Start of further anticancer therapy | 0 | 2 | 0 | 2 | 0 |
| Received Rituximab | Adverse Event | 0 | 0 | 0 | 0 | 1 |
| Received Rituximab | Progressive disease | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Rituximab Only | 100/20 | 100/15 | 100/10 | 60/10 |
|---|---|---|---|---|---|---|
| Age, Continuous | 73.5 years STANDARD_DEVIATION 12.85 | 72 years STANDARD_DEVIATION 7.07 | 81.0 years STANDARD_DEVIATION 7.07 | 77.3 years STANDARD_DEVIATION 76 | 56.7 years STANDARD_DEVIATION 10.21 | 69.0 years STANDARD_DEVIATION 16.09 |
| ECOG score Score 0 | 5 Participants | 0 Participants | 3 Participants | 0 Participants | 2 Participants | 0 Participants |
| ECOG score Score 1 | 8 Participants | 1 Participants | 3 Participants | 2 Participants | 0 Participants | 2 Participants |
| ECOG score Score 2 | 5 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 2 Participants | 5 Participants | 3 Participants | 3 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 2 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 | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 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 | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 16 Participants | 2 Participants | 5 Participants | 3 Participants | 3 Participants | 3 Participants |
| Sex: Female, Male Female | 9 Participants | 1 Participants | 3 Participants | 2 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 9 Participants | 1 Participants | 4 Participants | 1 Participants | 2 Participants | 1 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 1 / 3 | 2 / 3 | 4 / 7 | 2 / 18 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 5 / 7 | 10 / 18 |
| serious Total, serious adverse events | 2 / 3 | 0 / 3 | 2 / 3 | 3 / 7 | 4 / 18 |
Outcome results
Primary
Number of Participants With DLTs to Determine the MTD
To determine the MTD of Betalutin that can be administered to DBLCL patients with lilotomab. The MTD was the highest dose at which less than two out of six participants experienced a dose limiting toxicity (DLT) defined as: * Haematologic toxicity: * Grade 4 neutropenia observed for greater than 7 days' duration * Grade 4 thrombocytopenia observed for greater than 7 days' duration * Grade 3 or 4 neutropenia associated with fever (≥38.5°C) of any duration * Grade 3 or 4 thrombocytopenia with bleeding * Thrombocytopenia with any requirement for more than one platelet transfusion before recovering to Grade 1 or less * Grade 4 anaemia, unexplained by underlying disease * Non-haematologic toxicity: * Grade 3 nausea/vomiting/diarrhoea lasting longer than 72 hours despite maximal care or Grade 4 * Any other Grade 3 or 4 non-haematologic toxicities * Any Grade 3 or 4 electrolyte abnormalities that do not resolve to Grade 1 or baseline within 24 hours
Time frame: 12 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 60/10 | Number of Participants With DLTs to Determine the MTD | 0 Participants |
| 100/10 | Number of Participants With DLTs to Determine the MTD | 0 Participants |
| 100/15 | Number of Participants With DLTs to Determine the MTD | 0 Participants |
| 100/20 | Number of Participants With DLTs to Determine the MTD | 1 Participants |
Secondary
Dosimetry
Dosimetry will be evaluated by the estimated absorbed radiation dose to target organs.
Time frame: 3 weeks
Population: Participants having dosimetry evaluation and having the schedule of whole body imaging or SPECT/CT scans
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 60/10 | Dosimetry | Spleen | 1.39 Gray |
| 60/10 | Dosimetry | Image-based Red Marrow | 0.52 Gray |
| 60/10 | Dosimetry | Kidneys | 0.70 Gray |
| 60/10 | Dosimetry | Total Body | 0.07 Gray |
| 60/10 | Dosimetry | Liver | 1.33 Gray |
| 100/10 | Dosimetry | Total Body | 1.16 Gray |
| 100/10 | Dosimetry | Liver | 0.46 Gray |
| 100/10 | Dosimetry | Spleen | 2.63 Gray |
| 100/10 | Dosimetry | Kidneys | 0.73 Gray |
| 100/10 | Dosimetry | Image-based Red Marrow | 0.38 Gray |
Secondary
The Best Overall Tumour Response
Efficacy evaluations are measured by tumour response rates using CT and PET/CT imaging with responses classified as described in Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification (Cheson, 2014). The Cheson criteria, 2014 are a combined score taking into consideration, positive or negative scored PET scan, the contrast enhanced CT images and bone marrow biopsies when available.
Time frame: 3 months - 2 years
Population: Participants who had a baseline and at least one post-baseline computed tomography scan
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 60/10 | The Best Overall Tumour Response | Progressive disease | 1 Participants |
| 60/10 | The Best Overall Tumour Response | Complete response | 0 Participants |
| 60/10 | The Best Overall Tumour Response | No response/stable disease | 0 Participants |
| 100/10 | The Best Overall Tumour Response | Progressive disease | 1 Participants |
| 100/10 | The Best Overall Tumour Response | Complete response | 0 Participants |
| 100/10 | The Best Overall Tumour Response | No response/stable disease | 1 Participants |
| 100/15 | The Best Overall Tumour Response | No response/stable disease | 0 Participants |
| 100/15 | The Best Overall Tumour Response | Progressive disease | 1 Participants |
| 100/15 | The Best Overall Tumour Response | Complete response | 1 Participants |
| 100/20 | The Best Overall Tumour Response | Progressive disease | 1 Participants |
| 100/20 | The Best Overall Tumour Response | Complete response | 1 Participants |
| 100/20 | The Best Overall Tumour Response | No response/stable disease | 1 Participants |