Hodgkin Lymphoma
Conditions
Keywords
Nivolumab
Brief summary
This is a single-arm, phase II, multi-centre study of the safety and efficacy of the PD-1 inhibitor, nivolumab, as second-line or third-line salvage therapy as a bridge to stem cell transplant (SCT) in relapsed/ refractory classical Hodgkin lymphoma patients not achieving a complete metabolic response (CMR) on FDG-PET-CT scan after first or second line salvage therapy.
Detailed description
This is a single-arm, phase II, multi-centre study of the safety and efficacy of the programmed cell death protein 1 (PD-1) inhibitor, nivolumab, as second-line or third-line salvage therapy, and in particular as a bridge to stem cell transplant (SCT) in relapsed/ refractory classical Hodgkin lymphoma patients not achieving a complete metabolic response (CMR) on fluorodeoxyglucose positron emission tomography (FDG-PET) scan post first or second line salvage therapy. Approximately 120 patients with relapsed/refractory classical Hodgkin lymphoma will be registered while undergoing first or second line salvage therapy (first line is preferred). Patients will have a centrally reviewed PET CT scan after first or second line salvage therapy. Those with complete metabolic response (CMR) on PET CT scan (Deauville score 1-3) will not be eligible for trial treatment. They will be followed up for trial data collection purposes, and further management will be at their treating clinician's discretion. Patients achieving less than CMR on central review of FDG-PET (Deauville score 4-5) will be eligible to receive up to 8 x 2-weekly nivolumab infusions. 30 patients will be treated on the trial. After 4 courses of nivolumab, patients will have an additional centrally reviewed PET-CT scan (PET4). Patients achieving CMR will stop trial treatment, and enter follow up. Further treatment will be at their clinician's discretion but is likely to be stem cell transplant (SCT). Patients with partial metabolic response (PMR) or stable disease (SD) on PET4 will receive a further 4 cycles of nivolumab, again followed by a centrally reviewed PET-CT scan (PET8) to assess final response. Further management after PET8 will be at the discretion of the treating clinician, although it is anticipated that those with CMR or PMR will proceed to SCT. If PET8 shows less than CMR (i.e. PMR or SD), patients who consent will have a further biopsy to exclude false positive PET signal; this will be centrally reviewed. Patients with progressive metabolic disease (PMD) on nivolumab at any point will stop trial treatment. If a repeat biopsy is obtained to confirm progressive disease histologically, the biopsy material will be centrally reviewed. Patients will be followed up for a minimum of 3 years.
Interventions
DRUGNivolumab
Up to 8 cycles of nivolumab
Sponsors
Bristol-Myers Squibb
University College, London
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a single-arm, phase II, multi-centre study. It will use an Ahern single stage design with independent trials steering committee review to monitor for safety and efficacy.
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
for study registration: 1. Age 16 or over 2. Primary refractory classical Hodgkin lymphoma or classical Hodgkin lymphoma in first relapse 3. About to receive or receiving first or second line salvage therapy (up to a maximum of 14 days after last treatment) 4. Fit for autologous stem cell transplantation 5. Written informed consent 6. Willing to comply with the contraceptive requirements of the trial
Exclusion criteria
for study registration: 1. Nodular lymphocyte predominant Hodgkin lymphoma 2. Women who are pregnant or breastfeeding 3. History of colitis, inflammatory bowel disease or pneumonitis 4. Patients with autoimmune disorders, except patients with vitiligo, diabetes mellitus type 1, hypo- and hyperthyroidism not requiring immunosuppressive therapy 5. Known history of hepatitis B or C infection 6. Known HIV infection 7. History of allergy (including severe/life threatening skin reaction) to monoclonal antibodies, anaphylaxis or uncontrolled allergy 8. Major surgery within 4 weeks prior to registration 9. Myocardial infarction, unstable angina, coronary artery bypass graft, cerebrovascular accident or transient ischaemic attack within the past 6 months 10. Non-haematological malignancy within the past 3 years (with some exceptions - listed in protocol) Inclusion criteria for trial treatment: 1. Has received 2 cycles of first or second line salvage chemotherapy 2. PET positive (Deauville score 4 or 5) after first or second line salvage chemotherapy 3. Fit for further salvage chemotherapy 4. ECOG performance status 0-1 5. Creatinine clearance \>30ml/min calculated by Cockcroft-Gault formula 6. Bilirubin \<1.5 x ULN, ALT/AST \<2.5 x ULN 7. Adequate bone marrow function (Hb \>80g/l, Platelets \>50 x 10\^9/l, neutrophils \>1.0 x 10\^9/l)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall response rate (ORR) by PET-CT scan following 4-8 cycles of nivolumab | 4 months | Rate of patients achieving complete metabolic response (CMR) on PET-CT scan following 4 or 8 cycles of nivolumab |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of patients progressing to stem cell transplant | 1 year | Proportion of patients progressing to autologous or allogeneic stem cell transplant |
| Adverse events [Safety and toxicity of nivolumab] | 3 years | Adverse events and serious adverse events occurring in patients treated with nivolumab, in particular autoimmune toxicity |
| Transplant-related mortality | 3 years | Proportion of patients treated with nivolumab that subsequently die of transplant-related causes |
| Transplant-related morbidity | 3 years | Proportion of patients treated with nivolumab that go on to suffer serious complications of allogeneic transplant (grade 3-4 graft-versus-host disease, hyperacute graft-versus-host disease and steroid-responsive febrile syndrome) |
| Progression-free survival | 1 year | Progression-free survival at 1 year; also to be analysed stratified by partial metabolic response vs complete metabolic response. |
| Overall survival | 1 year | Overall survival at 1 year; also to be analysed stratified by partial metabolic response (PMR) vs complete metabolic response (CMR). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Serological biomarkers of response to nivolumab | 5 months | Correlation of disease response with serological markers such as serum Thymus and activation-regulated chemokine (TARC) levels |
| Immunological biomarkers of response to treatment | 4 months | Evaluate the correlation between response to nivolumab and biological parameters e.g. PD-L1 expression on Reed Sternberg cells |
| Biopsy-negative PMR rate | 4 months | Correlation of PET positive disease with histological evidence of disease on post-treatment repeat biopsy to establish biopsy negative PMR rate (subject to patient consent) |
Countries
United Kingdom
Outcome results
None listed