E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed/refractory Hodgkin lymphoma |
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E.1.1.1 | Medical condition in easily understood language |
Hodgkin lymphoma is a cancer of the lymphatic system due to abnormal lymphocytes. Refractory means not responding to initial treatment. Relapse is where disease returns after initial response. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10020266 |
E.1.2 | Term | Hodgkin's disease recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10020267 |
E.1.2 | Term | Hodgkin's disease refractory |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess whether nivolumab, given on its own, can be used effectively to treat patients with Hodgkin lymphoma that has either failed to respond to initial treatment or which has returned after initially responding to treatment, and has not responded fully to salvage chemotherapy. The trial aims to find out how many patients have a negative PET-CT scan after 4-8 cycles of nivolumab treatment. |
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E.2.2 | Secondary objectives of the trial |
To investigate whether patients' disease relapses after nivolumab treatment, and if so, how long this takes to happen.
To find out how long patients live after nivolumab treatment.
To find out if patients who have a negative PET-CT scan after nivolumab take longer to relapse than those who have a positive PET-CT scan after nivolumab
To investigate what side effects patients experience from nivolumab treatment.
To find out whether it is safe for patients to have a stem cell transplant after nivolumab treatment
To investigate whether PET scanning is an effective way of checking response to nivolumab treatment
To look at whether there are blood tests that can be used to monitor response to treatment for Hodgkin lymphoma
To understand more about the biology of Hodgkin lymphoma, and whether it is possible to predict response to salvage treatment
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion criteria for registration • Age 16 or over • Primary refractory classical Hodgkin lymphoma or classical Hodgkin lymphoma in first relapse • About to receive, receiving or within 14 days of first 2 cycles of first or second line salvage therapy (4 cycles if receiving treatment with brentuximab vedotin) • Fit for autologous stem cell transplantation • Written informed consent • Willing to comply with the contraceptive requirements of the trial
Inclusion criteria – trial treatment • Has received 2 cycles of first line or second line salvage chemotherapy (4 cycles if being treated with brentuximab vedotin) • PET positive (Deauville score 4 or 5) after 2 cycles of first or second line salvage chemotherapy (4 cycles if being treated with brentuximab vedotin) • Fit for further salvage chemotherapy • ECOG performance status 0-1 • Creatinine clearance >30ml/min calculated by Cockroft-Gault formula • Bilirubin <1.5 x ULN, ALT/AST <2.5 x ULN • Adequate bone marrow function (Hb >80g/l, Platelets >50 x 10^9/l, neutrophils >1.0 x 10^9/l |
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E.4 | Principal exclusion criteria |
Exclusion criteria for registration • Nodular lymphocyte predominant Hodgkin lymphoma • Women who are pregnant or breastfeeding • History of colitis, inflammatory bowel disease or pneumonitis • Patients with autoimmune disorders excluding patients with vitiligo, diabetes mellitus type 1, hypo- and hyperthyroidism not requiring immunosuppressive therapy • Known history of hepatitis B or C infection • Known HIV infection • History of allergy (including severe/life threatening skin reaction) to monoclonal antibodies, anaphylaxis or uncontrolled allergy • Major surgery within 4 weeks prior to registration • Myocardial infarction, unstable angina, coronary artery bypass graft, cerebrovascular accident or transient ischaemic attack within the past 6 months • Non-haematological malignancy within the past 3 years (some exceptions apply – listed in trial protocol)
Exclusion criteria for trial treatment • Deauville score 1-3 after 2 cycles of first or second line salvage chemotherapy (4 cycles if being treated with brentuximab vedotin) • Positive serology for hepatitis B or C (unless due to vaccination) • Active infection requiring systemic therapy • Ongoing immunosuppressive therapy, apart from inhaled, intranasal, topical corticosteroids or systemic corticosteroids at low doses (≤10mg prednisolone or equivalent per day). • Chemo- or radiotherapy or corticosteroids at a dose of more than 10mg/day prednisolone or equivalent within 14 days prior to response PET-CT. NOTE: corticosteroids can be used AFTER a positive PET-CT scan for symptomatic disease but must be weaned to a dose of prednisolone ≤10mg/day or less (or equivalent) at least 7 days prior to starting nivolumab. • Treatment with any investigational agent within 28 days prior to planned start of nivolumab • Ongoing grade 2-4 non-haematological toxicities related to prior Hodgkin lymphoma treatments, with the exception of alopecia and grade 2 fatigue • Pregnant or breastfeeding women |
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall response rate (ORR) by PET-CT scan following 4-8 cycles of nivolumab |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Response assessed by centrally reviewed PET CT scan after 4 and 8 cycles of nivolumab (approximately 2 & 4 months of treatment).
Scans are to be performed 11-13 days after trial treatment administration during cycles 4 and 8, as per trial requirements on an approved scanner, and images sent to the UK PET Core Lab at St Thomas' Hospital for expert central review. |
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E.5.2 | Secondary end point(s) |
(1)Progression-free survival at 1 year (2)Overall survival at 1 year (3)Proportion of patients proceeding to SCT (auto-SCT or allo-SCT) (4)Safety & toxicity of nivolumab, particularly autoimmune toxicity (5)OS and PFS stratified by partial metabolic response (PMR) versus complete metabolic response (CMR) on FDG-PET (6)Transplant-related mortality and rate of serious complications of allogeneic transplant (grade 3-4 graft-vs-host disease, hyperacute graft-vs-host disease and steroid-responsive febrile syndrome) (7)Correlate PET positive disease with histological evidence of disease on biopsy to establish biopsy negative PMR rate (subject to patient consent; exploratory) (8) Correlate disease response, as assessed by FDG-PET and histology, with serological markers, including serum TARC (exploratory) (9) Evaluate the correlation betweem response to nivolumab and biological parameters e.g. PD-1 expression on Reed-Sternberg cells (exploratory)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
(1), (2), (3), (5): assessed at 1 year after completion of trial treatment. Longer term survival follow up will also be presented. (4): from start of nivolumab until 5 month post last trial treatment administration; late toxicity during follow up will also be reported. (6): from transplant day 0 until day 100 post transplant (patients undergoing allogeneic transplant only) (7): following cycle 8 of nivolumab (patients who remain PET positive and consent to repeat biopsy only) (8): from start of treatment until end of treatment; based on sequential blood samples. (9): exploratory analysis based on archival biopsy material collected after study entry
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 30 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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End of trial will be declared when the last patient treated with nivolumab has completed three years of follow up. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 1 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 1 |