E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
High-risk Diffuse Large B-cell Lymphoma (DLBCL) |
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E.1.1.1 | Medical condition in easily understood language |
A type of lymph gland cancer |
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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 | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10012818 |
E.1.2 | Term | Diffuse large B-cell lymphoma |
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 determine minimal residual disease (MRD) negative rate following blinatumomab treatment in high-risk Diffuse Large B-cell Lymphoma (DLBCL) subjects who are MRD-positive post-autologous hematopoietic stem cell transplantation (aHSCT). |
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E.2.2 | Secondary objectives of the trial |
• To describe the efficacy of blinatumomab in relation to progression-free survival (PFS), duration of MRD-negative status, and overall survival (OS)
• To evaluate the safety and tolerability of blinatumomab |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Part 1
- Age ≥ 18 at time of informed consent
- Biopsy-proven DLBCL excluding DLBCL that represents transformation of indolent NHL (Lymphoblastic Lymphoma and Burkitt Lymphoma histology are not eligible)
- Subject has ≥ 1 characteristic feature of high-risk DLBCL:
• High-risk first complete remission (defined as interim PET-CT positive or < complete remission to frontline chemotherapy AND achieved complete remission to platinum-containing salvage)
• Relapse within 1 year of diagnosis
• Secondary aaIPI > 1 (see Appendix D)
• Partial response/partial metabolic response after minimum of 2 cycles of platinum-containing salvage chemotherapy
• C-myc rearrangement
- aHSCT with high-dose chemotherapy following first (or later) salvage treatment.
- PET-CT negative (Deauville score ≤ 3) 90 days (± 30 days) post aHSCT
- Available relapsed and/or diagnostic pathology formalin-fixed paraffin-embedded (FFPE) tumor block or slide samples at the time of enrollment including the successful identification of malignant clone sequences by the central laboratory.
- MRD plasma sample collected ≤ 3 weeks from post aHSCT PET-CT scan
Part 2
- MRD-positive assessment (by NGS analysis) at enrollment or at any time during the run-in 1 period
- PET-CT negative (defined by Deauville criteria ≤ 3) at run-in 2 performed ≤ 3 weeks from MRD-positive assessment at run-in 1. Historical PET-CT are allowed if performed ≤ 6 weeks from day 1 (first dose of blinatumomab) and subject has no clinical signs or symptoms suggestive of disease progression (eg, increase in lactate dehydrogenase [LDH] not otherwise explained) |
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E.4 | Principal exclusion criteria |
Part 1
- Clinically relevant CNS pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injury, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome, and psychosis
- Evidence of CNS involvement with DLBCL
- Current autoimmune disease or history of autoimmune disease with potential of CNS involvement
- Prior anti-CD19 directed therapies
- Prior alloHSCT
- Received radiation ≤ 2 weeks prior to enrollment
- Infection with HIV or chronic infection with HBV or HCV
- History of malignancy other than DLBCL within the past 3 years with the following exceptions:
• Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before enrollment and felt to be at low risk for recurrence by the treating physician
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
• Adequately treated cervical carcinoma in situ without evidence of disease
• Adequately treated breast ductal carcinoma in situ without evidence of disease
• Prostatic intraepithelial neoplasia without evidence of prostate cancer
• Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in situ
- Subject has known hypersensitivity to immunoglobulins or any of the products or components to be administered during dosing.
- History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.
- Women who are pregnant or breastfeeding or planning to become pregnant or breastfeed while receiving blinatumomab and for an additional 48 hours after the last treatment dose of blinatumomab. (Females of child bearing potential should only be included after a negative highly sensitive urine or serum pregnancy test.)
- Women of childbearing potential unwilling to use an acceptable method of effective contraception while receiving blinatumomab and for an additional 48 hours after last dose of blinatumomab.
- Currently receiving treatment in another investigational device or drug study or less than 30 days since ending treatment on another investigational device or drug study. Other investigational procedures while participating in this study are excluded.
Part 2
- Subject has active infection requiring systemic therapy
- Any change in the part 1 eligibility criteria during the run-in period. |
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E.5 End points |
E.5.1 | Primary end point(s) |
MRD-negative rate at the end of cycle 1 of blinatumomab |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary analysis will be triggered when the first 30 enrolled subjects have had the opportunity to complete cycle 1 of blinatumomab treatment.
The final analysis (see below) will also include updated estimates for the endpoints assessed at the primary analysis (MRD-negative rate and MRD prior to blinatumomab treatment). |
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E.5.2 | Secondary end point(s) |
• PFS
• Duration of MRD-negative status
• OS
• Incidence, grade and severity of treatment emergent adverse events |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The final analysis will be conducted when the subjects in the Primary Analysis Set have had an opportunity to complete the long-term follow-up visit 1 year from the first dose of blinatumomab.
The safety and tolerability of blinatumomab will be assessed at the time of the primary analysis (see above). |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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 | No |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 21 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Belgium |
Finland |
France |
Greece |
Italy |
Switzerland |
United States |
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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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Primary Completion: The primary completion date is defined as the date when the last subject is assessed or receives an intervention for the final collection of data for the primary endpoint.
End of Study: The end of study date is defined as the date when the last subject is assessed or receives an intervention for evaluation in the study (ie, last subject last visit). |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |