| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Diffuse large B-cell lymphoma (most common type of non-Hodgkins lymphoma) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Diffuse large B-cell lymphoma (most common type of non-Hodgkins lymphoma) |
|
| 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) |
|
| 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 document the durable anti-tumour activity of R-GemOx-Atezo in patients with relapsed or refractory DLBCL |
|
| E.2.2 | Secondary objectives of the trial |
Secondary:
To determine the safety and toxicity profile of R-GemOx-Atezo regimen
To document the anti-tumour activity of R-GemOx-Atezo in patients with relapsed or refractory DLBCL.
To document the durability of R-GemOx-Atezo in patients with relapsed or refractory DLBCL.
To determine the overall survival of patients treated R-GemOx-Atezo.
Tertiary:
To correlate clinical outcomes with gene expression analysis of PD-1, PD-L1, PD-L2 and other immune signatures from primary tumour material.
To correlate clinical outcomes with immunohistochemical expression in tumour material of PD-1, PD-L1, PD-L2 and other markers in both tumour and microenvironment.
To correlate clinical outcomes with expression of PD-1, PD-L1/L2 on peripheral blood T-cells. Sub division of T-lymphocyte sub-sets.
To determine the profile of recurrent mutations observed in patients with DLBCL in this population and correlate to clinical response.
To correlate clinical outcomes with known prognostic molecular marke |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Histologically proven CD20 +ve diffuse large B-cell lymphoma with sufficient diagnostic material, obtained either at diagnosis or relapse (the latter is preferable) that is available to forward to the Haematological Malignancies Diagnostic Service (HMDS) for gene expression profiling and central pathology review.
2) Refractory to, or relapsed following, first-line or second-line treatments with rituximab concurrently with anthracycline or anthracenedione-based chemotherapy (etoposide or gemcitabine allowed if comorbid).
Refractory disease must fulfil one of the following:
a) Continuing partial response (PR) from termination of first-line treatment. It is strongly recommended the lymphoma be reconfirmed by biopsy however, if these procedures are deemed to be inappropriate, the CI may determine eligibility following review of the imaging results and disease history.
b) Continuing stable disease (SD) from termination of first-line treatment. Reconfirmation of the lymphoma by biopsy (preferred) is recommended but not mandatory.
c) Progressive disease (PD). Biopsy or reconfirmation of the lymphoma is recommended but not mandatory.
3) Not eligible for high-dose therapy with peripheral blood progenitor cell rescue at Investigator discretion as a result of:
(a) Age
(b) Co-morbidity
(c) Previous HDT.
Rationale to be clearly documented on eCRF and medical notes.
4) Baseline FDG-PET scans must demonstrate positive lesions compatible with CT defined anatomical tumour sites.
5) CT/PET scan showing at least:
• 2 or more clearly demarcated lesions/nodes with a long axis >1.5cm and short axis ≥1.0cm
OR
• 1 clearly demarcated lesion/node with a long axis >2.0cm and short axis ≥1.0cm.
6) Resolution of toxicities from previous therapy to a grade that in the opinion of the investigator does not contraindicate study participation.
7) Patients aged 16 years or over.
8) Willingness to participate in appropriate pregnancy prevention measures.
• Female patients who are fertile and of childbearing potential must have a negative serum or urine pregnancy test during screening (within 7 days prior to the start of trial treatment) and agree to use two highly effective forms of contraception (oral, injected or implanted hormonal contraception and condom; an intra-uterine device and condom; diaphragm with spermicidal gel and condom) effective from the first administration of all study drugs, throughout the trial and for 12 months after last dose of rituximab are considered eligible. Unless they are surgically sterile or ≥ 2 years after the onset of menopause.
• Male patients with partners of child-bearing potential who agree to take measures not to father children by using one form of highly effective contraception (oral, injected or implanted hormonal contraception and condom; an intra-uterine device and condom; diaphragm with spermicidal gel and condom) effective from the first administration of all study drugs, throughout the trial and for 12 months after last dose of rituximab are considered eligible. Male subjects must also refrain from donating sperm during this period. Unless they are surgically sterile.
• Men with pregnant or lactating partners must be advised to use barrier method contraception (for example: condom plus spermicidal gel) to prevent exposure to the foetus or neonate
9) Written informed consent using current version of Protocol, Patient Information Sheet and Informed Consent Form.
10) ECOG performance status ≤3 |
|
| E.4 | Principal exclusion criteria |
1) Received any of the following treatments within two weeks prior to start of study therapy (unless otherwise stated):
• Anti-cancer cytotoxics (excluding corticosteroids)
• Radiotherapy unless it is to a limited field at to control life/organ-threatening symptoms.
2)DLBCL that is refractory to or relapsed within 3 months of a gemcitabine regimen for DLBCL
3) Major surgery within 4 weeks of registration.
4) Treatment with any known non-marketed drug substance or experimental therapy within 5 terminal half-lives or 4 weeks prior to registration.
5) History of stroke or intracranial haemorrhage within 6 months prior to registration.
6) Pre-existing peripheral neuropathy grade >2.
7) Clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to registration, congestive heart failure (NYHA III-IV), a current LVEF of <40%
8) Significant concurrent, uncontrolled medical condition that in the opinion of the investigator contraindicates participation in this study
9) Known lymphoma involvement of the CNS.
10) Known or suspected hypersensitivity to study treatments that in the opinion of the investigator contraindicates their participation. Patients with known history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug induced pneumonitis or idiopathic pneumonitis, or evidence of active pneumonitis will be excluded from study participation.
11) Known HIV positivity; positive serology for Hep B (defined as positivity for Hepatitis B surface antigen (HBsAg) or Hepatitis B core antibody (anti-HBc)) or C; chronic or current infectious disease (except evidence of prior vaccination).
12) Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection or any major episode of infection requiring treatment with IV antibiotics or hospitalization within 2 weeks of the start of Cycle 1. Suspected active or latent tuberculosis needs to be confirmed by positive interferon gamma (IFN-y) release assay.
13) Other past or current malignancy within 2 years prior to registration unless in the opinion of the investigator it does not contraindicate participation in the study. Subjects who have a history of completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma, are eligible.
14) Screening laboratory values:
• platelets <75x109/L (unless due to lymphoma involvement of the bone marrow)
• neutrophils <1.0x109/L (unless due to lymphoma involvement of the bone marrow)
• creatinine >2.0 times upper normal limit (unless due to lymphoma or unless creatinine clearance >60mL/min (calculated using Cockcroft and Gault equation))
• total bilirubin >1.5 times upper normal limit (unless due to lymphoma or a known history of Gilbert’s disease, no higher than >3 times upper normal limit)
• ALT/AST >2.5 times upper normal limit (unless due to lymphoma, no higher than >5 times upper normal limit)
• alkaline phosphatase >2.5 times upper normal limit (unless due to lymphoma, no higher than >5 times upper normal limit)
15) Subjects known or suspected of being unable to comply with the study protocol.
16) Pregnant or lactating women. Women of childbearing potential must have a negative pregnancy test at screening.
17) History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis (Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone will be eligible as will patients with controlled Type I diabetes mellitus on a stable dose of insulin). Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g. patients with psoriatic arthritis are excluded) are eligible for the study provided all of the following conditions are met:
- Rash must cover <10% of body surface area
- Disease is well controlled at baseline and requires only low-potency topical corticosteroids
- No occurance of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months
18) Patients who have previously undergone allogeneic transplantation.
19) Vaccination with a live vaccine within 28 days of study treatment or anticipation of need for such a vaccine during the course of the study and up to 5 months after the last dose of atezolizumab.
20) History of severe allergic anaphylactic reactions to chimeric, human or humanised antibodies, or fusion proteins.
21) Known hypersensitivity to CHO cell products or any component of the a |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression free-survival rate at 1 year from study entry |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Progression free survival rate to be assessed at 12 month follow up visit. |
|
| E.5.2 | Secondary end point(s) |
1) Determining the toxicity and causality of each adverse event (AE) G-GemOx-Atezo and grading severity according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03.
2) Objective response (partial or complete metabolic response (PR or CR)) (assessed by PET) in any of the patients as determined by the Lugano response criteria.
3) Progression free survival from study entry. Progression free survival will be measured from the day of registration to progression or the date of death from any cause. Patients who do not die will censored at their date of last follow up.
4) Overall survival from study entry. Overall survival will be measured from the day of registration to the date of death from any cause. Patients who do not die will be censored at their date of last follow up.
5) Gene expression profiling on FFPE tumour material using whole transcriptome profiling.
6) Immunohistochemical analysis of primary tumour material, with double staining techniques.
7) Flow cytometry of peripheral blood at baseline and during therapy.
8) Application of NGS DLBCL mutation panel to tumour material.
9) Examine translocations of Myc, Bcl6 and Bcl2 by fish.
10) Immunohistochemical analysis for dual protein expression on Myc and Bcl2.
11) Gene expression profiling on FFPE tumour material using whole transcriptome profiling.
12) Plasma lymphoma nucleic acid at baseline studied and compared with paired lymphoma tissue sample and repeated throughout the study period to examine dynamics of change and possible assessment of minimal residual disease, depending upon responses observed.
13) To examine the link between tumour-infiltrating T cell repertoire in pre-treatment biopsies and clinical outcomes.
14) Plasma samples will be obtained throughout treatment for a novel assay examining multiple serum checkpoint markers and correlating with timepoint and disease response. (30 patient pilot study) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) AE collection from consent through to 30 days post final study treatment
2) PET/CT or Contrast Enhanced CT with separate PET after treatment completion
3) 4 monthly follow up for first year and 6 monthly for second year to assess progression free survival
4) 4 monthly follow up for first year and 6 monthly for second year to assess overall free survival
5, 6, 8, 9, 10 and 11) Baseline tumour sample will be tested
7) Bloods taken at a regular timepoints throughout the study
12) Blood samples take through out the study and baseline tumour sample will be tested
13) DNA extracted from baseline tumour samples will be tested
14) Plasma samples collected through out the study |
|
| 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 | No |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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
|
LVLS.
The end of the trial is defined as: The patient reaches the final follow up visit, which will be 2 years after receiving the last study treatment and all data is collected and analysed. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 29 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 29 |
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