| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Previously untreated, high-risk diffuse-large B-cell lymphoma (DLBCL) |
|
| E.1.1.1 | Medical condition in easily understood language |
| A cancer of B-cells, a type of white blood cell responsible for producing antibodies |
|
| 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of the study is to explore the clinical activity of durvalumab (MEDI4736) in combination with R-CHOP (non-activated B-cell) or R2-CHOP (activated B-cell) followed by durvalumab consolidation therapy in previously untreated subjects diagnosed with high-risk DLBCL. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are:
- To evaluate the safety and tolerability of durvalumab when given in combination with R-CHOP or R2-CHOP followed by durvalumab consolidation therapy.
- To identify and develop biomarkers of the tumor microenvironment and of the host immune system which are predictive of clinical response to durvalumab, when administered in combination with R-CHOP or R2-CHOP, followed by durvalumab consolidation therapy that will be tested in further randomized clinical studies.
Examples of defined analytical methods that may be investigated include, but are not limited to:
- PD-L1 immunohistochemistry
- Gene Expression Signatures |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject is at least 18years of age at the time of signing the ICF
2. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted
3. Subject is willing and able to adhere to the study visit schedule and other protocol requirements
4. Subject has documented histologically confirmed CD20+ DLBCL of the WHO sub-classifications defined in the protocol
5. Subject has high-risk disease defined as:
a. Ann Arbor stage 3-4 or Ann Arbor stage 2 with bulky disease (tumor diameter ≥7.0cm)
b. Intermediate-high or high disease risk (IPI ≥3 or NCCN-IPI ≥4)
6. Subject has bi-dimensionally measurable disease on cross-sectional imaging by CT with at least one (post-biopsy) nodal or extranodal lesion ≥2.0cm in its longest dimension
7. Subject has not received prior anti-lymphoma treatment. However, for subjects with bulky disease, systemic symptoms, compressive disease, or rapidly progressing adenopathies, pre-phase treatment with up to 100mg/day prednisone, or equivalent, for a maximum of 7days is permitted prior to beginning the Treatment Period, at the discretion of the Investigator. A washout period does not apply.
8. Subject is willing and able to undergo tumor/lymph node biopsy during the Screening Period, during treatment when clinically feasible, and at the time of disease progression from subjects who have achieved objective response to study treatment
9. Subject is considered an appropriate candidate for induction therapy with 6-8 cycles of R-CHOP immuno-chemotherapy
10. Subject has a performance status of 0-2 according to the ECOG scale
11. Subject must fulfill the laboratory requirements as defined in the protocol.
12. Females of childbearing potential (FCBP) must:
a. Have 2 negative pregnancy tests as verified by the Investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the subject practices true abstinence from heterosexual contact.
b. Either commit to true abstinence from heterosexual contact or agree to use, and be able to comply with, 2 effective measures of contraception without interruption. Contraception methods must include 1 highly effective and 1 additional effective method of contraception from at least 28days prior to starting IP, during the study therapy including dose interruptions, and for 1yr following the last dose of rituximab, 28days following the last dose of lenalidomide, or 90days after the last dose of durvalumab, whichever is latest. Cessation of contraception after this point should be discussed with a responsible physician.
c. Agree to abstain from breastfeeding during study participation and for at least 28days after the last dose of lenalidomide or 90days after the last dose of durvalumab or 12months after the last dose of rituximab, whichever is longer.
d. Refrain from egg cell donation while taking durvalumab and for at least 28days after the last dose of lenalidomide or 90days after the last dose of durvalumab, whichever is longer.
13. Male subjects must:
a. Practice true abstinence or agree to use a condom during sexual contact with a pregnant female or a FCBP while participating in the study, during dose interruptions and for at least 28days after the last dose of lenalidomide or 90days after the last dose of durvalumab, whichever is longer, even if he has undergone a successful vasectomy.
b. Agree to not donate semen or sperm during the IP therapy and for 28days after the last dose of lenalidomide or 90days after the last dose of durvalumab, whichever is longer.
14. All subjects must:
a. Have an understanding that lenalidomide could have a potential teratogenic risk
b. Agree to abstain from donating blood while taking lenalidomide therapy and for 28days after the last dose of lenalidomide therapy or 90days after the last dose of durvalumab, whichever is longer
c. Agree not to share lenalidomide with another person
d. Agree to be counseled about pregnancy precautions and risk of fetal exposure |
|
| E.4 | Principal exclusion criteria |
1. Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
2. Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
3. Subject has any condition that confounds the ability to interpret data from the study.
4. The following WHO subcategories of DLBCL:
a. Active central nervous system (CNS) or meningeal lymphoma
b. Primary cutaneous, leg type
c. Primary mediastinal (thymic)
d. Lymphomatoid granulomatosis
e. ALK-positive lymphoma
f. Plasmablastic lymphoma
g. Large B-cell lymphoma arising in HHV8 associated multicentric Castleman disease
h. Primary effusion lymphoma
i. Intravascular large B-cell
j. B-cell unclassifiable cases with features intermediate between DLBCL and Burkitt's lymphoma
k. Unclassifiable cases with features intermediate between DLBCL and classical Hodgkin’s lymphoma.
5. Subject has evidence of composite DLBCL and FL, or of transformed NHL.
6. Subjects with primary CNS lymphoma or secondary CNS involvement by lymphoma. Subjects will be evaluated to assess the status and risk of CNS disease.
7. Subject is seropositive for or has active viral infection with HBV:
a. HBV surface antigen (HBsAg) positive
b. HBV surface antigen (HBsAg) negative, HBV surface antibody (anti-HBs) positive and/or HBV core antibody (anti-HBc) positive, and detectable viral DNA
8. Subjects known to be seropositive for hepatitis C virus (HCV) with chronic hepatitis C, or subjects with an active hepatitis C infection requiring anti-viral medication (at time of enrollment).
9. Subjects known to be seropositive for or active viral infection with HIV.
10. Subject has undergone major surgery (excluding lymph node or bone marrow biopsy) within 28 days from signing the informed consent document, unless the subject is recovered.
11. Subject with a life expectancy < 6 months.
12. Subject has a history of other malignancies, unless the subject has been free of the disease for ≥ 5 years. Exceptions to the ≥ 5-year time limit include history of the following:
a. Localized non-melanoma skin cancer
b. Carcinoma in situ of the cervix
13. Subject has a contraindication to any drug of the R-CHOP immune-chemotherapy regimen.
14. Left ventricular ejection fraction (LVEF) < 50% as assessed by multi gated acquisition scan (MUGA) or echocardiogram (2-D ECHO), or LVEF < local institutional normal limits for R-CHOP administration as assessed by echocardiography.
15. Subject has peripheral neuropathy ≥ Grade 2.
16. Subject with prior use of lenalidomide.
17. Subject with known allergy to thalidomide.
18. Subject with known sensitivity or allergy to murine products.
19. Subject with use of any investigational agent within 28 days or five half-lives, whichever is longer, prior to first dose of study drug treatment.
20. Subjects with a high risk of developing thromboembolic events, who are unwilling to take venous thromboembolism (VTE) prophylaxis.
21. Females who are pregnant or breastfeeding.
22. Subject having received any prior mAb against CTLA-4, PD-1, or PD-L1.
23. Subject has received live, attenuated vaccine within 30 days prior to the first dose of durvalumab.
Note: Subjects, if enrolled, should not receive live vaccine during the study and for 12 months after last dose of rituximab or until recovery of B-cells and for 120 days after last dose of durvalumab, whichever is longer.
24. Subject with active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis, Crohn’s disease], diverticulitis with the exception of a prior episode that has resolved or diverticulosis, celiac disease, irritable bowel disease, or other serious gastrointestinal chronic conditions associated with diarrhea; systemic lupus erythematosus; Wegener’s syndrome [granulomatosis with polyangiitis]; myasthenia gravis; Graves’ disease; rheumatoid arthritis; hypophysitis, uveitis; etc) within the past 3 years prior to the start of treatment. The following are exceptions to this criterion:
a. Subjects with vitiligo or alopecia.
b. Subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement.
c. Subjects with psoriasis not requiring systemic treatment.
25. Subject with current or prior use of immunosuppressive medication within 28 days prior to the first dose of durvalumab. The following are exceptions to this criterion:
a. Intranasal, inhaled, topical or local steroid injections (eg, intra-articular injection);
b. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent;
c. Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication).
26. Prior organ transplantation including allogeneic stem cell transplantation. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Efficacy - PFS at 24 months |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 24 months after the first dose of any IP |
|
| E.5.2 | Secondary end point(s) |
Biomarker - Clinical response to study treatment in biomarker defined subpopulations
Safety - TEAEs |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Biomarker - Tumor samples at baseline and during study treatment if available. Peripheral blood samples collected during Screening and during study treatment.
Safety - From the first dose of any IP until 90 days after the last dose of durvalumab or 28 days after the last dose of any other IP, whichever is later |
|
| 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 | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Biomarkers, Immunogenicity |
|
| 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.8.2.4 | 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 |
| Austria |
| Denmark |
| Estonia |
| Germany |
| Poland |
| Portugal |
| Slovakia |
| United Kingdom |
| United States |
|
| 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
|
| The End of Study is defined as either the date of the last visit of the last subject to complete the post treatment follow-up, or the date of receipt of the last data point from the last subject that is required for primary, secondary and/or exploratory analysis, as pre-specified in the protocol, whichever is the later date. |
|
| 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 | 8 |
| E.8.9.1 | In the Member State concerned days | 23 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| 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 | 13 |
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