A study to assess the safety and clinical activity of durvalumab as combination therapy on previously untreated people with high risk diffuse large b-cell lymphoma

• Register: EUCTR
• Last refreshed on: 8 August 2022
• Main ID: EUCTR2015-005173-20-AT
• Date of registration: 11/10/2016
• Prospective Registration: Yes
• Primary sponsor: Celgene International II Sàrl
• Public title: A study to assess the safety and clinical activity of durvalumab as combination therapy on previously untreated people with high risk diffuse large b-cell lymphoma
• Scientific title: A Phase 2, Open-label, Multicenter Study to Evaluate the Safety and Clinical Activity of Durvalumab in Combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (R-CHOP) or with Lenalidomide plus R-CHOP (R2-CHOP) in Subjects With Previously Untreated, High-Risk Diffuse Large B-Cell Lymphoma
• Date of first enrolment: 21/12/2016
• Target sample size: 45
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-005173-20
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Austria, Denmark, Estonia, Poland, Slovakia, United Kingdom, United States

Contacts

• Name: ClinicalTrialDisclosure
• Affiliation: Celgene Corporation

• Name: ClinicalTrialDisclosure
• Affiliation: Celgene Corporation

Key inclusion & exclusion criteria

Inclusion criteria:
1. Subject is at least 18 years 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 =7.0 cm)
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 = 2.0 cm 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 100 mg/day prednisone, or equivalent, for a maximum of 7 days 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 clinical 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 two 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 28 days prior to starting IP, during the study therapy including dose interruptions, and for 1 year following the last dose of rituximab, 28 days following the last dose of lenalidomide, or 90 days 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 90 days 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 female of childbearing potential while participating in the study, during dose interruptions and for at least 28days after the last dose of lenalidomide or 90 days after the last dose of durvalumab, whichever is longer, even if he has undergone a successful va
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 the last dose of durval

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Cancer [C04]

Previously untreated, high-risk diffuse-large B-cell lymphoma (DLBCL)
MedDRA version: 21.0 Level: PT Classification code 10012818 Term: Diffuse large B-cell lymphoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Intervention(s)

Product Name: Durvalumab
Product Code: MEDI4736
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: DURVALUMAB
Current Sponsor code: MEDI4736
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 50-

Trade Name: Revlimid 2.5 mg hard capsules
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: LENALIDOMIDE
CAS Number: 191732-72-6
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 2.5-

Trade Name: Revlimid 5 mg hard capsules
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: LENALIDOMIDE
CAS Number: 191732-72-6
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-

Trade Name: Revlimid 10 mg hard capsules
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: LENALIDOMIDE
CAS Number: 191732-72-6
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-

Trade Name: Revlimid 15 mg hard capsules
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: LENALIDOMIDE
CAS Number: 191732-72-6
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 15-

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: 6 to 8 cycles (4 to 6 months) after the first dose of any investigational product.

Main Objective: The primary objective of the study is to explore the clinical activity of
durvalumab (MEDI4736) in combination with R-CHOP (non-activated Bcell) or R2-CHOP (activated B-cell) followed by durvalumab consolidation therapy in previously untreated subjects diagnosed with high-risk DLBCL.

NOTE: Enrollment into Arm B (durvalumab in combination with
lenalidomide plus rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone [R2-CHOP]) has been discontinued.

NOTE: Subjects enrolled and treated in Arm B prior to the US FDA Partial Clinical Hold who are receiving clinical benefit, based on the discretion of the investigator, may continue study treatment after being reconsented. Any newly enrolled subject after the US FDA Partial Clinical Hold will continue induction therapy on Arm A (durvalumab + R-CHOP) after Cycle 1 regardless of DLBCL COO subtype.

Primary end point(s): Efficacy - Complete response rate (CRR) at the end of induction therapy.

Secondary Objective: 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

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Efficacy - 6 to 8 cycles of induction therapy and at least 1 cycle of consolidation therapy (4 to 6 months) after the first dose of any investigational product.
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

Note: After the last durvalumab subject's 90-day safety follow-up (data cutoff date 06-Jun-2019), the Follow-up Period will be discontinued. Subjects who received lenalidomide will continue to be followed for second primary malignancies as required by the study protocol and regulatory obligations.

Secondary end point(s): Efficacy - Rate of subjects who continue consolidation therapy
Biomarker - Clinical response to study treatment in biomarker defined subpopulations
Safety - TEAEs

Secondary ID(s)

MEDI4736-DLBCL-001

Source(s) of Monetary Support

Celgene International II Sàrl

Ethics review

Status: Approved
Approval date: 09/11/2016
Contact: