Improvement of Outcome in Elderly Patients or Patients not eligible for high-dose chemotherapy with Aggressive Non-Hodgkin Lymphoma in first Relapse or Progression by adding Nivolumab to a standard chemotherapy.

Phase 1

• Conditions: Patients with first relapse or progression of aggressive Non-Hodgkin’s Lymphoma who are not eligible neither for autologous nor allogeneic stem cell transplantation; MedDRA version: 22.0Level: PTClassification code 10029547Term: Non-Hodgkin's lymphomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

• Registration Number: EUCTR2016-002272-27-AT
• Lead Sponsor: Saarland University

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2019-06-03
• Last Update Posted: 2 August 2021

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 388

Inclusion Criteria

1. Age: all patient >65 years of age or > 18 years if not eligible for neither
autologous nor allogeneic stem cell transplantation
2. Ineligibility for neither autologous nor allogeneic stem cell transplantation as defined as:
>65 years of age or
older than 18 years if HCT-CI score > 2 (cf. Appendix 24.2) or
patients who underwent prior autologous stem cell transplantation and
are not eligible for allogeneic stem cell transplantation
3. Risk group: All risk groups (IPI 0 to 5)
4. Histology: Diagnosis of aggressive Non-Hodgkin’s lymphoma, based on an
excisional biopsy of a lymph node or on an appropriate sample of a
lymph node or of an extranodal involvement at initial diagnosis or
relapse or progression.The entities treated in the study will be based
on the WHO 2017 classification62.
B-NHL:
? Follicular lymphoma grade IIIb
? DLBCL, not otherwise specified (NOS)
? T-cell/histiocyte-rich large B-cell lymphoma
? primary cutaneous DLBCL, leg type
? EBV-positive DLBCL, NOS
? DLBCL associated with chronic inflammation
? primary mediastinal (thymic) large B-cell lymphoma
? intravascular large B-cell lymphoma
? ALK-positive large B-cell lymphoma
? plasmablastic lymphoma
? primary effusion lymphoma
? HHV8+ DLBCL, NOS
? high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements
? high-grade B-cell lymphoma, NOS
? B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and
classical Hodgkin lymphoma
T-NHL:
? Aggressive NK cell leukemia
? Enteropathy-associated T-cell lymphoma
? Hepatosplenic T-cell lymphoma
? Primary cutaneous gamma-delta T-cell lymphoma
? Peripheral T-cell lymphoma, NOS
? Angioimmunoblastic T-cell lymphoma
? Anaplastic large cell lymphoma, ALK-positive
? Anaplastic large cell lymphoma, ALK-negative
? Peripheral T-cell lymphoma with TFH phenotype
? Monomorphic epitheliotropic intestinal T-cell lymphoma
? Subcutaneous panniculitis-like T-cell lymphoma
5. Performance status: Performance status ECOG 0 – 2. Also patients with performance
status 0 – 2 are eligible when assessed after prephase treatment.
The performance status of each patient should be assessed before
the initiation and after the end of prephase treatment which, as
experience has shown, can result in its significant improvement. A
definition of the performance status is provided in Appendix 24.3.
6. Previous therapy: Patients must have only one prior chemotherapy regimen including an
anthracycline. The last cytotoxic drug must be given at least four
weeks prior randomization. Rituximab must be part of the first-line
regimen in case of B-cell lymphoma (except for primary CD20-
negative lymphoma). Patients may have received prior radiation
therapy as part of their first-line therapy.
7.Men who are sexually active with women of childbearing potential (WOCBP) must use any
contraceptive method with a failure rate of less than 1% per year.
Men who are sexually active with women of childbearing potential
(WOCBP) must not father a child during and up to 6 months after
GemOx and up to 12 months after Rituximab and/or Nivolumab. They
are advised to do cryoconservation of sperm prior to treatment.
Women who are not of childbearing potential ie, who are
postmenopausal or surgically sterile as well as azoospermic men do
not require contraception. A WOCBP is defined as any female who
has experienced menarche and who has not undergone surgical
sterilization (hysterectomy or bilateral oophorectomy) or who is not
postmenopausal. Menopause is defined clin

Exclusion Criteria

1. Already initiated lymphoma therapy after first relapse or progression (except for the
prephase treatment, cf. 8.6.1).
2. Serious accompanying disorder or impaired organ function (except when due to lymphoma
involvement), in particular:
? heart: angina pectoris CCS >2, cardiac failure e.g. NYHA >2
? liver: total bilirubin >1.5 times the upper reference limit (except
subjects with Gilbert Syndrome, who can have total bilirubin
<51 µmol/l), aspartate transaminase (AST) or alanine
transaminase (ALT) >3 x institutional upper reference limit
? kidney: creatinine clearance < 30 ml/min
3. WBC < 2.5 G/l, Neutrophils <2 G/l, Platelets <100G/l (does not apply if cytopenia is caused
by lymphoma)
4. Prolongation of QTc interval > 450 ms, demonstrated in one electrocardiogram (done as
triplicate). This does not apply for patients with a block of the right and/or left bundle branch.
5. Family history for Long QT-syndrome
6. Patients with an active, known or suspected autoimmune disease. Subjects are permitted
to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to
autoimmune condition only requiring hormone replacement, psoriasis not requiring
systemic treatment, or conditions not expected to recur in the absence of an external
trigger
7. There must also be no requirement for immunosuppressive doses of systemic
corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study
drug administration (except for treatment of lymphoma).
8. Chronic active hepatitis B or C as defined either HBs Ag positive or HBc Ac positive with
detectable viral DNA or hepatitis C virus ribonucleic acid positive.
9. HIV-infection
10. Patients with a severe immunodeficiency
11. Previous therapy with Nivolumab, Gemcitabine or Oxaliplatin.
12. Patients with a currently active” second malignancy other than non-melanoma skin cancer.
Patients are not considered to have a currently active” malignancy if they have completed
therapy since 6 months and are considered by their physician to be less than 30% risk of
relapse within one year.
13. CNS involvement of lymphoma (intracerebral, meningeal, intraspinal intradural) or primary
CNS lymphoma
14. Persistent neuropathy grade >2 (NCI CTC-AE v4.03) (unless due to lymphoma
involvement)
15. Pregnancy or breast-feeding women
16. Women of childbearing potential (WOCBP). A WOCBP is defined as any female who has
experienced menarche and who has not undergone surgical sterilization (hysterectomy or
bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as
12 months of amenorrhea in a woman over 45 in the absence of other biological or
physiological causes. In addition, women under the age of 62 must have a documented
serum follicle stimulating hormone (FSH) level higher than 40 mIU/mL.
17. Active serious infections not controlled by oral and/or intravenous antibiotics or antifungal
medication
18. Any medical condition which in the opinion of the investigator places the subject at an
unacceptably high risk for toxicities
19. Lymphomas other than those listed in the inclusion criteria notably indolent lymphoma,
Mantle cell lymphoma, Burkitt lymphoma, adult T-cell leukemia/lymphoma.
20. Persons not able to understand the impact, nature, risks and consequences of the trial
(including language barrier)
21. Persons not agreeing to the transmission of their pseudonymous data
22. Persons depending on sponsor or investigator
23. Persons from highly protected gr

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Secondary Objective: - To determine whether survival can be increased by adding nivolumab to standard (R)-GemOx.<br>- To determine whether outcome can be improved by adding nivolumab to standard (R)-GemOx.<br>- To determine toxicity and protocol adherence of standard (R)-GemOx with or without nivolumab.<br>- To evaluate quality of life of patients with relapsed or refractory aggressive Non-Hodgkin’s Lymphoma treated with (R)-GemOx with or without Nivolumab.<br>- To analyze outcome according to biological parameters.<br>;Main Objective: Improvement of 1-yr PFS by nivolumab plus (R)-GemOx followed by nivolumab consolidation instead of (R)-GemOx alone in patients with progressed or relapsed aggressive NHLs not eligible neither for autologous nor allogeneic stem cell transplantation;Primary end point(s): Progression-free survival;Timepoint(s) of evaluation of this end point: 1 year<br>(data collected during the restagings and the follow-up assessments as planned in the protocol (cf. chapter 8.9 in the protocol))