Improvement of Outcome in Elderly Patients or Patients Not Eligible for High-dose Chemotherapy With Aggressive NHL in First Relapse/Progression by Adding Nivolumab to Gemcitabine, Oxaliplatin Plus Rituximab in Case of B-cell Lymphoma
Short title: DSHNHL 2015-1_NIVEAU
Title: Improvement of Outcome in Elderly Patients or Patients Not Eligible for High-dose Chemotherapy With Aggressive NHL in First Relapse/Progression by Adding Nivolumab to Gemcitabine, Oxaliplatin Plus Rituximab in Case of B-cell Lymphoma
Status: active, not recruiting
Start: September 2019 (in Austria)
Coordinating Investigator: Univ. Prof. Dr. Ulrich Jäger
EudraCT Number: 2016-002272-27
Number of patients: 388 (international)
Sponsor: University Hospital, Saarland; AGMT Sponsor representative in Austria
This trial is designed as an international, multicentre, randomised, open-label, treatment optimisation study, preceded by safety run-in phases conducted for B-cell and T-cell lymphoma separately.
Aim of the phase-III trial is to test whether prognosis of patients with relapsed or refractory aggressive Non-Hodgkin Lymphoma not eligible for neither autologous nor allogeneic stem cell transplantation can be improved by combining nivolumab with (R)-GemOx.
All patients with first relapse or progression of an aggressive Non-Hodgkin’s lymphoma aged older than 65 years or older than 18 years with HCT-CI score > 2 are eligible for this study irrespective of their gender or stage of disease. There is no upper limit of age. Also patients not eligible neither autologous nor allogeneic stem cell transplantation are eligible for this study.
The duration of therapy according to study protocol ranges between 16 and 52 weeks. Patients randomised to receive eight 2-week cycles of (R)-GemOx are 16 weeks on therapy. Patients randomised to receive eight 2-week cycles nivolumab plus (R)-GemOx followed by 18 2-week applications of nivolumab are 52 weeks on treatment.
Follow-up observation within the study will end for all patients presumably in Q4/2024, which is 2 years after inclusion of the last patient. Thus duration within the clinical study will last at least 2 years for the individual patient.
- 1-year Progression free survival (PFS)
Secondary objectives (selected):
- Complete response rate after eight cycles of (R)-GemOx
- Partial response rate after eight cycles of (R)-GemOx
- Overall response rate after eight cycles of (R)-GemOx
- Duration of response
- Progression rate, relapse rate
- EFS, OS, Toxicity
Inclusion criteria (selected):
- Histologically proven aggressive Non-Hodgkin’s lymphoma
- Ineligibility for neither autologous nor allogeneic stem cell transplantation
- Patients must have only one prior chemotherapy regimen including an anthracycline
- All patient >65 years of age or older than 18 years if HCT-CI score > 2
- All risk groups (IPI 0 to 5)
- Performance status ECOG 0 – 2
Exclusion criteria (selected):
- Already initiated lymphoma therapy after rst relapse or progression
- Serious accompanying disorder or impaired organ function
- Previous therapy with Gemcitabine or Oxaliplatin
- Patients with an active, known or suspected autoimmune disease
- Prior chemo- or radiotherapy, long-term use of corticosteroids or anti-neoplastic drugs for previous disorder (except for rst-line therapy of lymphoma)
- CNS involvement of lymphoma or primary CNS lymphoma
An open-label, prospective Phase III clinical study to compare polatuzumab vedotin plus rituximab, ifosfamide, carboplatin and etoposide (Pola-R-ICE) with rituximab, ifosfamide, carboplatin and etoposide (R-ICE) alone as salvage therapy in patients with primary refractory or relapsed diffuse large B-cell lymphoma (DLBCL)
Short title: Pola-R-ICE
Title: An open-label, prospective Phase III clinical study to compare polatuzumab vedotin plus rituximab, ifosfamide, carboplatin and etoposide (Pola-R-ICE) with rituximab, ifosfamide, carboplatin and etoposide (R-ICE) alone as salvage therapy in patients with primary refractory or relapsed diffuse large B-cell lymphoma (DLBCL)
Start: November 2021 (in Austria)
Coordinating Investigator: Univ.-Prof. Dr. Richard Greil (in Austria)
EudraCT Number: 2019-002962-10
Number of patients: 334 (international)
Sponsor: GWT-TUD GmbH; AGMT Sponsor representative in Austria
The study is designed as an international, multicenter, open-label, two-arm, prospective phase III study to compare the treatment of polatuzumab vedotin plus rituximab, ifosfamide, carboplatin and etoposide (Pola-R-ICE) with the combination of rituximab, ifosfamide, carboplatin and etoposide (R-ICE) alone as salvage therapy in patients with primary refractory or relapsed DLBCL.
The study will involve study sites in Germany, UK, Spain, and Austria. It is planned to include 324 patients who will be randomized 1:1 to receive either treatment in the experimental arm (Pola-R-ICE) or in the standard arm (R-ICE) to end up with 308 evaluable subjects for the randomized part of the trial. Further 10 patients will be treated with Pola-R-ICE during the safety run-in phase.
The study consists of a screening/inclusion visit, three chemotherapy cycles, an end-of – treatment visit (EoT), and follow-up visits. For each subject, the total duration of the study will be approximately 3 months of treatment plus at least 21 months follow-up. The study will end when the last included patient will have passed the last follow-up visit (LPLFU). For the study as a whole, the primary outcome will be evaluated when the last included patient will have completed the 21 months follow-up period or has left the study prematurely.
For the study as a whole, the primary outcome will be evaluated when the last included patient will have completed the 21 months follow-up period or has left the study prematurely.
The primary objective of this study is to investigate the following question in patients with relapsed or primary refractory DLBCL: Does salvage therapy with Pola-R-ICE improve event-free survival (EFS) compared to R-ICE alone?
Secondary objectives (selected):
Secondary efficacy objectives of the study are to collect data in order to evaluate whether the addition of polatuzumab vedotin to standard therapy R-ICE
- enhances the rate of metabolic complete response (CR) at the end of study treatment;
- enhances the partial response (PR) rate and overall response rate (ORR) and decreases the progression rate and relapse rate;
- enhances the duration of response, progression-free survival (PFS) and overall survival (OS);
- impacts the mobilization of autologous CD34+ stem cells;
- enhances the rate of patients proceeding to transplantation;
- impacts the non-relapse mortality.
- The informed consent form must be signed before any study specific tests or procedures are done
- Adult male and female patients ≥18 years at the time of inclusion in the study
- Ability to understand and follow study-related instructions
- Risk group: All patients with one of the following histologically defined entities: Histological diagnosis of primary refractory or relapsed aggressive B-cell non-Hodgkin lymphoma (B-NHL), confirmed by a biopsy of involved nodal or extranodal site. Patients with any of the following histologies can be included:
- DLBCL not otherwise specified (NOS)
- T-cell/histiocyte-rich large B-cell lymphoma
- Primary cutaneous DLBCL, leg type
- Epstein-Barr virus (EBV)-positive DLBCL, NOS
- DLBCL associated with chronic inflammation
- Primary mediastinal (thymic) large B-cell lymphoma
- High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements
- High-grade B-cell lymphoma, NOS
Refractory disease is defined as no complete remission to first line therapy; subjects who are intolerant to first line therapy are excluded. Three groups of patients are eligible:
- Progressive disease (PD) as best response to first line therapy (biopsy not mandatory if diagnostic sample available).
- Stable disease (SD) as best response after at least 4 cycles of first line therapy (e.g., 4 cycles of R-CHOP) (biopsy not mandatory if diagnostic sample available).
- Partial response (PR) as best response after at least 6 cycles, and biopsy-proven residual disease or disease Progression after the partial response.
Relapsed disease is defined as complete remission to first line therapy followed by biopsy proven disease relapse.
- Performance Status ECOG 0-2 at time of randomization or ECOG 3 at screening if this is DLBCL-related and has improved to ECOG 2 or less with a 7-day steroid treatment during the screening Phase (e.g. 1 mg/kg prednisone).
- Information on all 5 International Prognostic Index (IPI) factors
- Staging (PET-CT based-staging according to Lugano criteria 2014). Patients must have PET-positive lesions.
- Subjects must have received adequate first line therapy including at a minimum: i) anti-CD20 monoclonal antibody unless Investigator determines that tumor is CD20 negative, and ii) an anthracycline containing chemotherapy Regimen
- Intent to proceed to high-dose therapy (HDT) and stem cell transplantation (SCT) if response to second line therapy
- Adequate hematological function, as defined by: hemoglobin ≥ 8 g/dL, absolute neutrophil count (ANC) ≥ 1.0 x 109/L OR ≥ 0.5 x 109/L if neutropenia is attributable to underlying disease and before the administration of steroids, and platelet count ≥ 75 x 109/L OR ≥ 50 x 109/L if thrombocytopenia is attributable to Underlying disease
- Women of childbearing potential must have a negative pregnancy test result within 7 days prior to the first study drug Administration
- For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating eggs
- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm
- Serious accompanying disorder leading to impaired organ function causing significant clinical problems and reduced life expectancy of less than 3 months. In particular, patients with the following organ dysfunction caused by accompanying disorders are to be excluded:
- Heart failure with left ventricular ejection fraction (LVEF) < 45%
- Impaired pulmonary function with vital capacity (VC) or forced expiratory volume (FEV1) < 50% of normal (only in case of history of significant pulmonary disease)
- Impaired renal function with glomerular filtration rate (GFR) < 50 mL/min (calculated)
- Impaired liver function with alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT) or Bilirubin > 1.5 x upper limit of normal (ULN). If elevation is caused by the disease, threshold of 2.5 x ULN is accepted
- Peripheral neuropathy > Grade II (2) Human immunodeficiency virus (HIV)-positivity with detectable viral load and/or a CD4+ count below 0.3/nL
- Hepatitis B and C as defined by seropositivity (HBsAG and anti HBe/ anti HBc; anti-Hc); in case of false positive serology (transfused antibodies) negative PCR-results will allow patient inclusion. Patients with occult or prior HBV infection (defined as negative HBsAg and positive hepatitis B core antibody [HBcAb]) may be included if HBV DNA is undetectable, provided that they are willing to undergo DNA testing on Day 1 of every cycle and monthly for at least 12 months after the last cycle of study Treatment
- Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study inclusion or any unresolved major episode of infection (as evaluated by the investigator) within 1 week prior to Cycle 1 Day 1
- Patients with suspected or latent tuberculosis. Latent tuberculosis needs to be confirmed by positive interferon-gamma release Assay
- Primary or secondary central nervous system (CNS) lymphoma at the time of recruitment
- Richter’s transformation or prior chronic lymphocytic leukemia (CLL)
- Vaccination with a live vaccine within 4 weeks prior to Treatment
- Recent major surgery (within 6 weeks before the start of Cycle 1 Day 1) other than for diagnosis
- Treatment with radiotherapy, chemotherapy, immunotherapy, immunosuppressive therapy, or any investigational agent for the purposes of treating cancer within 2 weeks prior to Cycle 1 Day1
- Received more than one line of therapy for DLBCL
- Received polatuzumab vedotin as part of the first line therapy
- Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
- Ongoing treatment or study procedures within any other Investigational Medicinal Product (IMP) clinical trial with the exception of follow-up. In case of a preceding clinical trial, last application of the respective IMP(s) must have been done more than five elimination half-lives before start of study medication in this trial.
- History of severe allergic or anaphylactic reactions to human, humanized, chimeric, or murine monoclonal antibodies
- History of hypersensitivity to any of the study drugs or their ingredients or to drugs with similar structure
- Contraindications according to the Investigator´s Brochure (IB) of polatuzumab vedotin or the local Summary of Product Characteristics (SmPCs) of the used rituximab, ifosfamide, carboplatin or etoposide products
- Criteria which in the opinion of the investigator preclude participation for scientific reasons, for reasons of compliance, or for reasons of the subject’s Safety
- Pregnancy or breastfeeding, or intending to become pregnant during the study or within 12 months after the last dose of study drug
- Close affiliation with the investigator (e.g. a close relative) or persons working at the study site
- Subject is an employee of the sponsor or involved Contract Research Organization