Non-Hodgkin Lymphom

NHL 15B
NIVEAU

NHL 15B

Phase II single-arm „window-of-opportunity“ study of a combination of obinutuzumab (GA-101) and venetoclax (ABT-199) in relapsed or refractory diffuse large B-cell lymphoma (DLBCL)

Synopsis

Short title: AGMT_NHL-15B

Title: Phase II single-arm „window-of-opportunity“ study of a combination of obinutuzumab (GA-101) and venetoclax (ABT-199) in relapsed or refractory diffuse large B-cell lymphoma (DLBCL)

Status: open

Start: January 2017

Coordinating Investigator: Univ. Prof. Dr. Ulrich Jäger

EudraCT Number: 2016-001760-10

ClinicalTrialsID: NCT02987400

Number of patients: 21

Sponsor: AGMT gemeinnützige GmbH

Design

Obinutuzumab is given i.v. at a dose of 1000 mg on days 1, 8, 15 in cycle 1 and on day 1 of each following cycle. Venetoclax is given at 800mg daily p.o. One cycle is 21 days. This combination treatment is repeated for up to 3 cycles. Eligible patients will then proceed to stem cell transplantation (in some patients stem cells were already harvested successfully).

A 9 cycles (27 weeks) maintenance phase with obinutuzumab and venetoclax will be given in patients ineligible for transplant.

The study had a 6 patient run-in phase to determine safety and to adjust treatment. A futility analysis is conducted when the first 10 patients have been evaluated for response: If at least two patients had an objective response (CR or PR) the study will be continued.

Primary objective:
  • To evaluate clinical activity and tolerability of obinutuzumab in combination with venetoclax in patients with relapsed/refractory DLBCL
Secondary objectives:
  • Safety: Incidence of dose-limiting toxicities of the combination treatment.
  • Response duration (from first documented response)
  • Progression-free survival
  • Overall survival
  • Ability to proceed to further stem cell transplantation (assessed by number of eligible
  • patients reaching transplant)
  • Identification of genetically/biomarker defined subgroups regarding response and survival

Inclusion/Exclusion criteria

Inclusion criteria (selected):
  • Patients ≥ 18 years of age
  • Diffuse large B-cell lymphoma (DLBCL)
    • with histologically confirmed relapse within 12 months after having achieved a PR or CR with initial R-anthracycline containing therapy, or
    • with refractoriness to initial R-anthracycline containing therapy (not achieving at least a partial response)
  • At least one bi-dimensionally measurable lesion on CT scan defined as > 1.5 cm in its longest dimension
  • ECOG Performance Status of 0, 1, or 2
  • Adequate organ function
Exclusion criteria (selected):
  • DLBCL transformed from other malignancies or CD20 negative DLBCL
  • Radiation, chemotherapy, or immunotherapy or any other anti-cancer therapy ≤ 4 weeks prior to Cycle 1 Day 1
  • Ongoing corticosteroid use > 30 mg/day of prednisone or equivalent
  • Acute or uncontrolled chronic infections
  • Presence of positive test results for Hepatitis B, Hepatitis C and CMV
  • Any sensory or motor peripheral neuropathy greater than or equal to Grade 2

DSHNHL_NIVEAU

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

Synopsis

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: open

Start: September 2019 (in Austria)

Coordinating Investigator: Univ. Prof. Dr. Ulrich Jäger

EudraCT Number: 2016-002272-27

ClinicalTrialsID: NCT03366272

Number of patients: 388 (international)

Sponsor: University Hospital, Saarland; AGMT Sponsor representative in Austria

Design

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.

Primary objective:
  • 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/Exclusion criteria

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

Studien