Clinical trial NCT03492775: First Line Therapy of Advanced Stage Follicular Lymphoma in Patients < 60 Years Not Eligible fo Standard Immunochemotherapy and in All Patients ≥ 60 Years
Official title: Prospective Randomized Evaluation of Single Agent GA101 Versus GA101 Plus Bendamustine Followed by GA101
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Indolent Non-hodgkin Lymphoma
Keywords: indolent lymphoma
Obinutuzumab
GA101
Bendamustine
medically non-fit patients
Lead sponsor: Ludwig-Maximilians - University of Munich
Sponsor class: OTHER
Collaborators: name: Hoffmann-La Roche
name: Mundipharma Research GmbH & Co KG
First posted: 2018-04-10
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The objective of this study is to test the efficacy and toxicity of a combined OBINUTUZUMAB/bendamustine therapy or single agent OBINUTUZUMAB in younger (\< 60 years) medically non-fit, 'compromised' patients and in all older patients (≥ 60 years). For the assessment of the antilymphoma activity the overall response rate (ORR)" will be applied as primary endpoint.

Overall response is defined as complete or partial response after 19 - 21 weeks.

Detailed description: Study design:

This is a randomized, open-label, multicenter phase II trial with a parallel-group design of two groups.

Randomization and Interventions:

Randomization between Obinutuzumab single agent treatment versus Obinutuzumab plus Bendamustine followed by Obinutuzumab

Treatment plans:

Arm A: Obinutuzumab single agent Obinutuzumab flat dose of 1000 mg on Day 1 of each of four 28 -day cycles and on Days 8 and 15 of Cycle 1

If at least 'stable disease':

Obinutuzumab flat dose of 1000 mg at weeks 21, 29, 37 and 45 Arm B: Obinutuzumab plus Bendamustine Obinutuzumab flat dose of 1000 mg on Day 1 of each of four 28 -day cycles and on Days 8 and 15 of Cycle 1 plus Bendamustine 70 mg/m2 iv d1+2 of each of four 28 -day cycles

If at least 'stable disease':

Obinutuzumab flat dose of 1000 mg at weeks 21, 29, 37 and 45

The project attempts to establish an evidence based treatment strategy for medically non-fit advanced stage FL-patients who are not eligible for standard therapeutic immunochemotherapy approaches to improve their long term perspectives.

It will furthermore provide a prospectively generated data set which will link performance in the assessment scores IADL, G8 and CIRS-G to medical fitness as judged by the treating physician. The generated data will allow using geriatric and functional tests to define medical fitness and to provide a more solid basis for future studies.

Eligibility criteria: Inclusion Criteria:

* Medically nonfit" patients \< 60 years defined by

  o ECOG \> 2 or ECOG 0-2 with co-morbidities excluding intensive therapy according to local investigator's discretion
* All patients ≥ 60 years in case of decision of investigator and patient to apply a reduced Treatment
* Documentation of the CIRS-G, IADL, G8 and ECOG Scores before start of treatment
* Histologically confirmed follicular lymphoma grade I, II or IIIa with material available for central pathology review
* Stage III/IV or stage II without the option of curative radiotherapy
* Age \> 18 years
* No prior therapy
* Presence of at least one of the following symptoms or conditions requiring initiation of treatment:

  * Bulky disease according to the GELF criteria: nodal or extranodal mass \> 7cm in its greater diameter
  * B symptoms (fever, drenching night sweats, or unintentional weight loss of \>10% of normal body weight over a period of 6 months or less)
  * Hematopoietic insufficiency (at least one of the following: granulocytopenia \<1500 cells/μl, Hb \< 10 g/dl, thrombocytopenia \<100.000 cells/μl)
  * Compressive syndrome
  * Pleural/peritoneal effusion
  * Symptomatic nodal or extranodal manifestations
* At least one bi-dimensionally measurable lesion (\> 1.5 cm in its largest dimension by CT scan or MRI)
* Adequate hematologic function (unless abnormalities are related to NHL), defined as follows:

  * hemoglobin ≥ 9.0 g/dl
  * absolute neutrophil count ≥ 1500 /μL
  * platelet count ≥ 75000 /μl
* Women who are not breast feeding, are using effective contraception, are not pregnant and agree not to become pregnant during participation in the trial and during the 18 months thereafter.
* Men who agree not to father a child during participation in the trial and during the 18 months thereafter.
* Written informed consent form

Exclusion Criteria:

"Medically fit" patients \< 60 years with the option for more intensive induction therapy such as R-CHOP

* Transformation to high-grade lymphoma (secondary to "low-grade" follicular lymphoma)
* Grade IIIb follicular lymphoma
* Presence or history of CNS disease (either CNS lymphoma or lymphomatous meningitis).
* Regular use of corticosteroids during the last 4 weeks, unless administered at a dose equivalent to \< 20 mg/day prednisone.
* Prior (\< 3 years) or concomitant malignancies except non-melanoma skin cancer or adequately treated in situ cervical cancer.
* Major surgery (excluding lymph node biopsy) within 28 days prior to registration.
* Necessity of rapid cytoreduction
* Serious underlying medical conditions, which could impair the ability of the patient to tolerate the therapy offered in this trial (e.g. ongoing infection, uncontrolled diabetes mellitus, gastric ulcers, active autoimmune disease).
* Severe hepatic impairment (serum bilirubin \> 3.0 mg/dl)
* Known sensitivity or allergy to murine products
* Known hypersensitivity to any of the study drugs
* Treatment within a clinical lymphoma trial within 30 days prior to trial entry
* Positive test results for chronic HBV infection (defined as positive HBsAg serology) (mandatory testing) Patients with occult or prior HBV infection (defined as negative HBsAg and positive total HBcAb) may be included if HBV DNA is undetectable, provided that they are willing to undergo monthly DNA testing. Patients who have protective titers of hepatitis B surface antibody (HBSAb) after vaccination or prior but cured hepatitis B are eligible.
* Positive test results for hepatitis C (mandatory hepatitis C virus \[HCV\] antibody serology testing). Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA
* Known history of HIV seropositive status.
* Patients with a history of confirmed PML
* Vaccination with a live vaccine within 28 days prior to registration
* Prior organ, bone marrow or peripheral blood stem cell transplantation
* Any other co-existing medical or psychological condition that will preclude participation in the study or compromise the ability to understand its nature,meaning and implications

Primary outcomes:
measure: ORR
timeFrame: week 19 to 21
Secondary outcomes:
measure: Event free survival, EFS
timeFrame: through study completion, up to 5 years
measure: CR
timeFrame: End of Induction of each patient, week 19 - 21
measure: TTF
timeFrame: Through study completion, up to 5 years
measure: PFS
timeFrame: Through study completion, up to 5 years
measure: RD
timeFrame: week 19 up to 5,5 years follow up
measure: Time to next anti-lymphoma treatment
timeFrame: Through study completion, up to 6.5 years
measure: Overall Survival
timeFrame: Through study completion, up to 5 years
measure: Number of SAEs
timeFrame: Through study completion, up to 5 years
measure: Frequency of Hospitalization
timeFrame: Through study completion, up to 3 years (per patient)
measure: Duration of Hospitalization
timeFrame: Through study completion, up to 3 years (per patient)
measure: Supportive Care
timeFrame: Through study completion, up to 5 years
measure: Incidence of secondary transformation to aggressive lymphoma
timeFrame: Through study completion, up to 5 years
measure: Number of AEs
timeFrame: Through study completion, up to 5 years
measure: Number of participants that had completed the therapy regularly (including: Total cumulative dose of obinutuzumab and bendamustine, number of cycles, duration of treatment)
timeFrame: Through study completion, up to 5 years
measure: QoL
timeFrame: Through study completion, up to 5 years
measure: Comorbidity assessment will be performed by using the Instrumental Activities of Daily Living (=IADL)
timeFrame: Through study completion, up to 6.5 years
measure: Comorbidity assessment will be performed by using the Cumulative Illness Rating Scale for Geriatrics (CIRS-G)
timeFrame: Through study completion, up to 5 years
measure: Comorbidity assessment will be performed by using the G 8 (=geriatric) 8 screening score
timeFrame: Through study completion, up to 5 years
Other outcomes:
Locations:
city: München
country: Germany
facility: Klinikum der Universität München
state: Bavaria
Study officials:
affiliation: Hospital of the University of Munich
name: Wolfgang Hiddemann, Prof.Dr.
role: STUDY_CHAIR
References: