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Nivolumab Plus Rituximab in First-line Follicular Lymphoma gr 1-3A (1stFLOR)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03245021
Recruitment Status : Active, not recruiting
First Posted : August 10, 2017
Last Update Posted : February 1, 2023
Bristol-Myers Squibb
Information provided by (Responsible Party):
Dr. Eliza Hawkes, Austin Health

Brief Summary:
Firstline treatment for grade 13a Follicular Lymphoma using Opdivo (nivolumab) plus Rituximab: The 1st FLOR trial

Condition or disease Intervention/treatment Phase
Follicular Lymphoma Drug: Opdivo Phase 1

Detailed Description:

This study will involve participants with a condition called Follicular NonHodgkin Lymphoma (Follicular Lymphoma).

The main purpose of this study is to see if it is safe to give drug Nivolumab before and in combination with drug Rituximab and to see how effective Nivolumab is in patients who have had no previous drug treatment for their lymphoma. In particular, we will be monitoring for any specific side effects which may be increased by adding Nivolumab to Rituximab treatment, including monitoring of the immune system.

Participants will be reviewed at baseline and prior to each cycle of treatment for toxicity, scans will be performed at baseline, after 4 cycles of nivolumab, after 8 cycles of nivolumab +/rituximab and at 6 months post induction treatment phase and following completion of treatment, participants will be followed up for a total of 5 years (every 3 months for 2 years, every 6 months for 3 years). In participants with relapsed disease, these will be followed for survival every 3 months.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 39 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: First-line Treatment for Grade 1-3A Follicular Lymphoma Using Opdivo (Nivolumab) Plus Rituximab: The 1st FLOR Study
Actual Study Start Date : September 7, 2017
Actual Primary Completion Date : May 11, 2022
Estimated Study Completion Date : June 2027

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arm Intervention/treatment
Opdivo - Single-arm open label study
Drug: Opdivo

All patients will receive:

Nivolumab 240mg IV q2-weekly for four cycles

Patients in complete remission (CR):

Nivolumab 240mg IV q2-weekly for four further cycles (8 in total)

Patients with partial response (PR), stable disease (SD), asymptomatic or minor progressive disease (PD) post 4cycles receive:

Nivolumab 240mg IV plus rituximab 375mg/m2 IV q2-weekly for four cycles

Patients in CR:

Nivolumab 240mg IV q2-weekly for four further cycles (8 in total)

Patients with PR, SD, asymptomatic or minor PD post 4 cycles receive:

Nivolumab 240mg IV plus rituximab 375mg/m2 IV q2-weekly for four cycles

Other Name: Rituximab

Primary Outcome Measures :
  1. To evaluate the feasibility and safety of combination nivolumab and rituximab as determined by the proportion of toxicity grade 3 or higher per CTCAE v4.0 occurring on induction treatment (ie first 16 weeks of therapy) [ Time Frame: 1st 16 weeks of therapy ]
    As determined by rate of toxicity grade 3 or higher per CTCAE v4.0

Secondary Outcome Measures :
  1. Overall toxicity [ Time Frame: 5 years ]
    As determined by rate of toxicity grade 3 or higher per CTCAE v4.0

  2. Response rate [ Time Frame: 1st 16 weeks of therapy ]
    Response Rate to Nivolumab + Rituximab according to the Lugano classification for Response Criteria for Non-Hodgkin Lymphoma

  3. Complete response rate [ Time Frame: 6 months post completion of induction treatment ]
    Response Rate to Nivolumab + Rituximab according to the Lugano classification for Response Criteria for Non-Hodgkin Lymphoma

  4. Time to treatment failure [ Time Frame: 5 years ]
    Time to progression

  5. Progression free survival [ Time Frame: 5 years ]
    Duration of survival without relapse or non-relapse mortality

  6. Overall survival [ Time Frame: 5 years ]
    Overall toxicity as assessed by CTCAE v4.0

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Age ≥ 18 years.
  2. Histologically proven Follicular non Hodgkin lymphoma (FL) grades 1-3A according to the current World Health Organization classification.29 The B cell nature of the proliferation must be verified by the positivity with an anti-CD20 antibody.
  3. No previous chemotherapy, or other investigational drug for this indication apart from focal radiotherapy.
  4. Stage II-IV disease (Ann Arbor criteria). Stage II disease must not be encompassable in a single radiotherapy field and being considered for definitive radiotherapy.
  5. Eastern Collaborative Oncology Group (ECOG) performance status 0 to 1 unless attributable to lymphoma, in which case patients of performance status 2 are also eligible.
  6. Deemed to need treatment by treating investigator. Reasons for treatment can include, but are not limited to:

a. Any nodal or extranodal tumour mass >7cm AND/OR multiple extranodal disease sites b. Involvement of at least 3 sites each with diameter >3cm c. Symptomatic splenic enlargement d. Organ involvement/compression e. Ascites or pleural effusion f. Lactate Dehydrogenase (LDH) elevated g. Presence of systemic symptoms h. Disease progression in preceding 3 months i. Evidence of marrow infiltration with marrow compromise. (eg Hb, WBC or plt count below lower limit of institutional normal range).

g) Adequate bone marrow function including:

  1. Haemoglobin >9.0 g/dL
  2. White blood cells (WBC) ≥2000/μL
  3. Neutrophils >1.5 x 109/L
  4. Platelets >100 x 109/L at the time of study entry, unless attributed to bone marrow infiltration by lymphoma.

h) Adequate renal function with serum creatinine ≤1.5 x ULN or creatinine clearance (CrCl) ≥ 40mL/min (using Cockroft-Gault formula) Female CrCl = (140 - age in years) x weight (kg) x 0.85 72 x serum creatinine (mg/dL) Male CrCl = (140 - age in years) x weight (kg) x 1.00 72 x serum creatinine (mg/dL) i) Adequate hepatic function with AST/ALT ≤3x ULN and total bilirubin ≤1.5 x ULN (except subjects with Gilbert syndrome, who can have a total bilirubin ≤3 mg/dL or ≤51.3 μmol/L) j) Life expectancy > 3 months. k) Patients of childbearing potential willing to adhere to contraceptive precautions

  1. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study treatment
  2. Women must not be breastfeeding
  3. WOCBP must use appropriate method(s) of contraception to avoid pregnancy for 23 weeks (30 days plus five half-lives of nivolumab) post-treatment completion
  4. Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. They must agree to adhere to contraception for a period of 31 weeks after the last day of nivolumab.
  5. Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However, they must still undergo pregnancy testing as described in this section.

l) Written, informed consent.

Exclusion Criteria:

  1. Grade 3B follicular lymphoma, transformed follicular lymphoma, other indolent lymphomas.
  2. Prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
  3. Central nervous system, meningeal involvement or cord compression by lymphoma.
  4. Patients with active, known or suspected autoimmune disease. Patients with well controlled type I diabetes mellitus, coeliac disease, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, vitiligo or psoriasis not requiring systemic treatment, or other conditions not expected to recur in the absence of an external trigger are permitted to enrol.
  5. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
  6. Past history of interstitial lung disease.
  7. Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
  8. Any other serious active disease.
  9. Any positive test result for hepatitis B or hepatitis C virus during screening indicating acute or chronic infection.
  10. Any positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
  11. Any history of severe hypersensitivity reactions to other monoclonal antibodies. A history of allergy or intolerance (unacceptable AEs) to study drug components or Polysorbate-80-containing infusions
  12. Medical or psychiatric conditions that compromise the patient's ability to give informed consent.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03245021

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Australia, Victoria
Ballarat Health
Ballarat, Victoria, Australia
Eastern Health
Box Hill, Victoria, Australia, 3128
Monash Health
Clayton, Victoria, Australia
Austin Health
Heidelberg, Victoria, Australia, 3084
St Vincent's Hospital
Melbourne, Victoria, Australia
Sponsors and Collaborators
Dr. Eliza Hawkes
Bristol-Myers Squibb
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Principal Investigator: Eliza Hawkes, MD Austin Health
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Responsible Party: Dr. Eliza Hawkes, Chief Principal Investigator, Austin Health
ClinicalTrials.gov Identifier: NCT03245021    
Other Study ID Numbers: CA209-676
First Posted: August 10, 2017    Key Record Dates
Last Update Posted: February 1, 2023
Last Verified: January 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: IPD is the property of the Sponsor (Austin Health). Results from the research intends to be published/presented in relevant publications/conferences for colleague review

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Lymphoma, Follicular
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action