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

Primary Purpose

Follicular Lymphoma

Status
Active
Phase
Phase 1
Locations
Australia
Study Type
Interventional
Intervention
Opdivo
Sponsored by
Dr. Eliza Hawkes
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Follicular Lymphoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Ballarat Health
  • Eastern Health
  • Monash Health
  • Austin Health
  • St Vincent's Hospital

Arms of the Study

Arm 1

Arm Type

Other

Arm Label

Open-Label

Arm Description

Opdivo - Single-arm open label study

Outcomes

Primary Outcome Measures

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)
As determined by rate of toxicity grade 3 or higher per CTCAE v4.0

Secondary Outcome Measures

Overall toxicity
As determined by rate of toxicity grade 3 or higher per CTCAE v4.0
Response rate
Response Rate to Nivolumab + Rituximab according to the Lugano classification for Response Criteria for Non-Hodgkin Lymphoma
Complete response rate
Response Rate to Nivolumab + Rituximab according to the Lugano classification for Response Criteria for Non-Hodgkin Lymphoma
Time to treatment failure
Time to progression
Progression free survival
Duration of survival without relapse or non-relapse mortality
Overall survival
Overall toxicity as assessed by CTCAE v4.0

Full Information

First Posted
August 7, 2017
Last Updated
January 30, 2023
Sponsor
Dr. Eliza Hawkes
Collaborators
Bristol-Myers Squibb
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1. Study Identification

Unique Protocol Identification Number
NCT03245021
Brief Title
Nivolumab Plus Rituximab in First-line Follicular Lymphoma gr 1-3A
Acronym
1stFLOR
Official Title
First-line Treatment for Grade 1-3A Follicular Lymphoma Using Opdivo (Nivolumab) Plus Rituximab: The 1st FLOR Study
Study Type
Interventional

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
September 7, 2017 (Actual)
Primary Completion Date
May 11, 2022 (Actual)
Study Completion Date
June 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Dr. Eliza Hawkes
Collaborators
Bristol-Myers Squibb

4. Oversight

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
Data Monitoring Committee
No

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Follicular Lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Model Description
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
39 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Open-Label
Arm Type
Other
Arm Description
Opdivo - Single-arm open label study
Intervention Type
Drug
Intervention Name(s)
Opdivo
Other Intervention Name(s)
Rituximab
Intervention Description
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
Primary Outcome Measure Information:
Title
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)
Description
As determined by rate of toxicity grade 3 or higher per CTCAE v4.0
Time Frame
1st 16 weeks of therapy
Secondary Outcome Measure Information:
Title
Overall toxicity
Description
As determined by rate of toxicity grade 3 or higher per CTCAE v4.0
Time Frame
5 years
Title
Response rate
Description
Response Rate to Nivolumab + Rituximab according to the Lugano classification for Response Criteria for Non-Hodgkin Lymphoma
Time Frame
1st 16 weeks of therapy
Title
Complete response rate
Description
Response Rate to Nivolumab + Rituximab according to the Lugano classification for Response Criteria for Non-Hodgkin Lymphoma
Time Frame
6 months post completion of induction treatment
Title
Time to treatment failure
Description
Time to progression
Time Frame
5 years
Title
Progression free survival
Description
Duration of survival without relapse or non-relapse mortality
Time Frame
5 years
Title
Overall survival
Description
Overall toxicity as assessed by CTCAE v4.0
Time Frame
5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age ≥ 18 years. 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. No previous chemotherapy, or other investigational drug for this indication apart from focal radiotherapy. 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. 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. 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: Haemoglobin >9.0 g/dL White blood cells (WBC) ≥2000/μL Neutrophils >1.5 x 109/L 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 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 Women must not be breastfeeding 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 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. 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: Grade 3B follicular lymphoma, transformed follicular lymphoma, other indolent lymphomas. 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. Central nervous system, meningeal involvement or cord compression by lymphoma. 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. 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. Past history of interstitial lung disease. 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. Any other serious active disease. Any positive test result for hepatitis B or hepatitis C virus during screening indicating acute or chronic infection. Any positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) 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 Medical or psychiatric conditions that compromise the patient's ability to give informed consent.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Eliza Hawkes, MD
Organizational Affiliation
Austin Health
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ballarat Health
City
Ballarat
State/Province
Victoria
Country
Australia
Facility Name
Eastern Health
City
Box Hill
State/Province
Victoria
ZIP/Postal Code
3128
Country
Australia
Facility Name
Monash Health
City
Clayton
State/Province
Victoria
Country
Australia
Facility Name
Austin Health
City
Heidelberg
State/Province
Victoria
ZIP/Postal Code
3084
Country
Australia
Facility Name
St Vincent's Hospital
City
Melbourne
State/Province
Victoria
Country
Australia

12. IPD Sharing Statement

Plan to Share IPD
Undecided
IPD Sharing 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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Nivolumab Plus Rituximab in First-line Follicular Lymphoma gr 1-3A

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