Clinical trial NCT03245021: Nivolumab Plus Rituximab in First-line Follicular Lymphoma gr 1-3A
Official title: First-line Treatment for Grade 1-3A Follicular Lymphoma Using Opdivo (Nivolumab) Plus Rituximab: The 1st FLOR Study
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Follicular Lymphoma
Lead sponsor: Austin Health
Sponsor class: OTHER_GOV
Collaborators: name: Bristol-Myers Squibb
First posted: 2017-08-10
Enrollment: 39
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Single Group Assignment
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: 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)
timeFrame: 1st 16 weeks of therapy
Secondary outcomes:
measure: Overall toxicity
timeFrame: 5 years
measure: Response rate
timeFrame: 1st 16 weeks of therapy
measure: Complete response rate
timeFrame: 6 months post completion of induction treatment
measure: Time to treatment failure
timeFrame: 5 years
measure: Progression free survival
timeFrame: 5 years
measure: Overall survival
timeFrame: 5 years
Other outcomes:
Locations:
city: Ballarat
country: Australia
facility: Ballarat Health
state: Victoria
city: Box Hill
country: Australia
facility: Eastern Health
state: Victoria
city: Clayton
country: Australia
facility: Monash Health
state: Victoria
city: Heidelberg
country: Australia
facility: Austin Health
state: Victoria
city: Melbourne
country: Australia
facility: St Vincent's Hospital
state: Victoria
Study officials:
affiliation: Austin Health
name: Eliza Hawkes, MD
role: PRINCIPAL_INVESTIGATOR
References: