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Treatment Of Newly-diagnosed Follicular Lymphoma With CELMoD BMS-986369, Rituximab +/- Nivolumab. (TOP-FLOR)

Primary Purpose

Follicular Lymphoma Stage II, Follicular Lymphoma Stage III, Follicular Lymphoma Stage IV

Status
Recruiting
Phase
Phase 2
Locations
Australia
Study Type
Interventional
Intervention
BMS-986369
Nivolumab 10 MG/ML
Rituximab
Sponsored by
Olivia Newton-John Cancer Research Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Follicular Lymphoma Stage II

Eligibility Criteria

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

Inclusion Criteria: Age 18+ years. Histologically proven CD20 positive Follicular non Hodgkin lymphoma (FL) grades 1-3A (i.e. classical follicular lymphoma according to the current World Health Organization classification).3 No previous chemotherapy, or other investigational drug for this indication apart from focal radiotherapy. Stage II-IV disease (Ann Arbor criteria). 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. (e.g., Hb, WCC or plt count below lower limit of institutional normal range). g) Adequate bone marrow function including: Haemoglobin >8.0 g/dL White cell count (WCC) ≥2000/μL Neutrophils >1.5 x 109/L Platelets >75 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) ≥ 60mL/min (using Cockcroft-Gault formula, 24hr urine collection or eGFR). 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) Adequate left ventricular ejection fraction of >45% as demonstrated on a Gated Cardiac Blood Pool Scan or echocardiogram. k) Life expectancy > 3 months. l) Patients of childbearing potential willing to adhere to the following contraceptive precautions. Refer to the Celgene-BMS-986369/CC-99282 Pregnancy Prevention Plan (Appendix 4) for additional guidance. Females of childbearing potential (FCBP) 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. Females must not be breastfeeding. FCBP must use appropriate method(s) of contraception to avoid pregnancy for 23 weeks (30 days plus five half-lives of nivolumab) and 28 days for BMS 986369 post-treatment completion. Men who are sexually active with FCBP 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 90 days from the last day BMS-986369 and refrain from donating sperm. Azoospermic males and FCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However, they must still undergo pregnancy testing as described in this section. m) Written, informed consent. Exclusion Criteria: Follicular large B-cell Lymphoma (Grade 3B) 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 spinal 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 therapy are permitted in the absence of active autoimmune disease. Past history of interstitial lung disease. Prior organ transplantation or allogeneic bone marrow transplantation. Prior malignancy active within the previous 2 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. Uncontrolled or severe cardiovascular disease (NYHA class III or IV heart failure; myocardial infarction within the last 6 months of study entry); unstable angina; unstable cardiac arrhythmias; clinically significant pericardial disease. Any other serious active disease. Any positive test result for hepatitis B or hepatitis C virus during screening indicating acute or chronic infection. Latent hepatitis B with undetectable viral load by PCR is allowable provided appropriate anti-viral prophylaxis is given as per institutional guidelines. 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.

Sites / Locations

  • Grampians HealthRecruiting
  • Eastern Health
  • University Hospital Geelong, Barwon HealthRecruiting
  • Austin HealthRecruiting
  • Fiona Stanley Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Arm A- BMS-986369 + Rituximab

Arm B- Nivolumab + BMS-986369 + Rituximab

Arm Description

Rituximab 375mg/m2 IV infusion Q4W + BMS-986369 0.4mg po D1-D14 of each cycle for 8 cycles, followed by Rituximab 375mg/m2 IV infusion Q12W in participants with CR/PR at end of induction

Nivolumab 480mg IV infusion Q4W, Rituximab 375mg/m2 IV infusion Q4W and BMS-986369 0.4mg po D1-D14 of each cycle for 8 cycles, followed by Rituximab 375mg/m2 IV infusion Q12W in participants with CR/PR at end of induction

Outcomes

Primary Outcome Measures

Proportion of patients who achieve a complete metabolic response in the absence of prohibitive toxicity with induction rituximab, BMS-986369 with or without nivolumab comprising 8 cycles of therapy with each cycle delivered every 4 weeks.
Metabolic response as assessed by PET/CT and defined by Lugano criteria; toxicities as defined by CTCAE v5

Secondary Outcome Measures

To assess overall toxicity
As determined by rate of toxicity grade 3 or higher per CTCAE V5
To assess time to treatment failure
Treatment response assessed by PET/CT according to the Lugano classification for Response Criteria for Non-Hodgkin Lymphoma
Progression free survival
Quantification of progression free survival
Overall survival
Quantification of OS

Full Information

First Posted
March 15, 2023
Last Updated
October 16, 2023
Sponsor
Olivia Newton-John Cancer Research Institute
Collaborators
Austin Health, Grampians Health, Fiona Stanley Hospital, Eastern Health, Barwon Health, Bristol-Myers Squibb
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1. Study Identification

Unique Protocol Identification Number
NCT05788081
Brief Title
Treatment Of Newly-diagnosed Follicular Lymphoma With CELMoD BMS-986369, Rituximab +/- Nivolumab.
Acronym
TOP-FLOR
Official Title
Treatment Of Newly-diagnosed Follicular Lymphoma With CELMoD BMS-986369, Rituximab +/- Nivolumab: An Umbrella Bayesian Optimal Phase II Study.
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
August 31, 2023 (Actual)
Primary Completion Date
January 1, 2027 (Anticipated)
Study Completion Date
June 1, 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Olivia Newton-John Cancer Research Institute
Collaborators
Austin Health, Grampians Health, Fiona Stanley Hospital, Eastern Health, Barwon Health, Bristol-Myers Squibb

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
First line treatment with combination rituximab and BMS-986369 with, or without nivolumab, in patients in previously untreated Follicular Lymphoma
Detailed Description
This study will involve participants with a condition called Follicular Non Hodgkin Lymphoma (Follicular Lymphoma). The main purpose of this study is to see if it is safe to give an induction schedule of the drug BMS-986369, in combination with Rituximab +/- Nivolumab, and to see how effective this combination 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 BMS-986369 to Rituximab treatment +/- Nivolumab for 8 cycles (28 days per cycle), with up to 2 years of maintenance treatment of rituximab in eligible patients following induction. Participants will be reviewed at baseline and prior to each cycle of treatment for toxicity, scans will be performed at baseline, after 2 and 5 cycles of induction treatment, and every 8 weeks during maintenance phase. Following completion of treatment, participants will be followed up for a total of 3 years (every 6 months). 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 Stage II, Follicular Lymphoma Stage III, Follicular Lymphoma Stage IV

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Study Design Open label multicentre umbrella Bayesian Optimal Phase II study
Masking
None (Open Label)
Allocation
Randomized
Enrollment
40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Arm A- BMS-986369 + Rituximab
Arm Type
Experimental
Arm Description
Rituximab 375mg/m2 IV infusion Q4W + BMS-986369 0.4mg po D1-D14 of each cycle for 8 cycles, followed by Rituximab 375mg/m2 IV infusion Q12W in participants with CR/PR at end of induction
Arm Title
Arm B- Nivolumab + BMS-986369 + Rituximab
Arm Type
Experimental
Arm Description
Nivolumab 480mg IV infusion Q4W, Rituximab 375mg/m2 IV infusion Q4W and BMS-986369 0.4mg po D1-D14 of each cycle for 8 cycles, followed by Rituximab 375mg/m2 IV infusion Q12W in participants with CR/PR at end of induction
Intervention Type
Drug
Intervention Name(s)
BMS-986369
Intervention Description
BMS-986369 is an orally administered Cereblon-modulating compound
Intervention Type
Drug
Intervention Name(s)
Nivolumab 10 MG/ML
Other Intervention Name(s)
Opdivo
Intervention Description
Nivolumab is a fully humanised IgG4 blocking monoclonal antibody against PD-1.
Intervention Type
Drug
Intervention Name(s)
Rituximab
Other Intervention Name(s)
Mabthera
Intervention Description
Rituximab is a chimeric anti-CD20 antibody containing human IgG lambda and kappa constant regions with murine variable regions
Primary Outcome Measure Information:
Title
Proportion of patients who achieve a complete metabolic response in the absence of prohibitive toxicity with induction rituximab, BMS-986369 with or without nivolumab comprising 8 cycles of therapy with each cycle delivered every 4 weeks.
Description
Metabolic response as assessed by PET/CT and defined by Lugano criteria; toxicities as defined by CTCAE v5
Time Frame
Consent to 8 weeks after last induction treatment (maximum 44 weeks)
Secondary Outcome Measure Information:
Title
To assess overall toxicity
Description
As determined by rate of toxicity grade 3 or higher per CTCAE V5
Time Frame
Day 1 to 30 days after the end of maintenance phase (up to maximum 32 months)
Title
To assess time to treatment failure
Description
Treatment response assessed by PET/CT according to the Lugano classification for Response Criteria for Non-Hodgkin Lymphoma
Time Frame
Day 1 end of follow up period (up to a maximum of 5 years)
Title
Progression free survival
Description
Quantification of progression free survival
Time Frame
Day 1 end of follow up period (up to a maximum of 5 years)
Title
Overall survival
Description
Quantification of OS
Time Frame
From date of enrolment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 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 CD20 positive Follicular non Hodgkin lymphoma (FL) grades 1-3A (i.e. classical follicular lymphoma according to the current World Health Organization classification).3 No previous chemotherapy, or other investigational drug for this indication apart from focal radiotherapy. Stage II-IV disease (Ann Arbor criteria). 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. (e.g., Hb, WCC or plt count below lower limit of institutional normal range). g) Adequate bone marrow function including: Haemoglobin >8.0 g/dL White cell count (WCC) ≥2000/μL Neutrophils >1.5 x 109/L Platelets >75 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) ≥ 60mL/min (using Cockcroft-Gault formula, 24hr urine collection or eGFR). 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) Adequate left ventricular ejection fraction of >45% as demonstrated on a Gated Cardiac Blood Pool Scan or echocardiogram. k) Life expectancy > 3 months. l) Patients of childbearing potential willing to adhere to the following contraceptive precautions. Refer to the Celgene-BMS-986369/CC-99282 Pregnancy Prevention Plan (Appendix 4) for additional guidance. Females of childbearing potential (FCBP) 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. Females must not be breastfeeding. FCBP must use appropriate method(s) of contraception to avoid pregnancy for 23 weeks (30 days plus five half-lives of nivolumab) and 28 days for BMS 986369 post-treatment completion. Men who are sexually active with FCBP 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 90 days from the last day BMS-986369 and refrain from donating sperm. Azoospermic males and FCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However, they must still undergo pregnancy testing as described in this section. m) Written, informed consent. Exclusion Criteria: Follicular large B-cell Lymphoma (Grade 3B) 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 spinal 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 therapy are permitted in the absence of active autoimmune disease. Past history of interstitial lung disease. Prior organ transplantation or allogeneic bone marrow transplantation. Prior malignancy active within the previous 2 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. Uncontrolled or severe cardiovascular disease (NYHA class III or IV heart failure; myocardial infarction within the last 6 months of study entry); unstable angina; unstable cardiac arrhythmias; clinically significant pericardial disease. Any other serious active disease. Any positive test result for hepatitis B or hepatitis C virus during screening indicating acute or chronic infection. Latent hepatitis B with undetectable viral load by PCR is allowable provided appropriate anti-viral prophylaxis is given as per institutional guidelines. 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Alexandra Romano
Phone
0394963573
Email
trials@onjcri.org.au
First Name & Middle Initial & Last Name or Official Title & Degree
Jodie Palmer, PhD
Phone
0394969674
Email
trials@onjcri.org.au
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Eliza Hawkes, MBBS
Organizational Affiliation
Austin Health
Official's Role
Principal Investigator
Facility Information:
Facility Name
Grampians Health
City
Ballarat
State/Province
Victoria
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Geoff Chong, MBBS
Email
geoff.chong@bhs.org.au
First Name & Middle Initial & Last Name & Degree
Geoff Chong, MBBS FRACP
Facility Name
Eastern Health
City
Box Hill
State/Province
Victoria
ZIP/Postal Code
3128
Country
Australia
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Denise Lee, MBBS
Email
denise.lee@monash.edu
First Name & Middle Initial & Last Name & Degree
Denise Lee, MBBS
Facility Name
University Hospital Geelong, Barwon Health
City
Geelong
State/Province
Victoria
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sonia Gauci
Email
sonia.gauci@barwonhealth.org.au
First Name & Middle Initial & Last Name & Degree
Sumita Ratnasingam, MBBS FRACP
Email
sumita.ratnasingam@barwonhealth.org.au
First Name & Middle Initial & Last Name & Degree
Sumita Ratnasingam, MBBS FRACP
Facility Name
Austin Health
City
Heidelberg
State/Province
Victoria
ZIP/Postal Code
3078
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Eliza Hawkes, MBBS, FRACP
Phone
+61394965000
Email
eliza.hawkes@austin.org.au
First Name & Middle Initial & Last Name & Degree
Kristen Houdyk, RN
Phone
+61394965000
Email
cctc.ethics@austin.org.au
First Name & Middle Initial & Last Name & Degree
Eliza Hawkes, MBBS, FRACP
First Name & Middle Initial & Last Name & Degree
Geoff Chong, MBBS, FRACP
Facility Name
Fiona Stanley Hospital
City
Perth
State/Province
Western Australia
Country
Australia
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Allison Barraclough, MBBS, FRACP
Email
allison.barraclough@health.wa.gov.au
First Name & Middle Initial & Last Name & Degree
Allison Barraclough, MBBS, FRACP

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Treatment Of Newly-diagnosed Follicular Lymphoma With CELMoD BMS-986369, Rituximab +/- Nivolumab.

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