Research Hypothesis: Treatment with nivolumab (BMS-936558) will lead to clinical benefit, as demonstrated by a clinically meaningful objective response rate, including durable responses with substantial magnitude of tumor burden reduction.Primary…
ID
Source
Brief title
Condition
- Lymphomas non-Hodgkin's B-cell
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective will be measured by the primary endpoint of independent
radiological review committee (IRRC)-assessed objective response rate (ORR). It
is defined as the number of subjects with a best overall response (BOR) of
complete remission (CR) or partial remission (PR), according to the revised
International Working Group Criteria for non-Hodgkin Lymphoma, divided by the
number of treated subjects. The final analysis of the primary endpoint will
occur at least 6 months after the last enrolled subject*s first dose of study
therapy. The BOR is defined as the best response designation recorded between
the date of first dose and the date of initial objectively documented
progression per the revised International Working group Criteria for
non-Hodgkin Lymphoma or the date of subsequent therapy, whichever occurs first.
For subjects without documented progression or subsequent therapy, all
available response designations will contribute to the BOR determination. For
purposes of analysis, if a subject receives one dose and discontinues the study
without assessment or receives subsequent therapy prior to assessment, this
subject will be counted in the denominator (as non-respondent).
Secondary outcome
The first secondary objective will be measured by the duration of ORR (DOR)
based on IRRC assessment. DOR is defined as the time from first response (CR or
PR) to the date of initial objectively documented progression as determined
using the revised International Working Group Criteria for non-Hodgkin Lymphoma
or death due to any cause, whichever occurs first. For subjects who neither
progress nor die, the DOR will be censored on the date of their last evaluable
tumor assessment. This endpoint will only be evaluated in subjects with
objective response of CR or PR.
The second secondary objective will be measured by the complete remission rate
(CRR) based on IRRC assessment. The CRR is defined as the number of subjects
with a BOR of CR according to the revised International Working Group Criteria
for non-Hodgkin Lymphoma, divided by the number of treated subjects. The BOR is
defined similarly as above.
The third secondary objective will be measured by IRRC-assessed progression
free survival (PFS). It is defined as the time from first dosing date to the
date of the first documented progression, as determined by an IRRC, or death
due to any cause, whichever occurs first.
Subjects who die without a reported progression will be considered to have
progressed on the date of their death. Subjects who did not progress or die
will be censored on the date of their last evaluable assessment. Subjects who
did not have any on study assessments and did not die will be censored on the
first dosing date. Subjects who started any subsequent anti-cancer therapy
without a prior reported progression will be censored at the last evaluable
assessment prior to initiation of the subsequent anti-cancer therapy.
The fourth secondary objective will be measured by investigator-assessed ORR.
Investigator-assessed ORR is defined similarly as described for the primary
endpoint above.
Background summary
Nivolumab (BMS-936558) is in clinical development for the treatment of subjects
with solid tumors and hematological malignancies as both monotherapy and in
combination with ipilimumab. The purpose of this study (CA209-139) is to
determine if nivolumab treatment of patients with diffuse large B-Cell lymphoma
(DLBCL) will lead to clinical benefit. The patients* targeted have previously
relapsed or were non-responsive to an autologous stem cell transplant (ASCT),
or have failed at least two prior multi-agent chemotherapies and are not
candidates for ASCT. In addition to study CA209139, studies to be conducted
in the hematologic malignancies program will assess the efficacy of nivolumab
in subjects with refractory follicular lymphoma. Nivolumab has shown
preliminary activity in subjects with DLBCL and FL.
DLBCL is the most common lymphoid malignancy in adults and while many respond
to initial chemotherapy, 30-40% fail first line therapy and have reduced
success to further regimens or ASCT, leaving 10-15% with a poor prognosis. The
initial approach to relapsed or refractory DLBCL management is to determine
whether the patient is a candidate for ASCT. In general, patients achieving a
complete response (CR) or partial response (PR) to 2nd line therapy, can be
considered for ASCT. Commonly used exclusion criteria include advanced age
(above 70 to 75 years), co-morbidities, and inadequate social support to assist
in post-transplantation care. Using these criteria, approximately 60% of
relapsed/refractory patients will be eligible for HD ASCT but only 20 to 25% of
these patients will be cured by high dose chemotherapy and ASCT. Although
chemosensitivity is clearly the most important determinant of outcome for ASCT
for relapsed or refractory DLBCL, a significant proportion of patients with
chemosensitive disease have progressive disease after ASCT. Treatment options
following ASCT failure are limited for patients with DLBCL; expectedly disease
recurrence remains the predominant cause of treatment failure. Optimal
management strategies for these patients have yet to be established and
outcomes for patients requiring subsequent lines of therapy remain particularly
poor. The median overall survival of non-responding patients after ASCT or
salvage therapy in transplant ineligible patients is approximately 4.3 months.
Study objective
Research Hypothesis: Treatment with nivolumab (BMS-936558) will lead to
clinical benefit, as demonstrated by a clinically meaningful objective response
rate, including durable responses with substantial magnitude of tumor burden
reduction.
Primary Objective
To assess the clinical benefit of nivolumab, as measured by independent
radiologic review committee (IRRC)
assessed objective response rate (ORR) in subjects with DLBCL who are
refractory or have relapsed following
ASCT (Autologous Stem Cell Transplant) or after failure of at least two prior
multi-agent chemotherapy regimens in ASCT ineligible patients.
Secondary Objectives(s)
- To assess the duration of response (DOR) based on IRRC assessments
- To assess the complete remission rate (CRR) based on IRRC assessment
- To assess the progression free survival (PFS) based on IRRC assessment
- To assess the ORR, based on investigator assessments
Exploratory Objective(s)
- To assess the overall safety and tolerability of nivolumab, as measured by
incidence and severity of adverse events, serious adverse events, and specific
laboratory abnormalities
-To assess the objective response rate and duration of objective response of
nivolumab in PD-L1 positive and PD-L1 negative subgroups, using both
investigator and IRRC assessments
- To assess progression-free survival in all treated subjects, as well as in
PD-L1 positive and PD-L1 negative subgroups, using both investigator and IRRC
assessments
-To assess overall survival in all treated subjects, as well as in PD-L1
positive and PD-L1 negative subgroups
- To characterize pharmacokinetics of nivolumab and explore exposure-response
relationships with respect to selected safety and efficacy endpoints
- To characterize the immunogenicity of nivolumab monotherapy
- To evaluate both generic health-related quality of life as assessed by the
EQ-5D and cancer-specific quality of life as assessed by the EORTC QLQ-C30
- To evaluate the pharmacodynamic activity of nivolumab monotherapy in the
peripheral blood and tumor tissue as measured by flow cytometry,
immunohistochemistry, soluble factor analysis, and gene expression (microarray
technology, quantitative RT-PCR)
Study design
This is a single-arm Phase 2 study in subjects * 18 years old with relapsed or
refractory DLBCL or
transformed lymphoma (TL) after failure of ASCT or after failure of at least
two prior multi-agent chemotherapy
regimens in subjects who are not ASCT candidates. Approximately 120 subjects
will be treated with nivolumab 3 mg/kg IV every 2 weeks. Subjects will be
placed into treatment groups based on prior ASCT failure [n=90] or ASCT
ineligibility [n=30].
For the ASCT-failed cohort, a two-stage design will be used to test whether
nivolumab yields a clinically compelling objective response rate. In the first
stage, responses will be evaluated by the IRRC on the first 37 subjects
treated. If there are 8 or fewer responses in these 37 subjects, the study will
be stopped. In this case, the study will be terminated in both the ASCT-failed
cohort as well as the ASCT ineligible cohort. Otherwise, approximately 53
additional subjects will be accrued into the ASCT-failed cohort to target a
total of 90 treated subjects.
The tolerability of the regimen will continue to be evaluated by the sponsor
with the investigators to
ensure that it is acceptable for continued enrollment. Recruitment and
treatment of subjects in both groups (ASCT failure and ASCT ineligible) will
continue as described during the evaluation of the first 37 ASCT failure
subjects treated.
For the ASCT ineligible cohort a single stage design will be used to estimate
the objective response rate using approximately 30 treated subjects.
This study will consist of three phases: screening, treatment, and follow-up.
Subjects will undergo screening evaluations to determine eligibility within 28
days prior to first dose. Study drug is administered as an IV infusion on
Treatment Day 1 of each Cycle. Each 14-day dosing period will constitute a
cycle. Subjects will be evaluated for tumor response by spiral CT/MRI
beginning at week 9 (Day 1 of Cycle 5) and continuing every 8 weeks (+/- 1
week) through the first 8 months, every 12 weeks (+/- 2 weeks) months 9-24, and
then every 6 months (+/-3 weeks) thereafter until disease progression is
documented.
Collection of fresh tumor tissue (FFPE tumor tissue block or 10 unstained
slides from a biopsy
performed during the screening phase or collected as a standard of care
procedure within 90 days prior to obtaining informed consent) for determination
of PD-L1 expression status is mandatory. Archival tissue should be submitted
for all subjects if available. Treatment will continue until disease
progression or discontinuation due to toxicity, withdrawal of study consent, or
the study ends. Subjects will be followed every 3 months for survival after
completion of the follow up visits.
Intervention
The medical intervention will be BMS-936558 (nivolumab) supplied by the Sponsor
company. BMS-936558 will be administered as a 60-minute IV infusion on
Treatment Day 1. A treatment cycle is determined as 2 weeks for BMS-936558.
Study burden and risks
As part of the trial, patients will be expected to attend multiple clinic
visits where they will undergo physical examinations, vital sign measurements
including oxygen saturation levels, blood tests for safety assessment,
pregnancy testing (for females of child bearing potential) and monitoring for
adverse events. In addition, every 8 weeks (from week 9 onwards) patients will
undergo radiographic assessment of their tumour(s) (by Spiral CT or MRI)
through the first 8 months, every 12 weeks through months 9-24, and then every
6 months thereafter until disease progression or treatment discontinuation
whichever occurs later. An additional PET scan would be required to confirm CR.
Blood samples will be collected at certain visits for research purposes (PK and
immunogenicity) including Biomarker samples. The frequency of visits and number
of procedures carried out during this trial would typically be considered over
and above standard over care. These procedures are carried out by trained
medical professionals and every effort will be made to minimize any risks or
discomfort to the patient. Treatment for cancer often have side effects,
including some that are life-threatening. Because of the potential for
clinically meaningful nivolumab related AEs requiring early recognition and
prompt intervention, management algorithms have been developed for suspected
pulmonary toxicity, GI toxicity, hepatotoxicity, endocrinopathy, skin toxicity,
neurological toxicity and nephrotoxicity.
The clinical benefit of nivolumab, as measured by independent radiologic review
committee (IRRC)
assessed objective response rate (ORR) will be utilized.
Bristol-Myers Squibb Pharmaceuticals Ltd Uxbridge Business Park, Sanderson Road
Uxbridge UB81DH
GB
Bristol-Myers Squibb Pharmaceuticals Ltd Uxbridge Business Park, Sanderson Road
Uxbridge UB81DH
GB
Listed location countries
Age
Inclusion criteria
1. a) Signed written Informed consent
b) Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests and other requirements of the study.
2. a) Tumor Biopsy confirmation of relapsed or refractory DLBCL, or transformed lymphoma (TL), prior to the initiation of study drug.
i) TL is limited to DLBCL. Subjects with Grade 3b follicular lymphoma are excluded.
ii) DLBCL or TL should be pathologically confirmed by standard immunohistochemical or flow cytometric techniques.
iii) Documentation of the above should be present in the subject*s medical record.
b) Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
c) Measurable disease: Subjects must have at least one lesion that is > 1.5 cm in the longest diameter on cross-sectional imaging and measureable in two perpendicular dimensions per computed tomography (spiral CT).
d) Prior treatment as defined below;
i) Subjects with relapsed DLBCL or TL after high-dose conditioning chemotherapy and ASCT, OR
ii) Subjects with relapsed or refractory DLBCL or TL after at least 2 prior multi-agent chemotherapy regimens if ASCT ineligible. Ineligibility for ASCT will be determined using local institutional criteria.
Definition of Relapsed DLBCL
- the appearance of new lesions > 6 months after obtaining a CR
-an increase <50% in the size of previously involved sites > 6 months after completing planned therapy.
Definition of Refractory DLBCL:
- < 50% decrease in lesion size after planned therapy,
- the appearance of new lesions < 6 months after completion of planned therapy
- an increase of >50% in the size of previously involved sites < 6 months after
completion of planned therapy.
e) Subject Re-enrollment: This study permits the re-enrollment of a subject that has
discontinued the study as a pre-treatment failure (ie, subject has not been randomized /has not been treated). If re-enrolled, the subject must be re-consented.
3. Screening laboratory values must meet the following criteria and should be obtained within
14 days prior to first dose:
i) Absolute Neutrophil Count * 750/µL (no WBC growth factors for prior 14 days)
ii) Platelets *50 x103/µL (no platelet transfusions for prior 14 days)
iii) Hemoglobin > 8.5 g/dL (no RBC transfusions for prior 7 days)
iv) Serum creatinine * 1.5 x ULN or creatinine clearance (CrCl)*40 ml/min (measured
using the Cockcroft-Gault formula below):;Female CrCl <= (140 - age in years) x weight in kg x 0.85
72 x serum creatinine in mg/dL
Male CrCl <= (140 - age in years) x weight in kg x 1.00
72 x serum creatinine in mg/dL
v) AST/ALT * 3 x ULN
vi) Total Bilirubin * 1.5 x ULN (except subjects with Gilbert*s Syndrome, who can have
total bilirubin < 3.0 mg/dL).
4. a) Men and women *18 years of age.
b) 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 drug.
c) Women must not be breastfeeding
d) WOCBP must agree to follow instructions for method(s) of contraception from the time of enrollment for the duration of treatment with nivolumab plus 5 half-lives of nivolumab plus 30 days (duration of ovulatory cycle) for a total of 23 weeks post treatment completion.
e) Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with nivolumab plus 5 half-lives of nivolumab plus 90 days (duration of sperm turnover) for a total of 31 weeks post-treatment completion.
f) 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 these sections
Exclusion criteria
1. a) Known central nervous system lymphoma.
2. a) History of interstitial lung disease.
b) Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results.
c) 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.
d) Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
e) Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg 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.
3. a) Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection.
b) Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
4. a) History of allergy to study drug components.
b) History of severe hypersensitivity reaction to any monoclonal antibody.
5. a) Autologous Stem Cell Transplant (ASCT) * 12 weeks prior to first dose of the study drug.
b) Prior chemotherapy within 2 weeks, nitrosureas within 6 weeks, therapeutic anticancer antibodies within 4 weeks, radio- or toxin immunoconjugates within 10 weeks, radiation therapy within 3 weeks, or major surgery within 2 weeks of first dose of the study drug.
c) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways
d) Prior allogeneic SCT.
e) Chest radiation * 24 weeks prior to the first dose of study drug
f) Carmustine (BCNU) * 1000 mg received as part of pre-transplant conditioning regimen
6. a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-003621-28-NL |
| CCMO | NL47125.041.14 |