The main research question is whether or not the administration of nivolumab increases "overall response rate" (ORR) in patients with classical Hodgkin Lymphoma who have progressed or relapsed following autologous stem cell transplant (…
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Brief title
Condition
- Lymphomas Hodgkin's disease
- Lymphomas Hodgkin's disease
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective will be measured by the primary endpoint of IRRC-assessed
ORR. It is defined as the number of subjects with a BOR of CR or PR, according
to the 2007 IWG criteria, based on IRRC assessment, divided by the number of
treated subjects. 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 2007 IWG criteria or the date of subsequent therapy,
whichever occurs first. Allogeneic SCT and ASCT will be considered as
subsequent anti-cancer
therapy. 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-responder).
Primary analysis will be performed separately for each cohort. (i.e. at
separate time points) upon completion of a pre-specified amount of follow-up
after last patient first treatment (LPFT).
Secondary outcome
Duration of Objective Response 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 2007 IWG
criteria 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 tumor assessment. Subjects who start subsequent therapy
without a prior reported progression will be censored at the last tumor
assessments prior to initiation of the subsequent anticancer therapy. This
endpoint will only be evaluated in subjects with objective
response of CR or PR.
Complete Remission Rate and Duration Based on IRRC Assessment:
The CR rate is defined as the number of subjects with a BOR of CR according to
the 2007 IWG criteria, based on IRRC assessment, divided by the number of
treated subjects. The duration of CR will only be evaluated in subjects with
BOR of CR and is defined as the time from first
documentation of CR (the date of first negative FDG-PET scan or the date of
first documentation of no disease involvement in the bone marrow (if required),
whichever occurs later) to the date of initial objectively documented
progression as determined using the 2007 IWG criteria or death
due to any cause, whichever occurs first. Censoring will be applied as per DOR
definition.
Partial Remission Rate and Duration Based on IRRC Assessment:
The PR rate is defined as the number of subjects with a BOR of PR according to
the 2007 IWG criteria, based on IRRC assessment, divided by the number of
treated subjects. The duration of PR will only be evaluated in subjects with
BOR of PR and is defined as the time from first documentation of PR to the date
of initial objectively documented progression as determined.
Objective Response Rate and Duration Based on Investigator Assessment:
Investigator-assessed ORR and DOR are defined similarly as described for ORR
and DOR per IRRC assessment above, but will be assessed per investigator.
Background summary
Cancers of the lymphatic system are called Lymphomas.There are two main types
of lymphoma* Hodgkin's lymphoma (HL)
and non-Hodgkins Lymphoma. HL is the much rarer of the two, accounting for only
about 1 in 5 of all lymphomas. It is characterised by the presence of
ReedSternberg cells.
The majority of cells in HL tumour tissue are a mixed combination of various
lymphoid cells, including regulatory Tcells and macrophages. The updated 2008
WHO classification guidelines recognise two histological types: nodular
lymphocyte predominant, which accounts for about 5% of all HL cases and
*classical* HL (cHL) which accounts for the remainder. In 2013, the National
Cancer Institute in the US estimated that 9,290 men and women would be
diagnosed with HL and 1,180 would die of HL. The prevalence of HL in the US in
2013 was estimated to be 181,928.
The treatment of limited stage cHL has improved significantly since the
adoption of combined therapy, with treatment failure occurring in approximately
10% of patients. However, approximately 30% of patients presenting with newly
diagnosed cHL have advanced stage disease (Stages IIB IV).
Improvements in the use of combined chemotherapy and radiotherapy in advanced
stage newly diagnosed cHL have resulted in durable remission rates of
approximately 60% to 80%. However, a substantial fraction of patients with cHL
are not cured* up to 10% of patients with advanced stage cHL will not achieve
an initial remission, and 30% of responding patients subsequently relapse. The
standard of care for patients with relapsed and refractory cHL is intensive
salvage chemotherapy followed by autologous stem cell transplant (ASCT), which
can produce long-term remissions in approximately 50% of patients.
Unfortunately, the remaining 50% of ASCT patients do not experience long-term
disease control with an average overall survival of approximately 27 months. In
particular, the prognosis remains exceedingly poor for patients who experience
relapse or progressive cHL within one year after ASCT where the average
survival time is approximately 1.2 years. Several small clinical studies have
examined various agents in the ASCT relapsed cHL population with uniformly poor
results.
Despite encouraging high response rates to a salvage drug called brentuximab
vedotin (currently with conditional approval in the EMEA) long-term disease
control remains challenging for classical Hodgkin Lymphoma patients as only a
small proportion of patients can maintain a complete response. In addition, the
tolerability of brentuximab may be of increased concern in older patients,
where higher rates of anaemia and peripheral neuropathy have been reported. For
the younger relatively young and otherise fit cHL population who have relapsed
after ASCT, there still remains a compelling unmet need for improved salvage
therapy.
The recent development of monoclonal antibodies (antibodies synthesised in a
lab, made to target particular damaged cells of the body) for targeted use in
cancer treatment has shown significant, documented improvements in increasing
the length of overall survival in patients and also increasing the time it
takes for the cancer to worsen (progression free survival, PFS) in several
different cancer types.
Nivolumab, an unlicenced monoclonal antibody, is currently under development at
Bristol Myers Squibb for the treatment of cancer (renal, melanoma, NSCLC and
lymphoma). In an ongoing Phase I study in subjects with relapsed haematologic
malignancies (CA209039), nivolumab has demonstrated preliminary activity in
subjects with cHL (23 treated cHL patients). Nivolumab has been well tolerated
to date, with a favourable safety profile. It has also demonstrated that used
on its own as a monotherapy, can increase not only the objective tumour
response rate (the amount the tumour has shrunk after receiving treatment) but
also the progression free survival of patients compared to
current standard of care chemotherapy.
In a healthy person the immune system (in the form of T-cells in this case)
attacks any cell it recognises as abnormal or foreign. When the human body has
finished attacking the abnormal cells or foreign body, the immune system sends
a signal (or checkpoint) to its Tcells to switch off the attack. This
signal/checkpoint or *off switch* is a protein called PDL1 (PD=Programmed
Death). Since cancer cells display abnormal or foreign proteins on their
surface, it is expected that the immune system should technically attack them
too. However, cancer cells are also known to cover their surface with the PDL1
*off switch*. The PDL1 on cancer cells attaches itself (binds) to a protein
found on the surface of the body*s attacking T-cells called PD1. When these two
proteins bind or connect, the *off switch* is activated and shuts down the
Tcell. This allows the cancer cells to continue to grow undetected by the
body*s immune system because the cancer cells are stopping the T-cells from
performing their job (to fight foreign bodies). Nivolumab is a drug designed to
bind directly to the PD1 protein on the body*s T-cell surface which effectively
protects it or stops it from binding to the PDL1 switch on the surface of
cancer cells. Nivolumab allows the T-cells to continue to function normally and
potentially continue to fight the cancer.
This study will specifically look to answer the question as to whether
nivolumab demonstrates a clinical benefit in overall tumour response rate in
patietns with classical Hodgkin's Lymphoma.
Study objective
The main research question is whether or not the administration of nivolumab
increases "overall response rate" (ORR) in patients with classical Hodgkin
Lymphoma who have progressed or relapsed following autologous stem cell
transplant (ASCT) and may or may not have received prior brentuximab treatment
after their transplant.
(Overall Response Rate: The percentage of patients whose cancer shrinks or
disappears after treatment as assessed using revised International Working
Group criteria for Malignant Lymphoma (2007 IWG criteria).
Secondary objectives of the study include:
-To look at the durability of the response to treatment with nivolumab i.e. the
length of time that the response to treatment is maintained.
-To assess the 'complete response rate'(CRR) i.e. the percentage of patients
who achieve 'complete response'. In complete response, all signs and symptoms
of cancer have disappeared. However, this does not always mean the cancer has
been cured.
-To assess the 'partial response rate'(PRR) i.e. the percentage of patients who
achieve 'partial response'. In partial response, all signs and symptoms of
cancer may have disappeared. However, this does not always mean the cancer has
been cured.
-To look at the "overall response rate" (ORR), based on investigator
assessments.
Exploratory Objectives
• To assess the Progression Free Survival (PFS) based on IRRC assessment
• To assess the Overall Survival (OS)
• To assess the overall safety and tolerability of nivolumab, as measured by
incidence and severity of AEs, serious adverse events, and specific laboratory
abnormalities
• To investigate the association between biomarkers in the peripheral blood and
tumour tissue, such as PD-L1 expression, with safety and efficacy measures
• To characterise pharmacokinetics of nivolumab and explore exposure-response
relationships
• To characterise 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 European
Organisation for Research and Treatment of Cancer (EORTC) quality of life
questionnaire (QLQ)-C30
• To evaluate the pharmacodynamic activity of nivolumab monotherapy in the
peripheral blood and tumor tissue as measured by flow cytometry,
immunohistochemistry (IHT), soluble factor analysis, and gene expression
(microarray technology, quantitative reverse transcription polymerase chain
reaction (RT-PCR).
• For Cohort C, to evaluate risk-benefit of discontinuation schedule of the
study drug for the subjects who have persistent CR for 1 year.
Study design
This is a non-comparative, three-cohort, single-arm Phase 2 study in cHL
subjects >= 18 years old who failed ASCT. Subjects may be brentuximab vedotin-
naïve (Cohort A), or may have had prior brentuximab vedotin treatment as a
salvage therapy after failure of ASCT (Cohort B). This cohort B is fully
enrolled and now closed to recruitment. Subjects who failed ASCT and who have
received prior treatment with brentuximab vedotin at any timepoint will now be
included in the study (Cohort C). Approximately 270 subjects with failure after
ASCT will be treated with nivolumab 240 mg IV every 2 weeks or 480 mg IV every
4 weeks until disease progression or unacceptable toxicity. Subjects will be
independently enrolled for each cohort. When one cohort completes enrolment,
the other cohort will remain open until its complete accrual is reached.
Primary analysis will be performed separately for each cohort. (i.e. at
separate time points) upon completion of a pre-specified amount of follow-up
after last patient first treatment (LPFT). All analyses will be performed
separately for each cohort upon completion of follow-up for the primary
endpoint in each cohort. In addition safety analyses will be performed on
combined cohorts. Subjects will undergo screening evaluations to determine
eligibility within 28 days prior to first dose. Each 14-day dosing period will
constitute a cycle. Radiographical tumour assessments by computed tomography
(CT) (preferred) or magnetic resonance imaging (MRI) will begin at screening,
then at Week 9 (± 7 days) after the start of therapy and will continue every 8
weeks until week 25, then every 12 weeks for the first year of treatment. CT
(preferred) or MRI will continue every 16 weeks (± 14 days) for the second year
of treatment. CT (preferred) or MRI will be performed every 26 weeks (± 21
days) for the third year or beyond of treatment. [18F]-fluorodeoxyglucose
positron emission tomography (FDG-PET) scan will be required in all subjects at
screening and at Weeks 17 and 25 (± 7 days). Additionally, a FDG-PET scan at
Week 49 (± 7 days) is required for subjects who do not have two consecutive
negative FDG-PET scans after Week 1 and prior to Week 49. FDG-PET scan will
also be required for confirmation of radiographic CR after initiation of the
study drug at other timepoints when FDG-PET is not otherwise scheduled; this
FDG-PET scan should be performed within 4 weeks of the CT scan. Tumor
assessments will follow the above schedule until disease progression is
documented or until the subject initiates a preparative regimen for allogeneic
SCT or ASCT, whichever occurs earlier. If the subject discontinues treatment
prior to disease progression, tumour assessment will continue in the follow-up
phase. If the subject discontinues study therapy by proceeding to allogeneic
SCT or ASCT, they will not undergo IRRC radiographic assessments described
here, but will be followed with a specific schedule. Nivolumab will be
administered until unacceptable toxicity or disease progression which is
defined by relapsed disease (after complete remission achieved during the
study) or progressive disease (after Partial Response, Stable Disease attained
during the study) according to the 2007 IWG criteria. An IRRC will also be
utilised. In Cohort C, subjects who have persistent CR for one year will
discontinue the study drug and continue in the follow-up (FU)/Observational
phase of the study. These patients will be closely observed for up to two years
from the date of last dose of study drug. Re-initiation of study therapy is
allowed should these subjects relapse according to the 2007 IWG criteria during
these two years. They will follow the original treatment schedule and
assessments. The primary endpoint of this study is objective response rate
(ORR) based on IRRC assessments, using the 2007 IWG criteria. Secondary
endpoints include DOR, as well as complete and partial remission rates and
durations based on IRRC assessments.Primary analysis will be performed
separately for each cohort. (i.e. at separate time points) upon completion of a
pre-specified amount of follow-up after last patient first treatment (LPFT).
Additional survival analysis will be conducted for up to 5 years beyond
analysis of the primary endpoint. Cohort C will provide an extended assessment
of the benefit-risk for this study drug in advanced stage cHL patients in a
larger patient population. Approximately 100 subjects recruited from Cohort C
will assist in the identification and characterisation of less common safety
events as well as further confirmation of the activity initially observed in
Cohort B. Importantly, Cohort C will also provide initial data concerning
whether discontinuation of nivolumab monotherapy is safe in patients who have
remained in CR for one year on nivolumab. All currently ongoing nivolumab Phase
2 and Phase 3 studies for solid tumour and hematologic malignancies permit
treatment until disease progression or unacceptable toxicity. Because nivolumab
is generally tolerable, some patients who have achieved CR may remain on study
therapy indefinitely unless disease progression occurs. Therefore, it will be
critical to answer whether these patients can safely stop treatment at some
point in order to avoid unnecessary exposure to study drug, and can experience
similar benefit. To address this scientific question, a discontinuation
schedule will be examined in Cohort C. Subjects who have persistent CR for one
year on study drug will discontinue the study drug. If 15 to 20% of the
subjects from Cohort C achieve CR and maintain their CR for one year, the
discontinuation schedule will be assessed on approximately 30 - 40 subjects. To
ensure that patients can safely discontinue study therapy, regular follow-up
observational visits will be conducted after treatment discontinuation for up
to two years. Furthermore, re-initiation of study therapy will be permitted for
those patients relapsing within two years of study drug discontinuation. This
discontinuation schedule will provide important information as to whether the
patients who have attained good disease control can safely discontinue study
drug without increasing risk of relapse. In addition, plasma samples will be
collected in cohort C subjects for, but not limited to, the determination of
Minimal Residual Disease (MRD).
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
Nivolumab may cause one or more of the side effects listed below. This
information is based on data from cancer subjects in other clinical trials of
nivolumab. In addition, there may be side effects that are not yet known that
may occur. Patients will be advised to tell the doctor or nurse right away
about any possible side effects they are experiencing. The research team are
experienced in dealing with this participant group.
The most common side effects of nivolumab are:
• Fatigue and Rash.
Less common side effects of nivolumab include:
• Abdominal pain
• Alkaline phosphatase increased: lab test result associated with liver or bone
abnormalities
• ALT increased: lab test result associated with abnormal liver function
• Amylase increased: lab test result associated with pancreas inflammation
• AST increased: lab test result associated with abnormal liver function
• Chills
• Constipation
• Cough
• Creatinine increased: lab test result associated with decreased kidney
function
• Decreased appetite
• Diarrhea
• Dry mouth
• Dry skin
• Fever
• Headache
• Lipase increased: lab test result associated with pancreas inflammation
• Inflammation of the colon
• Inflammation of the mouth
• Infusion related reaction
• Itching
• Joint pain or stiffness
• Loss of color (pigment) from areas of skin
• Lung inflammation (pneumonitis - see details below)
• Musculoskeletal pain
• Nausea
• Shortness of breath
• Swelling, including face, arms, and legs
• Thyroid gland function decreased
• Thyroid gland function increased
• Thyroid stimulating hormone increased: lab test result associated with
abnormal thyroid function
• Tingling, burning, numbness or weakness, possibly in arms, legs, hands and
feet
• Vomiting
Rare serious side effects of nivolumab include:
• Adrenal gland function decreased
• Allergic reaction
• Bilirubin (liver function blood test) increased
• Bronchitis
• Cranial nerve disorder
• Diabetes
• Dizziness
• Dry eye
• Hair loss
• Heart rate increased
• Heart rhythm abnormal
• High blood pressure
• Hives
• Increased blood sugar
• Inflammation of the eye
• Inflammation of the heart
• Inflammation of the kidney
• Inflammation of the pancreas
• Inflammation of the pituitary gland
• Inflammation of the stomach
• Inflammation of the thyroid gland
• Liver inflammation
• Low blood pressure
• Pituitary gland function decreased
• Psoriasis: characterized by patches of abnormal, scaly skin
• Redness
• Renal failure
• Respiratory failure
• Sodium levels in blood low
• Upper respiratory tract infection
• Vertigo
• Vision blurred
Very Rare side effects of nivolumab include:
• Anaphylactic reaction (severe allergic reaction)
• Damage to the protective covering of the nerves in the brain and spinal cord
• Diabetes complications resulting in excess blood acids and diabetic coma
• Erythema multiforme: skin inflammatory reaction
• Guillain-Barre syndrome, an autoimmune disorder associated with progressive
muscle weakness or paralysis
• Inflammation of blood vessels
• Inflammation of the brain, potentially life-threatening or fatal
• Lung infiltrates, associated with infection or inflammation
• Muscle inflammation
• Myasthenic syndrome (neurologic syndrome characterized by muscle weakness)
including myasthenia gravis, a nerve disease that may cause weakness of eye,
face, breathing, and swallowing muscles.
• Polymyalgia rheumatica, an inflammatory disorder causing muscle pain and
stiffness
• Rhabdomyolysis: muscle fiber released into the blood stream which could
damage your kidneys
• Rosacea: acne-like skin condition resulting in redness of face
• Sarcoidosis, a disease involving abnormal collections of inflammatory cells
(granulomas) in organs such as lungs, skin, and lymph nodes
• Stevens Johnson syndrome: inflammatory disorder of skin and mucous membranes,
resulting in blistering and shedding of skin
• Toxic epidermal necrolysis: a potentially fatal disease characterized by
blistering and peeling of the top layer of skin resembling a severe burn
• Histiocytic necrotizing lymphadenitis or Kikuchi lymphadenitis: disorder of
the lymph nodes which causes the lymph nodes to become enlarged, inflamed and
painful, commonly affecting lymph nodes of the neck and possibly associated
with fever or muscle and joint pains
It is possible that nivolumab may cause inflammation of the tissues of the
lung. This adverse effect has been reported infrequently in patients treated
with nivolumab. While many patients with x-ray or CT abnormalities have not
developed any symptoms, some patients have developed mild to severe symptoms
and in rare cases, death has occurred as a result of their lung inflammation.
Signs and symptoms of lung inflammation may include difficulty breathing, pain
or discomfort while breathing, chest pain, cough, shortness of breath,
increased rate of breathing, fever, low blood oxygen levels, or fatigue.
Also, Complications, including fatal events, have occurred in patients who
received allogeneic hematopoietic stem cell transplantation (HSCT) after
nivolumab.
Because of the potential for the development of nivolumab related AEs including
Adverse Events of Special Interest (AEOSI). management algorithms have been
developed by BMS for suspected pulmonary toxicity, diarrhoea or suspected
colitis, hepatotoxicity, endocrinopathy and renal toxicity and are contained
within the IB. Additional details on the safety profile of nivolumab, including
results from other clinical studies, are also available in the Investigator
Brochure. Procedures and assessments are in place to help detect and monitor
these potential adverse events (e.g. measurement of oxygen levels by pulse
oximetry, frequent safety blood testing, CT scans etc.) Risks for men/women of
childbearing potential (known and unknown). This risk will be minimised by
regularly performing pregnancy testing, informing the participants and their
partners that they must use contraception during study and for a specified time
following end of treatment. Mild discomfort and pain may be experienced from
taking vital signs and blood sampling (bruising, bleeding, and infection at the
site of the needle stick). These tests and procedures will be conducted by
trained medical professionals. Risks from exposure to radiation from CT/PET/MRI
scans - The risk of these has been reviewed by an Independent Clinical
Radiation Expert and they have concluded that the risk of a radiation induced
cancer in this study population is low. Sometimes patients have allergic
reactions to the dyes used in CT scans. This is rare. It can involve itching or
rash and in severe cases, breathing difficulties and low blood pressure levels.
Patients will be instructed to let the study doctor and radiologist know of any
known allergies. Risks of biopsy: This procedure can be painful and depending
on the location of the tumour may pose a substantial risk to the patient. This
procedure will be carried out by qualified medical professionals in the
hospital setting. Risks from taking prohibited medications. This risk will be
minimised as the study team will frequently review all concomitant medication
being taken by the subject* if applicable, cards listing all prohibited
medications will be given to site staff/ participants and the participant*s GP
will be informed of these prohibited medications. Participants will be required
to attend the research unit on a regular basis whilst they are on the trial
thus involving an increase in travel. Participants may have to alter any
pre*existing plans/appointments to fit in with the required visits as laid out
in the protocol. These visits are necessary to monitor the subject*s safety and
wellbeing. Reasonable travel expenses will be reimbursed. Risks associated with
a loss of privacy or confidentiality if a patient's identity as a participant
in this study or their identifiable genetic or health information were
disclosed to unauthorised persons. There is a possible risk of sponsor
organising the research) believes that the risks of such improper disclosure
are very small because they have adopted strict privacy and confidentiality
procedures for this research. Occasionally during the course of a study,
participants may be found to have a previously undiagnosed medical condition.
In this situation their study doctor will take the necessary steps to ensure
they receive appropriate treatment. If during the course of this study, new
information becomes available about the treatment/drug that is being studied,
it will be discussed with the participant and they will be asked if they would
like to continue in the study. As a consequence of this new information and to
ensure participant safety, it may be necessary to make modifications to the
study design which would include changing the timing of dosing, changing the
number of tests being performed or perhaps even stopping the study. In any
event, the participant and investigator will be fully informed and the patient
will be given every opportunity to consider their continued participation in
the trial.
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Age
Inclusion criteria
Signed Written Informed Consent
a) Subjects must have signed and dated an IRB/IEC approved written informed
consent
form in accordance with regulatory and institutional guidelines. This must be
obtained before the performance of any protocol related procedures that are not
part of normal subject care.
b) Subjects must be willing and able to comply with scheduled visits, treatment
schedule, laboratory tests and other requirements of the study.
Target Population:
a) Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1,
b) Must have received prior highdose conditioning chemotherapy followed by ASCT
as a part of salvage therapy for cHL:
i) Cohort A: Subjects who are naïve to brentuximab vedotin treatment and who
meet one of the following criteria according to the 2007 IWG criteria:
(1) Documented absence of CR after 90 days from stem cell infusion for the
most recent ASCT* or,
(2) Documented relapsed disease (after CR) or disease progression (after
PR or SD)
ii) Cohort B: Subjects who failed treatment with brentuximab vedotin which was
administered following failure of ASCT, and who meet one of the following
criteria
according to the 2007 IWG criteria:
(1) Documented failure to achieve at least PR after the most recent treatment*
or,
(2) Documented relapse disease (after CR) or disease progression (after PR or
SD)
C) Must have at least one lesion that is > 15mm (1.5cm) in the longest diameter
on
crosssectional imaging and measureable in two perpendicular dimensions on CT
(or MRI) and FDG avid by PET.
iii) Cohort C: Subjects who failed ASCT and who have received prior treatment*
with brentuximab vedotin at any timepoint, and who meet one of the following
criteria according to the 2007 IWG criteria:
(1) Documented absence of CR after 90 days from stem cell infusion for the most
recent ASCT; or,
(2) Documented failure to achieve at least PR after the most recent
chemotherapy or radiation therapy; or,
(3) Documented relapse disease (after CR) or disease progression (after PR or
SD)
*This includes brentuximab vedotin treatment as an initial therapy or salvage
therapy before ASCT, and/or brentuximab vedotin treatment after ASCT (eg
salvage and maintenance therapy after ASCT)
d) Biopsy confirmation of cHL prior to the initiation of study drug. cHL should
be pathologically confirmed by standard immunohistochemical or flow cytometric
techniques.
e) Subject re-enrolment:
This study permits the re-enrolment of a subject who has discontinued the study
as a pretreatment failure (ie, subject has not been randomised/has not been
treated). If re-enrolled, the subject must be reconsented.
Age and Reproductive Status:
a) Males and Females, >= 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 study drug plus 5
half lives of study drug 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 study drug plus 5
halflives of study drug plus 90 days (duration of sperm turnover) for a total
of 31 weeks posttreatment completion
f) Azospermic 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.
Physical and Laboratory Test Finding
a) 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 x10*3/µl (no platelet transfusions for prior 14 days).
iii) Haemoglobin >= 8.5 g/dL (no RBC transfusions for prior 7 days).
iv) Serum creatinine <= 1.5 x Upper Limit of Normal (ULN) or creatinine
clearance (CrCl) >= 40 ml/min (measured
using the CockcroftGault 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 Syndrome, who can
have total bilirubin < 3.0 mg/dL).
b) Subjects with a prior history of chemotherapyinduced or radiation induced
pulmonary toxicity require confirmation of diffusing capacity of the lung for
carbon monoxide (DLCO) over 60%
(adjusted for hemoglobin) by a pulmonary function
test prior to study enrolment.
Exclusion criteria
1. Target Disease Exceptions
a) Known central nervous system lymphoma.
b) Subjects with nodular lymphocytepredominant HL., 2. Medical History and
Concurrent Diseases, a) Subjects with active interstitial pneumonitis.
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. Physical and Laboratory Test Findings
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. Allergies and Adverse Drug
Reaction
a) History of allergy to study drug components.
b) History of severe hypersensitivity reaction to any monoclonal antibody., 5.
Prohibited Treatments and/or Therapies
a) Prior treatment history with brentuximab vedotin administered before first
ASCT (for cohorts A and B).
b) ASCT <= 90 days prior to first dose of study drug.
c) Prior chemotherapy within 4 weeks, nitrosureas within 6 weeks, therapeutic
anticancer antibodies within 4 weeks, radio or toxin immunoconjugates
(excluding brentuximab vedotin) within 10 weeks and brentuximab vedotin within
4 weeks or major surgery within 2 weeks prior to first dose of study drug.
d) Carmustine BCNU) >= 600 mg/m² received as part of the pretransplant
conditioning regimen.
e) Prior radiation therapy within 3 weeks, or chest radiation <= 24 weeks prior
to first dose of the study drug.
f) Prior treatment with an antiPD1, antiPDL1, antiPDL2, antiCD137, or antiCTLA4
antibody (including ipilimumab or any other antibody or drug specifically
targeting Tcell costimulation or checkpoint pathways).
g) Prior allogeneic SCT.
6. Other Exclusion Criteria
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
Eligibility criteria for this study have been carefully considered to ensure
the safety of the study subjects and that the results of the study can be used.
It is imperative that subjects fully meet all eligibility criteria.
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 | EUCTR2014-001509-42-NL |
| CCMO | NL49314.031.14 |