Primary objectivesCohort 1 Estimate the efficacy of nivolumab treatment in patients with relapsed/refractory ALK+ ALCL in terms of best objective response rate within thefirst 24 weeksCohort 2 Estimate the efficacy of nivolumab treatment as…
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Brief title
Condition
- Lymphomas non-Hodgkin's T-cell
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Cohort 1
Best objective response rate (CR+PR) within the first 24 weeks, according to
adapted Lugano 2014 Criteria for Malignant Lymphoma. In case of PETpositive
residual masses after 24 weeks of induction treatment, a resection/biopsy must
be performed by week 24. A residual mass proven to be pathologically negative
for disease after resection or limited biopsy is considered as CR after
discussion with the Coordinating investigator.
Cohort 2
3-year PFS
PFS is defined as the time since the inclusion in the trial, to the first event
among relapse (see definition below) and death, whatever the cause of death
Definition of relapse: In case of developpement of new lesion(s) based on CT
scan and/or MRI and/or PET-CT:
- In patients with clinical deterioration, a biopsy should be performed
whenever possible, in order to obtain histological confirmation of the relapse.
Additional MRD assessment (with quantitave PCR) is also recommended. In patient
in whom a biopsy is not feasisible, an increase of MRD quantitative PCR at 2
consecutive measures qualifying for a significant increase according to the
same reference laboratory, along with clinical signs and symptoms suggestive of
progressing disease and new lesion(s) on imagings will be considered as a
relapse. In this case, relapsed status must be reviewed and confirmed by the
international coordinating investigator.
- In patients without clinical deterioration (scheduled assessment imaging), a
confirmatory CT scan and/or MRI (+ optional PET-CT), along with MRD assessment
(with quantitave PCR) and a biopsy (whenever possible), should be performed 4
weeks later on, in order to confirm or not the relapse.
Secondary outcome
Cohort 1
- Time between the first dose of treatment and the confirmed CR/PR according to
adapted Lugano 2014 Criteria for Malignant Lymphoma.
- Duration of response (CR/PR), defined as the time between the CR or PR (first
met of these criteria of measurement), evaluated according to adapted Lugano
2014 Criteria for Malignant Lymphoma, until confirmed progression, or death.
- Progression-free survival, defined as the time since the inclusion in the
trial, to the first event among confirmed progression, relapse, and death,
whatever the cause of death.
- Confirmed progression is defined according to Lugano 2014 Criteria for
Malignant Lymphoma. However:
- In patients with clinical deterioration, a biopsy should be performed
whenever possible, in order to obtain histological confirmation of the
progression. Additional MRD assessment (with quantitave PCR) is also
recommended. An increase of MRD quantitative PCR at 2 consecutive measures
qualifying for a significant increase according to the same reference
laboratory, along with clinical signs and symptoms suggestive of
progressing disease and progression on imagings will be considered as a
progression/relapse. In this case, progressive/relapse status must be reviewed
and confirmed by the international coordinating investigator.
- In patients without clinical deterioration (scheduled assessment imaging), a
confirmatory CT scan and/or MRI (+ optional PET-CT), along with MRD assessment
(with quantitave PCR) and a biopsy (whenever possible), should be performed 4
weeks later on, in order to confirm or not the progression/relapse.
See chapt 7.3 for details
- Overall survival, defined as the time since the inclusion in the trial to
death, whatever the cause of death.
- Minimal residual disease (MRD) measured by quantitative PCR for NPM1-ALK in
the blood at various time-points (see Table 1 to Table 4)
Cohort 2
- Overall survival, defined as the time since the inclusion in the trial to
death, whatever the cause of death
- Progression-free survival, defined as the time since the inclusion in the
trial to the first event among confirmed relapse and death, whatever the cause
of death. (For definition of relapse, see primary criteria) Overall survival,
defined as the time since the inclusion in the trial to death, whatever the
cause of death
- Minimal residual disease (MRD) measured by quantitative PCR for NPM1-ALK in
the at various time-points (see Table 1 to Table 4)
In cohort 1 and cohort 2
Acute toxicity (according to NCI-CTCAE v5, Appendix 3) during treatment
(induction treatment, and maintenance treatment), and one month after the end
of treatment
- description of all observed adverse events (grade 1 to 5)
- rate of patients with at least one grade 3-4 AE
- rate of patients with at least one grade 4 AE rate of patients with at least
one grade 3-4 immune-related AE
- rate of SUSAR and rate of patients with at least one SUSAR
- rate of death related to AE
- rate of patients with at least one or more doses of nivolumab cancelled due
to AEs
- rate of patients with treament with nivolumab definitively stopped due to AEs
Long-term toxicity (according to NCI-CTCAE v5) defined by toxicity during the
off-therapy period up to 5 years after study inclusion:
- description of all observed adverse events grade >= 3
- rate of patients with at least one grade 3-4 AE
- rate of patients with at least one grade 3-4 immune-related AE
- duration of grade 3-4 immune-related AE
- rate of grade 3-4 immune-related AEs lasting more than one year
- rate of patients who need immune modulating medication,
- > 10 mg prednisone equivalents
Modification of biomarkers, at various time-points (see Table 1 to Table 4), in
tumor tissues, in blood and in bone marrow: PDL1 and PDL2 expression, tumor
infiltrating lymphocytes, anti-ALK antibody, and leucocytes populations/
cytokines.
Objective response rate and PFS in cohort 1, PFS in cohort 2
Background summary
Systemic anaplastic large cell lymphoma (ALCL) is a rare, aggressive,
CD30-positive non-Hodgkin lymphoma (NHL) affecting mostly children/adolescents
and young adults (Turner et al., 2016). Most patients with systemic ALCL
present at advanced stages (stages III-IV) with peripheral intraabdominal or
mediastinal lymph node involvement frequently associated with B symptoms and
extranodal spread including skin, liver, lung, soft tissue and bone
localization. ALK+ ALCL results from chromosomal translocations involving the
ALK gene and different partners
(Swerdlow et al., 2016). The most common ALK fusion protein is nucleophosmin
(NPM1)-ALK resulting from the t(2;5) translocation. This translocation induces
a constitutive phosphorylation of ALK associated with the activation of
multiple pathways such JAK/STAT3, AKT/PI3K, RAS/ERK leading to growth-factor
independent cell proliferation and inhibition of apoptosis.
Accumulating evidence indicates that the immune system plays a major role in
both the pathogenesis and final control of ALK+ ALCL. Antibodies against ALK
and cytotoxic T-cell and CD4 T-helper responses to ALK have been detected in
patients with ALK+ ALCL both at diagnosis and
during remission with a significant inverse correlation between ALK-antibody
titers and the incidence of relapses. Moreover, vaccination using trunked cDNA
ALK has been reported to induce potent and long lasting protection from local
and systemic lymphoma growth. However, it has also been shown that ALK+ ALCL
cells strongly express the immunosuppressive cell-surface protein PD-L1
(B7-H1), as determined on the mRNA and protein level in ALK-positive ALCL cell
lines. Furthermore, results of PD-L1 immunostaining on all patient tissue
samples reported so far showed a strong PD-L1 expression (Marzec et al., 2008).
Analysis revealed that PD-L1 expression is induced by the chimeric NPM1/ALK
tyrosine kinase, by activating STAT3, confirming a unique function for NPM/ALK
as a promoter of immune evasion by inducing PD-L1. These observations provide a
strong rationale to target PD1/PD-L1 in a subset of relapsed/refractory ALK+
ALCL.
Study objective
Primary objectives
Cohort 1
Estimate the efficacy of nivolumab treatment in patients with
relapsed/refractory ALK+ ALCL in terms of best objective response rate within
the
first 24 weeks
Cohort 2
Estimate the efficacy of nivolumab treatment as consolidative therapy after CR
in patients with relapsed/refractory ALK+ ALCL in terms of PFS
Study design
Prospective, non-randomized, single arm phase II trial with 2 cohorts of ALK+
ALCL treated with nivolumab, according to patient status after previous
treatment (patients in progression, into the Cohort 1; patients in CR, into the
Cohort 2)
Intervention
Cohort 1
Induction: nivolumab 3 mg/kg (maximal unitary dose: 240 mg) iv Q2W until CR
Evaluation of response as defined below, including biopsy in case of residual
masses at Week 24
Maintenance: nivolumab 3 mg/kg (maximal unitary dose: 240 mg) Q4W
Total duration of treatment (induction + maintenance) = 24 months
Cohort 2
Induction: nivolumab 3 mg/kg iv Q2W for 4 doses (Wk0, Wk2, Wk4 and Wk6)
Maintenance: nivolumab 3 mg/kg Q4W, for 25 doses, starting at Week 8 (14 days
after the last induction dose)
Total duration of treatment (induction + maintenance) = 24 months
Duration of treatment:
Patients will continue on study treatment up to progression, unacceptable
toxicities, patient refusal or for a total duration of treatment (induction +
maintenance) of 24 months.
Study burden and risks
Risks associated with this study are mainly the anticipated side-effects of
nivolumab (an overview of the adverse effects are found in the investigator
brochure (IB). However, due to the remarkable immunogenic properties of the
disease, the strong PD-L1 expression by tumors cells, the good tolerance
profile and the success of anti-PD1 therapies in other immunogenic diseases,
the option to use consolidative anti-PD1 immunotherapy rather than HSCT for
refractory/relapsed ALK+ ALCL with the highest risk of failures should be
considered.
The PK, clinical activity, and safety of nivolumab have been assessed in
completed Phase I and ongoing Phase II and III studies in adults with several
tumor types. Preliminary data show that the toxicity and PK profiles in
children are similar to those in adults. During the study, side effects will be
closely monitored and reported.
Additional blood tests are performed. Other additional tests (e.g. urinalysis,
pregnancy tests, compared to standard treatment) are not invasive.
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Age
Inclusion criteria
I-1. Histologically confirmed evidence of relapsed/refractory ALK+ ALCL. If
biopsy could not be performed, relapsed/refractory status should be confirmed
by molecular analysis whenever possible (increase of MRD quantitative PCR at 2
consecutive measures qualifying for a significant increase according to the
same reference laboratory, with clinical signs and symptoms suggestive of
progressing disease). In this case, relapsed/refractory status must be reviewed
and confirmed by the international coordinating investigator.
I-2. Age at inclusion > 6 months
I-3. No washout needed, but patients must have recovered from acute toxic
effects of all prior therapy before enrollment into the study. A short course
of steroids is allowed at the beginning of Nivolumab if it is clinical
indicated
I-4. Adequate organ function:
* Peripheral absolute neutrophil count (ANC) >=750/µL in patients without bone
marrow involvement and >=500/µL in patients with bone marrow involvement
(unsupported)
* Platelet count >=75,000/µL in patients without bone marrow involvement and 50
000 in patients with bone marrow involvement (unsupported)
* Hemoglobin >=8.0 g/dL (transfusion is allowed)
* Serum creatinine <=1.5 x upper limit of normal (ULN) for age
* Total bilirubin <=1.5 x ULN in patients without liver involvement and < 2.5
ULN in patients with liver involvment
* Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) <=3
x ULN in patients without liver involvement and < 5 ULN in patients with liver
involvement
* Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase/SGOT
<=3 x ULN in patients without liver involvement and < 5 ULN in patients with
liver involvment
I-5. Performance status: Karnofsky performance status (for patients >12 years
of age) or Lansky Play score (for patients <=12 years of age) >= 40%.
I-6. Able to comply with the scheduled disease management (treatment and
follow-up), and with the management of toxicity
I-7. Females of childbearing potential must have a negative serum β-HCG
pregnancy test within 24 hours prior to initiation of treatment. Sexually
active women of childbearing potential must agree to use acceptable and
appropriate contraception during the study and for at least 5 months after
the last study treatment administration. Sexually active males patients must
agree to use condom during the study and for at least 7 months after the last
study treatment administration. Acceptable contraception is listed in Appendix
5.
I-8. Written informed consent from parents/legal representative, patient, and
age-appropriate assent before any study-specific screening procedures are
conducted according to local, regional or national guidelines.
I-9. Patient affiliated to a social security regimen or beneficiary of the same
according to local requirements.
I-10. Patients will prior allogeneic HSCT may be included if clinically
indicated (see non-inclusion criteria regarding prior allogeneic HSCT). In this
case, study inclusion must be confirmed by the international coordinating
investigator.
Cohort 1:
For being enrolled in Cohort 1, all criteria from C1.I-1 to C1.I-2 are
required, in addition of I-1 to I-10 criteria
C1.I-1. Measurable progressive disease with at least one lesion measuring more
than 1.5 cm and/or evaluable disease on PET-CT
C1.I-2. Previous treatment including chemotherapy and ALK inhibitor or
brentuximab vedotin, if available.
Cohort 2:
For being enrolled in Cohort 2, all criteria from C2.I-1 to C2.I-2 are
required, in addition of I-1 to I-10 criteria
C2.I-1. Complete response (disappearance of all disease except for possible
detection of MRD in blood and/or bone marrow) with an on-going treatment of at
least 2 months with ALK inhibitor or brentuximab vedotin, if available combined
or not with chemotherapy
C2.I-2. High-risk relapsed/refractory ALK+ ALCL for whom an hematopoietic stem
cell transplantation is considered after CR (see Appendix 1 for criteria
according to the age) Of note, the inclusion of patients who have received more
than 12 months of ALK inhibitor or brentuximab will be closed after 8 patients
Exclusion criteria
E-1. Patients with prior allogeneic HSCT less than 3 months before study
inclusion
E-2. Patients with prior allogeneic HSCT and any active graft versus host
disease (GVHD) and/or any prior grade 3 or 4 GVHD according to International
Bone Marrow Transplant Registry (ITBMR)
E-3. Previous organ transplantation
E-4. Significant hemophagocytosis in bone marrow, spleen, lymph nodes, or liver
must be discussed with the Coordinating Sponsor before inclusion
E-5. Presence of any >= CTCAE grade 2 treatment-related toxicity with the
exception of alopecia, fatigue and peripheral neuropathy.
E-6. History or evidence of severe uncontrolled illness that contra-indicates
use of an investigational drug, or places the patient at unacceptable risk from
treatment complications
E-7. History or evidence of severe acute or chronic infection unless fully
healed at least four weeks prior to screening
E-8. Known human immunodeficiency virus (HIV) infection
E-9. Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis
C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.
E-10. History or evidence of any auto-immune 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-11. Subjects with another pathology 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.
E-12. Known hypersensitivity to any component of the products (study drug or
ingredients)
E-13. Concurrent administration of any other antitumor therapy
E-14. Clinically significant, uncontrolled heart disease (including history of
any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal
arrhythmias, or conduction abnormality within 12 months of screening).
E-15. Vaccinated with live attenuated vaccines within 4 weeks of the first dose
of the study drug
E-16. Pregnant or breast-feeding female patient
E-17. Patient under guardianship or deprived of his liberty by a judicial or
administrative decision, patients under safeguards of justice or incapable of
giving its consent, patients undergoing psychiatric care under duress
E-18. Participation in another clinical study with an investigational product
during the study
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 | EUCTR2018-001447-31-NL |
| ClinicalTrials.gov | NCT03703050 |
| CCMO | NL68699.041.22 |