Nivolumab for Pediatric and Adult Relapsing/Refractory ALK+, for Evaluation of Response in Patients With Progressive Disease (Cohort 1) or as Consolidative Immunotherapy in Patients in Complete Remission After Relapse (Cohort 2) (NIVO-ALCL)

  • End date
    Jun 24, 2028
  • participants needed
  • sponsor
    Gustave Roussy, Cancer Campus, Grand Paris
Updated on 24 May 2022


Prospective, non-randomized, single arm phase II trial with 2 cohorts of ALK+ ALCL treated with nivolumab


Prospective, non-randomized, single arm phase II trial with 2 cohorts of ALK+ ALCL treated with nivolumab

Cohort 1:

Population: relapsed/refractory ALK+ ALCL with progressive disease after treatment (including chemotherapy and ALK inhibitor and/or brentuximab vedotin).

Primary endpoint: ORR = best objective response rate (CR+PR) within the first 24 weeks, assessed according to adapted Lugano 2014 response criteria for Lymphoma.

Design: A one-stage phase II trial with unacceptable ORR = 40% and promising ORR = 70%. 12 eligible and evaluable patients are required.

Cohort 2 Population: patients with a relapsed/refractory ALCL, having achieved CR with a treatment including ALK-inhibitor or Brentuximab vedotin of at least 2 months and for whom HSCT is considered for their consolidation therapy. In this case, nivolumab for 24 months would be considered as consolidative immunotherapy instead as HSCT.

Primary endpoint: progression-free survival (PFS) A PFS rate ≤ 50% will be considered as unacceptable. Design: A four-stage phase II trial with unacceptable PFS rate = 50% and promising PFS rate = 75%. A maximum of twenty-six patients will be included: 4 at the 1st and 2nd stages, 8 at the 3rd stage and 10 at the 4th stage.

No more than one third of the included patients must have received more than 12 months of ALK inhibitor or brentuximab. Thus, the inclusion of these patients will be closed after 8 patients.

Condition Relapsing/Refractory ALK+ Anaplastic Large Cell Lymphoma
Treatment Nivolumab cohort 1, Nivolumab cohort 2
Clinical Study IdentifierNCT03703050
SponsorGustave Roussy, Cancer Campus, Grand Paris
Last Modified on24 May 2022


Yes No Not Sure

Inclusion Criteria

All criteria from I-1 to I-10 are required for all patients, in addition of the
cohort-specific 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
Peripheral absolute neutrophil count (ANC) ≥750/μL in patients without bone marrow
I-4. Adequate organ function
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 involvement
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 involvement
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. 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
Cohort 1
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
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
Cohort 2
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
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

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
corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive
E-11. Subjects with another pathology requiring systemic treatment with either
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
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