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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)

Primary Purpose

Relapsing/Refractory ALK+ Anaplastic Large Cell Lymphoma

Status
Recruiting
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Nivolumab cohort 1
Nivolumab cohort 2
Sponsored by
Gustave Roussy, Cancer Campus, Grand Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Relapsing/Refractory ALK+ Anaplastic Large Cell Lymphoma

Eligibility Criteria

6 Months - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

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 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.

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

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

Sites / Locations

  • RigshospitaletRecruiting
  • Gustave RoussyRecruiting
  • CHU Bordeaux Hopital PellegrinRecruiting
  • GROSRecruiting
  • SIBONRecruiting
  • BARBATIRecruiting
  • Centre Léon Berard LyonRecruiting
  • Hopital Saint Louis
  • Landman-ParkerRecruiting
  • CHU Toulouse Hopital des enfantsRecruiting
  • IUC ToulouseRecruiting
  • CHU de nancyRecruiting
  • Princess Maxima center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Cohort 1

Cohort 2

Arm Description

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

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 would be considered as consolidative immunotherapy instead as HSCT.

Outcomes

Primary Outcome Measures

Cohort 1 - Best objective response rate (Complete Response + Partial Response)
In case of PET-positive 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 - Progression Free Survival
PFS is defined as the time since the inclusion in the trial to the first event among relapse and death (whatever the cause of death).

Secondary Outcome Measures

Full Information

First Posted
October 9, 2018
Last Updated
October 9, 2023
Sponsor
Gustave Roussy, Cancer Campus, Grand Paris
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1. Study Identification

Unique Protocol Identification Number
NCT03703050
Brief Title
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)
Acronym
NIVO-ALCL
Official Title
Phase II Trial of Nivolumab for Pediatric and Adult Relapsing/Refractory Anaplastic Large Cell Lymphoma, for Evaluation of Response in Patients With Progressive Disease Cohort 1 or as Consolidative Immunotherapy in Patients in Complete Remission After Relapse Cohort 2
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
January 2, 2019 (Actual)
Primary Completion Date
December 2023 (Anticipated)
Study Completion Date
June 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Gustave Roussy, Cancer Campus, Grand Paris

4. Oversight

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

5. Study Description

Brief Summary
Prospective, non-randomized, single arm phase II trial with 2 cohorts of ALK+ ALCL treated with nivolumab
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Relapsing/Refractory ALK+ Anaplastic Large Cell Lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Model Description
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)
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
38 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Cohort 1
Arm Type
Experimental
Arm Description
Population: relapsed/refractory ALK+ ALCL with progressive disease after treatment (including chemotherapy and ALK inhibitor and/or brentuximab vedotin).
Arm Title
Cohort 2
Arm Type
Experimental
Arm Description
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 would be considered as consolidative immunotherapy instead as HSCT.
Intervention Type
Drug
Intervention Name(s)
Nivolumab cohort 1
Other Intervention Name(s)
OpDIVO
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Nivolumab cohort 2
Other Intervention Name(s)
opdivo
Intervention Description
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
Primary Outcome Measure Information:
Title
Cohort 1 - Best objective response rate (Complete Response + Partial Response)
Description
In case of PET-positive 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.
Time Frame
within the first 24 weeks
Title
Cohort 2 - Progression Free Survival
Description
PFS is defined as the time since the inclusion in the trial to the first event among relapse and death (whatever the cause of death).
Time Frame
up to 12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Months
Accepts Healthy Volunteers
No
Eligibility Criteria
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 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 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. 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 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Veronique Minard, Pr
Phone
+33 (0)1 42 11 41 70
Email
veronique.minard@gustaveroussy.fr
First Name & Middle Initial & Last Name or Official Title & Degree
Anne AUPERIN, MD
Phone
+33 (0)1 42 11 54 99
Email
anne.auperin@gustaveroussy.fr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Véronique Minard, Pr
Organizational Affiliation
Gustave Roussy, Cancer Campus, Grand Paris
Official's Role
Principal Investigator
Facility Information:
Facility Name
Rigshospitalet
City
Copenhagen
Country
Denmark
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Karsten Nysom, MD
Email
Karsten.Nysom@regionh.dk
Facility Name
Gustave Roussy
City
Villejuif
State/Province
Val De Marne
ZIP/Postal Code
94805
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Véronique Minard, MD
Phone
+33 (0)1 42 11 41 70
Email
veronique.minard@gustaveroussy.fr
Facility Name
CHU Bordeaux Hopital Pellegrin
City
Bordeaux
ZIP/Postal Code
33076
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
stephane DUCASSOU, MD
Email
stephane.ducassou@chu-bordeaux.fr
Facility Name
GROS
City
Bordeaux
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
GROS François, MD
Facility Name
SIBON
City
Créteil
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
SIBON David, MD
Phone
0145178245
Email
david.sibon@aphp.fr
Facility Name
BARBATI
City
Lille
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
BARBATI Melissa, MD
Phone
0320444105
Email
melissa.barbati@chu-lille.fr
Facility Name
Centre Léon Berard Lyon
City
Lyon
ZIP/Postal Code
69008
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Anne -Sophie Michalet, MD
Email
sophie.michallet@ihop.fr
Facility Name
Hopital Saint Louis
City
Paris
ZIP/Postal Code
75010
Country
France
Individual Site Status
Withdrawn
Facility Name
Landman-Parker
City
Paris
ZIP/Postal Code
75012
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
LANDMAN-PARKER Judith, MD
Phone
0171738857
Email
judith.landman-parker@aphp.fr
Facility Name
CHU Toulouse Hopital des enfants
City
Toulouse
ZIP/Postal Code
31059
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Marlène Pasquet, MD
Email
marlène.pasquet@chu-toulouse.fr
Facility Name
IUC Toulouse
City
Toulouse
ZIP/Postal Code
31059
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lucie Oberic, MD
Phone
+33 (0)5 31 15 63 53
Email
oberic.lucie@iuct-oncopole.fr
Facility Name
CHU de nancy
City
Vandœuvre-lès-Nancy
ZIP/Postal Code
54500
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
PHULPIN Aurélie, MD
Email
a.phulpin@chru-nancy.fr
Facility Name
Princess Maxima center
City
Utrecht
Country
Netherlands
Individual Site Status
Not yet recruiting

12. IPD Sharing Statement

Plan to Share IPD
Undecided

Learn more about this trial

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)

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