Phase II trial of nivolumab for pediatric and adult relapsing/refractory ALK+ 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) - NIVO ALCL

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Gustave Roussy

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

2 Jan 2019 → ongoing

Decision date (initial)

2024-09-25

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-516807-17-00

EudraCT number

2018-001447-31

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

Cohort 1: estimate the efficacy of nivolumab treatment in patients with relapsed/refractory ALK+ ALCL in terms of best objective response within the first 24 weeks
Cohort 2: estimate the efficacy of nivolumab treatment as consolidative immunotherapy after CR in patients with relapsed/refractory ALK+ ALCL in terms of progression-free survival

Secondary objectives 3

1. Efficacy: Cohort 1: estimate the efficacy of nivolumab, in terms of - time to response (CR or PR) to nivolumab treatment - response duration in patients who achieve PR/CR - progression-free survival (PFS) - overall survival (OS) - evolution of Minimal Residual Disease (MRD; quantitative PCR) - valuation MRD before inclusion, record MRD results at the last progression and the baseline value at inclusion in the study. MRD should be assessed at baseline before treatment, at week 4 (optional), 8, 16, 24 and every 12-16 weeks up to end of treatment. In case of progression MRD should be assessed at week 8, 16, 24 and every 12-16 weeks up to negativity or any new progression after the beginning of a new treatment. serum will be stored for centralized analysis (anti-ALK, MDD)  Cohort 2: estimate the nivolumab efficacy in terms of - OS in the full Cohort 2 - PFS and OS in the subgroup of Cohort 2 patients having received less than 12 months of ALK inhibitor or brentuximab - Evaluation MRD before inclusion, record MRD results at the last progression and any MRD analyses done between the last progression and the baseline value at inclusion in the study. MRD should be assessed at baseline before treatment and at week 8, 16, 24 and every 12-16 weeks up to end of treatment. In case of progression MRD should be assessed at week 8, 16, 24 and every 12-16 weeks up to negativity or any new progression after the beginning of a new treatment. - Serum will be stored for centralized analysis (anti-ALK, MDD) - evolution of MRD levels by quantitative PCR in patients with positive MRD at inclusion
2. Safety (in cohorts 1 and 2):Assess the short- and long-term safety of the treatment with nivolumab
3. Biology (in cohorts 1 and 2):Monitor the systemic immune effects of nivolumab  Study the associations between biomarkers (on tumour cells, microenvironment, blood, and bone marrow) and nivolumab efficacy

Conditions and MedDRA coding

Relapsing/Refractory ALK+ Anaplastic Large cell Lymphoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. All criteria from I-1 to I-10 are required for all patients, in addition of the cohort-specific criteria
2. 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.
3. I-2. Age at inclusion > 6 months
4. 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
5. 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 involvment - Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase/SGOT ≤3 x ULN in patients without liver involvement and < 5 ULN in patients with liver involvment
6. I-5. Performance status: Karnofsky performance status (for patients >12 years of age) or Lansky Play score (for patients ≤12 years of age) ≥ 40%.
7. I-6. Able to comply with the scheduled disease management (treatment and follow-up), and with the management of toxicity
8. 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 male 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.
9. 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.
10. I-9. Patient affiliated to a social security regimen or beneficiary of the same according to local requirements.
11. 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.
12. 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.
13. 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 18

1. E-1. Patients with prior allogeneic HSCT less than 3 months before study inclusion
2. 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)
3. E-3. Previous organ transplantation
4. E-4. Significant hemophagocytosis in bone marrow, spleen, lymph nodes, or liver must be discussed with the Coordinating Sponsor before inclusion
5. E-5. Presence of any ≥ CTCAE grade 2 treatment-related toxicities with the exception of alopecia, fatigue and peripheral neuropathy.
6. 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
7. E-7. History or evidence of severe acute or chronic infection unless fully healed at least four weeks prior to screening
8. E-8. Known human immunodeficiency virus (HIV) infection
9. 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.
10. 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.
11. 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.
12. E-12. Known hypersensitivity to any component of the products (study drug or ingredients)
13. E-13. Concurrent administration of any other antitumor therapy
14. 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).
15. E-15. Vaccinated with live attenuated vaccines within 4 weeks of the first dose of the study drug
16. E-16. Pregnant or breast-feeding female patient
17. 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
18. E-18. Participation in another clinical study with an investigational product during the study

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. 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 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.
2. Cohort 2: PFS. 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 endpoints 4

1. Efficacy: 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 according to adapted Lugano 2014 Criteria for Malignant Lymphoma (first met of these criteria) until confirmed progression or death  Best objective response rate (CR+PR) according to adapted Lugano 2014 Criteria for Malignant Lymphoma - Progression-free survival (PFS)
2. Efficacy : Cohort 2 : Overall survival  PFS and OS in the subgroup of patients having received less than 12 months of ALK inhibitor or brentuximab  Minimal Residual Disease blood level at various time-points
3. Safety in cohorts 1 and 2:  Acute toxicity (NCI-CTCAE v5) during induction treatment, during maintenance treatment, and one month after the end of treatment Long-term toxicity (toxicity during the off-therapy period up to 5 years after study inclusion)
4. Biology in cohorts 1 and 2:  Anti-ALK antibody blood level at various time-points  Biomarkers on tumor and its microenvironment, blood and bone marrow, including PDL1 and PDL2 expression, and tumor infiltrating lymphocytes and leucocytes populations/cytokines, at different time points.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut Gustave Roussy

Sponsor organisation

Institut Gustave Roussy

Address

114 Rue Edouard Vaillant

City

Villejuif

Postcode

94800

Country

France

Scientific contact point

Organisation

Institut Gustave Roussy

Contact name

Regulatory Affairs teams Bureau Projets et Promotion

Public contact point

Organisation

Institut Gustave Roussy

Contact name

Regulatory Affairs teams Bureau Projets et Promotion

Locations

2 EU/EEA countries · 15 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 19 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications