A Study of Safety and Efficacy of PET-adapted Treatment With Nivolumab at the Fixed Dose 40 mg, Ifosfamide, Carboplatin, Etoposide (NICE-40) in Patients With Relapsed/Refractory Hodgkin Lymphoma

Study Overview
=================
Brief Summary
-----------------
Nivolumab is an anti-PD-1 antibody highly effective in patients with relapsed/refractory classical Hodgkin lymphoma. A PET-adapted regimen of Nivo combined with ICE as first salvage therapy was shown to induce high response rates and favorable progression-free survival as a bridge to autologous stem cell transplantation, allowing to omit salvage chemotherapy in a substantial proportion of r\r cHL patients. This study evaluates the safety and efficacy of PET-adapted treatment of nivolumab at the fixed dose of 40 mg in combination with ifosfamide, carboplatin, and etoposide (NICE-40) in patients with relapsed/refractory Hodgkin Lymphoma.

Official Title
-----------------
Multicenter Study of Safety and Efficacy of PET-adapted Treatment With Nivolumab at the Fixed Dose 40 mg, Ifosfamide, Carboplatin, Etoposide (NICE-40) in Patients With Relapsed/Refractory Hodgkin Lymphoma

Conditions
-----------------
Hodgkin Lymphoma

Intervention / Treatment
-----------------
* Drug: Nivolumab
* Drug: Ifosfamide
* Drug: Carboplatin
* Drug: Etoposide


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis: Histologically confirmed Hodgkins lymphoma Relapsed or refractory disease after the first line of treatment Age 18-70 years old Ejection fraction greater than 50% ECOG 0-2 status Signed informed consent No severe concurrent illness Exclusion Criteria: Uncontrolled bacterial or fungal infection at the time of enrollment Requirement for vasopressor support at the time of enrollment Severe organ failure: creatinine more than 2 norms; ALT, AST more than 5 norms; bilirubin more than 1.5 norms Karnofsky index <30% Pregnancy Somatic or psychiatric disorder making the patient unable to sign an informed consent Active or prior documented autoimmune disease requiring systemic treatment.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Main arm<br>Patients will receive 6 cycles of nivolumab at the fixed dose of 40 mg, with subsequent assessment of response by PET-CT. Patients with CR will proceed to ASCT. Patients with <CR after nivolumab monotherapy will be treated with 2 cycles of a combination of nivolumab at the fixed dose 40 mg, ifosfamide, carboplatin and etoposide (NICE-40), with subsequent PET-CT assessment. | Drug: Nivolumab<br>* 6 infusions of nivolumab at a fixed dose of 40 mg, 14 days apart, and infusion of nivolumab on day 0 of the NICE-40.<br>Drug: Ifosfamide<br>* 5000 mg / m2, 24-hour infusion on day 2 of the NICE-40.<br>Drug: Carboplatin<br>* Optimized to get AUC = 5 (max. 800 mg) on day 2 of the NICE-40.<br>Drug: Etoposide<br>* 100 mg / m2 intravenously on 1-3 days of the NICE-40.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of grade 3 or higher treatment-related adverse events by CTCAE 4.03 | Toxicity parameters based on NCI CTCAE 4.03 grades: hematological toxicity (CBC), hepatotoxicity (liver function tests), nephrotoxicity (creatinine), neurotoxicity (attending physician assessment), fatigue (attending physician assessment), rash (attending physician assessment), colitis (attending physician assessment), pneumonitis (attending physician assessment), autoimmune disorders (level of hormones, presence of autoimmune antibodies, attending physician assessment). | 12 months | 
| Overall Response Rate (ORR) | Overall response rate (ORR), defined as the proportion of patients with complete response (CR) or partial response (PR) in measurable lesions as defined by LYRIC and Lugano 2014 criteria | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DOR) |  | 24 months | 
| Overall Survival (OS) |  | 24 months | 
| Progression-Free Survival (PFS) |  | 24 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Nivolumab, Ifosfamide, Carboplatin, Etoposide