Clinical trial NCT03769181: A Study of Isatuximab-based Therapy in Participants With Lymphoma
Official title: A Phase 1/2 Open-label, Multi-center, Safety, Preliminary Efficacy and Pharmacokinetic (PK) Study of Isatuximab in Combination With Other Anti-cancer Therapies in Participants With Lymphoma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Lymphoma
Keywords: Anti-CD38 monoclonal antibody
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2018-12-07
Enrollment: 58
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Primary Objectives:

Phase 1

-To characterize the safety and tolerability of isatuximab in combination with cemiplimab in participants with relapsed and refractory classic Hodgkin's lymphoma (cHL), diffuse large B-cell lymphoma (DLBCL) or peripheral T-cell lymphoma (PTCL), and to confirm the recommended Phase 2 dose (RP2D).

Phase 2

* Cohort A1 (anti-programmed cell death protein 1/ligand 1 \[PD-1/PD-L1\] naïve cHL): To assess the complete remission (CR) rate of isatuximab in combination with cemiplimab.
* Cohort A2 (cHL progressing from PD-1/PD-L1), B (DLBCL) and C (PTCL): To assess the objective response rate (ORR) of isatuximab in combination with cemiplimab.

Secondary Objectives:

* To evaluate the safety of the RP2D of the combination of isatuximab with cemiplimab.
* To evaluate the safety of the combination of isatuximab with cemiplimab and radiotherapy in participants with cHL.
* To evaluate the immunogenicity of isatuximab and cemiplimab when given in combination.
* To characterize the pharmacokinetic (PK) profile of isatuximab and cemiplimab when given in combination.
* To assess overall efficacy of isatuximab in combination with cemiplimab and isatuximab in combination with cemiplimab and radiotherapy.

Detailed description: The total study duration per participant was up to 28 months, including an up to 28-day screening period, an up to 96-week treatment period, and a 90-day safety follow up period.

Eligibility criteria: Inclusion criteria:

* Participants greater than or equal to (\>=) 12 years of age inclusive, at the time of signing the informed consent.
* Disease location amenable to tumor biopsy at Baseline.
* Measurable disease.
* For Cohort A1 (cHL anti-programmed cell death protein 1/ligand 1 \[PD-1/PD-L1\] inhibitor naïve): Histologically confirmed advanced cHL that had relapsed or progressed after at least 3 lines of systemic therapy that included autologous hematopoietic stem cell transplant (auto-HSCT) or auto-HSCT and brentuximab vedotin (BV).
* For Cohort A2 (cHL anti-PD-1/PD-L1 inhibitor progressor): Histologically confirmed advanced cHL which had relapsed or progressed after one previous anti-PD-1/PD-L1 containing regimen as the most recent prior therapy but no more than 4 lines of previous chemotherapy including the anti-PD-1/PD-L1 containing regimen and documentation of benefit during or after the anti-PD-1/PD-L1 containing regimen within 4 months prior to initiation of investigational medicinal product.
* For Cohort B (diffuse large B-cell lymphoma \[DLBCL\]): Histologically confirmed advanced DLBCL that had relapsed or progressed after 2 lines of systemic therapy including auto-HSCT or 2 lines of systemic therapy for participants who were not eligible for auto-HSCT.
* For Cohort C (peripheral T-cell lymphoma \[PTCL\]): Histologically confirmed advanced PTCL that had relapsed or progressed after either first-line chemotherapy and auto-HSCT as consolidation of first remission or first-line chemotherapy if participants were ineligible for auto-HSCT.
* Body weight of greater than (\>) 45 kilograms for participants with age less than (\<)18 years.

Exclusion criteria:

* Prior exposure to agent that blocks CD38.
* For participants with cHL (PD-1/PD-L1 naïve), DLBCL or PTCL prior exposure to any agent (approved or investigational) that blocks the PD-1/PD-L1, PD-L2, CD137, cytotic T-lymphocyte-associated protein 4 or LAG-3.
* Evidence of other immune related disease/conditions.
* Had received a live-virus vaccination within 28 days of planned treatment start; seasonal flu vaccines that do not contain live virus are permitted.
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) \>=2.
* Poor bone marrow reserve.
* Poor organ function.

The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Primary outcomes:
measure: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Cycle 1 (28 days)
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), and Treatment-Emergent Serious Adverse Events (TESAEs)
timeFrame: From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: up to 103 weeks)
measure: Number of Participants With Laboratory Abnormalities: Hematological Parameters
timeFrame: From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: up to 103 weeks)
measure: Number of Participants With Laboratory Abnormalities: Electrolytes
timeFrame: From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: up to 103 weeks)
measure: Number of Participants With Laboratory Abnormalities: Renal Parameters
timeFrame: From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: up to 103 weeks)
measure: Number of Participants With Laboratory Abnormalities: Liver Function Parameters
timeFrame: From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: up to 103 weeks)
measure: Cohort A1: Percentage of Participants With Complete Response (CR)
timeFrame: From the date of randomization until disease progression or death or study cut-off date, whichever comes first (maximum duration: up to 103 weeks)
measure: Cohort A2, B and C: Percentage of Participants With Objective Response (OR)
timeFrame: From the date of randomization until disease progression, or death or study cut-off date, whichever comes first (maximum duration: up to 103 weeks)
Secondary outcomes:
measure: Number of Participants With Treatment-Induced and Treatment Boosted Antidrug Antibodies (ADA) Against Isatuximab
timeFrame: From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: up to 103 weeks)
measure: Number of Participants With Treatment-Induced and Treatment Boosted Antidrug Antibodies (ADA) Against Cemiplimab
timeFrame: From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: up to 103 weeks)
measure: Pharmacokinetics (PK) Parameter: Plasma Concentration of Isatuximab at End of Infusion (CEOI)
timeFrame: End of infusion (EOI up to 3 hours) on Day 2 of Cycle 1
measure: PK Parameter: Maximum Observed Plasma Concentration (Cmax) After the First Infusion of Isatuximab
timeFrame: At Start of infusion (SOI; 0 hour), before actual EOI (up to 3 hours), EOI+ 4 hours, 72 hours and 144 hours post-dose on Day 2 of Cycle 1
measure: PK Parameter: Time to Reach Cmax (Tmax) After the First Infusion of Isatuximab
timeFrame: At SOI (0 hour), before actual EOI (up to 3 hours), EOI+ 4 hours, 72 hours and 144 hours post-dose on Day 2 of Cycle 1
measure: PK Parameter: Area Under the Plasma Concentration (AUClast) Versus Time Curve After the First Infusion of Isatuximab
timeFrame: At SOI (0 hour), before actual EOI (up to 3 hours), EOI+ 4 hours, 72 hours and 144 hours post-dose on Day 2 of Cycle 1
measure: PK Parameter: Last Concentration Observed Above the Lower Limit of Quantification (Clast) After the First Infusion of Isatuximab
timeFrame: At SOI (0 hour), before actual EOI (up to 3 hours), EOI+ 4 hours, 72 hours and 144 hours post-dose on Day 2 of Cycle 1
measure: PK Parameter: Time of Clast (Tlast) After the First Infusion of Isatuximab
timeFrame: At SOI (0 hour), before actual EOI (up to 3 hours), EOI+ 4 hours, 72 hours and 144 hours post-dose on Day 2 of Cycle 1
measure: PK Parameter: Area Under the Concentration Versus Time Curve Over the Dosing Interval (AUC0-168 Hours) After the First Infusion of Isatuximab
timeFrame: At SOI (0 hour), before actual EOI (up to 3 hours), EOI+ 4 hours, 72 hours and 144 hours post-dose on Day 2 of Cycle 1
measure: PK Parameter: Area Under the Concentration Versus Time Curve Over the Dosing Interval (AUC0-144 Hours) After the First Infusion of Isatuximab
timeFrame: At SOI (0 hour), before actual EOI (up to 3 hours), EOI+ 4 hours, 72 hours and 144 hours post-dose on Day 2 of Cycle 1
measure: PK Parameter: Plasma Trough Concentration (Ctrough) of Isatuximab
timeFrame: Pre-infusion on Cycle1:Day 2, 8, 15, & 22, Cycle 2:Day 1 &15, Cycle 3:Day 1 &15, Cycle 4:Day 1 &15, Cycle 5 Day1,Cycle 6 Day1,Cycle 7 Day 1, Cycle 8 Day1, Cycle 9 Day1, Cycle 10 Day1, Cycle 11 Day1, Cycle14 Day1, Cycle 17 Day1, Cycle 20 Day1,Cycle 23 Day1
measure: PK Parameter: Serum Concentration of Cemiplimab at End of Infusion (CEOI)
timeFrame: EOI (up to 30 minutes [min]) on Day 1 of Cycle 1
measure: PK Parameter: Maximum Observed Concentration (Cmax) After the First Infusion of Cemiplimab
timeFrame: At SOI (0 hour), before actual EOI (up to 30 min), EOI+4 hours, 96 hours, 168 hours, and 336 hours post-dose on Day 1 of Cycle 1
measure: PK Parameter: Time to Reach Cmax (Tmax) After the First Infusion of Cemiplimab
timeFrame: At SOI (0 hour), before actual EOI (up to 30 min), EOI+4 hours, 96 hours, 168 hours, and 336 hours post-dose on Day 1 of Cycle 1
measure: PK Parameter: Area Under the Serum Concentration (AUClast) Versus Time Curve After the First Infusion of Cemiplimab
timeFrame: At SOI (0 hour), before actual EOI (up to 30 min), EOI+4 hours, 96 hours, 168 hours, and 336 hours post-dose on Day 1 of Cycle 1
measure: PK Parameter: Last Concentration Observed Above the Lower Limit of Quantification (Clast) After the First Infusion of Cemiplimab
timeFrame: At SOI (0 hour), before actual EOI (up to 30 min), EOI+4 hours, 96 hours, 168 hours, and 336 hours post-dose on Day 1 of Cycle 1
measure: PK Parameter: Time of Clast (Tlast) After the First Infusion of Cemiplimab
timeFrame: At SOI (0 hour), before actual EOI (up to 30 min), EOI+4 hours, 96 hours, 168 hours, and 336 hours post-dose on Day 1 of Cycle 1
measure: PK Parameter: Area Under the Serum Concentration Versus Time Curve Over the Dosing Interval (AUC0-336 Hours) After the First Infusion of Cemiplimab
timeFrame: At SOI (0 hour), before actual EOI (up to 30 min), EOI+4 hours, 96 hours, 168 hours, and 336 hours post-dose on Day 1 of Cycle 1
measure: PK Parameter: Serum Trough Concentration (Ctrough) of Cemiplimab
timeFrame: Pre-infusion on Cycle 1:Day 1 & Day15,Cycle 2:Day 1 & Day 15,Cycle 3:Day 1 & Day 15,Cycle 4:Day 1 & Day15,Cycle 5 Day 1,Cycle 6 Day 1,Cycle7 Day1,Cycle 8 Day 1,Cycle 9 Day1,Cycle 10 Day1,Cycle11 Day1,Cycle14 Day 1,Cycle 17 Day1,Cycle20 Day 1,Cycle 23 Day1
measure: Percent Change From Baseline in Tumor Burden
timeFrame: Up to 103 weeks
measure: Duration of Response (DOR)
timeFrame: From the date of first response until disease progression or death, or study cut-off date whichever occurred first (maximum duration: up to 103 weeks)
measure: Percentage of Participants With Disease Control (DC)
timeFrame: From the date of first response until disease progression or death, or study cut-off date whichever occurred first (maximum duration: up to 103 weeks)
measure: Progression Free Survival (PFS)
timeFrame: From the date of randomization until disease progression, or death or study cut-off date, whichever comes first (maximum duration: up to 103 weeks)
measure: Cohort A1 and A2: Percentage of Participants With Objective Response
timeFrame: From the date of randomization until disease progression, or death or study cut-off date, whichever comes first (maximum duration: up to 103 weeks)
measure: Cohort A1 and A2: Percentage of Participants With Complete Response
timeFrame: From the date of randomization until disease progression, or death or study cut-off date, whichever comes first (maximum duration: up to 103 weeks)
Other outcomes:
Locations:
city: Dijon
country: France
facility: Investigational Site Number :2500005
city: Montpellier
country: France
facility: Investigational Site Number :2500004
city: Nantes
country: France
facility: Investigational Site Number :2500002
city: Pessac
country: France
facility: Investigational Site Number :2500007
city: Villejuif
country: France
facility: Investigational Site Number :2500001
city: Rozzano
country: Italy
facility: Investigational Site Number :3800003
state: Milano
city: Bologna
country: Italy
facility: Investigational Site Number :3800002
city: Brescia
country: Italy
facility: Investigational Site Number :3800006
city: Gangnam-gu
country: Korea, Republic of
facility: Investigational Site Number :4100001
state: Seoul-teukbyeolsi
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number :4100002
state: Seoul-teukbyeolsi
city: Amsterdam
country: Netherlands
facility: Investigational Site Number :5280002
city: Maastricht
country: Netherlands
facility: Investigational Site Number :5280001
city: Coimbra
country: Portugal
facility: Investigational Site Number :6200002
city: Lisboa
country: Portugal
facility: Investigational Site Number :6200004
city: Porto
country: Portugal
facility: Investigational Site Number :6200003
city: Barcelona
country: Spain
facility: Investigational Site Number :7240003
state: Barcelona [Barcelona]
city: Barcelona
country: Spain
facility: Investigational Site Number :7240005
state: Barcelona [Barcelona]
city: Hospitalet de Llobregat
country: Spain
facility: Investigational Site Number :7240002
state: Barcelona [Barcelona]
city: Madrid / Madrid
country: Spain
facility: Investigational Site Number :7240004
state: Madrid, Comunidad De
city: Taichung
country: Taiwan
facility: Investigational Site Number :1580002
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: Carlo-Stella C, Zinzani PL, Sureda A, Araujo L, Casasnovas O, Carpio C, Yeh SP, Bouabdallah K, Cartron G, Kim WS, Cordoba R, Koh Y, Re A, Alves D, Chamuleau M, Le Gouill S, Lopez-Guillermo A, Moreira I, van der Poel MWM, Abbadessa G, Meng R, Ji R, Lepine L, Saleem R, Ribrag V. A phase 1/2, open-label, multicenter study of isatuximab in combination with cemiplimab in patients with lymphoma. Hematol Oncol. 2023 Feb;41(1):108-119. doi: 10.1002/hon.3089. Epub 2022 Oct 31.