Classical Hodgkin lymphoma (CHL), diffuse large B-cell lymphoma(DLBCL) or Peripheral T-Cell Lymphoma

Primary 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) and peripheral T-cell lymphoma (PTCL), and to confirm the recommended Phase 2 dose (RP2D). Phase 2 : 1 - Cohort A1 (anti-PD-1/PD-L1 naive cHL) : To assess the complete remission (CR) rate of isatuximab in combination with cemiplimab. 2 - 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

Isatuximab

Isatuximab

vial

20 mg/25ml

Phase 1
Safety and tolerability will be assessed based on dose limiting
toxicities (DLTs, in Cycle 1), adverse events (AEs)/serious
adverse events (SAEs), and laboratory abnormalities

Phase 2:
1 - Cohort A1: CR rate as defined by as the proportion of
participants who have a CR as a best overall response during
the isatuximab + cemiplimab therapy period using the 5-point
scale per the Lugano classification (1)
(Appendix 6 Section 10.6).
2 - Cohorts A2, B, and C:
ORR defined as the proportion of participants who have a CR
or PR as a best overall response during isatuximab +
cemiplimab therapy period using the 5-point scale per the
Lugano classification, (1)

INCLUSION CRITERIA
Participants are eligible to be included in the study only if all of the following criteria apply:
I 01. Age: Participant must be ≥12 years of age inclusive (or the age deemed appropriate per
local health authority or IRB approval), at the time of signing the informed consent.
I 02. Disease location amenable to mandatory tumor biopsy at baseline (unless clinically
unfeasible and after discussion with Sanofi Medical Monitor for Phase 1 and
Phase 2 Stage 1; mandatory for Phase 2 Stage 2), and possibly at Cycle 2 Day 1. If disease
location is in a superficial lymph node, excisional biopsy or resected tissue is required if
clinically feasible; otherwise, core needle biopsy is acceptable. Fine needle aspirates are
not acceptable. Archival tumor biopsy sample may be used to replace mandatory baseline
biopsy, if the sample was obtained after progression from immediate prior therapy.
I 03. Measurable disease defined as at least one measurable node that must have an LDi (longest
diameter) >1.5 cm and/or measurable extranodal lesion that must an LDi >1cm according
to Lugano classification (1). Tumor sites that are considered measureable must not have
received prior radiotherapy.
For Phase 1 and Cohort A1 (cHL anti-PD-1/PD-L1 naïve):
I 04. Histologically confirmed advanced cHL that has relapsed or progressed after:
 At least 3 lines of systemic therapies that may include auto-HSCT (See Appendix 10
Section 10.10 for definition of one line of therapeutic regimen) OR
 Auto-HSCT and Brentuximab vedotin.
For Phase 1 and Cohort A2 (cHL anti-PD-1/PD-L1 inhibitor progressor):
I 05. Histologically confirmed advanced cHL which has relapsed or progressed after one
previous anti-PD-1/PD-L1 containing regimen as the most recent prior therapy.
I 06. Documentation of benefit (defined as CR, PR or stable disease [SD] ≥6 months at
≥1 radiographic imaging scans) but subsequent progression during or after the prior
anti-PD1/PDL1 containing regimen. Progression has to occur within 6 months from last
dose of the prior anti-PD1/PDL1 containing regimen. IMP must be started within
4 months from progression. The site’s study team must confirm that radiographic progression has occurred per IWG criteria for Malignant Lymphoma following initiation of
the anti PD-1/PD-L1 containing regimen.
For Phase 1 and Cohort B (DLBCL):
I 07. Histologically confirmed advanced DLBCL that has relapsed or progressed after:
 2 lines of systemic therapy including auto-HSCT, OR
 2 lines of systemic therapy for participants who are not eligible for auto-HSCT.
For Phase 1 and Cohort C (PTCL):
I 08. Histologically confirmed advanced PTCL that has relapsed or progressed after:
 Chemotherapy and auto-HSCT as consolidation of first remission, OR
 First-line chemotherapy if participants are ineligible for auto-HSCT.
Weight
I 09. Body weight of >45 kg.
Sex
I 10. Male or Female
Male participants: A male participant must agree to use contraception as detailed in Appendix 5
(Section 10.5) of this protocol during the intervention period and for at least 6 months, after the
last dose of study intervention and refrain from donating sperm during this period.
Female participants: A female participant is eligible to participate if she is not pregnant
(see Appendix 5 Section 10.5), not breast-feeding, and at least one of the following conditions
applies:
 Not a woman of childbearing potential (WOCBP) as defined in Appendix 5 (Section 10.5)
OR
 A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 (Section 10.5)
during the intervention period and for at least 6 months after the last dose of study
intervention.
Informed Consent
I 11. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1.3)
which includes compliance with the requirements and restrictions listed in the informed
consent form (ICF) and in this protocol. In countries where legal age of majority is above
18 years and for participants less than 18 years, a specific ICF must also be signed by the
participant’s legally authorized representative.

EXCLUSION CRITERIA
Participants are excluded from the study if any of the following criteria apply:
Medical conditions
E 01. Eastern Cooperative Oncology Group (ECOG) performance status of ≥2.
E 02. Predicted life expectancy <3 months.
E 03. Central nervous system lymphoma, active brain metastases or leptomeningeal metastases.
Participants with asymptomatic central nervous system metastases which have been stable
(defined as without evidence of progression by MRI or other imaging modality for at least
28 days prior to initiation of study intervention and any neurologic symptoms have
returned to baseline) following treatment with surgery or radiation therapy are allowed.
E 04. Symptomatic or impending cord compression at study entry.
E 05. Comorbidity requiring corticosteroid therapy (>10 mg prednisone/day or equivalent)
within 14 days of study intervention initiation. Physiologic replacement doses are allowed
even if they are >10 mg of prednisone/day or equivalent, as long as they are not being
administered for immunosuppressive intent. Inhaled, intranasal, local injection or topical
steroids are permitted, provided that they are not for treatment of an autoimmune disorder.
E 06. Significant cardiac dysfunction (defined as left ventricular ejection fraction [LVEF] of
<50%), New York Heart Association classification for chronic heart failure III-IV,
symptomatic coronary artery disease, major clinically significant electrocardiogram (ECG)
abnormality, significant ventricular arrhythmias; myocardial infarction within 6 months;
unstable or poorly controlled angina pectoris.
E 07. Active, known, or suspected autoimmune disease that has required systemic treatment in
the past 2 years (i.e., with use of disease modifying agents, corticosteroids or
immunosuppressive drugs), except for replacement therapy (e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc).
Vitiligo, hypothyroidism or Sjogren’s syndrome are eligible.
E 08. Known seropositive and requiring anti-viral therapy for human immunodeficiency (HIV)
virus, hepatitis B virus (HBV), or hepatitis C virus (HCV), unless they are negative when
tested by polymerase chain reaction (PCR) or equivalent. Active tuberculosis, or severe
infection requiring parenteral antibiotic treatment.
E 09. DLCO <60% for participants previously treated with bleomycin.
E 10. Known second malignancy either progressing or requiring active treatment within the last
3 years (except for basal cell carcinoma of the skin, squamous cell carcinoma of the skin,
DICT or in situ cervical cancer that has undergone potentially curative therapy).
E 11. History of or current interstitial lung disease or pneumonitis that requires oral or
IV glucocorticoids to assist with management (radiation pneumonitis in the radiation field
is permitted).
E 12. Participant has undergone major surgery ≤3 weeks prior to starting study treatment or has
not recovered from the side effects of major surgery.
E 13. Mediastinal lymphomas.
Phase 1 and Cohorts A1 and A2
E 14. Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) subtype is not allowed.
Phase 1 and Cohort B
E 15. tFL and CLL Richter transformation subtypes are not allowed.
Phase 1 and Cohort C
E 16. Cutaneous T-cell lymphoma subtype is not allowed.
Prior/concomitant therapy
E 17. Prior treatment with an agent (approved or investigational) that blocks CD38 (participants
who joined a study with an anti-CD38 but have written confirmation they were on control
arm are allowed providing that therapy is allowed).
E 18. Prior treatment with idelalisib.
E 19. Prior allogeneic HSCT.
E 20. Auto-HSCT less than 90 days prior to initiation of study intervention. Carmustine (BCNU)
≥600 mg/m² received as part of the pre-transplant conditioning regimen.
E 21. Receipt of a live-virus vaccination within 28 days of planned treatment start. Seasonal flu
vaccines that do not contain live virus are permitted.
E 22. Wash out period of less than 2 weeks from previous antitumor chemotherapy, tyrosine
kinase inhibitor immunotherapy or any palliative radiotherapy; less than 4 weeks from
previous antitumor biological therapy (e.g., rituximab and brentuximab vedotin).
E 23. Participant has received wide field radiotherapy ≤4 weeks prior to starting study treatment,
or limited field radiation for palliation ≤2 weeks prior to starting study treatment, or has
not recovered from the side effects of such therapy.
E 24. Treatment-related immune-mediated (or immune-related) AEs from immune-modulatory
agents (including but not limited to anti-PD-1/PD-L1 agents, anti-CTLA-4 monoclonal
antibodies, and PI3K δ inhibitors) that caused permanent discontinuation of the agent, or
that were Grade 3 or 4 in severity, or that have not resolved to baseline at least 3 months
prior to initiation of IMP. For other agents, treatment-related immune-mediated (or
immune-related) AEs that were Grade 2 or above.
Cohorts A1, B and C:
E 25. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti CTLA-4
antibody or LAG-3 (or any other antibody or drug specifically targeting T-cell
costimulation or checkpoint pathways).
Phase 1 and Cohort A2
E 26. No anti-cancer therapy including radiotherapy or auto-HSCT between failure of
anti-PD-1/PD-L1 therapy and initiation of IMP).
Prior/concurrent clinical study experience
E 27. Last dose of prior investigational agent within 28 days from initiation of study
intervention.
Diagnostic assessments
E 28. Treatment-related immune-mediated (or immune-related) AEs from immune-modulatory
agents (including anti PD-1/PD-L1 agents for Cohort A2) that caused permanent
discontinuation of the agent, or that were Grade 3 or 4 in severity, or that have not resolved
or improved to baseline at least 3 months prior to initiation of study intervention.
E 29. Ongoing AEs (excluding alopecia and fatigue) caused by any prior anti-cancer therapy
≥ Grade 2 (NCI-CTCAE version 5).
E 30. Inadequate organ and bone marrow function at the Screening visit:
a) Absolute neutrophil count <1000/mm^3 (1.0 × 10^9/L; after at least 2 weeks without
WBC growth factors).
b) Platelets <50 000/mm^3 (50 × 10^9/L; after at least a week without platelet
transfusion).
c) Hemoglobin <9 g/dL (<5.6 mmol/L; after at least a week without transfusion).
d) Total bilirubin >2 upper limit of normal (ULN), except for participants with Gilbert's
syndrome.
e) Aspartate aminotransferase and/or alanine aminotransferase >3 × ULN (or >5 × ULN
for participants with liver metastases).
f) Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 using Modified Diet
in Renal Disease Formula (MDRD).
E 31. Known intolerance or hypersensitivity to any component of isatuximab and/or cemiplimab.
E 32. History or current evidence of any condition, therapy, or laboratory abnormality that might
confound the results of the study, interfere with the participant’s participation for the full
duration of the study, or is not in the best interest of the participant to participate, in the
opinion of the treating Investigator.