BIOmarker-guided Study to Evaluate the Efficacy and Safety of cemipLimab for advancEd Cutaneous T-cell Lymphoma

An Interventional, Single-arm, Open-label Phase I/II Study Investigating the Efficacy and Safety of Anti-PD1 Immunotherapy for the Treatment of Patients With Cutaneous T-cell Lymphoma (Mycosis Fungoides)

Background - Advanced cutaneous T-cell lymphoma (mycosis fungoides, MF) is an incurable extranodal mature lymphoma with poor prognosis. Currently available therapies provide only short-term remissions.

Rationale - MF is an immunogenic cancer and expresses a high number of neoantigens. therefore it it reasonable to assume that it would respond to immune checkpoint inhibitors.

Objectives - The primary objective is to test the clinical efficacy (objective response rate) of the immune checkpoint inhibitor cemiplimab in patients with advanced mycosis fungoides (MF) who failed first-line therapy, defined as the sum of complete and partial responses (where at least 50% reduction of mSWAT is achieved).

Inclusion Criteria:

1. Patients with histological confirmation of mycosis fungoides; diagnosis must be confirmed by the Northern Alberta Cutaneous Lymphoma Review Board.

2. Minimum disease stage(s) for enrolment: stage IIB (see appendix B).

3. Patients must be 18 years of age or older.

4. Patients must be capable of providing consent to enrolment and willing to comply with study treatment and follow-up.

5. Patients with a performance status of ECOG 0-2(11) will be eligible for enrolment (see appendix A).

6. Previous failure of ≥1 prior therapies, including PUVA (psoralen and UVA phototherapy), systemic interferon α, systemic retinoid therapy (bexarotene, alliretinoin or acitretin), systemic histone deacetylase (HDAC) inhibitor (vorinostat or romidepsin), radiation therapy or systemic chemotherapy (including, but not limited to methotrexate and gemcitabine).

7. Women of child bearing potential (WOCBP) must have a negative serum (or urine) pregnancy test within 72 hours prior to the first dose of study treatment. WOCBP is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy or bilateral salpingectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in a woman over age 45 years in the absence of other biological or physiological causes.

8. Patients of childbearing/reproductive potential should use adequate birth control methods, as defined by the investigator, during the study treatment period and for a period of 30 days after the last dose of study drug. A highly effective method of birth control is defined as those that result in low failure rate (i.e. less than 1% per year) when used consistently and correctly. Note: abstinence is acceptable if this is established and preferred contraception for the patient and is accepted as a local standard.

9. Absence of any condition hampering compliance with the study protocol and follow- up schedule; those conditions should be discussed with the patient before registration in the trial.

10. The following adequate organ function laboratory values must be met:

    a. Hematological: i. Absolute neutrophil count (ANC) ≥ 1,500 /mcL ii. Platelet count ≥100,000 / mcL iii. Hemoglobin >90 mg/dL (transfusions are permitted) b. Renal serum creatinine or (measured or calculated) creatinine clearance (GFR can also be used in place of creatinine or CrCl)≤1.5 X upper limit of normal (ULN) OR ≥ 60 mL/min for subject with creatinine levels >1.5 X institutional ULN c. Hepatic: i. Total serum bilirubin <1.5 x ULN ii. AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN

Exclusion Criteria:

1. Known immunodeficiency (including known history of human immunodeficiency virus (HIV)).
2. Active Hepatitis B or Hepatitis C. Testing for HBV or HCV is not mandatory for enrolment to study, but may occur at the discretion of the investigator. Inactive HBsAg carriers with prophylactic antiviral agent are allowed.
3. Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids doses >20 mg daily for more that 2 months, or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
4. Patients who have been previously treated with a PD(L)-1 immune checkpoint inhibitor regimen are ineligible.
5. Patients with a requirement for concomitant radiation therapy are ineligible; prior treatment with radiation therapy is not exclusionary, but a wash-out period of no less than 28 days is required prior to study enrolment.
6. Patients receiving immunosuppressive agents within 30 days prior to the first dose of trial treatment, including non-steroid immunosuppressive agents (e.g. anti-TNFα biologic agents, methotrexate, mycophenolate mofetil, tacrolimus) or systemic corticosteroids.
7. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification Class II) or serious cardiac arrhythmia requiring medication.
8. Presence of a concurrent (synchronous) second primary malignancy.
9. Persisting toxicity related to prior therapy (NCI CTCAE v. 5.0 Grade > 1); however, alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based on the investigator's judgment are acceptable.
10. Known prior severe hypersensitivity to study drugs or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v5.0 Grade ≥ 3).
11. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
12. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial