IRB Study Number 23-374
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objective
To demonstrate superiority of fianlimab + cemiplimab compared to pembrolizumab, as measured by RFS.
2.2. Secondary Objective(s)
• To demonstrate superiority of fianlimab + cemiplimab compared to pembrolizumab, as measured by OS.
• To demonstrate superiority of fianlimab + cemiplimab compared to pembrolizumab, as measured by MSS.
• To evaluate whether post-operative adjuvant therapy improves DMFS, in stage IIC or III patients receiving fianlimab + cemiplimab compared to pembrolizumab.
• To assess impact of fianlimab + cemiplimab on quality of life as compared to pembrolizumab in adults.
• To assess safety and tolerability of fianlimab + cemiplimab compared to pembrolizumab.
• To characterize PK of fianlimab + cemiplimab using sparse PK sampling in patients 12 years of age and older.
• To assess immunogenicity of fianlimab and against cemiplimab.
Inclusion Criteria
At least 12 years of age on the date of providing informed consent. Note: Patients who are <18 years will be included in the territories where accepted per local laws, regulations and ECs. Before enrolling a patient < 18 years, every investigator must seek and document clearance from the study monitor and site staff to ensure adherence to local laws, regulations, and ECs.
All patients must be either stage IIC, III, or stage IV per AJCC 8th edition (Amin, 2017) and have histologically confirmed melanoma that is completely surgically resected in order to be eligible.
a. Patients with stage IIIA disease must have at least 1 lymph node micrometastasis measuring >1 mm in greatest diameter.
b. Patients with stage IIC, IIIA, and IV (M1c/d) are each capped at 10% of the total population (ie, 30% in total).
c. Patients with acral and mucosal melanoma are allowed, provided that they underwent complete resection, with 10% cap total for both types.
d. Patients with melanoma of unknown primary may be allowed, provided that they underwent complete resection, and that Investigator has discussed enrollment with the Sponsor.
e. Stage IIC melanoma must be confirmed by a pathologically negative SLNB specimen and no evidence of regional or distant metastasis.
- Complete surgical resection must be performed within 12 weeks prior to randomization, and enrollment may occur only after satisfactory wound healing from the surgery.
a. Complete surgical resection is defined as negative microscopic margins on resected primary tumors along with SLNB. Complete lymph node dissection in the case of a positive SLNB is not mandatory provided that patient is clinically lymph node negative and resection margins are microscopically clear. Surgical/pathology reports documenting complete resection must be reviewed and signed by the Investigator before study entry for all patients.
b. A solitary skin melanoma lesion without epithelial component should be treated as a primary tumor and must undergo SLNB.
c. For all resected stage IV M1d patients, neurosurgical and pathology reports documenting complete resection and clear margins must be reviewed and signed by the Investigator prior to enrollment.
- All patients must have disease-free status documented by a complete physical examination and imaging studies within 4 weeks prior to randomization. Imaging must include a scan of the chest, abdomen, pelvis (preferably using contrast X-ray CT. See Imaging Manual for details), and of all relevant anatomical areas and sites of resected disease (for patients with stage III and IV disease). Contrast-enhanced MRI of brain must be performed at staging for all patients.
a. For patients with abnormal or suspicious findings in the screening scans, residual malignancy and/or metastatic disease must be excluded by 18F-FDG PET-CT and/or biopsy.
b. For patients with resected stage IV M1d disease, repeat brain MRI with contrast showing no evidence of residual disease or disease relapse must be performed at least 4 weeks post-surgery/post-RT, and prior to study entry.
Patients must not have received systemic anti-cancer therapy or radiation therapy for melanoma in the previous 5 years, with the exception of stage IV M1d patients who may have had RT to the CNS following radical resection. Adjuvant radiation therapy to the primary site and/or to the nodal bed following radical surgical resection is allowed where it is considered institutional standard of care.
Performance status:
a. For adult patients: ECOG PS 0 or 1.
b. For patients <18 years of age: Karnofsky PS >70 (patients >16 years) or Lansky PS >70 (patients <16 years).
- Adequate bone marrow function, as determined by hematological parameters:
a. Absolute neutrophil count (ANC) ≥1.5 x 10^9/L (1500/mm3)
b. Hemoglobin ≥9.0 g/dL (5.59 mmol/L)
c. Platelet count ≥75,000/mm³
- Adequate hepatic function, as determined by:
a. AST/ALT for adults: aspartate aminotransferase (AST) ≤3x upper limit of normal (ULN) and alanine aminotransferase (ALT) ≤3x ULN
b. AST/ALT for adolescents: AST and ALT <2.5 ULN
c. serum bilirubin ≤1.5x ULN, except in patients with clinically documented Gilbert's Syndrome where ≤3x the ULN is permitted
- Adequate kidney function:
a. For adult patients: as determined by an estimated glomerular filtration rate (eGFR) ≥30 ml/min (using the creatine phosphokinase (CPK)-EPI equation)
b. For pediatric patients:
i. Creatinine clearance or radioisotope glomerular filtration rate (GFR) 70 mL/min/1.73 m2 or
ii. Serum creatinine based on age/gender as follows: (See protocol)
All patients must provide a minimum of 25 slides or 125 mm3 of a resected tumor tissue sample (FFPE) from tissue block for biomarker analyses. Cut slides must be shipped to testing lab within 2 weeks of slide preparation. Bone biopsies are not allowed.
Women of childbearing potential (WOCBP*) must have a negative serum (beta-human chorionic gonadotropin [beta-hCG]) at screening, and must agree to not get pregnant during the study treatment and for up to 6 months after receiving last dose of study treatment. *WOCBP are defined as women who are fertile following menarche until becoming postmenopausal, unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a postmenopausal state. The above definitions are according to the Clinical Trial Facilitation Group (CTFG) guidance. Pregnancy testing and contraception are not required for women with documented
hysterectomy. Male study participants with WOCBP partners are required to use condoms for 6 months after receiving the last therapy dose unless they are vasectomized or practice sexual abstinence. Vasectomized partner or vasectomized study participant must have received medical assessment of the surgical success. Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception. Female condom and male condom should not be used together.
WOCBP must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the entire trial and until 6 months after last treatment
All men must agree not to donate sperm during the trial and for 6 months after receiving the last therapy dose
Provide informed consent signed by study patient (patients aged 12-17 will provide assent complemented by parent or legal guardian consent).
Willing and able to comply with clinic visits and study-related procedures.
Able to understand and complete study-related questionnaires.
Exclusion Criteria
Uveal melanoma.
Any evidence of residual disease after surgery by imaging, pathology, or cytology (including clinical or radiological suspicion of leptomeningeal metastasis).
Ongoing or recent (within 2 years) evidence of clinically significant autoimmune disease that required systemic treatment with immunosuppressive agents. The following are nonexclusionary: vitiligo, childhood asthma that has resolved, residual hypothyroidism that requires only hormone replacement, psoriasis not requiring systemic treatment.
Uncontrolled infection with HIV, HBV, or HCV infection; or diagnosis of immunodeficiency that is related to, or results in chronic infection. Notes:
a. Patients with known HIV who have controlled infection (undetectable viral load and CD4 count above 350 either spontaneously or on a stable antiviral regimen) are permitted. For patients with controlled HIV infection, monitoring will be performed per local standards.
b. Patients with known hepatitis B (HepBsAg+) who have controlled infection (serum hepatitis B virus DNA PCR that is below the limit of detection AND receiving antiviral therapy for hepatitis B) are permitted. Patients with controlled infections must undergo periodic monitoring of HBV DNA per local standards and must remain on anti-viral therapy for at least 6 months beyond the last dose of investigational study drug.
c. Patients who are known HCV Ab+ who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) are permitted.
d. Patients with HIV or hepatitis must be reviewed by a qualified specialist (eg, infectious disease or hepatologist) managing this disease prior to commencing and regularly throughout the duration of their participation in the trial
Another malignancy that is currently progressing or that required active treatment in the past 5 years, with the exception of those with a negligible risk of metastasis or death (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized early stage prostate cancer, or ductal carcinoma in situ of the breast). Note: any uncertain case should be discussed with the Medical Monitor before enrollment.
Pregnant or breastfeeding women.
WOCBP who are unwilling to practice highly effective contraception prior to the initial dose/start of the first treatment, during the study, and for at least 6 months after the last dose. Highly effective contraceptive measures include:
a. stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening;
b. intrauterine device (IUD); intrauterine hormone-releasing system (IUS);
c. bilateral tubal ligation (occlusion);
d. vasectomized partner (provided that the male vasectomized partner is the sole sexual partner of the WOCBP study participant and that the vasectomized partner has obtained medical assessment of surgical success for the procedure); and/or
e. sexual abstinence†, ‡.
†Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drugs. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject.
‡Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception. Female condom and male condom should not be used together.
