IRB Study Number 23-1255
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objective: Phase 2
To compare the treatment effect of the combination of fianlimab and cemiplimab to cemiplimab alone as peri-operative therapy in patients with resectable melanoma, as measured by pCR rate assessed by local pathological review, in order to inform (along with the totality of data from other fianlimab studies) the dose of fianlimab to use in combination with cemiplimab for the Phase 3 part of the study.
2.2. Secondary Objectives: Phase 2
• Assess pCR by BIPR
• Assess EFS
• Assess DMFS in stage III patients
• Assess OS
• Assess the rate of MPR by local pathological review and BIPR
• Assess ORR to neo-adjuvant treatment by investigator and BICR
• Assess time to recurrence of disease, as measured by RFS
• Assess safety and tolerability of neo-adjuvant and adjuvant therapy
• To characterize the concentration of fianlimab and cemiplimab
• Assess immunogenicity of fianlimab and cemiplimab
• To evaluate the impact of treatment on functioning, symptoms, and quality of life per FACT-M Melanoma subscale, EORTC QLQ-C30, and EQ-5D-5L
2.3. Primary Objective: Phase 3
To assess the EFS for the combination of fianlimab and cemiplimab vs pembrolizumab alone as peri-operative therapy in patients with resectable melanoma.
2.4. Secondary Objectives: Phase 3
• Assess OS
• Assess DMFS in stage III patients
• Assess pCR by local pathological review and BIPR
• Assess the rate of MPR by local pathological review and BIPR
• Assess ORR to neo-adjuvant treatment by investigator and BICR
• Assess time to recurrence of disease, as measured by RFS
• Assess safety and tolerability of neo-adjuvant and adjuvant therapy
• To characterize the concentration of fianlimab and cemiplimab
• Assess immunogenicity of fianlimab and cemiplimab
• To evaluate the impact of treatment on functioning, symptoms, and quality of life per FACT-M Melanoma subscale, EORTC QLQ-C30, and EQ-5D-5L
Inclusion Criteria
At least 18 years of age on the date of providing informed consent.
All patients must be either stage III (IIIB, IIIC, IIID) or stage IV (M1a, M1b, M1c) per AJCC 8th edition (Amin 2017) and have histologically confirmed cutaneous melanoma that is deemed completely surgically resectable.
a. Patients with stage IIIA and M1d disease are excluded
b. Stage IV patients are capped at 10% of the total population for each phase of the study. Stage IV patients must have 3 or fewer resectable lesions (excluding CNS and bone metastases).
c. Patients with acral and mucosal melanoma are allowed, with a total combined cap of 10% for each phase of the study.
d. Patients with melanoma of unknown primary are allowed, provided that complete surgical resection is planned
e. Resectable in-transit metastases (up to 3 lesions) without nodal involvement are eligible
- Patients with stage III melanoma must have clinically detectable disease that is confirmed as malignant on the pathology report. The pathology report must be reviewed, signed and dated by the investigator; this process will be confirmed during the IVRS process.
• Clinically detectable is defined as disease which is clinically apparent and measurable disease, according to Response Evaluation Criteria in Solid Tumors (RECIST). Resectable nodal metastases should be a minimum short-axis diameter of 1.5 cm, whereas the minimum size for other metastases should be 1 cm.
• Patients who have local recurrence in the scar or surgical bed of melanoma as sole site of disease are not eligible.
Patients must be candidates for full resection with curative intent and must be able to be surgically rendered free of disease with negative margins on resected specimens at surgery. The treatment plan including date of surgery must be documented by the investigator prior to randomization.
All patients must undergo full disease staging through a complete physical examination and imaging studies within 4 weeks prior to randomization. Imaging must include a CT scan of the chest, abdomen, pelvis (if the primary tumor is on the head/neck then include a CT scan of head/neck), and all known sites of previously resected disease (if applicable) and brain MRI (or brain CT with contrast allowed if MRI is contraindicated).
ECOG PS 0 or 1
Adequate bone marrow function, as determined by hematological parameters:
a. ANC ≥1.5 x 109/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: AST ≤3x ULN, ALT ≤3x ULN, and alkaline phosphatase <2.5x ULN (or <5x ULN, if liver or bone metastases are present)
b. serum bilirubin ≤1.5x ULN, except in patients with clinically documented Gilbert's Syndrome where ≤3x the ULN is permitted
- Adequate kidney function as determined by creatine clearance ≥ 30 ml/min (using the Cockcroft-Gault equation), that is corrected for body weight, as follows:
a) Creatinine clearance (mL/min) = ([140 - age in years] × [body weight in kg] × [1.23 if male or 1.04 if female]) / (serum creatinine in micromol/L)
b) Creatinine clearance (mL/min) = ([140 - age in years] × [body weight in kg] × [0.85 if female]) / (72 × [serum creatinine in mg/dL]).
- WOCBP* must have a negative serum (beta-hCG) at screening.
a. *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 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 CTFG guidance. Pregnancy testing and contraception are not required for women with documented hysterectomy or tubal ligation.
b. Male study participants with WOCBP partners are required to use condoms during the study and until 6 months after the last dose of study treatment unless they are vasectomized or practice sexual abstinence.
c. Vasectomized partner or vasectomized study participant must have received medical assessment of the surgical success.
d. Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 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
Willing and able to comply with clinic visits and study-related procedures.
Provide informed consent signed by study patient or legally acceptable representative.
Able to understand and complete study-related questionnaires
Exclusion Criteria
Primary uveal melanoma
Ongoing or recent (within 2 years) evidence of an 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.
Patients must not have received any prior systemic anti-cancer therapy for melanoma. Prior radiotherapy for melanoma is allowed if not given to a target lesion or, if given to a target lesion, there is pathological evidence of disease progression in the same lesion.
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 hepatitis C virus antibody positive (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
Prior/concomitant therapy:
- Systemic immune suppression:
a. Use of immunosuppressive doses of corticosteroids (>10 mg of prednisone per day or equivalent) within 14 days of the first dose of study medication. Physiologic replacement doses are allowed up to 10 mg of prednisone/day or equivalent. Inhaled or topical steroids are permitted, provided that they are not for treatment of an autoimmune disorder
b. Other clinically relevant forms of systemic immune suppression
- Treatment with any anti-cancer therapy for malignancies other than melanoma, including immuno-therapy, chemotherapy, radiotherapy, or biological therapy in the 5 years prior to randomization. See Exclusion criterion 3 for prior therapies for melanoma. Adjuvant hormonotherapy used for breast cancer or other hormonesensitive cancers in long term remission is allowed
Other comorbidities:
Participants with a history of myocarditis.
TnT or troponin I TnI > 2x institutional ULN at baseline.
a. Patients with TnT or TnI levels between > 1 to 2x ULN are permitted if repeat levels within 24 hours are ≤ 1x ULN. If TnT or TnI levels are > 1 to 2x ULN within 24 hours, the subject may undergo a cardiac evaluation and be considered for treatment by the investigator based on the medical judgement in the patient’s best interest.
History or current evidence of significant (CTCAE grade ≥2) local or systemic infection (eg, cellulitis, pneumonia, septicemia) requiring systemic antibiotic treatment within 2 weeks prior to the first dose of trial medication.
Active infection requiring therapy.
Other exclusions:
Known hypersensitivity to the active substances or to any of the excipients.
Presence of a severe concurrent illness or other condition (eg, psychological, family, sociological, or geographical circumstances) that does not permit adequate follow-up and compliance with the protocol.
Received a live vaccine within 30 days of planned start of study medication.
a. Live or live attenuated vaccination with replicating potential. If a patient intends to receive a COVID-19 vaccine before the start of study drug, participation in the study should be delayed at least 1 week after any COVID-19 vaccination. During the treatment period, it is recommended to delay COVID-19 vaccination until patients are receiving and tolerating a steady dose of study drug. A vaccine dose should not be less than 48 hours before or after study drug dosing.
Major surgical procedure (ie, requiring general anesthesia), or significant traumatic injury within 4 weeks prior to screening.
Prior allogeneic stem cell transplant or solid organ transplant.
Any medical condition that in the opinion of the investigator would make participation in the study not in the best interest of the patient.
Members of the clinical site study team and/or his/her immediate family unless prior approval granted by the sponsor.
Pregnant or breastfeeding women.
Women of childbearing potential (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; intrauterine hormone-releasing system;
a. bilateral tubal occlusion/ligation;
c. 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
d. sexual abstinence†, ‡.
Pregnancy testing and contraception are required for WOCBP.
Pregnancy testing and contraception are not required for women who are post-menopausal or permanently sterile.
*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 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 CTFG guidance.
†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 LAM are not acceptable methods of contraception. Female condom and male condom should not be used together.
- Is committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
