FIH study of ALE.C04 anti-CLDN1 mAb monotherapy or in combination with pembrolizumab in patients with R/M HNSCC

Prior treatment

• Has had an allogeneic tissue/solid organ transplant.
• Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the clinical study, starting with the screening visit through 90 days or 5 half-lives whichever is longer after the last dose of ALE.C04 study medication or 4 months after the last dose of pembrolizumab when applicable.
• Has received prior therapy with an anti-PD-1, anti-PD-L1 or anti-PD-L2 (Phase II).
• Has received a live vaccine within 30 days of planned start of study therapy.
• Have known hypersensitivity to the investigational product or any of the excipients used in the formulation of the study drug or these medicinal products or history of allergic reactions attributed to drugs with a similar chemical or biologic structure or class to ALE.C04 or pembrolizumab.
• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy, used an investigational device, or received previous therapies, any of which occurred within 4 weeks of the first dose of treatment or within a period during which the IMP or systemic anticancer treatment has not been cleared from the body (e.g., a period of 5 ‘half-lives’), whichever is shorter and as judged by the investigator or patient does not recover from clinically significant AEs from their most recent therapy or intervention prior to study enrolment (e.g., baseline or ≤ CTCAE Grade 1). Has received last dose of anti-PD-1/PD-L1 within 60 days for Q2W/Q3W regimen or 120 days for Q4W/ Q6W regimen of the first ALE.C04 administration. Note: Participation in the follow-up Phase (receiving no study treatment) of a prior study is allowed.
• Treatment with complementary medications (e.g., herbal supplements or traditional Chinese medicines) to treat the disease under study within 2 weeks prior to first study treatment. Such medications are permitted if they are used as supportive care.
• Receiving systemic steroid therapy prednisone or prednisone 10mg/day dose equivalent, or any other form of immunosuppressive therapy within 7 days or 5 half-lives whichever is greater prior to the first dose of clinical study treatment. Corticosteroid use as pre-medication for allergic reactions (e.g., IV contrast), is allowed. The use of physiologic doses of corticosteroids may be approved after consultation with the Medical Monitor and the Sponsor.
• Has a diagnosed and/or treated additional second malignancy within 3 years prior to Cycle 1, Day 1 (C1D1) with the exception of: curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, curatively resected in situ cervical cancer, and curatively resected in situ breast cancer. Other exceptions may be considered with study Medical Monitor or designee consultation.
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Note: Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging (using the identical imaging modality for each assessment, either MRI or CT scan) for at least 4 weeks prior to the first dose of clinical study treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to clinical study treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.

Other illness

• Has progressive disease (PD) within 6 months of completion of curatively intended systemic treatment for locoregionally advanced HNSCC (Phase II evaluating ALE.C04 in combination with pembrolizumab versus pembrolizumab monotherapy).
• Active autoimmune disease including Graves’ disease that has required systemic treatment (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is allowed.
• Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
• Has an active infection requiring systemic treatment (e.g., intravenous or prolonged oral antibiotic treatment over 7 days).
• Dermatological conditions requiring active pharmacological treatment including psoriasis, atopic dermatitis, excessively dry skin or recurrent conjunctivitis, scleroderma, vitiligo, or any other active autoimmune dermatological disorder
• Untreated chronic hepatitis B or chronic HBV carriers with HBV DNA ≥ 500 IU/ML (or ≥ 2500 copies/mL) at screening. Note: Inactive hepatitis B surface antigen (HBsAg) carriers, treated and stable hepatitis B (HBV DNA < 500 IU/mL or < 2500 copies/mL) can be enrolled. Patients with detectable hepatitis B surface antigen (HbsAg) or detectable HBV DNA should be managed per institutional treatment guidelines.
• Patients with active hepatitis C. Note: Patients with a negative HCV antibody test at screening or positive HCV antibody test followed by a negative HCV RNA test at screening are eligible.
• History or current evidence of any condition or disease that could confound the results of the study or, in the opinion of Investigator, is not in the best interest of the patient to participate.
• Has a life expectancy of less than 3 months and/or has rapidly progressing disease (e.g., tumor bleeding, uncontrolled tumor pain) in the opinion of the treating investigator.

Lab values

• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the clinical study, interfere with the patient’s participation for the full duration of the clinical study, or is not in the best interest of the patient to participate, in the opinion of the treating investigator.
• Has had radiation therapy (or other non-systemic therapy) within 2 weeks prior to randomization or patient has not fully recovered (i.e., ≤Grade 1 or at baseline) from adverse events due to a previously administered treatment. Palliative radiotherapy to a limited field is allowed. Note: Patients with ≤Grade 2 neuropathy, ≤Grade 2 alopecia, or laboratory values as defined in the Protocol are an exception to this criterion and may qualify for the study. Note: If patients received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• Untreated HIV infection, if known. Patients with known HIV infection are eligible if the following criteria are met: a) Stable on antiretroviral therapy for ≥ 4 weeks before first dose of study drug b) Patient agrees to adhere to antiretroviral therapy per WHO guidelines  c) No documented multidrug resistance that would prevent effective antiretroviral therapy d) Viral load of < 400 copies per mL at screening  e) CD4+ T-cell count ≥ 350 cells per µL at screening f) No history of an AIDS-defining opportunistic infection ≤ 12 months before first dose of study drug unless eligibility is agreed to by the medical monitor after consultation  g) If prophylactic antimicrobial drugs are indicated, patients may still be eligible upon agreement with the medical monitor.
• Severe immune-related adverse events leading to discontinuation of prior immune-oncology agent (including but not limited to anti-PD-(L)1 or anti-CTLA-4) as per institutional tretament guidline. Note: Patients with ≤Grade 2 neuropathy, ≤Grade 2 alopecia, or laboratory values as defined in the protocol are an exception to this criterion and may qualify for the study. Immune mediated toxicities (e.g., hypothyroidism, adrenal insufficiency, diabetes) resulted from a prior anti-PD-1/L1 treatment may be considered in consultation with the Medical Monitor.

• Be willing and able to provide written informed consents (Pre-Screening informed consent will be considered in addition to main informed consent) for the clinical study. The patient may also provide consent for Future Biomedical Research. However, the patient may participate in the main clinical study without participating in Future Biomedical Research.
• Female patients of childbearing potential should not be breastfeeding and should be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity and must agree not to donate eggs (ova, oocytes) for the purpose of reproduction for the course of the study through 90 days or 5 half-lives whichever is longer after the last dose of ALE.C04 study medication or 4 months after the last dose of pembrolizumab when applicable. Patients of childbearing potential are those who have not been surgically sterilized or have not been free from menses for >1 year. Note: Non-child-bearing potential is defined by fulfilling one of the following criteria at screening: i. Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments (where applicable). The levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) must also be in the post-menopausal range (for the institution). ii. Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
• Male patients should agree to use an adequate method of contraception and to abstain from sperm donation starting with the first dose of study therapy through 90 days or 5 half-lives whichever is longer after the last dose of ALE.C04 study medication or 4 month after the last dose of pembrolizumab when applicable. Note: Abstinence is acceptable if this is the usual lifestyle and preferred method of contraception for the patient.
• Patients should have the ability and willingness to comply with the study and follow-up.
• Be at least 18 years of age on day of signing informed consent.
• Have histologically or cytologically confirmed R/M HNSCC that is considered incurable by local therapies. a) Phase I monotherapy: patients with documented disease progression to at least one prior line of systemic palliative treatment including a PD-1 monoclonal antibody as a single agent or in combination will be enrolled. i) The eligible primary tumor locations are oropharynx, oral cavity, hypopharynx, larynx, nasopharynx, and HPV-positive cancer of unknown primary site that is localized to the head and neck b) Phase II (randomized): Patients should not have had prior systemic palliative treatment administered in the recurrent or metastatic setting. Systemic therapy which was completed more than 6 months prior to signing consent if given as part of multimodal treatment for locally advanced disease is allowed. i) The eligible primary tumor locations are oropharynx, oral cavity, hypopharynx, and larynx.
• Have provided tissue for CLDN1, PD-L1 and biomarker analysis in a central Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. The newly obtained tumor tissue is mandatory at baseline (i.e. within 180 days prior to start of study treatment) but an archival sample is acceptable if biopsy procedure is deemed unsafe by PI; a biopsy on treatment is mandatory in dose escalation but optional in RDEs and Phase II. Repeat samples may be required if adequate tissue is not provided. The tumor tissue should be collected from a core or excisional biopsy (fine needle aspirate [FNA] is not adequate) a) Phase I-Dose Escalation: CLDN1 and PD-L1 testing performed retrospectively b) Phase I-RDEs: CLDN1 ≥ 75% of the tumor cells with CLDN1 protein expression of +2/+3 is required (PD-L1 testing is performed but not prospectively required) c) Phase II ALE.C04 + pembrolizumab vs pembrolizumab: CLDN1 ≥10% (any intensity) expression and programmed cell death ligand 1 (PD-L1) with a combined positive score (CPS) ≥1 as determined by an PD-L1 IHC 22C3 pharmDx approved by FDA and EMA.
• Have measurable disease based on RECIST 1.1 as determined by the site. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
• Have a performance status of 0 or 1 on the ECOG Performance Scale at screening with no deterioration prior to the first dose of study treatment (Cycle 1 Day 1).
• Demonstrate adequate organ function as defined in the protocol, all screening labs should be performed within 10 days of treatment initiation. Patient must not have required blood transfusion or growth factor support ≤ 14 days before sample collection at screening.
• Have results from testing of HPV status for oropharyngeal cancer defined as p16 IHC testing using CINtec® p16 Histology assay and a 75% cutoff point or other method institutionally approved for the testing of HPV in oropharyngeal cancer.
• Female patients of childbearing potential should have a negative blood pregnancy test within 72 hours prior to receiving the first dose of study medication. A urine test can be considered if a blood test is not appropriate.