Phase I/II Open-Label Multicenter Study of ALE.P03 in Adult Patients with Advanced or Metastatic CLDN1+ Solid Tumors

Trial ID: 2025-521441-24-00
Protocol: ALE.P03.01
Sponsor: Alentis Therapeutics AG

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Diseases & Conditions

Neoplasm

Objectives

Primary objective: evaluate the safety and tolerability of ALE.P03 in a phase‑I dose‑escalation cohort, determine the recommended phase‑2 dose, and assess anti‑tumor activity in a phase‑II cohort of adults with advanced or metastatic Claudin‑1‑positive solid tumors. Secondary objectives: confirm safety and tolerability across phase‑I and phase‑II dosing; obtain preliminary evidence of anti‑tumor activity in both phases; characterize the pharmacokinetic profile of total antibody, conjugated exatecan, and free payload and evaluate immunogenicity.

Participants

The trial enrolled 103 adult participants, including both male and female patients, with a minimum age of 18 years. All subjects had a diagnosis of advanced or metastatic solid tumors confirmed histologically or cytologically and exhibited measurable disease per RECIST 1.1 criteria. Enrollment required an Eastern Cooperative Oncology Group performance status of 0 or 1, adequate bone marrow and organ function, and provision of tumor tissue for central CLDN1 expression analysis. Participants were selected based on documented radiological disease progression and prior exposure to standard-of-care systemic therapies, including anti‑PD‑1/L1 agents, with refractory or intolerant status to those treatments. Both sexes were required to adhere to contraception requirements, and females of childbearing potential needed a recent negative pregnancy test. The cohort comprised patients who met the specified inclusion parameters and did not present with exclusion criteria such as recent transfusions, growth factor support, or unsafe biopsy conditions.

Plans and Procedures

The study is an open‑label, multicenter Phase I/II trial evaluating ALE.P03, an intravenous infusion of a claudin‑1‑targeted antibody‑drug conjugate, in adult patients with selected advanced or metastatic CLDN1‑positive solid tumors. During Phase I a dose‑escalation cohort will determine the maximum tolerated dose and the recommended Phase II dose, followed by an expansion cohort to assess anti‑tumor activity in Phase II. The protocol specifies a screening (inclusion) visit to confirm eligibility, obtain central CLDN1 expression testing, and collect baseline safety and efficacy data. Eligible participants then receive the investigational infusion on a regular schedule (e.g., every 3 weeks) with safety, laboratory, electrocardiogram, pharmacokinetic and immunogenicity assessments performed at each treatment visit. Follow‑up visits continue for the duration of treatment and include imaging assessments according to RECIST 1.1 to evaluate response. An end‑of‑study visit occurs after treatment discontinuation, disease progression, or completion of the predefined treatment period, at which final safety and efficacy endpoints are recorded. Participant involvement is expected to last up to 12 months, encompassing the screening period, multiple treatment cycles, and final follow‑up. Early termination may occur if a participant experiences a dose‑limiting toxicity, unacceptable adverse event, rapid disease progression, withdraws consent, or if the investigator determines that continued participation is not in the patient’s best interest.

Treatment

The investigational product, designated Claudin-1 Targeted Antibody-Drug Conjugate ALE.P03, is supplied as a powder for solution for infusion and administered by intravenous infusion. The formulation is reconstituted according to the investigational pharmacy manual and infused under controlled conditions. Dosing follows a dose-escalation schedule in Phase I, with each cohort receiving a single infusion on Day 1 of a 21‑day cycle; the recommended Phase II dose (RP2D) identified in Phase I will be administered on the same schedule in subsequent cycles. Dose levels and infusion rates are defined in the protocol, and adjustments are made based on safety and tolerability assessments.

No concomitant investigational agents are used; participants receive ALE.P03 as monotherapy without a placebo or active comparator. Standard supportive care measures permitted by the protocol are provided as needed to manage infusion‑related reactions or other adverse events. Compliance with the infusion schedule is monitored through treatment administration records, real‑time infusion monitoring, and documentation of any missed or delayed doses, with corrective actions outlined in the study conduct guidelines.

Efficacy

Efficacy will be evaluated using tumor response criteria defined by RECIST 1.1. Primary efficacy parameters in Phase 2 include objective response rate (ORR), defined as the proportion of patients achieving a complete or partial response, and duration of response (DoR). Secondary efficacy assessments comprise disease control rate (DCR), median progression‑free survival (PFS) with rates at 6 and 12 months, and median overall survival (OS) with survival rates at 6, 12, and 24 months. All radiologic assessments will be performed according to the protocol‑specified imaging schedule and analyzed centrally to ensure consistency across study sites.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Be voluntarily willing and able to provide written informed consent for the clinical study.
Be at least 18 years of age on the day of signing informed consent.
Have disease and treatment history as outlined below: • Have histologically or cytologically confirmed advanced locally recurrent and inoperable or metastatic CRC, iCCA, sqNSCLC, UC, or CSCC. • Have documented radiological disease progression at study entry. • Have adequate CLDN1 protein expression level as determined by a central laboratory: o For dedicated CLDN1+ backfilling cohorts in Phase I dose escalation, ≥ 75% of the tumor cells with CLDN1 protein expression of +2/+3, unless a different cut-off is recommended by the SRC. o For Phase I RDE part, ≥ 75% of the tumor cells with CLDN1 protein expression of +2/+3, unless a different cut-off is recommended by the SRC. o For Phase II part, ≥ 50% of the tumor cells with CLDN1 protein expression of +2/+3, unless a different cut-off is recommended by the SRC. • Phase I Dose Escalation: Have received the available systemic SOCs given in the advanced setting including an anti-PD-1/L1 monoclonal antibody (unless contraindicated) sequential or concurrent with chemotherapy and being refractory or intolerant to the treatment Phase I RDE and Phase II: o SqNSCLC: Have received one or two available systemic SOC regimens given in the advanced setting including an anti-PD-1/L1 monoclonal antibody (sequential or concurrent with cisplatin/carboplatin plus taxane) and being refractory or intolerant to the treatment. o iCCA: Have received one or two available systemic SOC regimens given in the advanced setting including an anti-PD-1/L1 monoclonal antibody (unless not reimbursed) and being refractory or intolerant to the treatment. o CRC: Have received at least two available systemic SOC regimens given in the advanced setting and being refractory or intolerant to the treatment. The following therapies might be included in prior lines of therapy:  Fluoropyrimidine, oxaliplatin, and/or irinotecan, anti-vascular endothelial growth factor, anti-EGFR unless contraindicated.  Anti-PD-1/L1 monoclonal antibody, if tumor is MSI-H/dMMR, or TMB-high, if clinically indicated and available. The corresponding targeted therapy for patients with known actionable alterations (e.g., HER2, KRAS G12C, BRAF V600E). o UC: Have received one or two available systemic SOC regimens given in the advanced setting including an anti-PD-1/L1 monoclonal antibody, EV, and being refractory or intolerant to the treatment. o CSCC: Have received one or two available SOC regimens given in the advanced setting including an anti-PD-1/L1 monoclonal antibody (for whose tumors express PD-L1 with Combined Positive Score ≥ 1), cisplatin/carboplatin plus taxane, TV and being refractory or intolerant to the treatment. Bevacizumab might be included in the SOC regimen as per local institutional guidelines. Applicable for Phase I Dose Escalation, Phase I RDE and Phase II: o Note 1: For patients with known actionable oncogenic drivers, they should have received the corresponding targeted therapy as deemed feasible. o Note 2: The availability of SOC should follow local institutional guidelines.
Have provided tissue for CLDN1 analysis in a central laboratory. Tumor tissue collection is mandatory at baseline (i.e., within 180 days prior to study enrollment) unless the biopsy procedure is considered a high risk for the patient’s safety as per the Investigator and local guidelines. In case the biopsy is not available, or the procedure is deemed unsafe, an archival tumor tissue sample older than 180 days can be submitted. However, preferably, this sample should have been collected no later than the start of the most recent previous anti-cancer treatment.
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 occurring after termination of the most recent anti-cancer regimen prior to study entry.
Have a performance status of 0 or 1 on the ECOG PS.
Demonstrate adequate bone marrow and organ function as defined in Table 5–1. All screening laboratory assessments should be performed within 14 days of study intervention initiation. Patients must not have received red blood cell or platelet transfusion or growth factor support within 1 week prior to screening assessment.
Female patients of childbearing potential should have a negative blood pregnancy test within 72 hours prior to receiving the first dose of study intervention. A urine test can be considered if a blood test is not appropriate.
Female patients of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study through 180 days after the last dose of study intervention. Patients of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
Male patients should agree to use an adequate method of contraception and to abstain from sperm donation starting with the first dose of study intervention through 90 days after the last dose of study intervention.

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Exclusion Criteria

SqNSCLC and CSCC: diagnosed with a tumor of predominantly non-squamous histology result (e.g., adenosquamous carcinoma) or adenocarcinoma.
Has received antineoplastic therapies prior to study intervention within specified time frame defined as follows: • Radiation therapy (or other non-systemic therapy) within 2 weeks prior to first dose of ALE.P03. Note: Palliative radiotherapy in a limited field is allowed. • Any other chemotherapy, immunotherapy (except for anti-PD-1/L1 defined as follows) or anti-cancer agents within 4 weeks or 5 times t1/2 of the first dose of ALE.P03, whichever is longer. • Anti-PD-1 Q2W/Q3W dose regimen (e.g., pembrolizumab 200 mg) or anti-PD-L1 Q3W/Q4W dose regimen (e.g., durvalumab 1,500 mg, pembrolizumab, nivolumab) within 60 days of the first dose of ALE.P03. • Anti-PD-1/L1 Q4W/Q6W dose regimen (e.g., pembrolizumab 400 mg, durvalumab, nivolumab) within 120 days of the first dose of ALE.P03. • Investigational therapy within 4 weeks of the first dose of ALE.P03 (Note: Participation in the follow-up phase, i.e., receiving no study intervention, of a prior study is allowed). • Has not fully recovered (i.e., ≤ Grade 1 or at baseline) from AEs due to a previously administered treatment. Note: Patients with ≤ Grade 2 neuropathy, ≤ Grade 2 alopecia, or laboratory values within those specified in Table 5–1, are an exception to this criterion and may qualify for the study after discussion with the Medical Monitor. • If patients underwent major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
Patients with active keratitis or corneal ulcerations. Patients with superficial punctate keratitis are allowed if the disorder is being adequately treated in the opinion of the Investigator.
Has known homozygous status for the UGT1A1*28 allele.
Has rapidly progressing disease in the opinion of the treating Investigator or designee, as evidenced by one or more of the following: • Uncontrolled tumor pain (e.g., pain > 6 on the EVA scale). • Condition requiring urgent medical treatment. • Undergoing evaluation for oncologic medical emergencies. • Advanced, symptomatic, visceral spread with risk of short -term life-threatening complications, including organ compromise and/or uncontrolled effusions (pleural, pericardial, peritoneal) requiring repeated drainage.
Has a diagnosed and/or treated additional second malignancy within 3 years prior to C1D1 except for: curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, curatively resected in situ cervical cancer (not applicable for patients enrolled with CSCC), and curatively resected in situ breast cancer. Other exceptions may be considered with the Medical Monitor or designee consultation.
Any of the following cardiac criteria: • Mean resting QTcF > 470 milliseconds obtained from triplicate ECGs. • Any factors that increase the risk of QT prolongation, shortening or risk of arrhythmic events such as hypokalemia, congenital long or short QT syndrome, family history of long QT syndrome, familial short QT syndrome, or unexplained sudden death under 40 years of age, or any concomitant medication known to prolong or shorten the QT interval (see Appendix 8, Section 10.8). • Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG, e.g., complete left bundle branch block, second-or third-degree atrioventricular block, and clinically significant sinus node dysfunction not treated with pacemaker.
Has known active CNS metastases and/or carcinomatous meningitis. Note: Patients with previously treated CNS metastases may participate provided they have received prior local therapy (e.g., surgery, stereotactic radiosurgery or whole brain radiotherapy) and 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 ALE.P03 and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging CNS metastases, and are not using steroids for at least 7 days prior to start of ALE.P03. This exception does not include leptomeningeal disease which is excluded regardless of clinical stability.
Has had an allogeneic tissue/solid organ transplant.
Has a history of (non-infectious) ILD/pneumonitis that required steroids or current symptomatic or clinically significant pneumonitis requiring steroids and/or immunosuppressive therapies.
For sqNSCLC patients: Has received radiation therapy to the lung that is > 30 Gy within 6 months of the first dose of study intervention.
Has clinically significant gastrointestinal bleeding (NCI CTCAE version 5.0 Grade 3 or higher) within 30 days prior to start of screening.
Has an active infection requiring systemic treatment (e.g., IV antibiotics, antivirals, or antifungals).
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.
Is pregnant, breastfeeding, or expecting to conceive within the projected duration of the clinical study, starting with the screening visit through 180 days after the last dose of study intervention or father children starting with the screening visit through 90 days after the last dose of study intervention.
Has untreated chronic hepatitis B or is a chronic HBV carrier with HBV DNA ≥ 500 IU/mL (or ≥ 2500 copies/mL) at screening. Note: Inactive HBsAg carriers, treated patients, and patients with stable hepatitis B (HBV DNA < 500 IU/mL or < 2500 copies/mL) can be enrolled. Patients with detectable HBsAg or detectable HBV DNA should be managed per institutional treatment guidelines.
Has active HCV. Note: Patients with a negative HCV antibody test at screening or positive HCV antibody test followed by a negative HCV ribonucleic acid test at screening are eligible.
Has untreated HIV infection, if known. Patients with known HIV infection are eligible if the following criteria are met: • Stable on antiretroviral therapy for ≥ 4 weeks before first dose of study intervention. • Patient agrees to adhere to antiretroviral therapy per WHO guidelines. • No documented multidrug resistance that would prevent effective antiretroviral therapy. • Viral load of < 400 copies/mL at screening. • CD4+ T-cell count ≥ 350 cells/µL at screening. • No history of an acquired immunodeficiency syndrome-defining opportunistic infection ≤ 2 months before first dose of study intervention unless eligibility is agreed to by the Medical Monitor after consultation. • If prophylactic antimicrobial drugs are indicated, patients may still be eligible upon agreement with the Medical Monitor.
Has received a live vaccine within 30 days of planned start of study intervention.
Has received previous ADC treatment with Topo-I payload.
Has received previous CLDN1 targeted therapy.
Has known hypersensitivity to the study intervention or any of the excipients used in the formulation of the study intervention.
Patients taking CYP1A2 substrates with a narrow therapeutic index (such as theophylline, tacrine, clozapine, olanzapine, and R-warfarin) (except for caffeine) that cannot be discontinued during the study intervention through 3 weeks after the last dose of ALE.P03.