Study of ALE.C04 in Patients With Head and Neck Cancer

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety profile of ALE.C04 monotherapy and in combination with pembrolizumab, to characterize pharmacokinetics profile of ALE.C04, recommended Phase II dose (RP2D) for ALE.C04 in combination with pembrolizumab and as monotherapy and to assess anti-tumor activity of ALE.C04 monotherapy and in combination with pembrolizumab in patients with Head and Neck Cancer.

Detailed Description
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The study comprises a phase I and a phase II. The phase I dose escalation part for both ALE.C04 monotherapy and in combination with pembrolizumab and a recommended dose for expansion (RDE) part for both ALE.C04 monotherapy and in combination with pembrolizumab. The phase II comprises a 1:1 randomized 2 arms assessing 2 dose levels of ALE.C04 as monotherapy and a 1:1 randomized 2 arms assessing ALE.C04 and pembrolizumab given in combination versus pembrolizumab monotherapy

Official Title
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A Phase I/II, Open-Label, Multi-Center Study of ALE.C04 as a Single Agent and in Combination With Pembrolizumab in Adult Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

Conditions
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Head and Neck Cancer, Head and Neck Squamous Cell Carcinoma

Intervention / Treatment
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* Drug: ALE.C04
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be willing and able to provide written informed consents Be 18 years of age on day of signing informed consent. Have histologically or cytologically confirmed Recurrent or Metastatic (R/M) Head and Neck Squamous Cell Carcinoma (HNSCC) that is considered incurable by local therapies. Have provided tissue for claudin-1 (CLDN1), programmed death ligand-1 (PD-L1) and biomarker analysis in a central Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. Have measurable disease based on RECIST 1.1 as determined by the site. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale. Have results from testing of human papillomavirus (HPV) status for oropharyngeal cancer Exclusion Criteria: Has progressive disease (PD) within 6 months of completion of curatively intended systemic treatment for locoregionally advanced HNSCC (Phase II randomized combination part only). 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. Severe immune-related adverse events leading to discontinuation of prior immune-oncology agent only for Phase I dose escalation monotherapy and combination and Phase II monotherapy. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. 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. 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 received prior therapy with an anti-programmed death (PD)-1, anti-PD-L1 or anti-PD-L2 (Phase II randomized combination part only).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Phase 1 will consist of i) a dose escalation of ALE.C04 monotherapy evaluating approximately 3 dose levels of ALE.C04, ii) a dose escalation of ALE.C04 and pembrolizumab combination evaluating approximately 2 dose levels of ALE.C04 and iii) one Recommended Dose for Expansion (RDE) evaluating one dose level of ALE.C04 monotherapy aiming to detect anti-tumor activity of ALE.C04 single agent and iv) a randomized two RDEs evaluating two dose level of ALE.C04 combined with pembrolizumab to establish Recommended Phase 2 Dose (RP2D). Phase 2 will consist of i) ALE.C04 randomized part evaluating two dose levels of the single agent to establish RP2D and ii) A randomized part comparing ALE.C04 (at the RP2D dose determined in the phase 1) combined to pembrolizumab with pembrolizumab alone.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 Dose Escalation<br>ALE.C04 single agent: Three planned doses of ALE.C04 and ALE.C04 in combination with pembrolizumab. Once a certain dose level of ALE.C04 is considered safe and well tolerated, the first cohort of patients receiving ALE.C04 at a lower dose level combined with pembrolizumab will be initiated | Drug: ALE.C04<br>* Q3W<br>Drug: Pembrolizumab<br>* 200mg Q3W<br>* Other names: Keytruda;|
| Experimental: Phase 1 Recommended Dose for Expansion<br>One dose of ALE.C04 will be considered (dose identified from Phase 1 Dose Escalation part) Two ALE.C04 dose levels (higher or lower) will be considered for the combination with pembrolizumab | Drug: ALE.C04<br>* Q3W<br>Drug: Pembrolizumab<br>* 200mg Q3W<br>* Other names: Keytruda;|
| Active Comparator: Phase 2 Randomized Combination part<br>ALE.C04 at RP2D combined to pembrolizumab compared to pembrolizumab monotherapy | Drug: ALE.C04<br>* Q3W<br>Drug: Pembrolizumab<br>* 200mg Q3W<br>* Other names: Keytruda;|
| Experimental: Phase 2 Randomized Monotherapy part<br>ALE.C04 monotherapy (DL1 Q3W) ALE.C04 monotherapy (DL2 Q3W) | Drug: ALE.C04<br>* Q3W<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Dose Limiting Toxicity (DLT) | Phase I dose escalation | 21 days | 
| Incidence and severity of adverse events (AEs), serious adverse events (SAEs) | Descriptive statistics will be used to summarize results | Up to 30 days after last dose - Approximately 4.5 years | 
| Confirmed Objective Response Rate (ORR) by investigators assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 | Proportion of patients with confirmed Complete Response (CR) or Partial Response (PR) according to RECIST 1.1 for Phase II | Up to 4.5 year | 
| Confirmed Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) assessment according to RECIST1.1 | Time from start of study treatment to first documentation of objective progressive disease (PD) as per RECIST1.1 or to death due to any causes whichever come first during phase II | Up to 4.5 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed ORR by investigators assessment according to RECIST1.1 | Proportion of patients with confirmed CR or PR according to RECIST1.1 | up to 4.5 year | 
| Confirmed immune Objective Response Rate (iORR) by investigators assessment according to immune RECIST | Proportion of patients with confirmed immune CR or immune PR according to immune RECIST | up to 4.5 year | 
| Disease Control Rate (DCR) as per investigator assessment according to RECIST1.1 | Proportion of patients with CR, PR or Stable Disease (SD) according to RECIST1.1 | up to 4.5 years | 
| Immune Disease Control Rate (iDCR) as per investigator assessment according to immune RECIST | Proportion of patients with immune CR, immune PR or immune SD according to immune RECIST | up to 4.5 years | 
| Duration Of Response (DOR) | The time from first documentation of objective response to the first documentation of PD per RECIST 1.1 or to death due to any cause, whichever comes first. | up to 4.5 years | 
| Immune Duration Of Response (iDOR) | The time from first documentation of objective response to the first documentation of immune PD per immune RECIST or to death due to any cause, whichever comes first. | up to 4.5 years | 
| Progression Free Survival (PFS) evaluated by investigators | The time from start of study treatment to first documentation of objective PD per RECIST1.1 following study therapy, or to death due to any cause, whichever comes first. | up to 4.5 years | 
| Immune Progression Free Survival (iPFS) evaluated by investigators | The time from start of study treatment to first documentation of objective immune PD per immune RECIST following study therapy, or to death due to any cause, whichever comes first. | up to 4.5 years | 
| Overall Survival (OS) | The time from start of study treatment to date of death due to any cause. | up to 4.5 years | 
| Maximum serum concentration (Cmax) pharmacokinetics (PK) of ALE.C04 | Maximum serum concentration (Cmax) will be derived by non-compartmental analysis and summarized by dose cohort | up to 4.5 years | 
| Minimum serum concentration (Cmin) pharmacokinetics (PK) of ALE.C04 | Minimum serum concentration will be derived by non-compartmental analysis and summarized by dose cohort | up to 4.5 years | 
| Area under the concentration-time curve (AUC) pharmacokinetics (PK) of ALE.C04 | Area under the concentration-time curve will be derived by non-compartmental analysis and summarized by dose cohort | up to 4.5 years | 
| Maximum serum concentration (Cmax) Pharmacokinetics (PK) of pembrolizumab | Maximun Serum concentration (Cmax) by time point will be reported | up to 4.5 years | 
| Minimum serum concentration (Cmin) Pharmacokinetics (PK) of pembrolizumab | Minimum serum concentration (Cmin) by time point will be reported | up to 4.5 years | 
| Area under the concentration-time curve (AUC) Pharmacokinetics (PK) of pembrolizumab | Area under the concentration-time curve (AUC) by time point will be reported | up to 4.5 years | 
| Immunogenicity of ALE.C04 | To assess the presence of serum anti-drug antibodies (ADA) against ALE.C04 | up to 4.5 years | 
| Change from baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 | The C30 has 30 items in total. Among those items, 28 items are symptoms scales with score range from 1 to 4. A high score represents a high level of symptomatology. The 2 other items are global health status with score range of 1 to 7. A high score represents high quality of life. | Phase II combination part only - Up to 4.5 year | 
| Change from baseline in European Organisation for Research and Treatment of Cancer Quality of Life Question Head and Neck module 43 (HN43) | The HN43 has 43 items of symptoms scale with score range of 1 to 4. A high score represents a high level of symptomatology. | Phase II combination part only - Up to 4.5 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunotherapy, Anti-Claudin1, ALE.C04, Phase I/II