Safety, Tolerability and Preliminary Efficacy of Engineered Red Blood Cell in Patients With Advanced Malignancies

Study Overview
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Brief Summary
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This phase studies the engineered red blood cells with PD-1 inhibitor pembrolizumab（WTX212）, the natural biological metabolic function of red blood cells can make the carried pembrolizumab directionally distributed in the spleen tissue and activitate T cells, suggesting that this product may solve the problem that PD-1 treatment failure.

Detailed Description
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The present study has 2 parts. The dose increasing stage is carried out according to the 3+3 increasing principle. A total of 3 dose groups are preset (calculated by the number of red blood cells of the pabolizumab loaded), which are respectively 20 × e10、60 × e10 and 100 × e10。 Subjects with IO resistant advanced solid tumor and recurrent refractory lymphoma were studied. After the subjects passed the screening, blood was taken to prepare the engineered red blood cell WTX212, and the test drug was administered once every 21 days. Subjects completed the collection of PK, PD, biomarkers and immunogenicity samples during the observation period of dose limiting toxicity (DLT) (within 21 days after the first administration) and the continuous treatment period. After the end of DLT period of the first subject in each dose group, the second subject can be accepted. The subject continues to receive treatment until the subject suffers from intolerable toxicity, or withdraws informed consent, or disease progression, or solid tumor subjects up to 12 months after the first administration (lymphoma subjects can complete up to 6 administration cycles), or the end of the study, or the investigator comprehensively decides to withdraw and start new anti-tumor treatment according to the benefit of the subject, whichever occurs first.

Official Title
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A Multicenter, Single-arm, Open-label, Dose-escalation and Dose-expansion Clinical Study Evaluating the Safety, Tolerability and Preliminary Efficacy of Engineered Red Blood Cell WTX212 in Patients With Advanced Malignancies

Conditions
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Cancer, Solid Tumor, Hematologic Malignancy

Intervention / Treatment
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* Drug: engineered red blood cell WTX212


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1.Histologically- or cytologically-proven advanced malignancies; 2.Male or female, 18 years of age or older but no more than 75 at the time of signing informed consent; 3.Dose escalation stage: (1) patients with advanced solid tumors who have received at least 2 regimens, and PDx monotherapy or combination therapy is included in the last regimen ; or patients received 1st regimen or above who cannot tolerate standard therapy but PDx monotherapy or combination therapy should be included in the last regimen.(2)Patients with relapsed and refractory malignant lymphomas (including: classic Hodgkin lymphoma (cHL), primary mediastinal large B-cell lymphoma PMBCL , Extranodal NK/T-cell lymphoma ENKTCL, mycosis fungoides/Sezari syndrome MF/SS) , or patients have no standard therapy, or are unable to receive standard therapy, PDx monotherapy or combination therapy is used in the last regimen.(3)The above patients should experience secondary resistance to immunotherapy , all patients did not receive systemic therapy after disease progression and the time of disease progression cannot exceed 3 months, radiotherapy was acceptable (definition of secondary resistance: achieved disease control (including CR/PR/ SD), but then disease progression after PDx therapy); 4.Dose expansion stage:(1)patients with advanced solid tumors who have received at least 1 regimen or these is no standard systematic therapy or patients can not recieve standard therapy, but PDx monotherapy or combination therapy should be included in the last regimen.(2)patients with relapsed and refractory malignant lymphomas who have no standard therapy or can not receive standard therapy, but PDx monotherapy or combination therapy should be included in the last regimen.(3)The above patients should experience secondary resistance to immunotherapy , all patients did not receive systemic therapy after disease progression and the time of disease progression cannot exceed 3 months, radiotherapy was acceptable (definition of secondary resistance: achieved disease control (including CR/PR/ SD), but then disease progression after PDx therapy); 5.Solid tumor：at least one lesion that is measurable according to RECIST 1.1;lymphomas:at least one visble or evaluable lesion that is measurable according to Lugano2014; 6.Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1; 7.Take the shorter one as the washout period before experimental treatment (28 days after the last tumor treatment, or 5 half lives); 8.Resolution of all acute reversible toxic effects of prior therapy or surgical procedure to baseline or Grade ≤1 (except alopecia and peripheral neurotoxicity); 9.Adequate organ function; 10.Estimated life expectancy of ≥12 weeks; 11.Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF). Exclusion Criteria: 1.Any active or recently diagnosed clear or suspected autoimmune disorder disease; 2. Other serious medical diseases, including but not limited to: uncontrolled diabetes, active peptic ulcer, liver cirrhosis, active bleeding, etc., and those with uncontrolled or serious cardiovascular disease, such as the NYHA II or higher heart failure, unstable angina, myocardial infarction and other cardiovascular disease within 6 months before first administration, and uncontrolled hypertension (systolic blood pressure ≥ 180 mmHg and/or diastolic blood pressure ≥ 100 mmHg); 3.Has known active Hepatitis B or Hepatitis C or HIV; 4.Active brain metastases and/or cancerous meningitis; 5.Known history of any diseases affecting the quality and stability of erythropoiesis; 6.The spleen has been removed or, as judged by the investigator, a splenectomy may be planned during the trial; 7.Received at least one alive virus vaccination within 6 months before the first dose (except for the COVID-19 inactivated vaccine); 8.Known history of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonia, drug-related pneumonia, severely impaired lung function, etc.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: he dose excalating stage is carried out according to the 3+3 increasing principle, with a total of 3 dose groups preset, only one group finishes safty evaluation, then entering next dose. After getting recommending dose , the extension part with two arms will start .
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Solid tumors after immunotherapy failure<br>In extension part， all patients will be administrated with recommend dose （WTX 212 IV infusion over 60 minutes on Day 1 of each cycle）confirmed by escalating part | Drug: engineered red blood cell WTX212<br>* engineered red blood cell WTX212<br>* Other names: WTX212;|
| Experimental: Hematologic malignancies after immunotherapy failure<br>In extension part， all patients will be administrated with recommend dose （WTX 212 IV infusion over 60 minutes on Day 1 of each cycle）confirmed by escalating part | Drug: engineered red blood cell WTX212<br>* engineered red blood cell WTX212<br>* Other names: WTX212;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing Dose-Limiting Toxicities (DLTs) According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v.5.0) in Participants in escalating part. | DLTs were assessed according to NCI-CTCAE v.5.0 during the first cycle (21 days) and were defined as occurrence of any of the following toxicities if judged by the investigator to be possibly, probably or definitely related to study drug administration。 | 21 days | 
| Number of Participants Who Experienced an Adverse Event (AE) | An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the Sponsor's product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which was temporally associated with the use of the Sponsor's product was also an AE. The number of participants who experienced an AE was reported for all patients. | Up to approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) | ORR was defined as the percentage of participants in the analysis population who had a confirmed Complete Response (CR: disappearance of all lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters [SOD] of target lesions, taking as reference the baseline SOD) according to RECIST 1.1(only for solid tumor) or Lugano2014( only for lymphomas) | per 6 weeks | 
| Anti-drug antibody (ADA) | Describe the number and percentage of anti-drug antibodies (ADA) produced by subjects at each time point after treatment, and the time of producing ADA. | 1 year | 
| Maximum Concentration (Cmax) of WTX212 in all Participants | Blood samples were collected at specified intervals for the determination of Cmax. Cmax was defined as the maximum concentration of WTX212 reached. Cmax was based on noncompartmental analysis and reported for all participants | Cycle 1: Pre-dose, post-dose at 0.5, 6 and 12 hours and Days 2, 3, 8 and 15 | 
| Time to Maximum Concentration (Tmax) f WTX212 in all Participants | Blood samples were collected at specified intervals for the determination of Tmax. Tmax was defined as time to the maximum concentration of WTX212 reached. Tmax was based on noncompartmental analysis and reported for all participants | Cycle 1: Pre-dose, post-dose at 0.5, 6 and 12 hours and Days 2, 3, 8 and 15 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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solid tumors, hematologic malignancies