Clinical trial NCT06556108: ALPP CAR-T Cells for ALPP-Positive Advanced Solid Tumors
Official title: A Single-Arm, Single-Center, Open-Label Pilot Study of Anti-ALPP CAR-T Cells for Alkaline Phosphatase, Placental (ALPP)-Positive Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Advanced Solid Tumors
Lead sponsor: Xinqiao Hospital of Chongqing
Sponsor class: OTHER
First posted: 2024-08-15
Enrollment: 9
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Alkaline phosphatase (ALP) is a membrane-bound glycoprotein that catalyzes the hydrolysis of phosphates at alkaline pH values. As one of the earliest discovered oncofetal antigens, ALP has emerged as a significant biomarker for various malignant tumors, such as ovarian cancer, breast cancer, trophoblastic tumors, germ cell tumors, endometrial cancer, testicular tumors, cervical intraepithelial neoplasia, and gastrointestinal tumors.

Detailed description: This is a single-center, open-label, study of CAR-T cells for the treatment of the recurrent/metastatic solid tumors patients who had failed standard therapy.

Objective:

To evaluate the safety and efficacy of CAR-T cells in the treatment of advanced solid tumors.

Eligibility:

Adults aging 18-70 with advanced solid tumors

Design:

1. Patients will undergo a comprehensive set of screening tests, including imaging procedures, evaluation of cardiac and pulmonary function, as well as a range of laboratory assessments.
2. After meeting the eligibility criteria and enrolling in the trial, patients will undergo leukapheresis for collection of autologous lymphocytes, which will be sent to manufacturing facilities.
3. Once cells have been manufactured, patients will then proceed to lymphodepleting chemotherapy followed by the infusion of ALPP CAR T-cells.

Eligibility criteria: Inclusion Criteria:

1. Be able to understand and sign the Informed of Consent Document. Be willing to follow the procedure and protocol of the clinical trial;
2. Age 18-70 (including boundary value), both male and female;
3. Expected life span is more than 3 months from the date of signing the informed consent;
4. ECOG score 0-1;
5. Metastatic or recurrent solid tumors confirmed by histopathology;
6. Refractory to standard treatment evaluated by radiological assessment;
7. Be able provide fresh or preserved tissue specimen;
8. At least 1 measurable lesion (according to RECIST 1.1);
9. ALPP expression positivity determined by IHC；
10. The organ marrow function of the subjects meets the following requirements:

    1. Marrow function：ANC≥ 1.5×109/L; PLT count≥ 75×109/L; HGB≥ 90 g/L;
    2. Coagulation function: Prothrombin Time (PT)≤ 1.5 times the Upper Limit of Normal (ULN), International Normalized Ratio (INR)≤ 1.5 times ULN, and Activated Partial Thromboplastin Time (APTT)≤ 1.5 times ULN;
    3. Liver function: ALT and AST≤ 2.5 times ULN (in cases of liver transfer/infiltration, ≤ 5.0 times ULN); Total Bilirubin (TBIL) ≤ 1.5 times ULN (with Gilbert's syndrome, \<3×ULN);
    4. Renal function: Serum Creatinine (Cr)≤ 1.5 times ULN or Creatinine Clearance Rate (CrCl) ≥ 60ml/min;
    5. Cardiac function: Left Ventricular Ejection Fractions (LVEF)≥45%;
    6. Pulmonary function: Forced Expiratory Volume in the first second (FEV1) ≥ 50%.
11. Prior to the first dose, subjects must have recovered from toxic effects of previous treatment (CTCAE grade ≤ 1, with the exception of specific criteria such as "alopecia"), and the investigator determines that the corresponding adverse events do not pose a safety risk.
12. For male or female subjects of childbearing potential: from the time of signing the ICF until at least 24 weeks after the last dose, they must agree to practice abstinence or use effective contraceptive methods, including intrauterine devices, etc.

    Note: Women of childbearing potential who have undergone surgical sterilization (including hysterectomy, bilateral oophorectomy, or salpingectomy) or who have been postmenopausal for more than 24 months are considered to have no potential for pregnancy.
13. A suitable venous access for the necessary blood collection can be established, and there are no contraindications for leukapheresis.

Exclusion Criteria:

Inclusion criteria:

1. Be able to understand and sign the Informed of Consent Document. Be willing to follow the procedure and protocol of the clinical trial;
2. Age 18-70 (including boundary value), both male and female;
3. Expected life span is more than 3 months from the date of signing the informed consent;
4. ECOG score 0-1;
5. Metastatic or recurrent solid tumors confirmed by histopathology;
6. Refractory to standard treatment evaluated by radiological assessment;
7. Be able provide fresh or preserved tissue specimen;
8. At least 1 measurable lesion (according to RECIST 1.1);
9. ALPP expression positivity determined by IHC；
10. The organ marrow function of the subjects meets the following requirements:

    1. Marrow function：ANC≥ 1.5×109/L; PLT count≥ 75×109/L; HGB≥ 90 g/L;
    2. Coagulation function: Prothrombin Time (PT)≤ 1.5 times the Upper Limit of Normal (ULN), International Normalized Ratio (INR)≤ 1.5 times ULN, and Activated Partial Thromboplastin Time (APTT)≤ 1.5 times ULN;
    3. Liver function: ALT and AST≤ 2.5 times ULN (in cases of liver transfer/infiltration, ≤ 5.0 times ULN); Total Bilirubin (TBIL) ≤ 1.5 times ULN (with Gilbert's syndrome, \<3×ULN);
    4. Renal function: Serum Creatinine (Cr)≤ 1.5 times ULN or Creatinine Clearance Rate (CrCl) ≥ 60ml/min;
    5. Cardiac function: Left Ventricular Ejection Fractions (LVEF)≥45%;
    6. Pulmonary function: Forced Expiratory Volume in the first second (FEV1) ≥ 50%.
11. Prior to the first dose, subjects must have recovered from toxic effects of previous treatment (CTCAE grade ≤ 1, with the exception of specific criteria such as "alopecia"), and the investigator determines that the corresponding adverse events do not pose a safety risk.
12. For male or female subjects of childbearing potential: from the time of signing the ICF until at least 24 weeks after the last dose, they must agree to practice abstinence or use effective contraceptive methods, including intrauterine devices, etc.

    Note: Women of childbearing potential who have undergone surgical sterilization (including hysterectomy, bilateral oophorectomy, or salpingectomy) or who have been postmenopausal for more than 24 months are considered to have no potential for pregnancy.
13. A suitable venous access for the necessary blood collection can be established, and there are no contraindications for leukapheresis.

Exclusion criteria:

1. Subjects with primary central nervous system (CNS) malignancies; subjects with CNS metastases who have failed local treatment; subjects without symptomatic brain metastases within 14 days before pretreatment, or with stable clinical symptoms and no requirement for corticosteroids or other treatment for brain metastases, may be included;
2. Prior history of malignancy with non-target indications within the past 5 years, with the exception of: adequately treated malignancies, with more than 5 years of stability and minimal risk of recurrence as judged by the investigator; and in situ carcinoma without evidence of recurrence after adequate treatment;
3. Subjects with any active autoimmune disease, history of autoimmune disease, or requiring systemic corticosteroids (≥10 mg/day prednisone equivalent) or immunosuppressive therapy, or syndromes (subjects with skin diseases that do not require systemic treatment or have resolved childhood asthma/allergies without any intervention as an adult; subjects with stable thyroid hormone replacement therapy for autoimmune hypothyroidism may be included);
4. History of immunodeficiency, including positive HIV testing or other acquired or congenital immunodeficiency diseases;
5. History of hereditary or acquired bleeding disorders;
6. Presence of cardiovascular clinical conditions or symptoms, including: a. History of thromboembolic events ≥ grade 3 in the past 6 months, or currently receiving thrombolytic or anticoagulant therapy due to high thrombotic risk; b. Chronic heart failure with reduced ejection fraction (NYHA class ≥ II); c. History of unstable angina; d. Myocardial infarction in the past 6 months; e. Clinically significant malignant arrhythmias (excluding atrial fibrillation, paroxysmal supraventricular tachycardia); f. Clinically significant QTcF prolongation (QTcF \> 450 ms for males, QTcF \> 470 ms for females, derived from Fridericia's formula); g. Poorly controlled hypertension.
7. Presence of active infection (fever due to tumor growth may be included as judged by the investigator);
8. Active pulmonary tuberculosis detected by history or CT scan, or history of active pulmonary tuberculosis within the past 1 year before inclusion, or history of active pulmonary tuberculosis more than 1 year ago without proper treatment;
9. Patients with active hepatitis B or hepatitis C virus infection (active hepatitis B defined as hepatitis B virus deoxyribonucleic acid (HBV-DNA) \> the lower limit of detection; active hepatitis C defined as hepatitis C virus ribonucleic acid (HCV-RNA) \> the lower limit of detection) or positive syphilis serology;
10. Pregnant or lactating women, or subjects with a positive blood pregnancy test;
11. Serious surgery or major trauma within 28 days before lymphodepletion;
12. Vaccination with live or attenuated vaccines within 28 days before Lymphodepletion;
13. Systemic corticosteroids (excluding inhaled therapy, topical treatment, or physiological replacement therapy) or other immunosuppressive treatments within 14 days before lymphodepletion;
14. Receiving any investigational drug or participating in another clinical study within 28 days before lymphodepletion (except for subjects participating in observational, non-interventional clinical studies, or in the survival follow-up period of an interventional clinical study);
15. Refractory or persistent seizures, significant pleural or abdominal effusions, active gastrointestinal bleeding, or subjects judged by the investigator to be at high risk of significant bleeding due to tumor necrosis;
16. Concomitant severe organic or psychiatric diseases;
17. Prior history of allogeneic bone marrow or solid organ transplantation, or renal replacement therapy;
18. Under the investigator's judgment, subjects with uncontrollable tumor-related pain or compression symptoms due to a large tumor burden that requires palliative treatment or radiation therapy should have completed treatment before entering the study;
19. History of substance abuse, or alcohol or drug abuse;
20. Prior cellular therapy (TCR-T, CAR-T, TIL, etc);
21. Prior severe allergic reaction to any drug or its components in this trial;
22. Subjects whose condition is judged by the investigator to be unsuitable for this study.

Primary outcomes:
measure: Dose Limiting Toxicity or Maximum Tolerated Dose (MTD)
timeFrame: Day 28 post-initial ALPP CAR-T infusion
measure: Overall response rate
timeFrame: Day 0 - Day 730
measure: Treatment-related adverse events as assessed by CTCAE v5.0
timeFrame: Day 0 - Day 730
Secondary outcomes:
measure: Duration of response
timeFrame: Day 0 - Day 730
measure: Progression free survival
timeFrame: Day 0 - Day 730
measure: Overall survival
timeFrame: Day 0 - Day 730
measure: Expansion and persistence of ALPP CAR-T cells in peripheral blood or serous effusion (if present)
timeFrame: Day 0 - Day 730
measure: Cell cytokine levels and tumor biomarkers in peripheral blood and serous effusion (if present)
timeFrame: Day 0 - Day 730
Other outcomes:
Locations:
city: ChongQing
country: China
facility: Department of Hematology, Xinqiao Hospital
state: Chongqing
Study officials:
affiliation: Xinqiao Hospital
name: Qingzhu Jia, M.D.
role: PRINCIPAL_INVESTIGATOR
References: