Investigator-initiated, first-in-human trial of non-virally engineered GMR CAR T cells against CD116-positive acute myeloid leukemia and juvenile myelomonocytic leukemia.

JRCT ID: jRCT2033210029

Registered date:09/04/2021

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: CD116-positive acute myeloid leukemia and juvenile myelomonocytic leukemia
• Date of first enrollment: 09/07/2021
• Target sample size: 21
• Study type: Interventional
• Intervention(s): Administration of CAR-T cells produced from eripheral blood

Outcome(s)

• Primary Outcome: Safety and adverse effects of GMR CAR-T therapy by day 56 after GMR CAR-T infusion or by the time of starting pretreatment for allogeneic hematopoietic stem cell transplantation from the day of GMR CAR-T infusion.

Secondary Outcome

(1) Complete remission rate (CR + CRi) 28 days after GMR CAR-T infusion.
-The time of second registration
-Day 28 after GMR CAR-T infusion
-The following time points which one is earlier: starting pretreatment for allogeneic hematopoietic stem cell transplantation, day 56 after GMR CAR-T infusion
-At the end of the observation period (day 180 after GMR CAR-T infusion)
(2) Cytogenetic and molecular response rates (if the patients have detectable cytogenetic and /or molecular minimal residual disease).
(3) Hematopoietic stem cell transplantation (HSCT) rate.
(4) Phenotypic analysis of GMR CAR-T cells.
(5) Pharmacokinetics of GMR CAR-T cells.
(6) Manufacturing success rate for GMR CAR-T cells.

Key inclusion & exclusion criteria

• Age minimum: >= 1age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

1.Subjects with CD116 positive myeloid malignancies who relapsed after HSCT or experienced induction failure.
2.Aged 18 or more in cohort 1, 1 or more and less than 18 in cohort 2 and 1 or more in cohort 3 at the time of study entry.
3.PS score (Age >= 16 years) >= 50 persent or Lansky score (Age < 15 years) >= 50 persent.
4.HSCT donors are available within 56 days after GMR CAR-T infusion.
5.Subjects capable of undergoing leukapheresis.
6.Adequate normal organ and tolerable disease control defined below.
a. WBC count <= 50,000 /micro-L
b. Absolute lymphocyte count >= 500/micro-L or CD3 positive T cells >= 150/micro-L.
c. Serum bilirubin <= 2.0 mg/dL.
d. AST <= 5-fold the upper limit of normal for age.
e. ALT <= 5-fold the upper limit of normal for age.
f. Serum creatinine <= 2.0 mg/dL.
g. SpO2 >= 95% (room air)
7.Left ventricular ejection fraction (EF) >= 50 persent, no pericardial effusion, and no abnormal electrocardiography findings requiring treatment.
8.Life expectancy >= 3 months.
9.Written informed consent can be obtained from patients and/or representatives.

Exclude criteria

1.Subjects with prior or concurrent malignancies other than myeloid malignancies.
2.Subjects with poor disease control such as increasing leukemia cell counts in peripheral blood.
3.Subjects who received other CAR-T therapy within 24 weeks.
4.Acute promyelocytic leukemia (APL ; FAB M3).
5.Subjects with the active central nervous system and/or extramedullary disease.
6.Subjects with acute graft-versus-host disease (GVHD) (Grade >= 2) or extensive chronic GVHD.
Extensive chronic GVHD is either of either generalized skin involvement (>= 50 persent), localized skin involvement in the association with eye and/or oral involvement, abnormal liver histology (chronic progressive hepatitis, bridging necrosis, or cirrhosis), or other target organ involvement.
7.History of coronary heart disease, acute brain ischemia, or cerebral hemorrhage, or any sequelae of stroke such as paralysis.
8.Poorly controlled high blood pressure (systolic blood pressure > 160 mmHg, diastolic blood pressure > 100 mmHg).
9.Subjects with uncontrollable and/or severe infections.
10.History of pulmonary fibrosis and/or interstitial pneumonia or radiological findings indicating the presence of pulmonary fibrosis and/or interstitial pneumonia.
11.Subjects with poorly controlled diarrhea and/or diabetes mellitus.
12.Subjects with poorly controlled severe heart diseases such as congestive heart failure and arrhythmia, acute brain ischemia, or cerebral hemorrhage. Heart failure is defined as class 3 or 4 cardiovascular disability according to New York Heart Association functional classification.
13.Subjects with severe organ complications such as renal failure, liver failure, or ileus.
14.Subjects who have psychological disorders affecting the participation in the trial.
15.HIV infection and/or HTLV-1 infection.
16.Positive for HBs antigen or HBc antigen and HBV-DNA.
17.Active hepatitis C infection.
18.Prior treatment with any investigational drugs within 30 days prior to enrollment.
19.Prior treatment with any investigational cell and gene therapies within 6 weeks prior to enrollment.
20.Subjects concurrently receiving the following treatments.
a. Corticosteroid (>= 6mg/m2/day equivalent prednisolone dose)
b. Donor lymphocyte infusion within 6 weeks prior to the enrollment
c. Treatment for GVHD (eg, calcineurin inhibitors, methotrexate, mycophenolate mofetil, TNF inhibitors, and IL-6 inhibitors)
d. Salvage chemotherapy must be completed by the time of second registration
21.Females who are pregnant and/or breastfeeding
22.Females of child-bearing potential who are not willing to practice highly effective methods of birth control from the time of consent through more than 12 months after GMR CAR-T cells and after confirmation of two consecutive negative test results of CAR-T in peripheral blood by qPCR. Male subjects with a female partner of childbearing potential who are unwilling to practice sexual abstinence (refrain from heterosexual intercourse) or use contraception from the time of consent to through more than 12 months after GMR CAR-T cells and after confirmation of two consecutive negative test results of CAR-T in peripheral blood by qPCR. As CAR-T cells can be transmitted through the sperm containing white blood cells, male subjects who underwent vasectomy must also practice sexual abstinence (refrain from heterosexual intercourse) or use contraception. Female subjects with no child-bearing potential (Age < 11 years old, amenorrhea for more than 24 months, hysterectomy, bilateral salpingectomy, and/or bilateral oophorectomy) can be enrolled even if they are unwilling to practice sexual abstinence. Female subjects who are becoming capable of pregnant during the study period must practice highly effective methods of birth control from the time of consent through more than 12 months after GMR CAR-T cells and after confirmation of two consecutive negative test results of CAR-T in peripheral blood by qPCR.
23.Subjects who are not inappropriate to participate in this study for any reason by the judgement of investigators.

Related Information

• Primary Sponsor: Nakazawa Yozo
• Source(s) of Monetary Support: Japan Agency for Medical Research and Development