Phase I/II Study of Engineered T Cell Receptor-Modified NK Cells Targeting PRAME in Conjunction With Lymphodepleting Chemotherapy for the Management of Relapse/Refractory Myeloid Malignancies

Myeloid Malignancies Clinical Trial

Official title:

Phase I/II Study of Engineered T Cell Receptor-Modified NK Cells Targeting PRAME in Conjunction With Lymphodepleting Chemotherapy for the Management of Relapse/Refractory Myeloid Malignancies

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06383572
• Other study ID #: 2024-0196
• Secondary ID: NCI-2024-03505
• Status: Not yet recruiting
• Phase: Phase 1/Phase 2
• Start date: October 31, 2024
• Est. completion date: April 1, 2029

Study information

• Verified date: June 2024
• Source: M.D. Anderson Cancer Center
• Contact: Jeremy Ramdial, MD
• Phone: (713) 745-0146
• Email: jlramdial[@]mdanderson.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

To find a recommended dose of PRAME-TCR-NK cells that can be given to patients with AML or MDS.

Description:

Primary Objectives To assess dose-limiting toxicity (DLT) and determine the safety, day 30 response rate, day 180 treatment failure rate (defined as disease progression or death) and optimal cell dose of T cell receptor (TCR) modified cord blood-natural killer (CB-NK) cells (TCR-NK) targeting PRAME in patients with relapsed/refractory myeloid malignances, for each of the following diseases; AML, MDS, and Multiple Myeloma. The day 30 response rate and day 180 treatment failure rate will be estimated, and the estimates will be used to identify an optimal dose of PRAME-TCR-NK cells.

Secondary Objectives

• To assess the preliminary efficacy of PRAME-TCR-NK cells (Day+ 30 complete and partial response rates; Day 180 progression-free survival rate) in patients with relapsed/refractory AML, MDS, and Multiple Myeloma.

• To quantify persistence of infused allogeneic donor PRAME-TCR CB-derived NK cells in the recipient as an integrated evaluation

• To conduct comprehensive immune reconstitution studies. 2.2.4 To obtain preliminary data on quality of life and patient experience (PROMIS-29 quality of life questionnaire score)

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 54
• Est. completion date: April 1, 2029
• Est. primary completion date: April 1, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. 18-75 years of age. English and non-English speaking participants are eligible

2. Participants with one of the following hematological malignances: AML, MDS/CMML, Multiple myeloma

3. Participants must meet disease specific eligibility criteria (see below)

4. Participants at least 3 weeks from last cytotoxic chemotherapy at the time of starting lymphodepleting chemotherapy, except for Hydroxyurea which is allowed for peripheral blood count control in AML patients until the day prior to administration of lymphodepleting chemotherapy. Patients may continue tyrosine kinase inhibitors or other targeted therapies until up to three days prior to administration of lymphodepleting chemotherapy.

5. Localized radiotherapy to one or more disease sites is allowed prior the infusion provided that there are additional disease sites that are not irradiated to assess response

6. Karnofsky Performance Scale > 50%.

7. Adequate organ function:as described in 7-10

8. Renal: Serum creatinine </= 2.0 mg/dL and estimated Glomerular Filtration Rate (eGFR using the CKD-EPI equation).GFR = 141 x [min(Scr/k), 1)a x max (Scr/k), 1) -1.209] x Age-0.993 x 1.018 [if female] x [ 1.157 if Black] (a is 0.329 for females and 0.411 for males; min indicates minimum of Scr/k or 1, and max indicates maximum of Scr/k or 1)

9. Hepatic: ALT/AST </= 2.5 x ULN or </= 5 x ULN if documented liver metastases, Total bilirubin </= 1.5 mg/dL, except in subjects with Gilbert's Syndrome in whom total bilirubin must be </= 3.0 mg/dL. No history of liver cirrhosis. No ascites.

10. Cardiac: Cardiac ejection fraction >/= 40%, no clinically significant pericardial effusion as determined by an ECHO, and no uncontrolled arrhythmias or symptomatic cardiac disease.

11. Pulmonary: No clinically significant pleural effusion (per PI discretion), baseline oxygen saturation > 92% on room air and adequate pulmonary function with FEV1, FVC and DLCO (corrected for Hgb) >50%.

12. Able to provide written informed consent.

13. All participants who are able to have children must practice effective birth control while on study and up to 3 months post completion of study therapy. Acceptable forms of birth control for female patients include: hormonal birth control, intrauterine device, diaphragm with spermicide, condom with spermicide, or abstinence, for the length of the study. If the participant is a female and becomes pregnant or suspects pregnancy, she must immediately notify her doctor. If the participant becomes pregnant during this study, she will be taken off this study.

a. Approved methods of birth control are as follows: Hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal ring), Intrauterine device (IUD), Tubal Ligation or hysterectomy, Subject/Partner post vasectomy, Implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice; however periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

14. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of study agent administration. Men who are able to have children must use effective birth control while on the study. If the male participant fathers a child or suspects that he has fathered a child while on the study, he must immediately notify his doctor.

15. Signed consent to long-term follow-up protocol PA17-0483 to fulfill the institutional responsibilities to various regulatory agencies.

16. Life Expectancy >=3 mo, by PI assessment

17. Participants are HLA-A*02:01 positive on HLA typing

17. Participants must have one of the following diseases:

Acute myeloid leukemia (AML): one of the following:

1. Greater than 1 cycle of induction therapy required to achieve morphologic remission (must still have MRD detectable)

2. Treatment-related AML

3. Primary induction failure

4. Have minimal residual disease by morphology, flow cytometry, FISH, detection of disease related mutations or cytogenetic abnormality after first course of induction chemotherapy

5. Have relapsed after prior allogeneic hematopoietic transplant

Myelodysplastic syndromes (MDS):

a. De novo MDS with intermediate or high-risk IPSS scores, chronic myelomonocytic leukemia (CMML) or treatment-related MDS. Patients with intermediate-1 features should have failed to respond to hypomethylating agent therapy.

Multiple myeloma (MM):

a. Participants with relapsed or refractory MM (patients with solitary plasmacytoma are not eligible) who meet the following criteria: i. > or = 4 prior lines of therapy (including exposure to at least one proteasome inhibitor, ImiD, and anti-cd38 antibody and +/- bcma targeted agent ii. have measurable disease (serum monoclonal (M) protein level =0.5 g/dL, and/or urine M protein level =200 mg/day, and/or involved serum FLC level =10 mg/dL provided the serum-free light-chain ratio is abnormal b. *refractory is defined as a documented progressive disease during or within 60 days [measured from the last dose of any drug within the regimen] of completing treatment with the last anti-myeloma regimen before study entry. c. Participants with relapsed or refractory plasma cell leukemia who have received at least two previous regimens d. Participants at least 2 weeks from the last anti-myeloma therapy at the time of starting lymphodepleting chemotherapy. Participants may continue tyrosine kinase inhibitors or other targeted therapies until at least three days prior to administration of lymphodepleting chemotherapy. Small molecule targeted therapies will not include targeted immune therapies, such as daratumumab, isatuximab or elotuzumab. e. Prior autologous/allogeneic transplants are allowed. f. Prior cell therapy is allowed against targets other than PRAME. g. Participants must have recovered from systemic toxicity of prior anti-myeloma therapy at the start of lymphodepletion. h. No active or uncontrolled infection at the start of lymphodepletion and/or cell infusion.

i. No therapeutic systemic corticosteroids (>/= 20 mg prednisone or equivalent) within 72 hours of lymphodepleting therapy. j. Participants with concurrent autoimmune diseases with neurologic involvement, such as multiple sclerosis will be excluded. k. Localized radiotherapy to one or more disease sites is allowed prior the infusion provided that there are additional disease sites that are not irradiated

Exclusion Criteria:

1. Positive beta HCG in female of child-bearing potential defined as not postmenopausal for 24 months or no previous surgical sterilization or lactating females.

2. Presence of clinically significant Grade 3 or greater toxicity from the previous treatment, as determined by PI.

3. Presence of uncontrolled fungal, bacterial, viral, or other infection not responding to appropriate therapy.

4. Known active hepatitis B or C.

5. Known HIV with detectable viral load

6. Presence of active neurological disorder(s).

7. Active autoimmune disease within 12 months of enrollment

8. Active cerebral or meningeal involvement by the malignancy

9. Active (defined as requiring therapy) acute or chronic GVHD

10. Any other malignancy known to be active, except for treated cervical intra-epithelial neoplasia and non-melanoma skin cancer.

11. Presence of any other serious medical condition that may endanger the patient at investigator discretion.

12. Major surgery <4 weeks prior to first dose of the preparatory chemotherapy

13. Allogeneic SCT or DLI <12 weeks prior to first dose of preparatory chemotherapy

14. Concomitant use of other investigational agents.

15. Concomitant use of other anti-cancer agents.

16. Participants receiving systemic steroid therapy at time of enrollment (physiological substitutive doses are allowed), or have received antithymocyte globulin or lymphocyte immune globulin within 14 days of enrollment or alemtuzumab within 28 days of enrollment.

17. Participants receiving immunosuppressive therapy

Related Conditions & MeSH terms

• Myeloid Malignancies
• Neoplasms

Intervention

Drug:
• Cyclophosphamide
Given by IV
• Fludarabine phosphate
Given by IV
• Decitabine
Given by IV

Locations

Country	Name	City	State
United States	MD Anderson Cancer Center	Houston	Texas

Sponsors (1)

Lead Sponsor	Collaborator
M.D. Anderson Cancer Center

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety and adverse events (AEs)	Incidence of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 5.0	Through study completion; an average of 1 year.

External Links

•   MD Anderson Cancer Center