Phase I Study of Preconditioning Radiation Therapy With IL-15 Transduced TGFBR2 KO CAR.TROP2-engineered Cord Blood-derived NK Cells in Patients With Advanced Head and Neck Cancer (RADIANCE-NK)
To find the recommended dose of an investigational therapy called chimeric antigen receptor (CAR).TROP2/interleukin (IL)15-transduced TGFBR2 KO cord blood (CB)-derived natural killer (NK) cells (TROP2 CAR/IL-15 TGFBR2 KO NK cells) that can be given with and without preconditioning radiation therapy in patients with advanced head and neck squamous cell carcinoma.
‣ Patients with histologically confirmed head and neck cancer, either HPV+ or HPV-, that is locally advanced AND unresectable OR metastatic (≤5 sites of disease), which has relapsed or progressed following local standard treatments that are known to prolong survival, or for which no standard treatment is available or are no longer effective, or refused such therapy.
‣ Patient tumors must demonstrate TROP2 expression of 2+ or 3+ as determined by IHC at the MDACC CAP and CLIA accredited Clinical Laboratories.
• 2 weeks from the last cytotoxic chemotherapy at the time of lymphodepleting chemotherapy; ≥3 days from last TKI or other targeted therapies at the time of lymphodepleting chemotherapy; ≥3 months from any cell therapy for any malignancy at the time of lymphodepleting chemotherapy; prior radiation therapy is allowed at the time of consent.
‣ RT allowed to ≥1 disease sites prior to the lymphodepleting chemotherapy. If there are additional measurable non-irradiated disease sites, this may be evaluated for response as well. If multiple lesions are irradiated, we advise that a single lesion will be treated to a higher dose and other lesions considered for lower doses, and that one site always remain unirradiated if a patient has ≥2 sites of disease.
‣ Age ≥18 years. Because no dosing or adverse event data are currently available on the use of TROP2 CAR/IL-15 TGFBR2 KO NK cells in combination with radiation therapy in patients \<18 years of age, children are excluded from this study.
‣ Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
‣ Life expectancy ≥3 months per PI or treating physician's discretion.
‣ A female patient is eligible to participate if at least one of the following conditions applies:
‣ a. Not a woman of childbearing potential (WOCBP). OR
‣ A WOCBP who agrees to follow the contraceptive guidelines in Appendix 5 during the study treatment period and for 6 months post-TROP2 CAR/IL-15 TGFBR2 KO NK cell infusion.
‣ WOCBP must have a negative urine pregnancy test within 72 hours prior to the start of lymphodepleting chemotherapy. If a WOCBP has a urine pregnancy test that cannot be confirmed as negative, a serum (beta-human chorionic gonadotropin \[B-hCG\]) pregnancy test will be required.
‣ The effects of TROP2 CAR/IL-15 TGFBR2 KO NK cells on the developing human fetus are unknown. Radiation therapy is absolutely contraindicated in pregnant women. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. (Refer to Pregnancy Assessment Policy MD Anderson Institutional Policy # CLN1114). This includes all female patients, between the onset of menses (as early as 8 years of age) and 55 years unless the patient presents with an applicable exclusionary factor which may be one of the following:
• Postmenopausal (no menses in greater than or equal to 12 consecutive months).
• History of hysterectomy or bilateral salpingo-oophorectomy.
• Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausal range, who have received Whole Pelvic Radiation Therapy).
• History of bilateral tubal ligation or another surgical sterilization procedure.
‣ 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.
‣ A female patient who becomes pregnant, or suspects pregnancy while she or her partner is participating in this study, must immediately notify her doctor. Female patients who become pregnant will be taken off study.
‣ Male patients treated or enrolled on this protocol must agree to follow the contraceptive guidelines in Appendix 5 prior to study entry and for the duration of study participation and for 6 months post-TROP2 CAR/IL-15 TGFBR2 KO NK cell infusion. Male patients who father a child or suspect that they have fathered a child must immediately notify their doctor.
‣ Patients must have measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
‣ Patients must have adequate organ function as defined below within 10 days prior to the start of lymphodepleting chemotherapy:
‣ Table 1. Adequate Organ Function Laboratory Values
‣ Systemic Function Test Laboratory Value Hematologic ANC ≥ 1500/µL Platelets ≥ 100,000/µL Hemoglobin ≥9.0 g/dLa Renal Creatinine ≤ 1.5 x ULNb OR CrCl by Cockcroft-Gault ≥30 mL/min for patients with creatinine formula \> 1.5 x ULNb Hepatic Total bilirubin ≤1.5 x ULN OR direct bilirubin ≤ ULN for patients with total bilirubin levels \>1.5 x ULN AST and ALT ≤2.5 x ULN (≤5 x ULN for patints with liver metastases) Coagulation PT/INR ≤1.5 x ULN unless patien is receiving anticoagulant aPTT therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
‣ ALT=alanine aminotransferase; ANC=absolute neutrophil count; aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase; CrCl=creatinine clearance; INR=international normalized ratio; PT=prothrombin time; ULN=upper limit of normal.
⁃ Criteria must be met without erythropoietin dependency and without packed red blood cell transfusion within last 2 weeks of the screening test. Patients may be on a stable dose of erythropoietin (≥ approximately 3 months).
⁃ Serum creatinine and CrCl should be interpreted and calculated per institutional standard.
⁃ Left ventricular ejection fraction \>50%.
⁃ Adequate respiratory reserve defined as dyspnea Grade 0 or 1 and saturated oxygen \>92% in room air. See Table 2 for a grading scale of dyspnea per the CTCAE v5.0.
⁃ Table 2. Dyspnea grading scale.
⁃ Grade 0 - No shortness of breath Grade 1 - Shortness of breath with moderate exertion Grade 2 - Shortness of breath with minimal exertion; limiting instrumental ADL Grade 3 - Shortness of breath at rest; limiting self-care ADL Grade 4 - Life threatening consequences; urgent intervention indicated Grade 5 - Death
⁃ Prior treatment with TROP2-targeted therapy will be allowed.
⁃ Willing to undergo mandatory blood collections and biopsies as required by the study.
⁃ Willing to sign consent for long-term follow-up on protocol PA17-0483.
⁃ Willing to stay within a 2-hour drive (approximately 100-mile radius) of the study site during the first 4 weeks after the TROP2 CAR/IL-15 TGFBR2 KO NK cell infusion.
⁃ Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
⁃ Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.
⁃ Ability to understand and the willingness to sign a written informed consent document.