Phase 1 Study Of LNK001 In Advanced Or Metastatic Clear Cell Renal Cell Carcinoma

Primary Objectives:

• To determine the occurrence of dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of LNK001 CAR T cells in patients with advanced clear cell RCC (ccRCC) to inform the selection of the recommended dose for expansion (RDE)/optimal cell dose (OCD).
• To assess the safety and tolerability of LNK001 in participants with advanced ccRCC.

Secondary Objective:

• To assess measures of anti-tumor efficacy, including the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) after LNK001 infusion. Although the clinical benefit of LNK001 has not yet been established, the intent of offering this treatment is to provide a possible therapeutic benefit, and thus the patient will be carefully monitored for tumor response and symptom relief in addition to safety and tolerability.

Exploratory Objectives:

• To characterize pharmacokinetics and pharmacodynamics of LNK001 (CAR T-cell levels, cytokine profiles, anti-drug antibodies).
• To assess baseline tumor molecular features (CAIX/ENPP3) and correlate with response.
• To identify predictive biomarkers of safety and efficacy.

Inclusion criteria

• Patients with histologically or cytologically confirmed metastatic/advanced RCC with a clear cell component who have received at least one prior line of systemic treatment in the advanced or metastatic setting, including at least one PD-1/PD-L1 immune checkpoint inhibitor (ICI) and one tyrosine kinase inhibitor (TKI). Patients with locally advanced disease who are eligible for curative resection are excluded.

• For patients who received one prior line of therapy, they must have had evidence of disease progression. For patients who received 2 or more prior lines of therapy, evidence of progression is not required if they stopped treatment for intolerance.
• Confirmation of CAIX expression ≥ 50% at any intensity (greater than 0) by immunohistochemistry staining of the patient's primary renal tumor or a metastatic lesion biopsy specimen will be required for enrollment in the study. Both overall extent of expression and staining intensity will be scored. Archival tissues that exist prior to the time of enrollment will be used for this purpose.
• Patients must have at least one measurable site of disease per RECIST version 1.1.4.
• ECOG performance status ≤ 1.
• Age ≥ 18 years.
• Patients must have adequate organ and marrow function as defined below:

• Hemoglobin ≥ 8 g/dl
• Absolute neutrophil count ≥1,500/mcL
• Platelets ≥100,000/mcL
• Total bilirubin ≤ 1.5 mg/dL; for patients with liver metastases or confirmed/suspected Gilbert syndrome, TBIL ≤3 × ULN
• AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN; for patients with liver metastases, AST and ALT ≤ 5 × ULN
• Creatinine (CrCl) ≥ 30 mL/min using either the Cockcroft-Gault formula or the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation
• INR and PT ≤ 1.5 x ULN and partial prothrombin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN (unless abnormalities are unrelated to coagulopathy). Therapeutic anticoagulation with low molecular weight heparin (LMWH) or direct oral anticoagulant (DOAC) is permitted if the participant is on a stable therapeutic dose for at least 2 weeks at the time of enrollment.
• Left ventricular ejection fraction ≥ 45% by echocardiogram or MUGA scan.
• For patients with a history of chronic hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections, the HBV and HCV viral loads must be undetectable.
• Patients with a history of major psychiatric illness must be judged (by the treating physician) able to fully understand the investigational nature of the study and the risks associated with the therapy.
• The effects of LNK001 on the developing human fetus are unknown. 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.
• Female patients of childbearing potential (not postmenopausal for at least 12 months and not surgically sterile) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) before study entry. Pregnancy test must be repeated on the day of first infusion, if test performed > 14 days before starting study drug.
• Female patient of childbearing potential having sex with an unsterilized male partner must agree to use a highly effective method of contraception from the beginning of screening until 90 days after the last dose of the LNK001. Unsterilized male patients having sex with a female partner of childbearing potential, or a pregnant or breastfeeding partner must agree to use barrier contraception (male condom) for the duration of the treatment period until 90 days after the last dose of LNK001. Male patients with female partners of childbearing potential must have the female partner agree to use at least 1 form of highly effective contraception for the duration of the treatment period until 90 days after the last dose of LNK001.

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
• Ability to understand and the willingness to sign a written informed consent document for the clinical trial.
• Willingness to enroll in a 15-year long term follow-up surveillance protocol post LNK001 dosing.

Exclusion criteria

• Participants must not have any other malignancies requiring active treatment within the past 2 years except for in situ carcinoma of any site, or adequately treated (without recurrence post-resection or post-radiotherapy) carcinoma of the cervix or basal or squamous cell carcinomas of the skin, ductal carcinoma in situ of the breast or low-risk early-stage prostate adenocarcinoma with negligible risk of metastasis or death.
• Major surgical procedures or serious trauma within 4 weeks prior to enrollment or plans for major surgical procedures within 4 weeks after cell infusion (as determined by the investigator). Minor local procedures (excluding central venous catheterization and port implantation) within 3 days prior to enrollment.
• History of major cardiovascular diseases prior to enrollment: unstable angina, myocardial infarction, congestive heart failure (New York Heart Association [NYHA] classification ≥ grade 2) or vascular disease (eg, aortic aneurysm at risk of rupture) that required hospitalization within 6 months prior to consenting, or other cardiac impairment that may affect the safety evaluation of the study drug (eg, poorly controlled arrhythmias, myocardial ischemia, clinically significant pericardial effusions).
• Symptomatic CNS metastases, leptomeningeal disease, CNS metastases with hemorrhagic features, CNS metastasis ≥ 1.5 cm, CNS radiation within 7 days prior to enrollment, or potential need for CNS radiation within the first 28 days from LNK001 therapy.

• Patients with treated/stable brain metastases are allowed on protocol if they had brain metastases that received CNS-directed therapy, such as surgery or treatment with radiosurgery or Gamma knife, without recurrence or edema for at least 1 month (4 weeks). Patients actively requiring glucocorticoids for uncontrolled brain or leptomeningeal metastases are not eligible. Patients must have stopped corticosteroids or be on physiologic corticosteroid replacement therapy (prednisone ≤ 10 mg daily or equivalent).
• Active autoimmune diseases requiring systemic therapy (e.g., with disease-modifying drugs, prednisone >10 mg daily or equivalent, immunosuppressant therapy). However, the following will be allowed:

• Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is permitted.
• Intermittent use of bronchodilators, inhaled corticosteroids, or local corticosteroid injections.
• Ongoing treatment with systemic corticosteroid therapy at doses of prednisone > 10 mg/day or equivalent.
• Prior allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.
• Prior ex vivo, in vivo, autologous or allogeneic CAR T therapy.
• Prior treatment with investigational therapeutics that target CAIX or ENPP3.
• Severe infection within 4 weeks prior to enrollment (e.g. patients requiring hospitalization, severe sepsis, or severe pneumonia with respiratory failure).

• Active ongoing infection requiring oral or IV antimicrobials prior to consenting.

Preventive antimicrobials are permitted

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
• Pregnant women are excluded from this study because LNK001 is a CAR T agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with LNK001, breastfeeding should be discontinued if the mother is treated with LNK001. These potential risks may also apply to other agents used in this study.
• Patient is breastfeeding or plans to breastfeed during the study.
• Patients with persistent non-hematological grade ≥2 adverse events per NCI CTCAE v6.0 from prior systemic therapies that would confound timely detection of adverse events due to LNK001 or otherwise hinder patient participation in the clinical trial.
• History or current evidence of any condition (medical [including adverse events from prior anticancer therapy, disorders secondary to tumor], surgical or psychiatric [including substance abuse]), or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, might lead to higher medical risk and/or is not in the best interest of the patient to participate, in the opinion of the treating investigator.