Gene-edited T Regulatory Cells (CRG-150) for the Treatment of Relapsed/Refractory Malignancies

This is a first-in-human, open-label, multicenter Phase 1/2a study of CRG-150, an autologous gene-edited Treg cell therapy that will follow a BOIN design of dose-escalating cohorts to determine a Recommended Phase 2 Dose (RP2D). Phase 2a participants will be treated with CRG-150 at the determined RP2D.

Following consent and screening assessments, enrolled participants will undergo an apheresis procedure to manufacture the autologous product. The time from apheresis to delivery of product back to the patient is anticipated to be approximately 28 days, and bridging therapy will be allowed between apheresis and CRG-150 infusion at the Investigator's discretion. No lymphodepleting chemotherapy will be administered prior to CRG-150 infusion.

Participants are followed for disease outcomes for 12 months and for long-term safety for up to 15 years, consistent with FDA guidance.

Inclusion criteria

• Capable of understanding, and willing to comply with, and voluntarily sign and date an informed consent form (ICF).
• Willing to adhere to the study visit schedule and other protocol requirements, including the required apheresis procedure/blood collection.
• Is ≥18 years old at the time consent is obtained.
• Must have one of the following metastatic cancer diagnoses:

• HR+HER2- breast cancer
• TNBC
• Prostate cancer
• Has received the following treatment lines for their disease, and in the opinion of the Investigator, the patient would unlikely tolerate or derive clinically meaningful benefit from available treatment options:

• Metastatic HR+HER2- breast cancer

• Patients previously treated for metastatic disease with at least two of the following: endocrine therapy (ET), CDK4/6 inhibitors, or antibody-drug conjugate, with disease progression or intolerance to therapy.
• Prior chemotherapy is not required but does not exclude the patient from the study.
• Metastatic TNBC (mTNBC, estrogen, progesterone, and human epidermal growth factor receptor 2 [HER2] negative)

• Patients previously treated for metastatic disease with at least two of the following: immunotherapy, antibody-drug conjugate, or chemotherapy with disease progression or intolerance to therapy.
• Metastatic prostate cancer (mPC)

• Previously treated for advanced or metastatic disease with the following, alone or in combination, and have demonstrated disease progression by PCWG3 and/or RECIST 1.1 by Investigator judgment, OR is intolerant to therapy:
• Patients previously treated for metastatic disease with at least two of the following: androgen deprivation therapy, oral androgen receptor pathway inhibitors, or taxane chemotherapy with disease progression or intolerance to therapy.
• Patient will be allowed if they refuse or are considered unfit for taxane chemotherapy.
• Has measurable disease as per RECIST 1.1 or bone-only disease (HR+HER2- breast cancer or TNBC only) OR by RECIST 1.1 or bone-only metastases with measurable prostate-specific antigen (PSA) (≥1 ng/mL) (mPC only).
• Has an ECOG performance status of 0 or 1 at screening.
• Has adequate organ function as defined by:

• Hematological parameters:

• Absolute neutrophil count (ANC) ≥1.0 × 109/L (1000/µL)
• Platelet count (PLT) ≥50.0 × 109/L (50,000/µL)
• Hemoglobin ≥7.0 g/dL
• Absolute lymphocyte count (ALC) >0.5 × 109/L (500/µL)
• Renal: Calculated creatinine clearance must be ≥40 mL/min/1.73 m2 (by the Chronic Kidney Disease Epidemiology Collaboration 2021 equation).
• Hepatic parameters:

• Serum total bilirubin ≤1.5x upper limit of normal (ULN) (or <3x ULN if liver metastases present or documented Gilbert's Syndrome).
• Aspartate aminotransferase (AST) ≤2.5x ULN; alanine aminotransferase (ALT) ≤2.5x ULN (AST, ALT ≤5x ULN if liver metastases present).
• Pulmonary: Oxygen saturation on room air >88% per pulse oximetry and not on supplemental oxygen.
• Cardiac: Hemodynamically stable and left ventricular ejection fraction ≥45% by echocardiogram (ECHO) or multigated acquisition scan (MUGA).
• Has met the minimum washout time for previous cancer therapies before apheresis, and in the Investigator's judgment, the patient is able to safely undergo the apheresis.
• If a woman of childbearing potential (WCBP), defined as a sexually mature woman who has not undergone surgical sterilization or who has not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months) must agree to use 2 effective contraceptive methods; examples include oral, parenteral, or implantable hormonal contraceptive, intra-uterine device, barrier contraceptive with spermicide, partner's latex condom or vasectomy) while on study treatment and for at least 1 year after the last dose of the study drug.
• If a WCBP, she must have a negative serum pregnancy test prior to the dose of the study drug.
• If male, a patient must agree to use a latex condom, even if he had a successful vasectomy, while on study treatment and for at least 1 year after the last dose of the study drug.

• If male, a patient must agree not to donate sperm, and if female, a patient must agree not to donate eggs for at least 1 year after the last dose of the study drug.

Exclusion criteria

• On systemic corticosteroid therapy (>5 mg prednisone daily or its equivalent) for an underlying condition (if they were receiving corticosteroid therapy (>5 mg prednisone daily or its equivalent), it must have been stopped >7 days prior to apheresis for cell manufacturing). Note: Use of topical, inhaled, nasal, or ophthalmic steroids is allowed.
• Previous treatment with any investigational agent within 14 days of Screening Period.
• Has an active autoimmune disease (including but not limited to systemic lupus erythematosus, Sjögren's Syndrome, rheumatoid arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease) that has required systemic treatment in the past 12 months (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
• Active malignancies other than the primary cancer indication, other than non-melanoma skin cancer or carcinoma-in-situ (cervix, bladder, or breast). Patients may be eligible if they have shown no evidence of active disease for two years prior to the first dose of the study drug.
• Clinically significant, active, uncontrolled, systemic infection; the following are not exclusionary:

• Patients with human immunodeficiency virus (HIV) must have been on effective antiretroviral therapy for ≥4 weeks prior to enrollment; must have an HIV viral load below the limits of detection; no acquired immunodeficiency syndrome-related opportunistic infections in the past 12 months; and a cluster of differentiation (CD)4+ cell count ≥350 cells/µL.
• Patients with chronic hepatitis B virus (HBV) infection must be on antiviral therapy and have an HBV viral load below the limits of detection.
• Patients with chronic hepatitis C virus (HCV) infection must have completed therapy and have an HCV viral load below the limits of detection.
• Had major surgery (not including placement of vascular access device or tumor biopsies) within 28 days prior to screening, or no recovery from side effects of such intervention, or has planned elective surgery.
• Presence of active and clinically relevant central nervous system disorder, such as epilepsy, stroke, or symptomatic or uncontrolled brain metastases.
• Patients with severe chronic diseases of the kidney, liver, heart, lung, or any other serious illness that, in the opinion of the Investigator, may affect the patient's therapies, follow up, or assessments, including but not limited to uncontrolled clinically significant neurological or psychiatric disorders or metabolic diseases.

• Has significant cardiac disease, such as recent (within 6 months prior to first dose of the study drug) myocardial infarction or acute coronary syndromes (including unstable angina pectoris), congestive heart failure (New York Heart Association class III or IV), uncontrolled hypertension, uncontrolled cardiac arrhythmias, or severe aortic stenosis.
• Has a history of thromboembolic or cerebrovascular events, including transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis, or pulmonary emboli within 6 months prior to the first dose of the study drug.

Patients with deep vein thrombosis or pulmonary embolism initially diagnosed within 6 months prior to the first dose of the study drug may be eligible if they are appropriately treated with anticoagulants (or are off anticoagulants if no longer indicated) and have no evidence of such disease at Screening.

• Has mental or medical conditions that prevent the patient from giving informed consent or participating in the trial or other severe acute or chronic medical or psychiatric conditions or laboratory abnormality that may increase the risk associated with the study participation or the study drug administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for enrollment in this study.
• Has known or suspected intolerance to the components of the study drug, such as dimethyl sulfoxide.
• Is concurrently participating in another investigational therapeutic clinical trial.
• Prior treatment with gene or cell therapy.
• Is a pregnant or breastfeeding female.