IRB Study Number 25-587
Status Recruiting
Phase Phase 1
Location Cleveland Clinic Main Campus
Institute Taussig Cancer Institute
Description
4.1.1. Primary Objectives
• To evaluate the overall safety and tolerability of NKT5097
• To identify the RDEs of NKT5097 in adult subjects with advanced/metastatic solid tumors
• To determine the RP2D of NKT5097 based on an analysis of safety, preliminary antitumor activity, PK properties, and PDy effects
4.1.2. Secondary Objectives
• To determine a MTD of NKT5097, if applicable
• To characterize the PK properties of NKT5097
• To evaluate the objective response rate (ORR)
• To evaluate the progression-free survival (PFS), duration of response (DOR), time to response (TTR), and disease control rate (DCR) of NKT5097
4.1.3. Exploratory Objectives
• To evaluate overall survival (OS)
• To evaluate the effect of NKT5097 on the QT/corrected QT (QTc) interval
• To evaluate the effect of food on NKT5097 PK
• To explore the potential effects of polymorphisms of drug metabolizing enzymes and/or transporters on NKT5097 PK
• To explore biomarkers potentially predictive of response and/or resistance to NKT5097
• To evaluate the effects of NKT5097 on CDK2- and/or CDK4-related PDy markers
• To evaluate cancer antigen 125 (CA-125) response (Gynecologic Cancer Intergroup [GCIG] criteria [Appendix 2]) (for subjects with ovarian cancer)
Inclusion Criteria
Understand and sign a written ICF before the performance of any study procedures
Pathologically confirmed, advanced and unresectable or metastatic solid tumor listed below with documented disease progression on last standard treatment.
Part 1 Dose Escalation and Part 2 Food Effect Analysis: Subjects must be refractory to or intolerant of existing therapy(ies) known to provide clinical benefit for their condition
• HR+/HER2- breast cancer that is locally advanced and unresectable or metastatic; and previously treated with ≥ 1 line of SOC, including CDK4/6 inhibitor plus ET; and have documented evidence of disease progression on a prior line of ET. Subjects must have progressed after receiving therapy for ≥ 3 months in the metastatic setting or for ≥ 6 months in the adjuvant setting.
• HR+ breast cancer with any HER2 expression (except HR+/HER2-) that is advanced and unresectable or metastatic; and previously treated with ≥ 1 line of SOC therapy for advanced/metastatic disease
• TNBC that is advanced and unresectable or metastatic; and previously treated with ≥ 1 line of SOC therapy for advanced/metastatic disease
• Advanced/metastatic solid tumors with CCNE1 amplification Note: CCNE1 amplification should be determined by NGS by local liquid or tissue test using the test’s analysis cutoff for amplifications. If a local NGS report only reports CCNE1 copy number instead of defining the “amplification” status, copy number ≥ 6 is considered as amplification. "Intolerant of existing therapy(ies) known to provide clinical benefit" is defined as the documented inability to continue receiving standard therapy due to unacceptable toxicity despite appropriate dose modifications and supportive care measures.
Part 3 Tumor-specific Expansion:
• Part 3A: HR+/HER2- breast cancer that is locally advanced and unresectable or metastatic; previously treated with ≥ 1 line of SOC, including CDK4/6 inhibitor plus ET; and have documented evidence of disease progression on a prior line of ET. Subjects must have progressed after receiving therapy for ≥ 3 months in the metastatic setting or for ≥ 6 months in the adjuvant setting. Subjects must have received ≤ 2 lines of systemic cytotoxic therapy (chemotherapy or cytotoxic ADC) in the metastatic setting
• Part 3B: HR+ breast cancer with any HER2 expression (except HR+/HER2- that falls into Part 3A) that is advanced and unresectable or metastatic; and previously treated with ≥ 1 line of SOC therapy for advanced/metastatic disease
• Part 3C: TNBC that is advanced and unresectable or metastatic; previously treated with ≤ 4 lines of systemic therapy for metastatic disease
• Part 3D: Advanced/metastatic solid tumors with CCNE1 amplification Note: CCNE1 amplification should be determined by NGS by local liquid or tissue test using the test’s analysis cutoff for amplifications. If a local NGS report only reports CCNE1 copy number instead of defining the “amplification” status, copy number ≥ 6 is considered as amplification.
Measurable or evaluable (including skin or bone lesion only) disease for Part 1 and Part 2; measurable disease for Part 3
Age ≥ 18 years
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
Adequate organ function defined as follows:
a. Hematology: ANC ≥ 1.0×109/L; hemoglobin level ≥ 9 g/dL; platelet count ≥ 75,000/μL without transfusion or growth factor support within 21 days prior to first dose of study drug
b. Hepatic: transaminase levels (AST/ALT) ≤ 2.5 × ULN (≤ 5 × ULN if liver metastases present); total bilirubin ≤ 1.5 × ULN in the absence of Gilbert’s Syndrome; ≤ 3 × ULN for subjects with Gilbert’s Syndrome
c. Renal: calculated or measured creatinine clearance (CrCl) ≥ 50 mL/min (Cockcroft-Gault formula or other institutionally approved methods for calculating CrCl)
- Subjects with female reproductive organs must be surgically sterile, post-menopausal, or, if of child-bearing potential, must meet all the following criteria:
a. Have a negative serum pregnancy test result during Screening and within 21 days before the first dose of study drug
b. Are willing to not breastfeed while taking the study drug
c. Are willing to use highly effective method(s) of contraception and 1 additional barrier method or to abstain from intercourse with partners capable of insemination during Screening, while taking the study drug, and for at least 3 months after the last dose of study drug Note: A subject with female reproductive organs is considered to be of childbearing potential unless they have had a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; has medically documented ovarian failure (with serum estradiol and follicle-stimulating hormone levels within the institutional laboratory post-menopausal range and a negative serum or urine beta human chorionic gonadotropin); or is menopausal (age ≥ 55 years with amenorrhea for at least 12 months)
- Subjects who are capable of insemination must meet all the following criteria:
a. Are willing to use highly effective contraception method(s) and 1 additional barrier method or to abstain from intercourse with partners of child-bearing potential from the start of treatment until at least 28 days after the last dose of study drug
b. Are willing to refrain from sperm donation from the start of treatment until at least 28 days after the last dose of study drug Note: A subject with male reproductive organs is considered capable of insemination unless he has had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy
Able to swallow oral medications
Consent to provide archived tumor tissues and paired tissue biopsy at pretreatment and on-treatment. Section 10.2.2 outlines which subjects are required, optional, or waived for paired tumor biopsies
Exclusion Criteria
Locally advanced solid tumor that is a candidate for curative treatment through radical surgery, radiotherapy, or chemotherapy
History of another malignancy except for the following: adequately treated local basal cell or squamous carcinoma of the skin, in situ cervical cancer, adequately treated papillary noninvasive bladder cancer, other adequately treated Stage I or Stage II cancers currently in complete remission, or any other cancer, other than lymphoma, that has been in complete remission for at least 2 years (subjects with history of Stage III malignancies who are stable for at least 6 months may be considered after discussion with NiKang Therapeutics' Medical Monitor)
Failed to recover from the effects of prior anticancer therapy (except for alopecia) to baseline level or Grade 1 severity per NCI CTCAE with the exception of subjects with stable or treatable adverse effects such as neuropathy, hypothyroidism, or hypertension if the adverse effect is well controlled
Clinically significant cardiovascular event, including myocardial infarction, arterial thromboembolism, or cerebrovascular thromboembolism, within 6 months prior to start of NKT5097 treatment; has symptomatic dysrhythmias or unstable dysrhythmias requiring medical therapy; symptomatic peripheral vascular disease; New York Heart Association Class III or IV congestive heart failure (Appendix 4); Grade ≥ 3 hypertension (diastolic blood pressure ≥ 100 mmHg or systolic blood pressure ≥ 160 mmHg) despite adequate use of antihypertensives; or history of congenital prolonged QT syndrome or repeated demonstration of a QTcF interval ≥ 470 msec; family history of sudden death
Known active CNS metastases and/or carcinomatous meningitis
a. Exception: Subjects with a history of CNS metastases or cord compression may be enrolled if they have been definitively treated with local therapy (e.g., radiotherapy, stereotactic surgery) and are clinically stable with no evidence of progression or hemorrhage, and have discontinued dexamethasone (or other steroid) treatment at least 4 weeks before the first study drug administration, and have no ongoing requirement for treatment with dexamethasone or antiepileptic drugs
Active interstitial lung disease currently requiring treatment (e.g., systemic corticosteroids, immunosuppressants)
History of uveitis, retinopathy, or other clinically significant retinal disease in the opinion of the Investigator
Active or chronic corneal disorders, other active ocular conditions requiring ongoing therapy, or any clinically significant corneal disease that prevents adequate monitoring of drug-induced keratopathy
History of major surgery (e.g., gastrointestinal surgery, removal, or biopsy of brain metastasis) within 30 days before administration of the first dose of study drug. Complete wound healing from major surgery must have occurred 30 days before administration of the first dose of study drug and from minor surgery (e.g., simple excision, tooth extraction) at least 10 days before administration of the first dose of study drug. Subjects with clinically relevant ongoing complications from prior surgery are not eligible
Active uncontrolled infectious diseases (bacteria, fungus, or virus) except for known human immunodeficiency virus (HIV) or active hepatitis B or C infection, provided the following criteria are met:
a. Subjects with HIV infection who are on established antiretroviral therapy that meets the concomitant medication requirements (outlined in Section 7.3); have CD4+ T-cell counts > 350 cells/μL and an HIV viral load < 400 copies/mL; and have no history of acquired immune deficiency syndrome (AIDS)-defining opportunistic infections
b. Subjects with chronic hepatitis B virus (HBV) infection with active disease who meet the criteria for anti-HBV therapy and are on a suppressive antiviral therapy that meets the concomitant medication requirements (outlined in Section 7.3)
c. Subjects with hepatitis C virus (HCV) must have completed curative antiviral treatment and have an HCV viral load below the limit of quantification or have a negative HCV RNA; or be on concurrent HCV treatment that meets the concomitant medication requirements (outlined in Section 7.3) and have an HCV viral load below the limit of quantification
Received prior investigative treatment with a selective or nonselective CDK2 inhibitor or degrader
Childs-Pugh class B or C cirrhosis, or any other clinically significant liver disorder (e.g., chronic hepatitis) that in the opinion of the Investigator may cause unacceptable safety risks or compromise compliance with the protocol
Actively receiving investigational therapies in another clinical study or has received prior investigational therapy or standard anticancer therapy within 5 t1/2 of the agent or 4 weeks (whichever is shorter) before the first administration of study drug other than GnRHa (e.g., goserelin) and bone-stabilizing agents (e.g., zoledronic acid, denosumab)
Current use of any drugs, investigational agents, fruits, or herbs that are strong CYP3A4 inhibitors or inducers or P-gp inhibitors within 21 days prior to C1D1 (or 5 t1/2 of the drug, whichever is longer). This includes grapefruit, grapefruit juice, pomelo, Seville oranges, and St. John’s wort.
Use of any proton pump inhibitors within 7 days prior to C1D1
Part 1 and Part 2 only: Continued use of medication that is known to prolong the QT interval. These include drugs with known risk of Torsades de Pointes (TdP). See https://crediblemeds.org/
Malabsorption syndrome or any other gastrointestinal disorder or defect that would interfere with enteral absorption
Palliative radiation therapy within 21 days or other radiation therapy within 4 weeks prior to C1D1
