A Study With NKT3964 for Adults With Advanced/Metastatic Solid Tumors

Inclusion criteria

• Must have a pathologically confirmed, advanced and unresectable or metastatic solid tumor listed below with documented disease progression on last standard treatment.

For Part 1 only: Patients must be refractory to, or intolerant of existing therapy(ies) known to provide clinical benefit for their condition.

Part 1 Dose Escalation and Food Effect Sub-study:

• Ovarian cancer
• Endometrial cancer (only 'endometrioid' subtype requires CCNE1 amplification)
• Gastric, gastroesophageal junction (GEJ) or esophageal adenocarcinoma with CCNE1 amplification
• Small cell lung cancer (SCLC)
• Triple-negative breast cancer (TNBC; HER2, estrogen receptor and progesterone receptor negative)
• HR+ (includes estrogen-receptor or progesterone-receptor) and HER2- breast cancer (must have progressed following treatment with a CDK4/6 inhibitor, and is not suitable for endocrine therapy [ET])
• Other solid tumors with CCNE1 amplification

Part 2 Dose Expansion:

Part 2A: HR+ and HER2- breast cancer that is locally advanced and unresectable (Stage III) or metastatic (Stage IV); previously treated with ≥1 line of SOC including CDK4/6 inhibitor plus ET and not suitable for further 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 antibody drug conjugate) in the metastatic setting.

Part 2B: Advanced platinum-based chemotherapy- resistant or refractory epithelial ovarian/fallopian/primary peritoneal carcinoma or clear cell ovarian cancer (defined as recurrence ≤6 months after completing platinum-based regimen) with progression on at least one platinum containing therapy and previously treated with ≤4 prior lines of systemic therapy administered for advanced/metastatic disease and with CCNE1 amplification.

Part 2C: Advanced unresectable or metastatic gastric, GEJ or esophageal adenocarcinoma with progression on at least one systemic therapy and previously treated with ≤3 prior lines of systemic therapy administered for advanced/metastatic disease, with CCNE1 amplification as determined by NGS by local liquid or tissue test.

Part 2D: Advanced endometrial adenocarcinoma or uterine papillary serous carcinoma previously treated with ≤4 prior lines of systemic therapy administered for advanced/metastatic disease with CCNE1 amplification.

Part 2E: Advanced/recurrent uterine carcinosarcoma previously treated with 1 prior platinum-based chemotherapy regimen and ≤3 prior lines of systemic therapy. Prior bevacizumab or PARP inhibitors are allowed and must be at least 3 weeks prior to the start of study drug.

• Measurable disease per RECIST v1.1, except for subjects with HR+/HER2- breast cancer or endometrial cancer (Part 1) who must have measurable or evaluable (including skin or bone lesion only) disease.
• Age ≥18 years
• ECOG PS 0-1
• Have adequate organ function
• Subjects with female reproductive organs must be surgically sterile, post-menopausal, or, if of child-bearing potential, must meet pre-specified criteria
• Subjects who are capable of insemination must meet pre-specified criteria
• Ability to swallow oral medications.
• Consent to provide archived tumor tissues and paired tumor biopsy at pretreatment and on-treatment.

Exclusion criteria

• Locally advanced solid tumor that is a candidate for curative treatment through radical surgery and/or radiotherapy, or chemotherapy.
• History of another malignancy with exceptions
• History of lymphohistiocytic or lymphoid hyperplasia; hemophagocytic lymphohistiocytosis.
• Failed to recover from effects of prior anticancer treatment therapy to baseline or Grade ≤ 1 severity (per CTCAE)
• Clinically significant cardiovascular event within 6 months prior to start of NKT3964 treatment
• Known active CNS metastases and/or carcinomatous meningitis
• Clinically active interstitial lung disease currently requiring treatment
• History of uveitis, retinopathy or other clinically significant retinal disease
• Active or chronic corneal disorders, other active ocular conditions requiring ongoing therapy, or any clinically significant corneal disease
• Active wound healing from major surgery within 1 month or minor surgery within 10 days before the first dose of NKT3964.
• Known human immunodeficiency virus (HIV), active hepatitis B or C infection
• 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
• Palliative radiation therapy within 14 days or other radiation therapy within 4 weeks prior to C1D1

Inclusion criteria

• Must have a pathologically confirmed advanced and unresectable or metastatic solid tumor listed below with documented disease progression on last standard treatment. Part 1 only: subjects must be refractory to, or intolerant of existing therapy(ies) known to provide clinical benefit for their condition.

Dose Escalation:

• Ovarian cancer
• Endometrial cancer (only endometrioid subtype will require CCNE1 amplification)
• Gastric, gastroesophageal junction (GEJ) or esophageal adenocarcinoma with CCNE1 amplification
• Small cell lung cancer (SCLC)
• Triple-negative breast cancer (TNBC; HER2, estrogen receptor and progesterone receptor negative)
• HR+ (includes estrogen-receptor or progesterone-receptor) and HER2- breast cancer (must have progressed following treatment with a CDK4/6 inhibitor, and is not suitable for endocrine therapy [ET])
• Other solid tumors with CCNE1 amplification

Dose Expansion:

Part 2A: HR+ and HER2- breast cancer that is locally advanced and unresectable (Stage III) or metastatic (Stage IV); previously treated with ≥1 line of standard of care (SOC) including CDK4/6 inhibitor plus ET and not suitable for further 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 antibody drug conjugate [ADC]) in the metastatic setting..

Part 2B: Advanced platinum-based-chemotherapy resistant or refractory epithelial ovarian/fallopian/primary peritoneal carcinoma or clear cell ovarian cancer (defined as recurrence ≤6 months after completing platinum-based regimen) with progression on at least one platinum containing therapy and previously treated with ≤4 prior lines of systemic therapy administered for advanced/metastatic disease and with CCNE1 amplification.

Part 2C: Advanced unresectable or metastatic gastric, GEJ or esophageal adenocarcinoma with progression on at least one systemic therapy and previously treated with ≤3 prior lines of systemic therapy administered for advanced/metastatic disease, with CCNE1 amplification as determined by NGS by local liquid or tissue test.

Part 2D: Advanced endometrial adenocarcinoma or uterine papillary serous carcinoma previously treated with ≤4 prior lines of systemic therapy administered for advanced/metastatic disease with CCNE1 amplification.

Part 2E: Advanced/recurrent uterine carcinosarcoma previously treated with 1 prior platinum-based chemotherapy regimen and ≤3 prior lines of systemic therapy. Prior bevacizumab or PARP inhibitors are allowed and must be at least 3 weeks prior to the start of study drug.

• Have adequate organ function
• Subjects with female reproductive organs must be surgically sterile, post-menopausal, or must be willing to use highly effective method(s) of contraception
• Ability to swallow oral medications.
• Consent to provide archived tumor tissues and paired tumor biopsy at pretreatment

Exclusion criteria

• Locally advanced solid tumor that is a candidate for curative treatment through radical surgery and/or radiotherapy, or chemotherapy.
• History of another malignancy with exceptions
• History of lymphohistiocytic or lymphoid hyperplasia; hemophagocytic lymphohistiocytosis.
• Failed to recover from effects of prior anticancer treatment therapy to baseline or Grade ≤ 1 severity (per CTCAE)
• Clinically significant cardiovascular event within 6 months prior to start of NKT3964 treatment
• Known active CNS metastases and/or carcinomatous meningitis
• Active interstitial lung disease currently requiring treatment
• History of uveitis, retinopathy or other clinically significant retinal disease
• Active or chronic corneal disorders, other active ocular conditions requiring ongoing therapy, or any clinically significant corneal disease
• Active wound healing from major surgery within 1 month or minor surgery within 10 days before the first dose of NKT3964.
• Known human immunodeficiency virus (HIV), active hepatitis B or C infection
• 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
• Palliative radiation therapy within 14 days or other radiation therapy within 4 weeks prior to C1D1