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

The goal of the Dose Escalation phase of the study is to evaluate the safety, tolerability, pharmacokinetics (PK) and preliminary anti-tumor activity to determine the preliminary recommended dose for expansion (RDE) of NKT3964 in adults with advanced or metastatic solid tumors. The goal of the Expansion phase of the study is to evaluate the preliminary anti-tumor activity of NKT3964 at the RDEs based on objective response rate (ORR) and determine the preliminary recommended Phase 2 dose (RP2D).

Inclusion Criteria:

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

Dose Escalation:

1. Ovarian cancer with CCNE1 amplification
2. Endometrial cancer with CCNE1 amplification
3. Gastric cancer, gastroesophageal junction (GEJ) or esophageal adenocarcinoma with CCNE1 amplification
4. Small cell lung cancer (SCLC)
5. Triple-negative breast cancer (TNBC; human epidermal growth factor receptor 2, estrogen receptor and progesterone receptor negative)
6. Pathologically confirmed HR+ (includes estrogen-receptor or progesterone-receptor) and human epidermal growth factor receptor 2 negative (HER2-) breast cancer (BrCa; must have progressed following treatment with a CDK4/6 inhibitor, and is not suitable for endocrine therapy)
7. Other solid tumors with CCNE1 amplification

Dose Expansion:

Part 2A: Pathologically confirmed HR+ and HER2- breast cancer which must have progressed following treatment with a CDK4/6 inhibitor, are not suitable for further endocrine therapy and have had no more than one line of prior systemic chemotherapy in the metastatic setting.

Part 2B: Platinum resistant or refractory ovarian cancer (defined as recurrence ≤6 months after completing platinum-based regimen) with progression on at least one platinum containing therapy, with CCNE1 amplification as determined by NGS by local liquid or tissue test.

Part 2C: Advanced unresectable or metastatic gastric, GEJ or esophageal adenocarcinoma with progression on at least one systemic therapy, with CCNE1 amplification as determined by NGS by local liquid or tissue test.

* Measurable 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.
* Subjects must 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
* Visceral spread with life-threatening complications, lymphangitic spread, known CNS metastases and/or carcinomatous meningitis
* Clinically active interstitial lung disease
* 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
* Major surgery within 2 months or minor surgery within 10 days before the first dose of NKT3964.
* Has known human immunodeficiency virus (HIV), active hepatitis B or C infection
* Prior treatment with a selective or nonselective CDK2 inhibitor
* Childs-Pugh class B or C cirrhosis or any other clinically significant liver disorder
* Radiation therapy within 4 weeks prior to C1D1

Eligibility Criteria:
Inclusion Criteria:

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

Dose Escalation:

1. Ovarian cancer with CCNE1 amplification
2. Endometrial cancer with CCNE1 amplification
3. Gastric cancer, gastroesophageal junction (GEJ) or esophageal adenocarcinoma with CCNE1 amplification
4. Small cell lung cancer (SCLC)
5. Triple-negative breast cancer (TNBC; human epidermal growth factor receptor 2, estrogen receptor and progesterone receptor negative)
6. Pathologically confirmed HR+ (includes estrogen-receptor or progesterone-receptor) and human epidermal growth factor receptor 2 negative (HER2-) breast cancer (BrCa; must have progressed following treatment with a CDK4/6 inhibitor, and is not suitable for endocrine therapy)
7. Other solid tumors with CCNE1 amplification

Dose Expansion:

Part 2A: Pathologically confirmed HR+ and HER2- breast cancer which must have progressed following treatment with a CDK4/6 inhibitor, are not suitable for further endocrine therapy and have had no more than one line of prior systemic chemotherapy in the metastatic setting.

Part 2B: Platinum resistant or refractory ovarian cancer (defined as recurrence ≤6 months after completing platinum-based regimen) with progression on at least one platinum containing therapy, with CCNE1 amplification as determined by NGS by local liquid or tissue test.

Part 2C: Advanced unresectable or metastatic gastric, GEJ or esophageal adenocarcinoma with progression on at least one systemic therapy, with CCNE1 amplification as determined by NGS by local liquid or tissue test.

* 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.
* Subjects must 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
* Visceral spread with life-threatening complications, lymphangitic spread, known CNS metastases and/or carcinomatous meningitis
* Clinically active interstitial lung disease
* 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
* Major surgery within 2 months or minor surgery within 10 days before the first dose of NKT3964.
* Has known human immunodeficiency virus (HIV), active hepatitis B or C infection
* Prior treatment with a selective or nonselective CDK2 inhibitor
* Childs-Pugh class B or C cirrhosis or any other clinically significant liver disorder
* Radiation therapy within 4 weeks prior to C1D1