Summary

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).

Objectives

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:

1. Ovarian cancer

2. Endometrial cancer (only 'endometrioid' subtype requires CCNE1 amplification)

3. Gastric, gastroesophageal junction (GEJ) or esophageal adenocarcinoma with CCNE1
amplification

4. Small cell lung cancer (SCLC)

5. Triple-negative breast cancer (TNBC; HER2, estrogen receptor and progesterone
receptor negative)

6. 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])

7. 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.

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 (only endometrioid subtype will require CCNE1 amplification
as determined by NGS by local liquid or tissue test).

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

Eligibility

1. 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:
2. Ovarian cancer
3. Endometrial cancer (only endometrioid subtype will require CCNE1 amplification)
4. Gastric, gastroesophageal junction (GEJ) or esophageal adenocarcinoma with CCNE1 amplification
5. Small cell lung cancer (SCLC)
6. Triple-negative breast cancer (TNBC; HER2, estrogen receptor and progesterone receptor negative)
7. 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])
8. 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. 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 (only 'endometrioid' subtype will require CCNE1 amplification as determined by NGS by local liquid or tissue test). 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.
9. Have adequate organ function
10. Subjects with female reproductive organs must be surgically sterile, post-menopausal, or must be willing to use highly effective method(s) of contraception
11. Ability to swallow oral medications.
12. Consent to provide archived tumor tissues and paired tumor biopsy at pretreatment

Treatment Sites in Georgia