A Phase 1, First-in-human, open-label study to evaluate the safety, tolerability, PK, and preliminary anti-tumor activity of the novel oral CDK2 DEGRADER NKT3964 in 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 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:

1. Ovarian cancer

2. Endometrial cancer (only endometrioid subtype will require 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

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.

- 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