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

Brief Summary

Detailed Description

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 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

Primary Outcomes

Secondary Outcomes

• Progression-free survival (PFS)(2 Year)
• Duration of Response (DOR)(2 Year)
• Disease control rate(1 Year)
• Overall Survival (OS)(2 Year)
• Time to Response (TTR)(1 Year)
• Number of Participants with Adverse Events(2 Year)
• Observed trough concentration of NKT3964 (Ctrough)(88 Weeks)
• Progression-free survival (PFS)(2 Year)
• Duration of Response (DOR)(2 Year)
• Disease control rate(1 Year)
• Overall Survival (OS)(2 Year)
• Time to Response (TTR)(1 Year)
• Number of Participants with Adverse Events(2 Year)
• Maximum observed plasma concentration (Cmax) of NKT3964 with and without a high-fat and/or low-fat meal(1 Month)
• Time to maximum observed plasma concentration of NKT3964 (Tmax) with and without a high-fat and/or low-fat meal(1 Month)
• Observed trough concentration of NKT3964 (Ctrough)(88 Weeks)
• Area under the plasma concentration-time curve (AUC0-t) of NKT3964 with and without a high-fat and/or low-fat meal(1 Month)
• Apparent clearance (CL/F) of NKT3964(1 Month)
• Apparent volume of distribution (V/F) of NKT3964(1 Month)
• Half-life (t1/2) of NKT3964(1 Month)
• Accumulation ratio (AR) of NKT3964(1 Month)