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

Phase 1

Recruiting

• Conditions: Solid Tumor; Advanced Solid Tumor; Solid Tumor, Adult; Metastatic Tumor; Ovarian Cancer; Ovarian Neoplasms; Ovarian Carcinoma; Metastatic Ovarian Carcinoma; Endometrial Neoplasms; Endometrial Diseases
• Interventions: Drug: NKT3964

• Registration Number: NCT06586957
• Lead Sponsor: NiKang Therapeutics, Inc.

Brief 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).

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:

1. Ovarian cancer with CCNE1 amplification

2. Endometrial cancer with 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, 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 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 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, with CCNE1 amplification as determined by NGS by local liquid or tissue test. 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

Study Timeline

• Study First Submitted: 2024-09-04
• Study First Submitted QC: 2024-09-04
• Study Start: 2024-09-19
• Study First Posted: 2024-09-19
• Status Verified: 2025-08
• Last Update Submitted: 2025-08-12
• Last Update Posted: 2025-08-15
• Primary Completion: 2029-01
• Study Completion: 2029-05-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 150

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 with CCNE1 amplification
2. Endometrial cancer with 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 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 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 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, with CCNE1 amplification as determined by NGS by local liquid or tissue test. 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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Dose Escalation	NKT3964	Dose escalation will assess the safety, efficacy, and PK/PD data of oral dosing NKT3964 at increasing dosage levels to determine the MTD and/or preliminary RDEs.
Dose Expansion	NKT3964	Dose expansion will include 2 RDEs selected to determine the preliminary antitumor activity and the RP2D.

Primary Outcome Measures

Name	Time	Method
Number of Participants with Dose Limiting Toxicity (DLT) events	28 Days	DLTs graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0
Objective Response Rate (ORR)	1 Year	ORR defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as determined by the Investigator

Secondary Outcome Measures

Name	Time	Method
Progression-free survival (PFS)	2 Year	PFS defined as the time from the date the participant started study drug to the date the participant experiences an event of disease progression or death.
Duration of Response (DOR)	2 Year	Duration of overall response is defined as the time from the date of first confirmed CR or PR, assessed by investigator and based on RECIST v. 1.1, to the documented date of progressive disease (PD) including clinical progression, or death due to any cause, or the start of subsequent anticancer therapy, whichever occurred first.
Disease control rate	1 Year	Disease control rate defined as CR + PR + stable disease \[SD\] for at least 8 weeks
Overall Survival (OS)	2 Year	OS defined as the time from the date the participant started study drug to death for any reason.
Time to Response (TTR)	1 Year	TTR is defined as the time from first dose to the first documented CR or PR which is subsequently confirmed.
Number of Participants with Adverse Events	2 Year	An adverse event (AE) is defined as any untoward medical occurrence in a patient and which does not necessarily have a causal relationship with this treatment. The investigator assessed the relationship of each event to the use of study drug as either probably related, possibly related, probably not related or not related.
Maximum observed plasma concentration (Cmax) of NKT3964	1 Month	Maximum observed plasma concentration (Cmax) of NKT3964
Time to maximum observed plasma concentration of NKT3964 (Tmax)	1 Month	Time to maximum observed plasma concentration of NKT3964 (Tmax)
Observed trough concentration of NKT3964 (Ctrough)	88 Weeks	Observed trough concentration of NKT3964 (Ctrough)
Area under the plasma concentration-time curve (AUC0-t) of NKT3964	1 Month	Area under the plasma concentration-time curve (AUC0-t) of NKT3964
Apparent clearance (CL/F)	1 Month	Apparent clearance (CL/F)
Apparent volume of distribution (V/F)	1 Month	Apparent volume of distribution (V/F)
Half-life (t1/2)	1 Month	Half-life (t1/2)
Accumulation ratio (AR)	1 Month	Accumulation ratio (AR)

Trial Locations

Locations (8)

University of Arkansas Medical School; 🇺🇸 Little Rock, Arkansas, United States

Florida Cancer Specialists & Research Institute; 🇺🇸 Lake Mary, Florida, United States

Dana Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

John Theurer Cancer Center at Hackensack UMC; 🇺🇸 Hackensack, New Jersey, United States

Sidney Kimmell Cancer Center - Jefferson Health; 🇺🇸 Philadelphia, Pennsylvania, United States

Sarah Cannon Research Institute (SCRI); 🇺🇸 Nashville, Tennessee, United States

NEXT Oncology; 🇺🇸 Austin, Texas, United States

Intermountain Health; 🇺🇸 Salt Lake City, Utah, United States