Clinical trial NCT06586957: A Study With NKT3964 for Adults With Advanced/Metastatic Solid Tumors
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Solid Tumor
Advanced Solid Tumor
Solid Tumor, Adult
Metastatic Tumor
Ovarian Cancer
Ovarian Neoplasms
Ovarian Carcinoma
Metastatic Ovarian Carcinoma
Endometrial Neoplasms
Endometrial Diseases
Metastatic Endometrial Cancer
Triple Negative Breast Cancer
Metastatic Endometrial Carcinoma
Advanced Endometrial Carcinoma
Advanced Ovarian Carcinoma
Gastric Cancer
Advanced Gastric Carcinoma
Metastatic Gastric Cancer
Metastatic Gastric Carcinoma
Small Cell Lung Cancer
Small Cell Lung Carcinoma
Triple Negative Breast Neoplasms
Platinum-resistant Ovarian Cancer
Platinum-refractory Ovarian Carcinoma
CCNE1 Amplification
Hormone Receptor Negative Breast Carcinoma
Human Epidermal Growth Factor 2 Negative Carcinoma of Breast
Progesterone-receptor-positive Breast Cancer
Keywords: CDK 2 Inhibitor
CDK 4 Inhibitor
CDK 6 Inhibitor
Lead sponsor: NiKang Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2024-09-19
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Dose Escalation and Dose Expansion
Primary purpose: TREATMENT

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 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

Primary outcomes:
measure: Number of Participants with Dose Limiting Toxicity (DLT) events
timeFrame: 28 Days
measure: Objective Response Rate (ORR)
timeFrame: 1 Year
Secondary outcomes:
measure: Progression-free survival (PFS)
timeFrame: 2 Year
measure: Duration of Response (DOR)
timeFrame: 2 Year
measure: Disease control rate
timeFrame: 1 Year
measure: Overall Survival (OS)
timeFrame: 2 Year
measure: Time to Response (TTR)
timeFrame: 1 Year
measure: Number of Participants with Adverse Events
timeFrame: 2 Year
measure: Maximum observed plasma concentration (Cmax) of NKT3964
timeFrame: 1 Month
measure: Time to maximum observed plasma concentration of NKT3964 (Tmax)
timeFrame: 1 Month
measure: Observed trough concentration of NKT3964 (Ctrough)
timeFrame: 88 Weeks
measure: Area under the plasma concentration-time curve (AUC0-t) of NKT3964
timeFrame: 1 Month
measure: Apparent clearance (CL/F)
timeFrame: 1 Month
measure: Apparent volume of distribution (V/F)
timeFrame: 1 Month
measure: Half-life (t1/2)
timeFrame: 1 Month
measure: Accumulation ratio (AR)
timeFrame: 1 Month
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: University of Arkansas Medical School
state: Arkansas
city: Lake Mary
country: United States
facility: Florida Cancer Specialists & Research Institute
state: Florida
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Hackensack
country: United States
facility: John Theurer Cancer Center at Hackensack UMC
state: New Jersey
city: Philadelphia
country: United States
facility: Sidney Kimmell Cancer Center - Jefferson Health
state: Pennsylvania
city: Nashville
country: United States
facility: Sarah Cannon Research Institute (SCRI)
state: Tennessee
city: Austin
country: United States
facility: NEXT Oncology
state: Texas
city: Salt Lake City
country: United States
facility: Intermountain Health
state: Utah
Study officials:
References: