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
Trial Snapshot
- Phase
- Phase 1
- Status
- Recruiting
- Sponsor
- NiKang Therapeutics, Inc.
- Enrollment
- 238
- Locations
- 30
- Primary Endpoint
- Number of Participants with Dose Limiting Toxicity (DLT) events
Study Overview
Brief Summary
The goal of the Monotherapy Dose Escalation phase (Part 1) 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 Monotherapy Expansion phase of the study (Part 2) is to evaluate the preliminary anti-tumor activity of NKT3964 at the RDE based on objective response rate (ORR) and determine the preliminary recommended Phase 2 dose (RP2D).
The goal of the Combination Dose Escalation phase (Part 3) of the study is to identify the RDE of NKT3964 in combination with chemotherapy in adult subjects with advanced/metastatic endometrial cancer. The goal of the Combination Expansion phase of the study (Part 4) is to evaluate the preliminary anti-tumor activity of NKT3964 in combination with chemotherapy at the RDE based on ORR.
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 Monotherapy Dose Escalation (including Food Effect Sub-study): Patients must be refractory to, or intolerant of existing therapy(ies) known to provide clinical benefit for their condition.
Part 1 Monotherapy Dose Escalation and Food Effect Sub-study:
- Ovarian cancer
- Endometrial cancer (only 'endometrioid' subtype requires CCNE1 amplification)
- Gastric, gastroesophageal junction (GEJ) or esophageal adenocarcinoma with CCNE1 amplification
- Small cell lung cancer (SCLC)
- Triple-negative breast cancer (TNBC; HER2, estrogen receptor and progesterone receptor negative)
- 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])
- Other solid tumors with CCNE1 amplification
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 19 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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 Monotherapy Dose Escalation (including Food Effect Sub-study): subjects must be refractory to, or intolerant of existing therapy(ies) known to provide clinical benefit for their condition.
- •Part 1 Monotherapy Dose Escalation:
- •Ovarian cancer
- •Endometrial cancer (only endometrioid subtype will require CCNE1 amplification)
- •Gastric, gastroesophageal junction (GEJ) or esophageal adenocarcinoma with CCNE1 amplification
- •Small cell lung cancer (SCLC)
- •Triple-negative breast cancer (TNBC; HER2, estrogen receptor and progesterone receptor negative)
- •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])
- •Other solid tumors with CCNE1 amplification
- •Part 2 Monotherapy 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 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.
- •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. Subjects with clear cell carcinoma or uterine serous carcinoma histology may be considered regardless of CCNE1 status after discussion and approval from the Sponsor. 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.
- •- Part 3 Combination Dose Escalation:
- •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. Subjects with clear cell carcinoma or uterine serous carcinoma histology may be considered regardless of CCNE1 status after discussion and approval from the Sponsor
- •Part 4 Combination Dose Expansion:
- •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. ο Subjects with clear cell carcinoma or uterine serous carcinoma histology may be considered regardless of CCNE1 status after discussion and approval from the Sponsor
- •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 NKT
- •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
- •Prior severe hypersensitivity reaction to paclitaxel or other drugs formulated in Polyoxyl 35 Castor Oil (Cohort 3A and 4A only) or severe hypersensitivity reaction to doxorubicin or any other component of the product, other anthracyclines or anthracenediones (Cohort 3B and 4B).
- •For subjects in Cohort 3B or 4B only:
- •Left ventricular ejection fraction (LVEF) <50% as measured by echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 4 weeks prior to first dose
- •Active cardiac conditions including myocarditis, pericarditis, or clinically significant valvular heart disease
- •Known elevated cardiac biomarkers at baseline
- •History of anthracycline-related cardiomyopathy regardless of recovery
- •Cumulative lifetime exposure to doxorubicin, including planned doxorubicin in Part 3b or Part 4b, exceeding 450 mg/m2
Arms & Interventions
Combination Dose Expansion 4A
Combination Dose expansion 4A will evaluate the preliminary anti-tumor activity of NKT3964 in combination with chemotherapy (Paclitaxel) at the RDE from Part 3 based on ORR
Intervention: Paclitaxel (Drug)
Combination Dose Expansion 4B
Combination Dose expansion 4B will evaluate the preliminary anti-tumor activity of NKT3964 in combination with chemotherapy (Doxorubicin) at the RDE from Part 3 based on ORR
Intervention: NKT3964 (Drug)
Combination Dose Expansion 4B
Combination Dose expansion 4B will evaluate the preliminary anti-tumor activity of NKT3964 in combination with chemotherapy (Doxorubicin) at the RDE from Part 3 based on ORR
Intervention: Doxorubicin (Drug)
Monotherapy Dose Escalation
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.
Intervention: NKT3964 (Drug)
Monotherapy Dose Expansion 2B
Monotherapy Dose expansion 2B will include the RDE selected to determine the preliminary antitumor activity and the RP2D in CCNE1-amplified ovarian cancer
Intervention: NKT3964 (Drug)
Monotherapy Dose Expansion 2E
Monotherapy Dose expansion 2E will include the RDE selected to determine the preliminary antitumor activity and the RP2D in uterine carcinosarcoma
Intervention: NKT3964 (Drug)
Monotherapy Dose Expansion 2C
Monotherapy Dose expansion 2C will include the RDE selected to determine the preliminary antitumor activity and the RP2D in CCNE1-amplified upper gastrointestinal adenocarcinoma cancer
Intervention: NKT3964 (Drug)
Monotherapy Dose Expansion 2A
Monotherapy Dose expansion 2A will include the RDE selected to determine the preliminary antitumor activity and the RP2D in HR+/HER2- breast cancer
Intervention: NKT3964 (Drug)
Monotherapy Dose Expansion 2D
Monotherapy Dose expansion 2D will include the RDE selected to determine the preliminary antitumor activity and the RP2D in endometrial cancer
Intervention: NKT3964 (Drug)
Combination Dose Escalation 3A
Combination Dose escalation Part 3A will evaluate the safety, tolerability, PK, and preliminary antitumor activity as well as determine the MTD and/or the preliminary RDE of NKT3964 in combination with chemotherapy (Paclitaxel) in endometrial cancer.
Intervention: Paclitaxel (Drug)
Combination Dose Expansion 4A
Combination Dose expansion 4A will evaluate the preliminary anti-tumor activity of NKT3964 in combination with chemotherapy (Paclitaxel) at the RDE from Part 3 based on ORR
Intervention: NKT3964 (Drug)
Combination Dose Escalation 3B
Combination Dose escalation Part 3B will evaluate the safety, tolerability, PK, and preliminary antitumor activity as well as determine the MTD and/or the preliminary RDE of NKT3964 in combination with chemotherapy (Doxorubicin) in endometrial cancer.
Intervention: Doxorubicin (Drug)
Combination Dose Escalation 3A
Combination Dose escalation Part 3A will evaluate the safety, tolerability, PK, and preliminary antitumor activity as well as determine the MTD and/or the preliminary RDE of NKT3964 in combination with chemotherapy (Paclitaxel) in endometrial cancer.
Intervention: NKT3964 (Drug)
Combination Dose Escalation 3B
Combination Dose escalation Part 3B will evaluate the safety, tolerability, PK, and preliminary antitumor activity as well as determine the MTD and/or the preliminary RDE of NKT3964 in combination with chemotherapy (Doxorubicin) in endometrial cancer.
Intervention: NKT3964 (Drug)
Outcomes
Primary Outcomes
Number of Participants with Dose Limiting Toxicity (DLT) events
Time Frame: 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)
Time Frame: 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 Outcomes
- Maximum observed plasma concentration (Cmax) of NKT3964 under fed vs fasted conditions(1 Month)
- Time to maximum observed plasma concentration of NKT3964 (Tmax) under fed vs fasted conditions(1 Month)
- Area under the plasma concentration-time curve (AUC0-t) of NKT3964 under fed vs fasted conditions(1 Month)
- 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)