A Study With NKT5097 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 Selective CDK2/CDK4 Dual Degrader NKT5097 in Adults With Advanced/Metastatic Solid Tumors

Overview

The goal of this open-label dose escalation and expansion study is to evaluate the safety and tolerability of NKT5097 in adults with advanced/metastatic tumors (emphasis on breast cancer and solid tumors with CCNE1 amplification). Main questions to answer include: * What is the recommended dose for expansion and/or Phase 2, for both monotherapy and in combination with ET * What medical issues/symptoms do participants experience when taking NKT5097 as monotherapy as well as in combination with ET

Detailed description

This First-in-Human, Open-Label Study to Evaluate the Safety, Tolerability, PK, and Preliminary Anti-tumor Activity of NKT5097, a novel dual protein degrader of CDK2 and CDK4, is split into 3 Parts:

Part 1: Monotherapy Dose Escalation in selected advanced/metastatic non-CNS primary solid tumors will be enrolled based on a projected total of 5 dose levels

Part 2: Food Effect Analysis: Subjects with solid tumors (as noted in Part 1) will be enrolled (by backfilling selected dose cohorts) to evaluate the effect of dosing with food on NKT5097.

Part 3: Monotherapy Tumor-specific Expansion: Subjects may be enrolled (by backfilling selected dose cohorts) into each selected tumor-specific cohort. One or more of these cohorts may be opened at the discretion of the Sponsor in consultation with the DEC

Part 4: Combination Dose Escalation with ET in selected HR+/HER2- breast cancer will be enrolled based on a projected 2 dose levels

Part 5: Combination Dose Expansion with ET in HR+/HER2- breast cancer in one or more various cohorts

In addition to the above, the study will explore pharmacokinetics, various pharmacodynamic biomarkers, gene mutations, and tumor responses such as PFS and DOR.

Interventions

• Drug NKT5097 CDK2/CDK4 dual degrader
  NKT5097 will be distributed in tablet form and dosed daily or twice a day
• Drug Fulvestrant
  Fulvestrant will be administered as an injection and dosed on C1D1, C1D15 and Day 1 of every cycle thereafter.
• Drug Letrozole
  Letrozole will be administered orally once daily.

Primary outcome measures

• Incidence of dose-limiting toxicities as Assessed by CTCAE [Time frame: From enrollment through end of safety monitoring period of 28 days from first dose]

Secondary outcome measures (9)

• Incidence of adverse events (AEs) as defined by CTCAE Version 5 [Time frame: From enrollment through end of treatment up to 2 years]
• Maximum concentration Cmax after a single dose and multiple doses [Time frame: Day 1 and Day 15 of Cycle 1 (Cycle 1 is 28 days)]
• Area under the concentration-time curve (AUC last) after a single dose and multiple doses from first dose through the last timepoint with quantifiable concentration (Tlast) [Time frame: Day 1 and Day 15 of Cycle 1 ((Cycle 1 is 28 days)]
• Maximum concentration (Cmax) when dosed with and without food [Time frame: Day 1 and Day 2 of Cycle 1 (Cycle 1 is 28 days)]
• Area under the concentration-time curve (AUC last) when dosed with and without food from dosing through the last timepoint with quantifiable concentration (Tlast) [Time frame: Day 1 through Day 3 of Cycle 1 (Cycle 1 is 28 days)]
• Time to maximum plasma concentration (Tmax) after a single dose and multiple doses [Time frame: Day 1 through Day 3 and Day 15 of Cycle 1 (Cycle 1 is 28 days)]
• Investigator-assessed ORR by RECIST v1.1 [Time frame: From enrollment (Day 1) through end of treatment (up to 3 years) with an average of 4 months]
• Investigator-assessed PFS by RECIST v1.1 [Time frame: From enrollment (Day 1) through end of treatment (up to 3 years) with an average of 4 months]
• Duration of Response (DOR) [Time frame: From enrollment (Day 1) through end of treatment (up to 3 years) with an average of 4 months]

Eligibility criteria

Inclusion criteria

• Able to provide written informed consent
• Advanced unresectable or metastatic solid tumor (Part 1, 2 \& 3 only)
• Advanced unresectable or metastatic HR+/HER2- breast cancer (Part 4 \& 5 only)
• Refractory to or unable to tolerate existing therapies (Part 1, 2 \& 4 only)
• Measurable or evaluable disease (Part 1, 2, \& 4 only).
• Measurable disease (Part 3 \& 5 only)
• Eighteen years of age or older
• ECOG status of 0 or 1
• Adequate organ function
• Patients with female reproductive organs must be surgically sterile, post- menopausal or willing to use effective contraception per protocol
• Patients who are capable of insemination must be willing to use highly effective contraception and to refrain from sperm donation during treatment and for 28 days after the last dose
• Able to swallow oral meds
• Willing to provide tumor tissue

Exclusion criteria

• Advanced solid tumor that is a candidate for curative treatment
• History of another malignancy except for the following: adequately treated local basal cell or squamous carcinoma of the skin, in situ cervical cancer, adequately treated papillary noninvasive bladder cancer, other adequately treated Stage I or Stage II cancers currently in complete remission
• Not recovered from the effects of prior anticancer therapy
• Clinically significant cardiovascular event, including myocardial infarction, arterial thromboembolism, or cerebrovascular thromboembolism, within 6 months
• Known active CNS metastases and/or carcinomatous meningitis
• Active interstitial lung disease requiring treatment
• History of uveitis, retinopathy, or other clinically significant retinal disease
• Major surgery within 30 days of administration of first dose
• Active uncontrolled infectious disease
• Significant liver disease (Child Pugh class B or C)
• Should not have received any prior selective investigational inhibitors or degraders (Part 5 only)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 18 centers

• City of Hope — Duarte
• UC San Diego Moores Cancer Center — La Jolla
• Sarah Cannon Research Institute at HealthONE — Denver
• Yale Cancer Center — New Haven
• SCRI Florida Cancer Specialists - Sarasota — Sarasota
• University of Iowa — Iowa City
• Dana-Farber Cancer Institute — Boston
• South Texas Accelerated Research Therapeutics (START) Midwest — Grand Rapids
• … and 10 more centers

Identifiers

NCT: NCT07029399 · NKT5097-101

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗