Study of ARTS-021 in Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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This study, the first clinical trial of ARTS-021, aims to determine the safety, tolerability, pharmacokinetics, pharmacodynamics, maximum tolerated dose, and anti-tumor effects of ARTS-021 in patients with advanced solid tumors. ARTS-021 is an oral medication that inhibits cyclin-dependent kinase 2 (CDK 2).

Detailed Description
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ARTS-021 is a compound being developed for the treatment of patients with solid tumors, specifically, cyclin E1 (CCNE1) altered malignancies. ARTS-021 is a selective and potent cyclin-dependent kinase 2 (CDK 2) inhibitor, which plays an important role in cell cycle regulation. This is a Phase 1/2 first-in-human, open-label, nonrandomized, multicenter study of ARTS-021. Phase 1 is a dose-escalation phase aimed at assessing the safety and tolerability of ARTS-021 and determining the recommended phase 2 dose (RP2D) in patients with relapsed/refractory, unresectable locally advanced, or metastatic solid tumors. Phase 2 is a dose-expansion phase that will be conducted to assess the antitumor activity of ARTS-021 in patients with relapsed/refractory, unresectable locally advanced, or metastatic solid tumors.

Official Title
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A Phase 1/2, First-in-Human Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, MTD/RP2D, and Antitumor Activity of ARTS-021 as a Single Agent and in Combination Therapy in Patients With Solid Tumors

Conditions
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Solid Tumors

Intervention / Treatment
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* Drug: ARTS-021
* Drug: Palbociclib 125mg
* Drug: Fulvestrant 50 MG/ML Prefilled Syringe
* Drug: Letrozole 2.5mg
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing to participate in the study, give written informed consent, and comply with the study restrictions. Male or female aged ≥18 years old at screening; females may be of childbearing potential, of nonchildbearing potential, or postmenopausal. At screening, females must not be pregnant or lactating, or of nonchildbearing potential (either surgically sterilized or physiologically incapable of becoming pregnant, or at least 1 year postmenopausal [amenorrhea duration of 12 consecutive months]); nonpregnancy will be confirmed for all females of childbearing potential by a negative pregnancy test at screening and on Day 1 of each treatment cycle. Willingness of men and women of reproductive potential to observe conventional and effective birth control for the duration of treatment and for 6 months following the last dose of study treatment (Appendix 8.5). Patients enrolled to the combination therapy (Part 1b and Part 2b) shall also follow palbociclib, fulvestrant, letrozole, or carboplatin contraception duration requirements as determined by labels and/or local guidelines. Patients with advanced/metastatic malignancies, and preferred indications as identified in Inclusion Criterion 10 were histologically or cytologically proven. Eastern Cooperative Oncology Group (ECOG) 0-1. Adequate organ function. System Laboratory Value Hepatic ALT or AST ≤ 2.5 × the upper limit of normal (ULN) in the absence of liver metastases, OR 5 × ULN with documented liver metastases Total bilirubin ≤ 1.5 × ULN in the absence of Gilbert's Disease, OR 3 × ULN with Gilbert's Disease provided direct bilirubin is ≤ ULN Renal Calculated creatinine clearance ≥ 60mL/min Creatinine clearance is calculated using Cockcroft/Gault Formula: CrCl = [(140 - age) × body weight] / (SCr × 72) (× 0.85 if female) Age = years Body weight = kg SCr (serum creatinine) = mg/dL Hematologic Hemoglobin ≥ 9 g/dL (≥ 90 g/L) Absolute neutrophil count ≥ 1.5 × 109/L Platelets ≥ 100 × 109/L Notes: Transfusions to increase a patient's hemoglobin level or initiation of erythropoietin or G-CSF therapy to meet enrollment criteria are not allowed in the 7 days preceding the first dose of study drug. If a patient receives transfusions, erythropoietin, or G-CSF therapy ≥ 7 days prior to the first dose, the hematologic criteria listed above must be met following the 7 day window and prior to the first dose of study therapy INR or PT, aPTT or PTT ≤ 1.5 × ULN unless participant is receiving anticoagulant therapy ALT = alanine transaminase; AST = aspartate aminotransferase; G-CSF = granulocyte-colony stimulating factor; INR = international normalized ratio; PT = prothrombin time; aPTT = activated partial thromboplastin time; PTT = partial thromboplastin time; ULN = upper limit of normal Ability to swallow capsules or tablets. Ability to comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation. Select locally advanced or metastatic solid tumor, for which standard therapies are no longer effective, appropriate, or safe in the opinion of the investigator. If the available standard therapy is not considered appropriate or safe in the opinion of the investigator, the rationale for ineligibility shall be provided and documented in the electronic case report form (eCRF). Furthermore, if in the opinion of the investigator, patient is intolerant to standard therapy, drug information, toxicity, and grade will be documented in the eCRF. a) Phase 1 Monotherapy dose escalation i) Locally advanced or metastatic solid tumor, for which standard therapies are no longer effective, appropriate, or safe in the opinion of the investigator (Cohort 1A). b) Phase 1 Combination dose escalation i) Histologically or cytologically confirmed diagnosis of advanced or metastatic HR+ HER2- (HER2 low may be allowed if failed standard of care therapy) breast cancer who have been previously treated with inhibitors of CDK4/6 and endocrine therapy (Cohort 1B), OR Histologically or cytologically confirmed diagnosis of CCNE1 amplified advanced or metastatic EOC who are platinum-refractory or platinum-resistant (Cohort 1C). ii) Previously treated in the advanced or metastatic setting including 1 prior line of combined CDK4/6 inhibitor and endocrine therapy(Cohort 1B) iii) And previously treated with cytotoxic chemotherapy (Cohort 1C) are permitted except for CDK2 inhibitors that are not allowed (Cohort 1B and 1C) c) Phase 2 Monotherapy dose expansion i) Histologically or cytologically confirmed diagnosis of advanced or metastatic CCNE1 amplified solid tumors (eg, EOC, TNBC, endometrial cancer, lung cancer, gastroesophageal cancer, urothelial cancer) (Cohort 2A). ii) Previous treatment in the advanced or metastatic setting is permitted except for CDK2 inhibitors that are not allowed. d) Phase 2 Combination dose expansion i) Histologically or cytologically confirmed diagnosis of advanced or metastatic HR+ HER2- (HER2 low may be allowed if failed standard of care therapy) breast cancer who have been previously treated with inhibitors of CDK4/6 (Cohort 2B), OR Histologically or cytologically confirmed diagnosis of advanced or metastatic EOC with CCNE1 amplified tumor who are platinum-refractory or platinum-resistant (Cohort 2C). ii) Previously treated in the advanced or metastatic setting including 1 prior line of combined CDK4/6 inhibitor and endocrine therapy (Cohort 2B); previous treatments with cytotoxic chemotherapies (Cohort 2C) are permitted except for CDK2 inhibitors that are not allowed. Measurable or nonmeasurable disease as determined by RECIST version 1.1 as appropriate by tumor type. Exclusion Criteria: A patient who meets any of the following exclusion criteria will not be eligible for inclusion in the study: All patients Have received an investigational agent or anticancer therapy within 2 weeks prior to planned start of ARTS-021. Have received any CDK2 inhibitor, protein kinase membrane associated tyrosine/threonine 1 (PKMYT1) inhibitor, or WEE1 inhibitor anticancer therapy. Have undergone major surgery within 4 weeks prior to planned start of ARTS-021. Have received radiotherapy with a limited field of radiation for palliation within 7 days of the first dose of study treatment, except for patients receiving whole brain radiotherapy, which must be completed at least 4 weeks prior to the first dose of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1 week washout is permitted for palliative radiation with a limited port ≤ 2 weeks of radiotherapy to noncentral nervous system (CNS) disease. Active CNS metastases are not eligible. Patients with asymptomatic and treated brain metastases may participate if they are stable and are not requiring steroid treatment. Patients with suspected or confirmed leptomeningeal disease are not eligible even if treated. Have any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 Grade >1 at the time of starting study treatment except for alopecia of any grade or Grade 2 peripheral neuropathy. Have clinically significant, active cardiovascular disease or history of myocardial infarction within 6 months prior to planned start of ARTS-021, or prolongation of the QT interval corrected for heart rate (QTcF) > 470 msec on at least 2/3 consecutive electrocardiograms (ECGs), and mean QTcF > 470 msec on all 3 ECGs, during screening. QTcF is calculated using Fridericia's formula (QTcF): QTcF = QT RR0.33 Correction of suspected drug-induced QTcF prolongation can be attempted at the investigator's discretion and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation. Have immunodeficiency or chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug. Inhaled or topical steroids are permitted in the absence of active autoimmune disease. Have active uncontrolled systemic bacterial, viral, fungal, or parasitic infection (except for fungal nail infection), or coronavirus disease 2019 (COVID-19) infection, or other clinically significant active disease process which in the opinion of the investigator and the sponsor makes it undesirable for the patient to participate in the trial. Screening for chronic conditions is not required. Have active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Note: Controlled (treated) hepatitis will be allowed if they meet the following criteria, antiviral therapy for HBV must be given for at least 1 month prior to first dose of study drug, and HBV viral load must be less than 2000 IU/mL (104 copies/mL) prior to the first dose of study drug. Those on active HBV therapy with viral loads below 2000 IU/mL (104 copies/mL) should stay on the same therapy throughout the study treatment. Note: Untreated patients with chronic infection by HCV are allowed on study. In addition, successfully treated patients (defined as sustained virologic response SVR12 or SVR24) are allowed, if there are 4 weeks between achieving sustained viral response (SVR12 or SVR24) and starting study drug. Have known HIV; excluded due to potential drug-drug interactions between antiretroviral medications and ARTS-021. Current treatment with strong or moderate cytochrome P450 (CYP)3A4 inhibitors or inducers. Have clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of the study drug. Have active second malignancy unless in remission with life expectancy > 2 years and with documented sponsor approval. Examples include: Adequately treated nonmelanomatous skin cancer or lentigo maligna melanoma without current evidence of disease. Adequately treated cervical carcinoma in situ without current evidence of disease. Localized (eg, lymph node negative) breast cancer treated with curative intent with no evidence of active disease present for more than 5 years. Localized prostate cancer undergoing active surveillance. Pregnancy, lactation, or plans to breastfeed during the study or within 3 months of the last dose of study intervention. Have known hypersensitivity to any component of ARTS-021, its formulation, or any combination drug (palbociclib, fulvestrant, letrozole, or carboplatin) for patients in the combination therapy (Part 1b and Part 2b). Have clinically significant gastrointestinal abnormality affecting digestive function that in the opinion of the investigator would affect study drug therapy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Phase 1 dose-escalation Phase 2 dose-expansion
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1, Part 1a: Cohort 1A<br>Once daily (QD), oral doses of ARTS-021 until intolerable toxicities to determine the MTD/RP2D. Each cycle is 28 days. | Drug: ARTS-021<br>* ARTS-021 is a selective and potent oral inhibitor of CDK2 being developed for the treatment of patients with CCNE1-amplified solid tumors.<br>|
| Experimental: Phase 1, Part 1b: Cohort 1B<br>Once daily oral doses of ARTS-021 at 1 to 2 dose levels below the MTD/RP2D (starting dose [DL 0]) followed by dose escalation to the MTD/RP2D (DL 1) or dose de-escalation to 2 to 3 dose levels below the MTD/RP2D in combination with either palbociclib plus letrozole or palbociclib plus letrozole. Each cycle is 28 days for ARTS-021. | Drug: ARTS-021<br>* ARTS-021 is a selective and potent oral inhibitor of CDK2 being developed for the treatment of patients with CCNE1-amplified solid tumors.<br>Drug: Palbociclib 125mg<br>* Antineoplastic agent, cyclin-dependent kinase 4/6 inhibitor<br>Drug: Fulvestrant 50 MG/ML Prefilled Syringe<br>* Antineoplastic agent, estrogen receptor antagonist<br>Drug: Letrozole 2.5mg<br>* Antineoplastic agent, aromatase inhibitor<br>|
| Experimental: Phase 2, Part 2a: Cohort 2A<br>Once daily oral doses of ARTS-021 at the MTD/RP2D until disease progression or toxicity. | Drug: ARTS-021<br>* ARTS-021 is a selective and potent oral inhibitor of CDK2 being developed for the treatment of patients with CCNE1-amplified solid tumors.<br>|
| Experimental: Phase 2, Part 2b: Cohort 2B<br>Once daily oral doses of ARTS-021 at the RP2D in combination with either palbociclib plus fulvestrant or palbociclib plus letrozole until disease progression or toxicity. | Drug: ARTS-021<br>* ARTS-021 is a selective and potent oral inhibitor of CDK2 being developed for the treatment of patients with CCNE1-amplified solid tumors.<br>Drug: Palbociclib 125mg<br>* Antineoplastic agent, cyclin-dependent kinase 4/6 inhibitor<br>Drug: Fulvestrant 50 MG/ML Prefilled Syringe<br>* Antineoplastic agent, estrogen receptor antagonist<br>Drug: Letrozole 2.5mg<br>* Antineoplastic agent, aromatase inhibitor<br>|
| Experimental: Phase 2, Part 2b: Cohort 2C<br>Once daily oral doses of ARTS-021 at the RP2D in combination with carboplatin until disease progression or toxicity. | Drug: ARTS-021<br>* ARTS-021 is a selective and potent oral inhibitor of CDK2 being developed for the treatment of patients with CCNE1-amplified solid tumors.<br>Drug: Carboplatin<br>* Alkylating agent<br>|
| Experimental: Phase 1, Part 1a: Cohort 1C<br>Once daily oral doses of ARTS-021 at 1 to 2 dose levels below MTD/RP2D determined in Part 1a (starting dose [DL 0]) followed by dose escalation to the MTD/RP2D (DL 1) or dose de-escalation to 2 or 3 dose levels below the MTD/RP2D in combination with carboplatin. Each cycle is 28 days for ARTS-021. | Drug: ARTS-021<br>* ARTS-021 is a selective and potent oral inhibitor of CDK2 being developed for the treatment of patients with CCNE1-amplified solid tumors.<br>Drug: Carboplatin<br>* Alkylating agent<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of Dose Limiting Toxicities (DLTs) during the first cycle | Number of participants with DLTs assessed for severity using CTCAE v5.0 criteria will be summarized by dose level. | 28 Days | 
| Number of Participants with Treatment Emergent Adverse Events (TEAEs) and laboratory abnormalities | To evaluate the type, incidence, severity, timing, seriousness, and relationship to study treatment of adverse events and any laboratory abnormalities summarized by dose level. | Approximately 12 months | 
| Determination of Recommended Phase 2 Dose (RP2D) | RP2D for ARTS-021 is less than or the same as the maximum tolerated dose (MTD) as defined by the occurrence of DLTs and TEAEs calculated using isotonic regression. | Approximately 12 months | 
| Objective Response Rate (ORR) | Defined as the proportion of patients with a confirmed Complete Response (CR) or Partial Response (PR), as determined by the investigator by radiographic disease assessment according to RECIST v1.1. | Approximately 34 months | 
| Progression Free Survival (PFS) | Defined as the time from study drug treatment to disease progression, as determined by the investigator by radiographic disease assessment according to RECIST v1.1 | Approximately 34 months | 
| Overall Survival (OS) | Defined as the time from study drug treatment initiation to death from any cause. | Approximately 34 months | 
| Time to Tumor Progression (TPP) | Defined as the time from study drug treatment initiation to radiographic disease progression as determined by the investigator according to RECIST v1.1. | Approximately 34 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK Parameters: Maximum plasma concentration (Cmax) |  | Cycle 1 days 1, 2, 8, 14, and 15 (each cycle is 28 days) | 
| PK Parameters: Time to maximum plasma concentration (Tmax) |  | Cycle 1 days 1, 2, 8, 14, and 15 (each cycle is 28 days) | 
| PK Parameters: Area under the plasma concentration-time curve from time 0 to last measurable concentration (AUC 0-last) |  | Cycle 1 days 1, 2, 8, 14, and 15 (each cycle is 28 days) | 
| PK Parameters: Area under the plasma concentration-time curve from time 0 to last measurable concentration (AUC 0-tau) |  | Cycle 1 days 1, 2, 8, 14, and 15 (each cycle is 28 days) | 
| PK Parameters: Minimum observed plasma concentration at steady state (Cmin, ss) |  | Cycle 1 days 1, 2, 8, 14, and 15 (each cycle is 28 days) | 
| PK Parameters: Accumulation ration (Rac) |  | Cycle 1 days 1, 2, 8, 14, and 15 (each cycle is 28 days) | 
| PK Parameters: Elimination half-life (t1/2) |  | Cycle 1 days 1, 2, 8, 14, and 15 (each cycle is 28 days) | 
| PK Parameters: Apparent clearance (CL/F) |  | Cycle 1 days 1, 2, 8, 14, and 15 (each cycle is 28 days) | 
| PK Parameters: Apparent volume of distribution during terminal phase (Vz/F) |  | Cycle 1 days 1, 2, 8, 14, and 15 (each cycle is 28 days) |