Study of ART0380 in Patients With Biologically Selected Solid Tumors

Study Overview
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Brief Summary
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This interventional study will evaluate the efficacy and safety of ART0380 as monotherapy in patients whose tumors have a biology to predict for sensitivity to inhibition of Ataxia-Telangiectasia Mutated and Rad3-related protein kinase (ATR).

Detailed Description
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ART0380 is being developed as an oral anti-cancer agent for the treatment of patients with cancers that have defects in deoxyribonucleic acid (DNA) repair. The study will recruit selected patients with advanced or metastatic solid tumors, specifically: Patients with persistent or recurrent endometrial cancer (EC) Patients with advanced or metastatic solid tumors of any histology Above patients will be randomized in a 1:1 ratio to one of two dose regimens of ART0380. Safety will be evaluated on a quarterly basis, at a minimum. Patients may continue to receive ART0380 as long as they are continuing to derive benefit from treatment or until disease progression, withdrawal of consent, or until they experience unacceptable drug-related toxicity.

Official Title
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A Phase II, Open-label, Multi-center, Basket Study of the ATR Kinase Inhibitor ART0380 Administered Orally as Monotherapy to Patients With Biologically Selected Advanced or Metastatic Solid Tumors (ARTIST)

Conditions
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Advanced Solid Tumor, Recurrent Endometrial Cancer, Metastatic Cancer

Intervention / Treatment
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* Drug: ART0380


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who have discontinued all previous treatments for cancer for at least 21 days or 5 half-lives (not including palliative radiotherapy at focal sites), whichever is shorter. Palliative radiotherapy must have completed 1 week prior to start of study treatment. Resolution of all toxicities of prior therapy or surgical procedures to baseline or Grade 1 (except for hypothyroidism requiring medication, neuropathy, and alopecia, which must have resolved to Grade ≤2). Have adequate organ function. Patients of childbearing potential and patients with partners of childbearing potential are required to use highly effective contraception. Have an estimated life expectancy of ≥12 weeks, in the judgment of the investigator. Performance status of 0-1 on the Eastern Cooperative Oncology Group scale. Have a non-irradiated tumor tissue sample (archival or newly obtained core biopsy of a tumor lesion) available. Inclusion Criteria specific to each Arm Inclusion Criteria for Arm 1 [ART0380 monotherapy (endometrial cancer patients)] Persistent or recurrent EC with biological selection. Patients should have received taxane/platinum chemotherapy unless contraindicated. Measurable disease. Inclusion Criteria for Arm 2 [ART0380 monotherapy (solid tumors patients)] Advanced or metastatic solid cancers of any histology with biological selection. If a Programmed cell death protein-1 /Programmed death-ligand-1 inhibitor (e.g., pembrolizumab) is approved and available for the patient's cancer, the patient should have received such treatment before participating in this study. Radiologically evaluable disease. Exclusion Criteria: Patients who are pregnant. Prior treatment with an inhibitor of ATR, WEE1, checkpoint kinase 1 or PKMYT1. Have a serious concomitant systemic disorder that would compromise the patient's ability to adhere to the protocol. Have ongoing interstitial lung disease or pneumonitis (whether symptomatic or asymptomatic). Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS) directed therapy shows no evidence of progression. Have any major gastrointestinal issues that could impact absorption of ART0380. Have a history of allergy or hypersensitivity to study drug components. Have a significant bleeding disorder or vasculitis or had a Grade ≥3 bleeding episode within 12 weeks prior to enrollment. Patients receiving potent inhibitors and inducers of CYP3A4 or CYP3A4 substrates which have a narrow therapeutic range or CYP3A4 sensitive substrates within 2 weeks before the first dose of study treatment will be excluded. Patients receiving the following within 2 weeks of the first dose will be excluded from study treatment. P-glycoprotein or breast cancer resistance protein (BCRP) inhibitors Statins Patients who plan to father a child while in the study or within 16 weeks (5 months in France) after the last administration of study treatment.

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 [ART0380 monotherapy (endometrial cancer patients)]<br>Patients with persistent or recurrent endometrial cancer (EC) will receive ART0380 monotherapy on either a continuous daily dose or on an intermittent schedule for a 21-day cycle. | Drug: ART0380<br>* Randomized patients will orally receive ART0380.<br>|
| Experimental: Arm 2 [ART0380 monotherapy (solid tumors patients)]<br>Patients with advanced or metastatic solid tumors will receive ART0380 monotherapy on either a continuous daily dose or on an intermittent schedule for a 21-day cycle. | Drug: ART0380<br>* Randomized patients will orally receive ART0380.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | Objective Response Rate (ORR) is defined as the proportion of patients with a complete response (CR) or partial response (PR) to treatment according to Response evaluation criteria in solid tumors (RECIST v1.1). | Until disease progression (Every 6 weeks from randomization Upto 2 Years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with adverse events | To assess the safety and tolerability of ART0380 in patients with solid tumors. | From Cycle 1 (each Cycle is 21-day) Day 1 until 30-day follow-up visit (Upto 2 Years) | 
| Progression free survival (PFS) | The PFS is defined as the time from randomization until the earliest objective disease progression defined by RECIST v1.1 or Prostate Cancer Working Group 3 (PCWG-3) (for patients with prostate cancer in Arm 2) or death by any cause in the absence of progression, regardless of whether the patient withdraws from study medication or receives another anti-cancer therapy prior to progression. | Screening (≤28 days) Until disease progression (Every 6 weeks from randomization Upto 2 Years) | 
| Best overall response (BOR) | The best overall response is the best response (complete response, and partial response) recorded from the date of randomization for each patient until the progression or censoring date in the absence of progression. | Screening (≤28 days) Until disease progression (Every 6 weeks from randomization Upto 2 Years) | 
| Disease control rate (DCR) | To further explore the efficacy of ART0380 in patients with solid tumors enrolled in each of the biologically defined arms. | Screening (≤28 days) Until disease progression (Every 6 weeks from randomization Upto 2 Years) | 
| Duration of response (DOR) | The DOR will be defined for patients with a BOR of CR/PR, as the time from the date of first documented response until date of documented progression (by RECIST v1.1) or death in the absence of disease progression. | Screening (≤28 days) Until disease progression or death (Every 6 weeks from randomization Upto 2 Years) | 
| Change in tumor size | The best percentage change in tumor size from baseline will be determined for each patient, ie, the maximum reduction from baseline or the minimum increase from baseline in the absence of a reduction. | Screening (≤28 days) Until disease progression (Every 6 weeks from randomization Upto 2 Years) | 
| Overall survival (OS) | The OS is defined as the time from the randomization until death due to any cause. | Screening (≤28 days) Until overall survival follow-up (Every 12 weeks until data cut-off) | 
| Maximum plasma concentration (Cmax) | To determine the Cmax of ART0380 following single oral dosing of ART0380 in patients with solid tumors enrolled in each of the biologically defined arms. | Pre-dose Cycle 1 day 1, 2, 15, 16, 17, 18, Cycle 2 day 1, Cycle 3 day 1 Upto 2 Years (Each Cycle is 21-days) | 
| Half life (t1/2) | To determine the t1/2 of ART0380 following single oral dosing of ART0380 in patients with solid tumors enrolled in each of the biologically defined arms. | Pre-dose Cycle 1 days 1, 2, 15, 16, 17, 18, Cycle 2 day 1, Cycle 3 day 1 Upto 2 Years (Each Cycle is 21-days) | 
| Area under the plasma concentration-time curve from zero to infinity (AUC0-inf) | To determine the AUC0-inf of ART0380 following single oral dosing of ART0380 in patients with solid tumors enrolled in each of the biologically defined arms. | Pre-dose Cycle 1 days 1, 2, 15, 16, 17, 18, Cycle 2 day 1, Cycle 3 day 1 Upto 2 Years (Each Cycle is 21-days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Solid Tumors, Monotherapy, Cancer cell, Oral anti-cancer