Study of ART6043 in Advanced/Metastatic Solid Tumors Patients

Study Overview
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Brief Summary
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This interventional study will evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of ART6043 as monotherapy or in combination with Olaparib or Talazoparib.

Detailed Description
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ART6043 is being developed as an oral anti-cancer agent in combination with a poly (adenosine diphosphate ribose) polymerase (PARP) inhibitor (PARPi) in patients with cancers that harbor defects in DNA repair. The study will consist of two parts: Part A (dose-escalation phase) & Part B (dose-expansion phase). Part A will evaluate ART6043 as monotherapy (Part A1) and in combination with either Olaparib (Part A2) or Talazoparib (Part A3), in patients with advanced and metastatic solid malignancies with genetic lesions. Olaparib or Talazoparib are collectively referred to as PARPi. Part B will evaluate the preliminary efficacy, safety profile, and PK of ART6043 in combination with a PARPi compared to PARPi alone. Part B will randomize patients with human epidermal growth factor receptor 2 negative (HER2-ve) locally advanced or metastatic breast cancer with a germline or somatic breast cancer gene (BRCA) mutation (g/sBRCA-m) who have received no or ≤1 month of prior treatment with a PARPi, in a 1:1 to an RP2D of ART6043 in combination with a PARPi vs a PARPi alone. Patients may continue to receive ART6043 and/or PARPi as long as they may be continuing to derive clinical benefit as assessed by the investigator and/or until disease progression, withdrawal of consent or until they experience unacceptable drug-related toxicity.

Official Title
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A Phase I/IIa, Open-label, Multi-center Study to Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of the DNA Polymerase Theta Inhibitor ART6043 Administered Orally as Monotherapy and in Combination to Patients With Advanced or Metastatic Solid Tumors

Conditions
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Advanced Solid Tumor, Metastatic Solid Tumor

Intervention / Treatment
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* Drug: ART6043
* Drug: Olaparib
* Drug: Talazoparib
* Drug: Olaparib
* Drug: Talazoparib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who have discontinued all previous chemotherapeutic agents, non-hormonal targeted therapy, or investigational drugs for at least 21 days or 5 half-lives (not including palliative radiotherapy at focal sites), whichever is longer. Endocrine and hormonal therapies for the treatment of cancer must have been discontinued at least 7 days before receiving study medication. Palliative radiotherapy must have completed prior to start of study treatment. Resolution of all toxicities of prior therapy or surgical procedures. Performance status of 0-2 on the Eastern Cooperative Oncology Group (ECOG) scale. 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. Radiologically evaluable and measurable and/or non-measurable (prostate cancer patients only) disease. Inclusion Criteria specific to Part A1 (ART6043 as Monotherapy) • Advanced or metastatic cancer with genetic lesions known to cause loss of function of known DDR genes. Inclusion criteria specific to Part A2/A3 (ART6043 in combination with Olaparib/Talazoparib) Advanced or metastatic cancer with genetic lesions known to cause loss of function of known DDR genes. Patients for whom a PARPi is an appropriate treatment option. Patients may have received prior treatment with a PARPi. Inclusion criteria specific to Part B (ART6043 in combination with a PARPi or a PARPi alone) Histologically or cytologically confirmed HER2-ve locally advanced or metastatic carcinoma of the breast. Documentation of a deleterious or suspected deleterious g/sBRCA mutation. No more than 3 prior chemotherapy-inclusive schedules (including antibody conjugates) for locally advanced and/or metastatic disease. Prior treatment with a taxane in the neoadjuvant, adjuvant, locally advanced, or metastatic setting unless medically contraindicated. Patients must have received no or ≤1 month of prior treatment with a PARPi. Exclusion Criteria: Patients who are pregnant. Patients with Myelodysplastic syndrome (MDS)/Acute myeloid leukemia (AML) or with features suggestive of MDS/AML. Have ongoing interstitial lung disease or pneumonitis. Have any major gastrointestinal issues that could impact aabsorption of ART6043, Talazoparib or Olaparib. Patients with brain metastases (patients with treated brain metastases could be eligible if follow-up brain imaging after central nervous system-directed therapy shows no evidence of progression). Have received a live vaccine within 30 days before the first dose of study treatment. Recent major surgery within 4 weeks prior to entry into the study. Have a significant bleeding disorder or vasculitis or had a Grade ≥3 bleeding episode within 12 weeks prior to enrollment. Have a history of allergy or hypersensitivity to study drug components. Exclusion criteria specific to Part B First-line locally advanced and/or metastatic breast cancer with no prior adjuvant chemotherapy. Inflammatory breast cancer.

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A1 (ART6043 as monotherapy)<br>Patients with advanced or metastatic cancer will receive ART6043 administered in 21-day cycles. | Drug: ART6043<br>* Patients will orally receive ART6043.<br>|
| Experimental: Part A2 (ART6043 in combination with Olaparib)<br>Patients with advanced or metastatic cancer and with PARPi as an appropriate treatment option will receive ART6043 in combination with Olaparib twice daily (BID) in 21-day cycles. | Drug: ART6043<br>* Patients will orally receive ART6043.<br>Drug: Olaparib<br>* Patients will orally receive ART6043 in combination with Olaparib.<br>|
| Experimental: Part A3 (ART6043 in combination with Talazoparib)<br>Patients with advanced or metastatic cancer and with PARPi as an appropriate treatment option will be given ART6043 in combination with Talazoparib once daily (QD) in 21-day cycles. | Drug: ART6043<br>* Patients will orally receive ART6043.<br>Drug: Talazoparib<br>* Patients will orally receive ART6043 combination with Talazoparib.<br>|
| Experimental: Part B (ART6043 in combination with a PARPi or a PARPi alone)<br>Patients with g/sBRCA-m, HER2-ve locally advanced or metastatic breast cancer will be randomly assigned to receive ART6043 in combination with a PARPi or a PARPi alone (Olaparib and Talazoparib). | Drug: Olaparib<br>* Patients will orally receive ART6043 in combination with Olaparib.<br>Drug: Talazoparib<br>* Patients will orally receive ART6043 combination with Talazoparib.<br>Drug: Olaparib<br>* Patients will orally receive Olaparib.<br>Drug: Talazoparib<br>* Patients will orally receive Talazoparib.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Number of participants with Dose Limiting Toxicities (DLTs) | Severity of adverse events as assessed by the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) v5.0. | From first dose of study treatment until the end of Cycle 1 (each cycle is 21-day) | 
| Part B: Progression free survival (PFS) | PFS is defined as the time from the start of treatment (Part A) or from randomization (Part B) until objective disease progression as defined by Response evaluation criteria in solid tumors (RECIST) v1.1 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. | Until disease progression (Upto 3.7 years). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part B: Number of participants with Adverse events | To assess the safety and tolerability of ART6043 given orally in combination with PARPi at the Recommended Phase II dose(s) [RP2D(s)]. | Screening (≤28 days) Until follow-up visit (90 days after discontinuation)] (up to 3.7 years) | 
| Best overall response (BOR) | The best overall response is the best response (complete response [CR] or partial response [PR]) 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/recurrence (Upto 3.7 years) | 
| Objective Response Rate (ORR) | Objective Response Rate (ORR) is defined as the proportion of patients with a CR or PR to treatment according to RECIST v1.1. | Screening (≤28 days) Until disease progression/recurrence (Upto 3.7 years) | 
| Disease control rate (DCR) | To assess preliminary signs of efficacy for ART6043 as monotherapy, in combination with olaparib and in combination with talazoparib. | Screening (≤28 days) Until disease progression (Upto 3.7 years) | 
| Duration of response (DOR) | The DOR will be defined for patients with a BOR of CR/PR (with a Prostate Cancer Working Group [3PCWG-3] response of non-PD/NE for patients with prostate cancer), as the time from the date of first documented response until date of documented progression (by RECIST v1.1 or PCWG-3) or death in the absence of disease progression. | Screening (≤28 days) Until disease progression (Upto 3.7 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 (Upto 3.7 years) | 
| Change in level of cancer antigen 125 (CA-125) | To assess preliminary signs of efficacy for ART6043 as monotherapy, in combination with Olaparib and in combination with Talazoparib. | Screening (≤28 days) Until follow-up visit (Upto 3.7 years) | 
| Part A: 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 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 (Upto 3.7 years) | 
| Overall survival (OS) | OS is defined as the time from the start of study treatment (Part A) or randomization (Part B) until death due to any cause. | Screening (≤28 days) Until overall survival follow-up (Upto 3.7 years) | 
| Plasma concentration | To determine the plasma concentration of ART6043 and its potential active metabolite ART7276 following both single and multiple oral dosing of ART6043 monotherapy and following multiple oral dosing of ART6043 in combination with Olaparib and in combination with Talazoparib. Also, to explore the effect of ART6043 on the Cmax of Olaparib and Talazoparib. | Pre-dose Cycle 0 Days -2, -1 , Cycle 1 Days 1, 8, 15, 16, Cycle 2 Days 1, 8, 15, Cycle 3 Day 1 Upto 3.7 Years (Each Cycle is 21-Days) | 
| Half life (t1/2) | To determine the t1/2 of ART6043 and its potential active metabolite ART7276 following both single and multiple oral dosing of ART6043 monotherapy and following multiple oral dosing of ART6043 in combination with Olaparib and in combination with Talazoparib. Also, to explore the effect of ART6043 on the t1/2 of Olaparib and Talazoparib. | Pre-dose Cycle 0 Days -2, -1 , Cycle 1 Days 1, 8, 15, 16, Cycle 2 Days 1, 8, 15, Cycle 3 Day 1 Upto 3.7 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 ART6043 and its potential active metabolite ART7276 following both single and multiple oral dosing of ART6043 monotherapy and following multiple oral dosing of ART6043 in combination with Olaparib and in combination with Talazoparib. Also, to explore the effect of ART6043 on the AUC0-inf of Olaparib and Talazoparib. | Pre-dose Cycle 0 Days -2, -1 , Cycle 1 Days 1, 8, 15, 16, Cycle 2 Days 1, 8, 15, Cycle 3 Day 1 Upto 3.7 Years (Each Cycle is 21-Days) | 
| Renal clearance | To determine renal clearance of ART6043 and its potential active metabolite ART7276 following both single and multiple oral dosing of ART6043 monotherapy and following multiple oral dosing of ART6043 in combination with olaparib and in combination with talazoparib. | Cycle 0 Days -2, -1 (Each Cycle is 21-Days) | 
| Percent of ART6043 excreted in urine | To determine percent of ART6043 excreted in urine of following both single and multiple oral dosing of ART6043 monotherapy and following multiple oral dosing of ART6043 in combination with Olaparib and in combination with Talazoparib. | Cycle 0 Days -2, -1 (Each Cycle is 21-Days) | 
| Cancer antigen 125 levels in pre-dose tumor samples | To assess CA-125 levels in pre-dose tumor samples that may be predictive of the activity of ART6043. | At Screening (≤28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Oral anticancer, Metastatic Cancer, HER2-negative Breast Cancer, Poly (adenosine diphosphate ribose) polymerase (PARP) inhibitor (PARPi), Human epidermal growth factor receptor 2 negative (HER2-ve), Sensitivity to Polymerase Theta Inhibitor