Evaluation of ART6043 Monotherapy and Combination Therapy with Olaparib and Niraparib in Patients with Advanced or Metastatic Solid Tumors
- Trial ID
- 2023-509220-17-00
- Protocol
- ART6043C001
- Sponsor
- Artios Pharma Limited
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **safety** and tolerability of ART6043, a DNA polymerase theta inhibitor, when administered orally to patients with advanced or metastatic solid tumors. This includes determining the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of ART6043 as monotherapy, and in combination with olaparib and niraparib. Additionally, the study aims to evaluate the preliminary signs of efficacy of ART6043 in combination with PARP inhibitors compared to PARP inhibitors alone in patients with HER2-negative locally advanced or metastatic breast cancer with a germline or somatic BRCA mutation. These objectives are clinically relevant as they aim to establish a safe and effective dosing regimen for ART6043, potentially offering a new therapeutic option for patients with these challenging cancer types.
Secondary objectives include:
- Further assessing the safety and tolerability of ART6043 in combination with PARP inhibitors at the RP2D.
- Evaluating preliminary signs of efficacy for ART6043 as monotherapy, and in combination with olaparib and niraparib.
- Determining the pharmacokinetics (PK) of ART6043 and its potential active metabolite ART7276 following both single and multiple oral dosing, as well as in combination with olaparib and niraparib.
- Exploring the effect of ART6043 on the PK of olaparib and niraparib.
- Assessing markers in pre-dose tumor samples that may predict the activity of ART6043.
Participants
The clinical trial involves a total of **65 participants** diagnosed with **metastatic solid tumors** or **advanced solid tumors**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific inclusion criteria, such as having discontinued previous chemotherapeutic agents and possessing adequate organ function. The trial does not include vulnerable populations. Participants are required to have a performance status of 0-2 on the Eastern Cooperative Oncology Group (ECOG) scale and an estimated life expectancy of at least 12 weeks. Lifestyle considerations, such as diet and physical activity, are not specified. The trial aims to assess the safety and tolerability of ART6043, both as a monotherapy and in combination with other treatments, in patients with advanced or metastatic conditions.
Plans and Procedures
The clinical trial is designed as a **Phase I/IIa**, open-label, multi-center study to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of the **DNA polymerase theta inhibitor ART6043**. The trial involves administering ART6043 orally as monotherapy and in combination with other agents to patients with advanced or metastatic solid tumors. The study is structured into two parts: Part A focuses on determining the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of ART6043, while Part B assesses the safety and preliminary efficacy of ART6043 in combination with PARP inhibitors (PARPi) in patients with HER2-negative locally advanced or metastatic breast cancer with a g/sBRCA mutation.
The trial is expected to commence recruitment on July 1, 2024, and conclude by September 30, 2026. Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as prior treatment history, performance status, and organ function. Following the screening, participants will attend regular follow-up visits to monitor safety, adverse events, and drug efficacy. The end-of-study visit will evaluate the overall outcomes and any long-term effects of the treatment.
Participant involvement is anticipated to last throughout the trial duration, with specific timelines dependent on individual response and treatment regimen. Conditions that may lead to early termination from the study include the occurrence of dose-limiting toxicities, severe adverse events, or disease progression. The primary endpoints include the incidence of dose-limiting toxicities and adverse events, while secondary endpoints focus on progression-free survival, overall survival, and various response rates. The trial employs a scientifically rigorous methodology to ensure the collection of reliable and valid data, contributing to the understanding of ART6043's therapeutic potential in treating advanced solid tumors.
Treatment
The clinical trial involves the administration of **ART6043**, a potent and selective inhibitor of deoxyribonucleic acid (DNA) polymerase theta. ART6043 is provided in a **tablet** form and is administered **orally**. The dosing schedule for ART6043 is determined based on the study protocol, with the aim to assess its safety, tolerability, and preliminary efficacy in patients with advanced or metastatic solid tumors. ART6043 is not a pediatric formulation and is not classified as an orphan drug. The product is developed by Artois Pharma Limited and is used as a monotherapy and in combination with other agents in this study.
**Zejula** (Niraparib Tosilate Monohydrate) is another investigational product used in this trial. It is an **antineoplastic agent** provided as **100 mg film-coated tablets** and administered **orally**. Zejula is used outside the conditions of its Summary of Product Characteristics (SmPC) and is relabeled for clinical trial use. The product is manufactured by GlaxoSmithKline (Ireland) Limited. The trial involves the use of Zejula in combination with ART6043 to evaluate the safety and efficacy of the combination therapy.
**Lynparza** (Olaparib) is also included in the trial as an **antineoplastic agent**. It is available in **100 mg and 150 mg film-coated tablets** and is administered **orally**. Similar to Zejula, Lynparza is used outside the conditions of its SmPC and is relabeled for clinical trial use. The product is developed by AstraZeneca AB. Lynparza is used in combination with ART6043 to assess the safety and efficacy of the combination therapy in patients with advanced or metastatic solid tumors.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol. The trial aims to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of ART6043 as monotherapy and in combination with the other investigational products. The study also evaluates preliminary signs of efficacy of ART6043 in combination with PARP inhibitors compared to PARP inhibitors alone in patients with HER2-negative locally advanced or metastatic breast cancer with a germline or somatic BRCA mutation.
Efficacy
The clinical trial aims to assess the efficacy of the **DNA Polymerase Theta Inhibitor ART6043** in patients with advanced or metastatic solid tumors. Efficacy will be evaluated through several primary and secondary endpoints. For Part B2 of the trial, the primary endpoint is **Progression Free Survival (PFS)**, assessed based on RECIST v1.1 criteria. Secondary endpoints include the incidence and severity of adverse events as per CTCAE v5.0, Best Overall Response (BOR), Objective Response Rate (ORR), Disease Control Rate (DCR), Duration of Response (DOR), and changes in tumor size. Additionally, serological tumor markers and overall survival (OS) will be measured. Pharmacokinetic data will be collected, including plasma and urine concentrations of ART6043, as well as plasma concentrations of olaparib and niraparib. Archival tumor or pre-dose tumor biopsy samples will also be analyzed.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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 shorter. Endocrine hormonal therapies for the treatment of cancer must have been discontinued at least 7 days before receiving study medication. Where the investigator wishes to continue GNRH analogues, this should be discussed with the medical monitor. Palliative radiotherapy must have completed 14 days prior to randomization
- 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 must be willing to follow contraceptive requirements during their participation in the study and for the appropriate period after the last dose of study drug
- Have an estimated life expectancy of ≥12 weeks, in the judgment of the investigator.
- Part A1 only: Advanced or metastatic cancer with genetic lesions known to cause loss of function of known DDR genes
- Part A1 for Spain only: Patient that is not eligible for curative treatment, for whom standard of care therapies have failed.
- Part A1 only: At least 1 radiologically evaluable lesion (measurable and/or non-measurable) that can be assessed at baseline and is suitable for repeated radiological evaluation (prostate cancer patients only).
- Part B only: At least 1 lesion (measurable according to RECIST v1.1 criteria or, in the absence of measurable disease, at least 1 evaluable lytic or mixed (lytic + sclerotic) bone lesion that can be assessed using CT or MRI. Note that patients with sclerotic/osteoblastic lesions only in the absence of measurable disease are not eligible. Previously irradiated lesions may not be considered target lesions.
- Part A2 only: Advanced or metastatic cancer with genetic lesions known to cause loss of function of known DDR genes based on available, pre-existing testing
- Part A2 only: Patients for whom a PARPi is an appropriate treatment option. Patients may have received prior treatment with a PARPi.
- Part B only: Histologically or cytologically confirmed HER2-ve locally advanced or metastatic carcinoma of the breast.
- Part B only: Documentation of a deleterious or suspected deleterious gBRCA mutation.
- Part B only: Patients must be considered suitable for PARP inhibition and should have received indicated prior therapies in alignment with local practice guidelines. Patients may have been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting.
- Part B: Patients must have received no or ≤1 month of prior treatment with a PARPi in any setting (including for prior ovarian cancer). Patients receiving any prior PARPi must not have progressed or recurred whilst receiving PARPi.
- Resolution of all toxicities of prior therapy or surgical procedures to baseline or Grade 1 (except for alopecia or peripheral neuropathy, which must have resolved to Grade ≤2) unless discussed with the medical monitor.
Exclusion Criteria
- Patients who are pregnant (lack of pregnancy confirmed by a urine or serum pregnancy test within 5 days prior to receiving first dose of study treatment in patients of childbearing potential) or breast feeding.
- Known hypersensitivity/history of allergy to any of the components of ART6043 or olaparib.
- Part B only: Inflammatory breast cancer.
- Have a serious concomitant systemic disorder that would compromise the patient's ability to adhere to the protocol.
- Patients with Myelodysplastic syndrome (MDS)/Acute myeloid leukemia (AML) or with features suggestive of MDS/AML.
- Have ongoing interstitial lung disease or pneumonitis.
- Patients who have refractory nausea and vomiting, chronic gastrointestinal diseases, or previous significant small bowel resection, with clinically significant sequelae that would preclude adequate absorption of ART6043 or olaparib.
- Patients with brain metastases are not eligible unless treated and stable, defined as: • Prior local therapy (surgery, stereotactic radiosurgery, and/or whole-brain radiotherapy) completed ≥14 days prior to study entry, and • Neurologically stable, with: o No new or worsening neurologic symptoms attributable to CNS disease within 14 days prior to enrollment. o Corticosteroid requirement limited (defined as being either off systemic corticosteroids or on a stable/decreasing dose equivalent to ≤10 mg prednisone daily for at least 14 days prior to enrollment). • No leptomeningeal disease
- 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 (excluding the placement of vascular access), or minor surgery within 1 week of entry into the study.
- Have a significant bleeding disorder or vasculitis or had a Grade ≥3 bleeding episode within 12 weeks prior to enrollment.
- Patients with a second primary malignancy are excluded (except for adequately treated non-melanoma skin cancer or curatively treated in-situ cancer of the cervix), unless treated with curative intent, in complete remission and with no therapy for at least 5 years. For patients with a history of other cancers within 5 years that are considered at very low risk of recurrence per investigator’s judgement (eg, papillary thyroid cancer treated with surgery), eligibility must be discussed with the medical monitor.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Recruiting | 31 Mar 2026 | 55 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
ART6043 | Test | TABLET | ORAL | — | — | PRD11268621 |
ART6043 | Test | TABLET | ORAL | — | — | PRD11075948 |
ART6043 | Test | TABLET | ORAL | — | — | PRD11076117 |
Lynparza 150 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | — | — | PRD6152234 |
ART6043 | Test | TABLET | ORAL | — | — | PRD11076098 |
ART6043 | Test | TABLET | ORAL | — | — | PRD11076113 |
Lynparza 100 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | — | — | PRD6163466 |