Study of ART6043 in Advanced/Metastatic Solid Tumors Patients (POLKA)

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

This interventional study will evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of ART6043 as monotherapy or in combination with olaparib.

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:

1. Part A (Dose-escalation phase): Part A will evaluate ART6043 as monotherapy (Part A1) in patients with advanced or metastatic cancer and in combination with olaparib (Part A2), in patients with advanced or metastatic cancer with genetic lesions that cause loss of function of known DNA Damage Response (DDR) genes. Olaparib is also referred as PARPi.
2. Part B (dose-expansion phase): To further confirm the safety of ART6043 and assess its initial effectiveness in combination compared to olaparib alone (Part B2) in patients with a germline BRCA mutation who have HER2-ve advanced or metastatic breast cancer

Patients may continue to receive ART6043 and/or olaparib 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.

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 shorter. Endocrine and hormonal therapies for the treatment of cancer must have been discontinued (unless for the treatment of Prostate Cancer) 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.

Inclusion Criteria specific to Part A1 (ART6043 as Monotherapy)

• Advanced or metastatic cancer. Tumors with genetic lesions known to cause loss of function of known DDR genes based on available pre-existing testing are encouraged.

Inclusion criteria specific to Part A2 (ART6043 in combination with olaparib)

• Advanced or metastatic cancer with genetic lesions known to cause loss of function of known DDR genes based on available, pre-existing testing.
• 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 olaparib or olaparib alone)

• Histologically or cytologically confirmed HER2-ve locally advanced or metastatic carcinoma of the breast.
• Documentation of a deleterious or suspected deleterious gBRCA mutation.
• Previously treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting unless medically contraindicated.
• 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 absorption of ART6043 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.