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.

Study Overview

• Status: Recruiting
• Conditions: Advanced Solid Tumor; Metastatic Solid Tumor
• Intervention / Treatment: Drug: ART6043; Drug: Olaparib

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 181
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Artios Pharma; Phone Number: +44 (0)1223 867 900; Email: info@artios.com

Study Locations

• Spain
  • Andalusia
    • Granada, Andalusia, Spain, 18007
      • Recruiting
      • Hospital Universitario Clínico San Cecilio
  • Castille and León
    • Valladolid, Castille and León, Spain, 47003
      • Recruiting
      • Hospital Clinico Universitario de Valladolid
  • Catalonia
    • Barcelona, Catalonia, Spain, 08025
      • Recruiting
      • Hospital de la Santa Creu i Sant Pau
  • Extremadura
    • Cáceres, Extremadura, Spain, 10003
      • Recruiting
      • Hospital San Pedro De Alcantara
  • Madrid
    • Madrid, Madrid, Spain, 28041
      • Recruiting
      • Hospital Universitario 12 de Octubre
• United States
  • Michigan
    • Grand Rapids, Michigan, United States, 49546
      • Active, not recruiting
      • South Texas Accelerated Research Therapeutics (START) - Midwest
  • New York
    • New York, New York, United States, 10065-6800
      • Active, not recruiting
      • Memorial Sloan-Kettering Cancer Center (MSKCC)
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Active, not recruiting
      • Stephenson Cancer Center - Oncology
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 17107
      • Active, not recruiting
      • Jefferson University Hospitals - Kimmel Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Completed
      • SCRI Oncology Partners
  • Texas
    • Dallas, Texas, United States, 75251
      • Completed
      • Mary Crowley Cancer Center - Clinic
    • Houston, Texas, United States, 77030
      • Active, not recruiting
      • The University of Texas - MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A1 (ART6043 as monotherapy); Patients with advanced or metastatic cancer will receive ART6043 administered in 21-day cycles.	Drug: ART6043; ART6043 will be given orally.
Experimental: Part A2 (ART6043 in combination with olaparib); 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; ART6043 will be given orally.; Drug: Olaparib; Olaparib will be given orally.
Experimental: Part B2 (ART6043 in combination with olaparib); Patients with gBRCA-m, HER2-ve locally advanced or metastatic breast cancer will be randomly assigned to receive ART6043 in combination with olaparib or olaparib alone.	Drug: ART6043; ART6043 will be given orally.; Drug: Olaparib; Olaparib will be given orally.

What is the study measuring?

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-days)
Part B2: Progression free survival (PFS)	PFS is defined as the time from randomization 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
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)
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)
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)
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)
Part B2: Number of participants with Adverse events	To assess the safety and tolerability of ART6043 given orally in combination with olaparib 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)
Disease control rate (DCR)	To assess preliminary signs of efficacy for ART6043 as monotherapy and in combination with olaparib.	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 and in combination with olaparib.	Screening (≤28 days) Until follow-up visit (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.	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)

Collaborators and Investigators

• Sponsor: Artios Pharma Ltd

Study record dates

Study Major Dates

• Study Start (Actual): June 30, 2023
• Primary Completion (Estimated): June 30, 2028
• Study Completion (Estimated): September 30, 2028

Study Registration Dates

• First Submitted: May 15, 2023
• First Submitted That Met QC Criteria: June 1, 2023
• First Posted (Actual): June 12, 2023

Study Record Updates

• Last Update Posted (Actual): May 1, 2026
• Last Update Submitted That Met QC Criteria: April 27, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Metastatic Cancer; HER2-negative Breast Cancer; BRCA; Poly (adenosine diphosphate ribose) polymerase (PARP) inhibitor (PARPi); Human epidermal growth factor receptor 2 negative (HER2-ve); Oral anticancer; Sensitivity to Polymerase Theta Inhibitor
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Neoplastic Processes; Pathological Conditions, Signs and Symptoms; Neoplasm Metastasis; Poly(ADP-ribose) Polymerase Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; olaparib
• Other Study ID Numbers: ART6043C001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No