Study of ART6043 in Advanced/Metastatic Solid Tumors Patients

Advanced Solid Tumor Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05898399
• Other study ID #: ART6043C001
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: June 30, 2023
• Est. completion date: December 14, 2026

Study information

• Verified date: May 2024
• Source: Artios Pharma Ltd
• Contact: Artios Pharma
• Phone: +44 (0)1223 867 900
• Email: info[@]artios.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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: Part A (dose-escalation phase) & Part B (dose-expansion phase).

Part A will evaluate ART6043 as monotherapy (Part A1) in patients with advanced or metastatic cancer and in combination with either Olaparib (Part A2) or Niraparib (Part A3), in patients with advanced or metastatic cancer with genetic lesions that cause loss of function of known DNA Damage Response (DDR) genes. Olaparib or Niraparib 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 240
• Est. completion date: December 14, 2026
• Est. primary completion date: May 14, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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/A3 (ART6043 in combination with Olaparib/Niraparib)

• 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 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 absorption of ART6043, Niraparib 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.

Related Conditions & MeSH terms

• Advanced Solid Tumor
• Metastatic Solid Tumor
• Neoplasms

Intervention

Drug:
• ART6043
Patients will orally receive ART6043.
• Olaparib
Patients will orally receive ART6043 in combination with Olaparib.
• Niraparib
Patients will orally receive ART6043 combination with Niraparib.
• Olaparib
Patients will orally receive Olaparib.
• Niraparib
Patients will orally receive Niraparib.

Locations

Country	Name	City	State
United States	Mary Crowley Cancer Center - Clinic	Dallas	Texas
United States	South Texas Accelerated Research Therapeutics (START) - Midwest	Grand Rapids	Michigan
United States	The University of Texas - MD Anderson Cancer Center	Houston	Texas
United States	Stephenson Cancer Center - Oncology	Oklahoma City	Oklahoma

Sponsors (1)

Lead Sponsor	Collaborator
Artios Pharma Ltd

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	Part B: 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	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)
Secondary	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)
Secondary	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)
Secondary	Disease control rate (DCR)	To assess preliminary signs of efficacy for ART6043 as monotherapy, in combination with Olaparib and in combination with Niraparib.	Screening (=28 days) Until disease progression (Upto 3.7 years)
Secondary	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)
Secondary	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)
Secondary	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 Niraparib.	Screening (=28 days) Until follow-up visit (Upto 3.7 years)
Secondary	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)
Secondary	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)
Secondary	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 Niraparib. Also, to explore the effect of ART6043 on the Cmax of Olaparib and Niraparib.	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)
Secondary	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 Niraparib. Also, to explore the effect of ART6043 on the t1/2 of Olaparib and Niraparib.	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)
Secondary	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 Niraparib. Also, to explore the effect of ART6043 on the AUC0-inf of Olaparib and Niraparib.	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)
Secondary	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 Niraparib.	Cycle 0 Days -2, -1 (Each Cycle is 21-Days)
Secondary	Percent of ART6043 excreted in urine	To determine percent of ART6043 excreted in urine following single oral dosing of ART6043.	Cycle 0 Day -2 ((Each Cycle is 21-Days)
Secondary	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)