Clinical trial NCT05898399: Study of ART6043 in Advanced/Metastatic Solid Tumors Patients
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Advanced Solid Tumor
Metastatic Solid Tumor
Keywords: Metastatic Cancer
HER2-negative Breast Cancer
Poly (adenosine diphosphate ribose) polymerase (PARP) inhibitor (PARPi)
Human epidermal growth factor receptor 2 negative (HER2-ve)
Oral anticancer
Sensitivity to Polymerase Theta Inhibitor
Lead sponsor: Artios Pharma Ltd
Sponsor class: INDUSTRY
First posted: 2023-06-12
Enrollment: 260
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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

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 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.
2. Part B (dose-expansion phase):

Part B: To further confirm the safety of ART6043 in combination with PARPi (Part B1) and to assess initial effectiveness of ART6043 in combination compared to PARPi alone (Part B2) in patients with certain types of breast cancer.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Part A: Number of participants with Dose Limiting Toxicities (DLTs)
timeFrame: From first dose of study treatment until the end of Cycle 1 (each cycle is 21-days)
measure: Part B1: Number of participants with adverse events
timeFrame: Screening (≤28 days) Until follow-up visit (90 days after discontinuation)] (up to 3.7 years)
measure: Part B2: Progression free survival (PFS)
timeFrame: Until disease progression (Upto 3.7 years).
Secondary outcomes:
measure: Part B2: Number of participants with Adverse events
timeFrame: Screening (≤28 days) Until follow-up visit (90 days after discontinuation)] (up to 3.7 years)
measure: Best overall response (BOR)
timeFrame: Screening (≤28 days) Until disease progression/recurrence (Upto 3.7 years)
measure: Objective Response Rate (ORR)
timeFrame: Screening (≤28 days) Until disease progression/recurrence (Upto 3.7 years)
measure: Disease control rate (DCR)
timeFrame: Screening (≤28 days) Until disease progression (Upto 3.7 years)
measure: Duration of response (DOR)
timeFrame: Screening (≤28 days) Until disease progression (Upto 3.7 years)
measure: Change in tumor size
timeFrame: Screening (≤28 days) Until disease progression (Upto 3.7 years)
measure: Change in level of cancer antigen 125 (CA-125)
timeFrame: Screening (≤28 days) Until follow-up visit (Upto 3.7 years)
measure: Part A and B1: Progression free survival (PFS)
timeFrame: Screening (≤28 days) Until disease progression (Upto 3.7 years)
measure: Overall survival (OS)
timeFrame: Screening (≤28 days) Until overall survival follow-up (Upto 3.7 years)
measure: Plasma concentration
timeFrame: 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)
measure: Half life (t1/2)
timeFrame: 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)
measure: Area under the plasma concentration-time curve from zero to infinity (AUC0-inf)
timeFrame: 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)
measure: Renal clearance
timeFrame: Cycle 0 Days -2, -1 (Each Cycle is 21-Days)
measure: Percent of ART6043 excreted in urine
timeFrame: Cycle 0 Day -2 ((Each Cycle is 21-Days)
measure: Cancer antigen 125 levels in pre-dose tumor samples
timeFrame: At Screening (≤28 days)
Other outcomes:
Locations:
city: Grand Rapids
country: United States
facility: South Texas Accelerated Research Therapeutics (START) - Midwest
state: Michigan
city: Oklahoma City
country: United States
facility: Stephenson Cancer Center - Oncology
state: Oklahoma
city: Philadelphia
country: United States
facility: Jefferson University Hospitals - Kimmel Cancer Center
state: Pennsylvania
city: Nashville
country: United States
facility: SCRI oncology partners
state: Tennessee
city: Dallas
country: United States
facility: Mary Crowley Cancer Center - Clinic
state: Texas
city: Houston
country: United States
facility: The University of Texas - MD Anderson Cancer Center
state: Texas
Study officials:
References: