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

Официальное название

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

Обзор

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

Подробное описание

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.

Вмешательства

• Препарат ART6043
  ART6043 will be given orally.
• Препарат Olaparib
  Olaparib will be given orally.

Первичные конечные точки

• Part A: Number of participants with Dose Limiting Toxicities (DLTs) [Срок оценки: From first dose of study treatment until the end of Cycle 1 (each cycle is 21-days)]
• Part B2: Progression free survival (PFS) [Срок оценки: Until disease progression (Upto 3.7 years).]

Вторичные конечные точки (11)

• Part B2: Number of participants with Adverse events [Срок оценки: Screening (≤28 days) Until follow-up visit (90 days after discontinuation)] (up to 3.7 years)]
• Best overall response (BOR) [Срок оценки: Screening (≤28 days) Until disease progression/recurrence (Upto 3.7 years)]
• Objective Response Rate (ORR) [Срок оценки: Screening (≤28 days) Until disease progression/recurrence (Upto 3.7 years)]
• Disease control rate (DCR) [Срок оценки: Screening (≤28 days) Until disease progression (Upto 3.7 years)]
• Duration of response (DOR) [Срок оценки: Screening (≤28 days) Until disease progression (Upto 3.7 years)]
• Change in tumor size [Срок оценки: Screening (≤28 days) Until disease progression (Upto 3.7 years)]
• Change in level of cancer antigen 125 (CA-125) [Срок оценки: Screening (≤28 days) Until follow-up visit (Upto 3.7 years)]
• Part A: Progression free survival (PFS) [Срок оценки: Screening (≤28 days) Until disease progression (Upto 3.7 years)]
• Overall survival (OS) [Срок оценки: Screening (≤28 days) Until overall survival follow-up (Upto 3.7 years)]
• Plasma concentration [Срок оценки: 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)]
• Cancer antigen 125 levels in pre-dose tumor samples [Срок оценки: At Screening (≤28 days)]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 7 центров

• South Texas Accelerated Research Therapeutics (START) - Midwest — Grand Rapids
• Memorial Sloan-Kettering Cancer Center (MSKCC) — New York
• Stephenson Cancer Center - Oncology — Oklahoma City
• Jefferson University Hospitals - Kimmel Cancer Center — Philadelphia
• SCRI oncology partners — Nashville
• Mary Crowley Cancer Center - Clinic — Dallas
• The University of Texas - MD Anderson Cancer Center — Houston

Испания · 5 центров

• Hospital Universitario Clínico San Cecilio — Granada
• Hospital Clínico Universitario de Valladolid — Valladolid
• Hospital de la Santa Creu i Sant Pau — Barcelona
• Hospital San Pedro de Alcántara — Cáceres
• Hospital Universitario 12 de Octubre — Madrid

Публикации

• Robinson HMR, Grinkevich V, Majithiya JB, Mann SE, McWhirter C, Rajendra E, Ranzani M, Stockley ML, Costales P, Davis OA, Elinati E, Galbiati A, Geo L, Toste Rego A, Mason B, Armstrong L, Grande D, Neves J, Roy Luzarraga M, Cooper H, Edwardes L, Konstantinou T, van de Ven M, Moises da Silva A, Moser SC, Charles MD, Finch H, Higgins GS, Boulton SJ, Jonkers J, Martin NMB, Heald RA, Smith GCM. The ph PMID 42440368

Идентификаторы

NCT: NCT05898399 · ART6043C001

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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