A Study of ART4215 for the Treatment of Advanced or Metastatic Solid Tumors

A Phase I/IIa, Open-label, Multi-centre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of the DNA Polymerase Theta Inhibitor ART4215 Administered Orally as Monotherapy and in Combination to Patients With Advanced or Metastatic Solid Tumors

This clinical trial is evaluating a drug called ART4215 in participants with advanced or metastatic solid tumors. The main goals of this study are to:

• Find the recommended dose of ART4215 that can be given safely to participants alone and in combination with talazoparib
• Learn more about the side effects of ART4215 alone and in combination with talazoparib
• Learn more about the effectiveness of ART4215 alone and in combination with talazoparib
• Learn more about the effectiveness of ART4215 alone and in combination with niraparib

This is an open-label Phase I/IIa study designed to evaluate ART4215, a new first-in-class investigational medicinal product that is a potent and selective inhibitor of deoxyribonucleic acid (DNA) polymerase (pol) theta. ART4215 is being developed as an oral anti-cancer agent for monotherapy treatment of patients with cancers that harbor defects in DNA repair and in combination with anticancer medicines that cause DNA damage.

This study was intended to be a Phase I/IIa trial, however the trial did not proceed to the Phase IIa portion of the study.

General Inclusion Criteria:

• Signed informed consent
• Discontinued all previous treatments for cancer for at least 21 days or 5 half-lives, whichever is shorter (except in Germany where local regulation requires the longer of 21 days or 5 half-lives washout), and recovered from the acute effects of therapy. Palliative radiotherapy must have completed 1 week prior to start of study treatment.
• At least 1 radiologically evaluable lesion (measurable and/or non-measurable) that can be assessed at baseline and is suitable for repeated radiological evaluation by RECIST v1.1 or Prostate Cancer Working Group-3 (PCWG-3) for patients with prostate cancer
• Acceptable hematologic, renal, hepatic, and coagulation functions independent of transfusions and granulocyte colony-stimulating factor
• Willingness to abide by protocol defined contraceptive requirements for the duration of the study.
• Estimated life expectancy of ≥12 weeks

Additional inclusion criteria for participants in dose escalation (Part A1):

• Advanced or metastatic cancer, which is refractory to standard therapies, or for which no standard therapies exist, or for which the investigator feels no other active therapy is required for the duration of the study
• Non-irradiated tumor tissue sample (archival or newly obtained core biopsy of a tumor lesion) available for submission for analysis

Additional inclusion criteria for participants in dose escalation (Part A2):

• Advanced or metastatic cancer for which a PARP inhibitor is an appropriate treatment option. Participants may have received prior treatment with PARP inhibitor
• Optional baseline biopsy for BRCA1/2 mutations and prior PARP inhibitor
• Non-irradiated tumor tissue sample (archival or newly obtained core biopsy of a tumor lesion) available for submission for analysis

Additional inclusion criteria for participants in dose escalation (Part A3):

• Advanced or metastatic cancer for which a PARP inhibitor is an appropriate treatment option. Prior treatment with PARP inhibitor
• Non-irradiated tumor tissue sample (archival or newly obtained core biopsy of a tumor lesion) available for submission for analysis

Additional inclusion criteria for participants in dose expansion (Part B1):

• Advanced or metastatic solid tumors that have undergone disease progression during treatment with a PARP inhibitor for an approved indication
• At least 1 measurable lesion assessable using standard techniques by RECIST v1.1 or PCWG-3 guidelines
• Non-irradiated tumor tissue sample (archival or newly obtained core biopsy of a tumor lesion) available for submission for analysis

Additional inclusion criteria for participants in dose expansion (Part B2):

• Advanced or metastatic cancer that is refractory to standard therapies, or for which no standard therapies exist, or for which the investigator feels no other active therapy is required for the duration of the study with characteristics indicative of sensitivity to pol theta inhibition
• No prior treatment with a PARP inhibitor and must not have a disease for which there is an approved PARP inhibitor
• At least 1 measurable lesion assessable using standard techniques by RECIST v1.1 or PCWG-3 guidelines
• Non-irradiated tumor tissue sample (archival or newly obtained core biopsy of a tumor lesion) available for submission for analysis

Additional inclusion criteria for participants in dose expansion (Part B3):

• HER2-negative locally advanced or metastatic breast cancer
• Deleterious or suspected deleterious germline or somatic BRCA1 or BRCA2 mutation
• No more than 3 prior chemotherapy-inclusive regimens (including antibody conjugates)
• Prior treatment with a taxane or anthracycline unless contraindicated
• No or </= 1 month of prior treatment with a PARP inhibitor
• At least 1 measurable lesion assessable using standard techniques by RECIST v1.1
• Non-irradiated tumor tissue sample (archival or newly obtained core biopsy of a tumor lesion) available for submission for analysis

General Exclusion Criteria:

• Women who are pregnant, breast feeding, or who plan to become pregnant while in the study or within the protocol defined timeframe after the last administration of study specified treatment.
• Men who plan to father a child while in the study or within the protocol defined timeframe after the last administration of study specified treatment.
• Serious concomitant systemic disorder that would compromise the participants ability to adhere to the protocol including: opportunistic HIV/AIDs-related infection(s) within the past 12 months, hepatitis B virus, or hepatitis C virus; documented active or chronic tuberculosis infection; malignancy prior to the one currently being treated [including myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)] that is not in remission
• Have MDS/AML or features suggestive of MDS/AML
• Ongoing interstitial lung disease or pneumonitis (whether symptomatic or asymptomatic)
• Moderate or severe cardiovascular disease
• Symptomatic or uncontrolled brain metastases, spinal cord compression, or leptomeningeal disease requiring concurrent treatment; stable brain metastases are eligible
• Received a live vaccine within 30 days before the first dose of study treatment
• History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate
• Recent major surgery within 4 weeks prior to entry into the study or minor surgery within 1 week of entry into the study
• Significant bleeding disorder or vasculitis or had a Grade ≥3 bleeding episode within 12 weeks prior to enrollment
• Currently enrolled in a clinical trial involving an investigational product or any other type of medical research judged not to be scientifically or medically compatible with this study

Additional exclusion criteria for participants in dose expansion (Part B3):

• First-line locally advanced and/or metastatic breast cancer with no prior adjuvant chemotherapy
• Inflammatory breast cancer
• Known hypersensitivity to any of the components of talazoparib
• Prior treatment with a PARP inhibitor that was discontinued due to a treatment related toxicity.

Additional exclusion criteria for participants in dose escalation (Part A3):

• Hypersensitivity to any of the components of niraparib