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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:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Part A1 | Experimental | Part A1 will evaluate ART4215 monotherapy administered in 21 day cycles. Up to 90 participants will participate in this dose escalation arm. |
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| Part A2 | Experimental | Part A2 will evaluate ART4215 given in combination with talazoparib in 21 day cycles. Up to 50 participants will participate in this dose escalation arm. |
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| Part B1 | Experimental | In Part B1 dose expansion, up to 30 participants with solid cancers that have been treated with a PARP inhibitor for an approved indication will receive ART4215. |
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| Part B2 | Experimental | In Part B2 dose expansion, up to 20 participants with solid cancers with characteristics indicative of sensitivity to pol theta inhibition will receive ART4215. |
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| Part B3 | Experimental | In Part B3, approximately 120 participants with HER2 negative BRCA breast cancers will be randomized 1:1 to either ART4215 in combination with talazoparib or talazoparib alone. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| ART4215 | Drug | Participants will receive ART4215 by mouth daily in 21-day cycles. |
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| Measure | Description | Time Frame |
|---|---|---|
| Part A: Number of participants with dose limiting toxicities (DLTs) from ART4215 monotherapy, in combination with talazoparib or in combination with niraparib | DLTs are defined as adverse events (graded according to NCI CTCAE v5.0) during Cycle 1 that are related to ART4215 monotherapy, in combination with talazoparib or in combination with niraparib | 21 days (Cycle 1) |
| Part B1 and B2: Number of participants with adverse events following administration of ART4215 | Number of adverse events as characterized by type, frequency, seriousness (graded according to NCI CTCAE v5.0) and relationship to ART4215 | From the first dose until up to 30 days after the last dose of ART4215. Each cycle is 21 days. |
| Part B3: Progression free survival (PFS) as a measure of efficacy for ART4215 in combination with talazoparib or talazoparib alone | PFS is defined as the time from the start of randomization until the earliest objective disease progression defined by RECIST v1.1 or death by any cause in the absence of progression. | Every 6 weeks (±7 days) from date of randomization for 18 weeks, then every 9 weeks (±7 days) up to approximately 24 months. Each cycle is 21 days. |
| Measure | Description | Time Frame |
|---|---|---|
| Part B3: Number of participants with adverse events following administration of ART4215 in combination with talazoparib | Number of adverse events as characterized by type, frequency, seriousness (graded according to NCI CTCAE v5.0) and relationship to ART4215 in combination with talazoparib | From the first dose until up to 30 days after the last dose of ART4215. Each cycle is 21 days. |
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General Inclusion Criteria:
Additional inclusion criteria for participants in dose escalation (Part A1):
Additional inclusion criteria for participants in dose escalation (Part A2):
Additional inclusion criteria for participants in dose escalation (Part A3):
Additional inclusion criteria for participants in dose expansion (Part B1):
Additional inclusion criteria for participants in dose expansion (Part B2):
Additional inclusion criteria for participants in dose expansion (Part B3):
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| Name | Affiliation | Role |
|---|---|---|
| Erika Hamilton, MD | Tennessee Oncology | Study Chair |
| Timothy Yap, MBBS, PhD | M.D. Anderson Cancer Center | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Yale School of Medicine | New Haven | Connecticut | 06520 | United States | ||
| Florida Cancer Specialists |
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| ID | Term |
|---|---|
| D009362 | Neoplasm Metastasis |
| D001943 | Breast Neoplasms |
| ID | Term |
|---|---|
| D009385 | Neoplastic Processes |
| D009369 | Neoplasms |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| C586365 | talazoparib |
| C545685 | niraparib |
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| Part A3 | Experimental | Part A3 will evaluate ART4215 given in combination with niraparib in 21-day cycles. Up to 30 participants will participate in this dose escalation arm. |
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| Talazoparib | Drug | Talazoparib will be administered at a dose of 1 mg or 0.75 mg by mouth daily in 21-day cycles. |
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| Niraparib | Drug | Niraparib will be administered at a dose of 200 mg or 300 mg by mouth daily in 21-day cycles. |
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| Best overall response (BOR) as a measure of efficacy for ART4215 as monotherapy, in combination with talazoparib or in combination with niraparib | BOR will be calculated as the best response from date study treatment started until progression or censoring date in the absence of progression. BOR will be based on RECIST v1.1 and Prostate Cancer Working Group-3 (PCWG-3) (for prostate cancer). | Every 6 weeks (±7 days) from the first dose for 18 weeks, then every 9 weeks (±7 days) up to approximately 24 months. Each cycle is 21 days. |
| Objective response rate (ORR) as a measure of efficacy for ART4215 as monotherapy, in combination with talazoparib or in combination with niraparib | ORR is defined as the proportion of patients who have a best response of either complete response (CR) or partial response (PR) based on RECIST v1.1 or PCWG-3. Response must be confirmed (at least two responses of CR or PR a minimum of 4 weeks apart and prior to progression/subsequent therapy) for Parts A, B1 and B2. | Every 6 weeks (±7 days) from the first dose for 18 weeks, then every 9 weeks (±7 days) up to approximately 24 months. Each cycle is 21 days. |
| Disease control rate (DCR) as a measure of efficacy for ART4215 as monotherapy, in combination with talazoparib or in combination with niraparib | DCR is defined as the proportion of patients with CR, PR, or SD based on RECIST v1.1 or PCWG-3. | Every 6 weeks (±7 days) from the first dose for 18 weeks, then every 9 weeks (±7 days) up to approximately 24 months. Each cycle is 21 days. |
| Duration of response (DOR) as a measure of efficacy for ART4215 as monotherapy, in combination with talazoparib or in combination with niraparib | DOR will be defined for patients with a BOR of CR/PR 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. BOR should be confirmed in Parts A, B1, and B2. | Every 6 weeks (±7 days) from the first dose for 18 weeks, then every 9 weeks (±7 days) up to approximately 24 months. Each cycle is 21 days. |
| Change in tumor size as a measure of efficacy for ART4215 as monotherapy, in combination with talazoparib or in combination with niraparib | Change in tumor size will be assessed for all patients with target lesion measurements at baseline. | Every 6 weeks (±7 days) from the first dose for 18 weeks, then every 9 weeks (±7 days) up to approximately 24 months. Each cycle is 21 days. |
| Parts A, B1, and B2: Progression free survival (PFS) as a measure of efficacy for ART4215 as monotherapy, in combination with talazoparib or in combination with niraparib | PFS is defined as the time from the start of study treatment until the earliest objective disease progression defined by RECIST v1.1 or PCWG-3 or death by any cause in the absence of progression. | Every 6 weeks (±7 days) from the first dose for 18 weeks, then every 9 weeks (±7 days) up to approximately 24 months. Each cycle is 21 days. |
| Overall survival (OS) as a measure of efficacy for ART4215 as monotherapy, in combination with talazoparib or in combination with niraparib | OS is defined as the time from the start of study treatment until death due to any cause. | Assessed every 12 weeks after treatment discontinuation for up to 24 months. |
| Pharmacokinetic Analysis (single dose): maximum plasma concentration (Cmax) of ART4215 when given alone, in combination with talazoparib or in combination with niraparib | PK will be measured at each cycle from Cycle 0 to Cycle 3, and then every third cycle beginning at Cycle 5 for up to approximately 24 months. Each cycle is 21 days. |
| Pharmacokinetic Analysis (single dose): time to maximum plasma concentration (tmax) of ART4215 when given alone, in combination with talazoparib or in combination with niraparib | PK will be measured at each cycle from Cycle 0 to Cycle 3, and then every third cycle beginning at Cycle 5 for up to approximately 24 months. Each cycle is 21 days. |
| Pharmacokinetic Analysis (single dose): area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC(0-inf)) of ART4215 when given alone, in combination with talazoparib or in combination with niraparib | PK will be measured at each cycle from Cycle 0 to Cycle 3, and then every third cycle beginning at Cycle 5 for up to approximately 24 months. Each cycle is 21 days. |
| Pharmacokinetic Analysis (multiple dose): maximum plasma concentration (Cmax) of ART4215 when given alone, in combination with talazoparib or in combination with niraparib | PK will be measured at each cycle from Cycle 0 to Cycle 3, and then every third cycle beginning at Cycle 5 for up to approximately 24 months. Each cycle is 21 days. |
| Pharmacokinetic Analysis (multiple dose): time to maximum plasma concentration (tmax) of ART4215 when given alone, in combination with talazoparib or in combination with niraparib | PK will be measured at each cycle from Cycle 0 to Cycle 3, and then every third cycle beginning at Cycle 5 for up to approximately 24 months. Each cycle is 21 days. |
| Pharmacokinetic Analysis (multiple dose): area under the concentration-time curve over the dosing interval (AUC tau) of ART4215 when given alone, in combination with talazoparib or in combination with niraparib | PK will be measured at each cycle from Cycle 0 to Cycle 3, and then every third cycle beginning at Cycle 5 for up to approximately 24 months. Each cycle is 21 days. |
| Pharmacokinetic Analysis (single dose): maximum plasma concentration (Cmax) of ART4215 when given with or without food | 8 days (Cycle 0) |
| Part A2: Pharmacokinetic Analysis (multiple dose): maximum steady state plasma concentration (Cmax ss) of talazoparib when given in combination with ART4215 | 1 day (Cycle 2 Day 1; Cycle 2 is 21 days) |
| Pharmacokinetic Analysis (single dose): time to maximum plasma concentration (tmax) of ART4215 when given with or without food | 8 days (Cycle 0) |
| Pharmacokinetic Analysis (single dose): area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC(0-inf)) of ART4215 when given with or without food | 8 days (Cycle 0) |
| Assessment of lesions in (or indicative of lesions in) DNA repair pathways by immunohistochemistry for loss of shieldin complex and/or TP53BP1 or other relevant pathways | Within 28 days prior to the first dose of ART4215. |
| Pharmacokinetic Analysis (Part A1): renal clearance of ART4215 monotherapy will be calculated as the cumulative amount of ART4215 excreted unchanged in the urine (Ae) divided by the appropriate AUC. | PK will be measured on Cycle 0 Day -4 and Cycle 1 Day 8. Cycle 0 is 4 days. Cycle 1 is 21 days. |
| Pharmacokinetic Analysis (Parts A2/B3) : renal clearance of ART4215 in combination with talazoparib will be calculated as the cumulative amount of ART4215 excreted unchanged in the urine (Ae) divided by the appropriate AUC. | PK will be measured on Cycle 1 Day 1 and Cycle 1 Day 8. Cycle 1 is 21 days. |
| Orlando |
| Florida |
| 32827 |
| United States |
| Memorial Sloan Kettering Cancer Center | New York | New York | 10065 | United States |
| Oklahoma University | Oklahoma City | Oklahoma | 73104 | United States |
| University of Pennsylvania/Abramson Cancer Center | Philadelphia | Pennsylvania | 19104 | United States |
| Tennessee Oncology | Nashville | Tennessee | 37203 | United States |
| MD Anderson Cancer Center | Houston | Texas | 77030 | United States |
| Sarah Cannon Research Institute | London | England | UK/W1G 6AD | United Kingdom |
| D009371 | Neoplasms by Site |
| D001941 | Breast Diseases |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |