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The purpose of this study is to find out if a new drug, M4344, is safe and has beneficial effects when given in combination with the PARP inhibitor, Niraparib, in women with recurrent ovarian cancer that has progressed while on a PARP inhibitor.
The primary, secondary, and exploratory objective are to assess the safety of the combination of M4344 and Niraparib in a phase 1 trial of patients with PARP resistant recurrent ovarian cancer; to determine the response rate and percentage of participants who remain progression free survival (PFS) at 6 months (%PFS) among ovarian cancer participants that have become resistant to poly (adenosine diphosphate [ADP]) ribose polymerase inhibitors (PARPi) who are treated with ataxia telangiectasia and Rad3-related protein inhibitors (ATRi) + Niraparib in the dose expansion cohort; and to identify potential biological predictors of response and progression of disease with the combination of M4344 and Niraparib.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| M4344+Niraparib | Experimental | all PARP resistant, recurrent ovarian cancer |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| M4344+Niraparib | Drug | The first phase will be a 3+3 design of fixed dose Niraparib by mouth (PO) every day (QD) and M4344 will be escalated from 100-200 mg PO QD (28-day cycle). There will be a 4-week lead in with niraparib only. |
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of patients with treatment emergent adverse events as defined by CTCAE v.4.03 | Number and percentage of patients with treatment emergent adverse events and toxicity based upon CTCAE v.4.03 scoring. | Baseline through 1 year |
| Maximum tolerated dose (MTD) of M4344 and Niraparib as defined by CTCAE 4.03 | To determine the MTD of M4344 and Niraparib during the dose escalation as defined by CTCAE v.4.03 | Baseline through 1 year |
| Measure | Description | Time Frame |
|---|---|---|
| Overall Response Rate (ORR) as defined by RECIST v.1.1 | To determine response rate among ovarian cancer patients that have become resistant to PARPi who are treated with ATRi + Niraparib as defined by RECIST v.1.1. | Baseline through 6 months |
| Percentage progression free survival (PFS) as defined by RECIST v.1.1 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Rebecca C Arend, MD, MSPH | University of Alabama at Birmingham | Principal Investigator |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 34045232 | Derived | Jo U, Senatorov IS, Zimmermann A, Saha LK, Murai Y, Kim SH, Rajapakse VN, Elloumi F, Takahashi N, Schultz CW, Thomas A, Zenke FT, Pommier Y. Novel and Highly Potent ATR Inhibitor M4344 Kills Cancer Cells With Replication Stress, and Enhances the Chemotherapeutic Activity of Widely Used DNA Damaging Agents. Mol Cancer Ther. 2021 Aug;20(8):1431-1441. doi: 10.1158/1535-7163.MCT-20-1026. Epub 2021 May 27. |
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To-Be-Determined
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| ID | Term |
|---|---|
| D010051 | Ovarian Neoplasms |
| ID | Term |
|---|---|
| D004701 | Endocrine Gland Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D010049 | Ovarian Diseases |
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| M4344+Niraparib | Drug | In the second phase eligible patients will receive combination Niraparib + the determined dose of M4344 from the first phase. |
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To determine percentage of patients who remain progression free at 6 months (%PFS) among ovarian cancer patients that have become resistant to PARPi who are treated with ATRi + Niraparib as defined by RECIST v.1.1. |
| Baseline through 6 months |
| D000291 |
| Adnexal Diseases |
| D005831 | Genital Diseases, Female |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D005833 | Genital Neoplasms, Female |
| D014565 | Urogenital Neoplasms |
| D000091662 | Genital Diseases |
| D004700 | Endocrine System Diseases |
| D006058 | Gonadal Disorders |