A Phase 1 Clinical Study of NXP800 in Subjects With Advanced Cancers and Expansion in Subjects With Ovarian Cancer

Study Overview
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Brief Summary
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The purpose of the dose escalation phase is to evaluate the safety profile of escalating doses and dose schedules of NXP800. In the expansion phase the preliminary efficacy in subjects with ARID1a mutated ovarian clear cell and ovarian endometrioid cancers will be estimated.

Detailed Description
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Part A of the study is a dose escalation by cohort study of NXP800 administered to patients with advanced cancers. The study will identify the maximum tolerated dose (MTD) and propose dose and dose schedules for future studies. In Part B doses selected in Part A are administered to patients with platinum-resistant, ARID1a-mutated ovarian carcinoma.

Official Title
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A Phase 1 Clinical Study of NXP800 in Subjects With Advanced Cancers and Expansion in Subjects With Ovarian Cancer

Conditions
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Advanced Solid Tumor, Ovarian Cancer, Ovarian Clear Cell Carcinoma, Ovarian Clear Cell Tumor, Ovarian Clear Cell Adenocarcinoma, Ovarian Endometrioid Adenocarcinoma, Ovarian Endometrioid Tumor, ARID1A Gene Mutation

Intervention / Treatment
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* Drug: NXP800


Participation Criteria
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Eligibility Criteria
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Part A Inclusion Criteria: Provide written informed consent. 18 years old or older. Life expectancy of at least 12 weeks. Histologically- or cytologically-confirmed, advanced, metastatic, and/or progressive solid tumors for whom there is no authorized or effective therapy available, or for whom such therapies are considered inappropriate by the Investigator (in Part B, subjects with specific cancer types will be enrolled; Specific criteria will be introduced in a protocol amendment). Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. Part A Exclusion Criteria: Radiotherapy (except for palliative reasons), endocrine therapy, chemotherapy, or investigational agent within 28 days, (42 days for nitrosoureas, mitomycin-C) of first dose of NXP800. Subjects can continue to receive bisphosphonates due to metastatic bone disease or GnRH agonists if they have prostate cancer. Ongoing toxic manifestations of previous treatments > Grade 2. Subjects with treated brain metastases are eligible if there is no evidence of progression for at least 28 days after central nervous system (CNS) directed treatment, as ascertained by clinical examination and brain imaging (magnetic resonance imaging [MRI] or computed tomography [CT] scan) during the Screening period. Female subjects who can become pregnant (or are already pregnant or lactating). Male subjects with partners of childbearing potential (unless they agree to take measures not to father children by using a barrier method of contraception (condom plus spermicide) or to sexual abstinence). Part B Inclusion Criteria: Provide written informed consent. 18 years old or older. Subjects with the following ARID1a mutated, ovarian/fallopian tube/primary peritoneal cancer histologies (ARID1a mutation status determined by a DNA-based Next Generation Sequencing test): Clear cell ovarian carcinoma (≥ 50% clear cell carcinoma with no serous differentiation) Endometrioid ovarian carcinoma Subjects must have disease progression within 6 months (182 days) from completion of platinum-based therapy (6 months should be calculated from the date of the last administered dose of platinum therapy to the date of radiographic imaging showing progression) Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. Subjects with a BRCA mutation must have received prior treatment with a PARP inhibitor. Subjects must have received at least 1 but not more than 3 prior systemic lines of anticancer therapy, including at least 1 line of therapy containing bevacizumab. Adjuvant + neoadjuvant are considered one line of therapy Maintenance therapy (i.e., bevacizumab, PARP inhibitors) will be considered as part of the preceeding line of therapy and are not counted independently. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Subjects must have a sufficient archival Formalin-Fixed Paraffin-Embedded (FFPE) tissue specimen, or be willing to consent to a fresh tissue biopsy during the study. Part B Exclusion Criteria: Subjects with disease that did not respond to, or has progressed during or within 4 weeks of the last dose of first-line platinum containing chemotherapy. Radiotherapy (except for palliative reasons), endocrine therapy, chemotherapy, or investigational agent within 28 days, (42 days for nitrosoureas, mitomycin-C) of first dose of NXP800. Ongoing toxic manifestations of previous treatments > Grade 2, with the exception of alopecia. Subjects with treated brain metastases are eligible if there is no evidence of progression for at least 12 weeks while off corticosteroids after central nervous system (CNS) directed treatment, as ascertained by clinical examination and brain imaging (magnetic resonance imaging [MRI] or computed tomography [CT] scan) during the Screening period. Female subjects who can become pregnant (or are already pregnant or lactating).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Part A dose escalation followed by Part B, expansion in ovarian cancers.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: Dose Escalation<br>Escalating doses of NXP800. | Drug: NXP800<br>* NXP800 is an anti-neoplastic, oral small molecule.<br>|
| Experimental: Part B: Expansion in Ovarian Cancers Cohort 1<br>Subjects will be treated with NXP800 at 50 mg/day. | Drug: NXP800<br>* NXP800 is an anti-neoplastic, oral small molecule.<br>|
| Experimental: Part B: Expansion in Ovarian Cancers Cohort 2<br>Subjects will be treated with NXP800 at 75 mg/day. | Drug: NXP800<br>* NXP800 is an anti-neoplastic, oral small molecule.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Number of patients with treatment related adverse events, clinical laboratory abnormalities, dose limiting toxicities |  | Day 28 | 
| Part B: Estimates of disease response by RECIST v 1.1 |  | Baseline to 30 days post last dose of NXP800 | 
| Part B: Number of patients with treatment related adverse events, and/or clinical laboratory abnormalities. |  | Baseline to 30 days post last dose of NXP800 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the concentration-time curve (AUC) of NXP800 |  | First dose through Day 29 | 
| Maximum observed concentration (Cmax) of NXP800 |  | First dose through Day 29 | 
| Time to peak concentration (Tmax) of NXP800 |  | First dose through Day 29 | 
| Half-life (T1/2) of NXP800 |  | First dose through Day 29 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Solid Tumor, Carcinoma, Neoplasms, Adenocarcinoma, ARID1a