Evaluation of the Safety and Tolerability of Niraparib With Everolimus in Advanced Gynecologic Malignancies and Breast

Study Overview
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Brief Summary
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Open-label, cohort study to determine the feasibility and tolerability of the combination of daily niraparib and daily or thrice weekly everolimus for one 28-day cycle in patients with advanced ovarian and breast cancer.

Detailed Description
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The goal of this study is to determine a maximum tolerated dose of the combination of niraparib and everolimus. To do this, investigators will estimate the maximum tolerated dose that is defined as the dose level at which less than one-third of patients will experience a dose-limiting toxicity. A traditional dose escalation design will be used, beginning with the lowest dose level and escalating to the maximum allowable dose level as specified in the protocol. One of the following outcomes will determine the treatment of subsequent patients: If none of the three patients experiences a dose-limiting toxicity , the next group of patients will be entered in the next higher dose cohort. All patients within a cohort must have completed at least one cycle (28 days) prior to initiation of the next cohort of patients. If one of the three patients experiences a dose-limiting toxicity , three more patients will be accrued at the current dose level. Subsequently, if only one of the six patients treated at this level experiences a dose-limiting toxicity , the dose will be escalated to the next higher dose in the next group of patients. If two or more of the six patients experiences a dose-limiting toxicity , the maximum tolerated dose has been exceeded and is defined as the previous dose at which no more than 1/3 experienced a dose-limiting toxicity . If at least two of the three experience a dose-limiting toxicity , the maximum tolerated dose has been exceeded and is defined as the previous dose at which no more than 1/3 experienced a dose-limiting toxicity . If the lowest allowable dose level exceeds the maximum tolerated dose, the study will be terminated and the combination will not be deemed safe for use in this population. Additionally, the highest dose level will not be exceeded, even if no dose-limiting toxicities are experienced at that dose. Investigators will summarize the adverse events overall and by individual adverse event categories. Serious adverse events will be summarized in a similar manner. These summaries will be performed overall and for each dose cohort. Investigators will summarize all events as well as the highest grade for a given subject. Investigators will summarize the number of subjects that exhibit a dose-limiting toxicity at each dose cohort and describe the dose-limiting toxicity for each subject, if applicable.

Official Title
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A Phase 1 Evaluation of the Safety and Tolerability of Niraparib in Combination With Everolimus in Advanced Gynecologic Malignancies and Breast Cancer

Conditions
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Breast Cancer, Ovarian Cancer

Intervention / Treatment
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* Drug: niraparib
* Drug: everolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have a gynecologic malignancy or breast cancer (triple negative or hormone receptor positive only) that is refractory/intolerant to all therapies known to confer clinical benefit in the advanced or metastatic setting or if the patient's clinical team and the PI believe that the study treatment gives the patient the best chance for clinical benefit Patients with breast cancer must have measurable disease per RECIST 1.1. criteria. Patients with ovarian cancer are eligible with or without measurable disease Patients with ovarian cancer must have had appropriate surgical management for their disease and should be platinum resistant (recurrence within 6 months of last platinum-containing regimen) or be refractory to platinum-containing regimens Patients with endometrial, cervical, or any other advanced gynecologic malignancy must have already received or not be a candidate for all therapy proven to have a survival benefit Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 Patients must be ≥18 years of age Patients must have adequate organ function, defined as follows: Absolute neutrophil count ≥1,500/µL Platelets ≥125,000/µL Hemoglobin ≥10 g/dL Serum creatinine ≤1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥60 mL/min using the Cockcroft-Gault equation Total bilirubin ≤ 1.5 x ULN OR direct bilirubin ≤1 x ULN Aspartate aminotransferase and alanine aminotransferase ≤2.5 x ULN unless liver metastases are present, in which case they must be ≤5 x ULN Patient agrees to blood draws during screening and at the end of treatment for molecular and cytogenetic analysis Female patients of childbearing potential must have a negative serum pregnancy test (beta hCG) at Screening Female patients of childbearing potential must agree to use an acceptable method of birth control (excluding hormonal birth control methods, see Section 3.0.5) for 72 hours prior to initiation of therapy and to continue its use during the study and for at least 180 days after the final dose Male patients must agree to use an acceptable form of birth control (see Section 3.0.5) from study Day 1 through at least 180 days after the final dose Patients must be able to understand the study procedures and agree to participate in the study by providing written informed consent Exclusion Criteria: Patients with HER2+ breast cancer measured by standard IHC or FISH testing Patients must not be simultaneously enrolled in any other interventional clinical trial Patients must not have had major surgery ≤3 weeks of starting the study and patient must have recovered from any effects of any major surgery Patients must not have had investigational therapy administered ≤4 weeks, or within a time interval less than at least 5 half-lives of the investigational agent, whichever is longer, prior to the first scheduled day of dosing in this study Patients must not have had radiotherapy encompassing >20% of the bone marrow Patients must not have received prior treatment with a known PARP inhibitor or have participated in a study where any treatment arm included administration of a known PARP inhibitor Patients must not have a known hypersensitivity to the components of niraparib, everolimus, rapamycin analogues, or the excipients Patients must not be immunocompromised (patients with splenectomy are allowed) Patients must not have had any known, persistent >Grade 2 toxicity from prior cancer therapy Patients must not have had any known, persistent (>4 weeks), ≥Grade 3 hematological toxicity or fatigue from prior cancer therapy Patients must not have received a transfusion (platelets or red blood cells) ≤4 weeks of the first dose of study treatment Patients must not have current evidence of any condition, therapy, or laboratory abnormality (including active or uncontrolled myelosuppression [ie, anemia, leukopenia, neutropenia, thrombocytopenia]) that might confound the results of the study or interfere with the patient's participation for the full duration of the study treatment or that makes it not in the best interest of the patient to participate Patients must not have had diagnosis, detection, or treatment of another type of cancer ≤2 years prior to randomization (except basal or squamous cell carcinoma of the skin that has been definitively treated) Patients must not have known, symptomatic brain or leptomeningeal metastases Patients must not be considered a poor medical risk due to a serious, uncontrolled medical disorder, nonmalignant systemic disease, or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, interstitial lung disease, HIV or Hepatitis B, or any psychiatric disorder that prohibits obtaining informed consent Patients must not have any known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) Patient is a woman with a positive serum pregnancy test ≤3 days prior to study drug administration, is breast-feeding, or is planning to conceive children within the projected duration of the study treatment Patients with uncontrolled or poorly controlled hypertension Patients taking ACE inhibitors (patients that have no known medical reason to require therapy with ACE inhibitors may be switched to another appropriate antihypertensive treatment prior to initiation of study treatment) Patients taking strong or moderate CYP3A4/PgP inhibitors or strong CYP3A4/PgP inducers (appendix 2) (if medically appropriate, patients may be switched to another appropriate therapy at least 14 days prior to initiation of study treatment)

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: Single Group Assignment
Interventional Model Description: The statistical analysis will be mainly descriptive. Continuous variables will be summarized using descriptive statistics: N, mean, standard deviation, median, minimum and maximum. Categorical variables will be presented using frequencies and percentages. Time-to-event will be described by N, median, range, number censored, and Kaplan-Meier plots. A traditional dose escalation design will be used, beginning with the lowest dose level and escalating to the maximum allowable dose level as specified in the protocol. Three patients will be treated one at a time at a given dose level. A maximum of 4 dosing levels results in a maximum sample size of n=24 subjects.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>(each cycle is 28 days long) Everolimus 5mg daily on Mondays, Wednesdays, and Fridays Niraparib 100mg daily | Drug: niraparib<br>* Niraparib 100 mg will be administered orally once daily continuously. Niraparib will be administered as a flat-fixed dose (100mg, 200 mg, or 300 mg daily) depending on the cohort the patient is enrolled to, and not by body weight or body surface area. Each dose should be swallowed whole without chewing. The consumption of water is permissible. Patients should take doses at approximately the same times each day, and record this information in the patient diary. Patients will be provided with a diary in which to record their intake of study drug. However, the actual number of doses taken by the patient must be calculated from the number of tablets dispensed and returned.<br>* Other names: MK-4827;Drug: everolimus<br>* Everolimus 5 mg tablets will be used. Everolimus will be self-administered orally on a daily basis and doses will either be 5 mg (1 tablet) thrice weekly or 5 mg daily depending on the cohort the patient is enrolled to. Each cycle will be 28 days; everolimus will be taken continuously with no rest between cycles.<br>* Other names: Afinitor;|
| Experimental: Cohort 2<br>(each cycle is 28 days long) Everolimus 5 mg daily on Mondays, Wednesdays, and Fridays Niraparib 200 mg daily | Drug: niraparib<br>* Niraparib 100 mg will be administered orally once daily continuously. Niraparib will be administered as a flat-fixed dose (100mg, 200 mg, or 300 mg daily) depending on the cohort the patient is enrolled to, and not by body weight or body surface area. Each dose should be swallowed whole without chewing. The consumption of water is permissible. Patients should take doses at approximately the same times each day, and record this information in the patient diary. Patients will be provided with a diary in which to record their intake of study drug. However, the actual number of doses taken by the patient must be calculated from the number of tablets dispensed and returned.<br>* Other names: MK-4827;Drug: everolimus<br>* Everolimus 5 mg tablets will be used. Everolimus will be self-administered orally on a daily basis and doses will either be 5 mg (1 tablet) thrice weekly or 5 mg daily depending on the cohort the patient is enrolled to. Each cycle will be 28 days; everolimus will be taken continuously with no rest between cycles.<br>* Other names: Afinitor;|
| Experimental: Cohort 3<br>(each cycle is 28 days long) Everolimus 5 mg daily Niraparib 200 mg daily | Drug: niraparib<br>* Niraparib 100 mg will be administered orally once daily continuously. Niraparib will be administered as a flat-fixed dose (100mg, 200 mg, or 300 mg daily) depending on the cohort the patient is enrolled to, and not by body weight or body surface area. Each dose should be swallowed whole without chewing. The consumption of water is permissible. Patients should take doses at approximately the same times each day, and record this information in the patient diary. Patients will be provided with a diary in which to record their intake of study drug. However, the actual number of doses taken by the patient must be calculated from the number of tablets dispensed and returned.<br>* Other names: MK-4827;Drug: everolimus<br>* Everolimus 5 mg tablets will be used. Everolimus will be self-administered orally on a daily basis and doses will either be 5 mg (1 tablet) thrice weekly or 5 mg daily depending on the cohort the patient is enrolled to. Each cycle will be 28 days; everolimus will be taken continuously with no rest between cycles.<br>* Other names: Afinitor;|
| Experimental: Cohort 4<br>(each cycle is 28 days long) Everolimus 5 mg daily Niraparib 300 mg daily | Drug: niraparib<br>* Niraparib 100 mg will be administered orally once daily continuously. Niraparib will be administered as a flat-fixed dose (100mg, 200 mg, or 300 mg daily) depending on the cohort the patient is enrolled to, and not by body weight or body surface area. Each dose should be swallowed whole without chewing. The consumption of water is permissible. Patients should take doses at approximately the same times each day, and record this information in the patient diary. Patients will be provided with a diary in which to record their intake of study drug. However, the actual number of doses taken by the patient must be calculated from the number of tablets dispensed and returned.<br>* Other names: MK-4827;Drug: everolimus<br>* Everolimus 5 mg tablets will be used. Everolimus will be self-administered orally on a daily basis and doses will either be 5 mg (1 tablet) thrice weekly or 5 mg daily depending on the cohort the patient is enrolled to. Each cycle will be 28 days; everolimus will be taken continuously with no rest between cycles.<br>* Other names: Afinitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose | To determine the maximum tolerated dose of the combination of niraparib and everolimus for the treatment of patients with advanced ovarian or breast cancer. The maximum tolerated dose (MTD) that is defined as the dose level at which less than one-third of patients will experience a dose-limiting toxicity (DLT). | Three patients will be treated one at a time at a given dose level. All patients within a cohort must have completed at least once cycle (28 days) prior to initiation of the next cohort of patients | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the toxicity of the combination of niraparib and everolimus in each cohort by number of participants with treatment related adverse events as assessed by CTCAE v4.03 | To assess the toxicity of the combination of niraparib and everolimus in each cohort | Every 12 weeks, study follow up could occur up to 24 months after study drug discontinuation | 
| Response rate | To determine the response rate (according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 response criteria) | After the completion of 2 cycles (56 days +/- 7 days) patients will be assessed for disease response utilizing the same analysis that was used at baseline and then again at 16 weeks (112 days +/- 7 days) if the patient has stable disease or better. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast, Ovarian