Evaluation of the Safety and Tolerability of Niraparib Wi... | NCT03154281

Description Module

Detailed Description

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.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Cohort 1	Experimental	(each cycle is 28 days long) Everolimus 5mg daily on Mondays, Wednesdays, and Fridays Niraparib 100mg daily	Drug: niraparib Drug: everolimus
Cohort 2	Experimental	(each cycle is 28 days long) Everolimus 5 mg daily on Mondays, Wednesdays, and Fridays Niraparib 200 mg daily	Drug: niraparib Drug: everolimus
Cohort 3	Experimental	(each cycle is 28 days long) Everolimus 5 mg daily Niraparib 200 mg daily	Drug: niraparib Drug: everolimus
Cohort 4	Experimental	(each cycle is 28 days long) Everolimus 5 mg daily Niraparib 300 mg daily	Drug: niraparib Drug: everolimus

Interventions

Name	Type	Description	Arm Group Labels	Other Names
niraparib	Drug	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.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Number of Patients Who Developed Does-limiting Toxicity (DLT)	The DLT criteria for adverse events occurring in Cycle 1 while determining the maximum tolerated dose (MTD) are described in the protocol. The number of patients who experience DLT from the trial treatment is recorded.	From the start of treatment to 30 days after the first dose of study drug

Secondary Outcomes

Measure	Description	Time Frame
Number of Patients With Beneficial Clinical Response	Tumor objective response is evaluated according to RECIST 1.1 response criteria. Number of patients with beneficial clinical response (SD, PR and CR) are recorded in each group.	From beginning of study to the end of the 2nd cycle, and then at 16 weeks if the patient has stable disease or better.

Other Outcomes

Measure	Description	Time Frame
Progression Free Survival (in Months)	Tumor assessment according to RECIST 1.1 was performed at the end of the second cycle, and then again at 16 weeks if the patient has stable disease or better. Scans may be performed every 8-12 weeks thereafter at the discretion of the investigators.	From beginning of study to the end of the 2nd cycle, and then at 16 weeks if the patient has stable disease or better

Eligibility Module

Eligibility Criteria

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)

Name	Affiliation	Role
Casey Williams	Avera Cancer Institute	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Avera Cancer Institute		Sioux Falls	South Dakota	57105	United States

Arm/Group Information

ID	Title	Description
FG000	Cohort 1	(each cycle is 28 days long) Everolimus 5mg daily on Mondays, Wednesdays, and Fridays Niraparib 100mg daily niraparib: 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. everolimus: 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.
FG001	Cohort 2	(each cycle is 28 days long) Everolimus 5 mg daily on Mondays, Wednesdays, and Fridays Niraparib 200 mg daily niraparib: 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. everolimus: 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.
FG002	Cohort 3	(each cycle is 28 days long) Everolimus 5 mg daily Niraparib 200 mg daily niraparib: 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. everolimus: 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.
FG003	Cohort 4	(each cycle is 28 days long) Everolimus 5 mg daily Niraparib 300 mg daily niraparib: 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. everolimus: 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.

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Cohort 1	(each cycle is 28 days long) Everolimus 5mg daily on Mondays, Wednesdays, and Fridays Niraparib 100mg daily niraparib: 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. everolimus: 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.

Units	Counts
Participants	BG000

Baseline Measures

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Categorical			Count of Participants

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Number of Patients Who Developed Does-limiting Toxicity (DLT)

The DLT criteria for adverse events occurring in Cycle 1 while determining the maximum tolerated dose (MTD) are described in the protocol. The number of patients who experience DLT from the trial treatment is recorded.

No patient was enrolled in Cohort 3 or Cohort 4.

Posted

Count of Participants

Participants

From the start of treatment to 30 days after the first dose of study drug

ID	Title	Description
OG000	Cohort 1	(each cycle is 28 days long) Everolimus 5mg daily on Mondays, Wednesdays, and Fridays Niraparib 100mg daily niraparib: 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. everolimus: 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.

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Cohort 1	(each cycle is 28 days long) Everolimus 5mg daily on Mondays, Wednesdays, and Fridays Niraparib 100mg daily niraparib: 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. everolimus: 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.

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot_SAP	Yes	Yes	No	Study Protocol and Statistical Analysis Plan	Aug 31, 2020	Mar 16, 2023	Prot_SAP_000.pdf
ICF	No	No	Yes	Informed Consent Form	Sep 17, 2020	Jan 30, 2023	ICF_001.pdf

ID	Term
D001943	Breast Neoplasms
D010051	Ovarian Neoplasms

ID	Term
D009371	Neoplasms by Site
D009369	Neoplasms
D001941	Breast Diseases
D012871	Skin Diseases

ID	Term
D020123	Sirolimus
D018942	Macrolides
D007783	Lactones
D009930	Organic Chemicals