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

NCT03154281 | Completed Phase 1 Results FDA Drug

• 1 other identifier: TNE001
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Breast Cancer; Ovarian Cancer

Keywords

Breast; Ovarian

Outcome Measures

Primary Outcomes (1)

• 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 (2)

• Number of Patients With Beneficial Clinical Response

  From beginning of study to the end of the 2nd cycle, and then at 16 weeks if the patient has stable disease or better.

• Number of Patients With Tumor Objective Response

  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 (2)

• Progression Free Survival (in Months)

  From beginning of study to the end of the 2nd cycle, and then at 16 weeks if the patient has stable disease or better

• Overall Survival

  From the end of treatment till 2 years following the last dose

Study Arms (4)

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

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.

Also known as: MK-4827

Cohort 1; Cohort 2; Cohort 3; Cohort 4

everolimus DRUG

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.

Also known as: Afinitor

Cohort 1; Cohort 2; Cohort 3; Cohort 4

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Avera McKennan Hospital & University Health Center: lead

Study Sites (1)

Avera Cancer Institute

Sioux Falls, South Dakota, 57105, United States

Location

MeSH Terms

Conditions

Breast Neoplasms; Ovarian Neoplasms

Interventions

niraparib; Everolimus

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Endocrine Gland Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Dr. Casey Williams
• Organization: Avera Cancer Institute

Casey.Williams@avera.org

6053223588

Study Officials

• Casey Williams

  Avera Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: May 8, 2017
• First Posted: May 16, 2017
• Study Start: July 26, 2017
• Primary Completion: April 21, 2021
• Study Completion: May 1, 2023
• Last Updated: August 1, 2024
• Results First Posted: August 1, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)