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Evaluation of the Safety and Tolerability of Niraparib With Everolimus in Ovarian and Breast

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ClinicalTrials.gov Identifier: NCT03154281
Recruitment Status : Recruiting
First Posted : May 16, 2017
Last Update Posted : July 24, 2019
Sponsor:
Information provided by (Responsible Party):
Avera McKennan Hospital & University Health Center

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.

Condition or disease Intervention/treatment Phase
Breast Cancer Ovarian Cancer Drug: niraparib Drug: everolimus Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Intervention 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)
Primary Purpose: Treatment
Official Title: A Phase 1 Evaluation of the Safety and Tolerability of Niraparib in Combination With Everolimus in Advanced Ovarian and Breast Cancer
Actual Study Start Date : July 17, 2017
Estimated Primary Completion Date : August 2019
Estimated Study Completion Date : June 2021


Arm Intervention/treatment
Experimental: Cohort 1
(each cycle is 28 days long) Everolimus 5mg daily on Mondays, Wednesdays, and Fridays Niraparib 100mg daily
Drug: 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.
Other Name: MK-4827

Drug: 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.
Other Name: Afinitor

Experimental: Cohort 2
(each cycle is 28 days long) Everolimus 5 mg daily on Mondays, Wednesdays, and Fridays Niraparib 200 mg daily
Drug: 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.
Other Name: MK-4827

Drug: 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.
Other Name: Afinitor

Experimental: Cohort 3
(each cycle is 28 days long) Everolimus 5 mg daily Niraparib 200 mg daily
Drug: 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.
Other Name: MK-4827

Drug: 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.
Other Name: Afinitor

Experimental: Cohort 4
(each cycle is 28 days long) Everolimus 5 mg daily Niraparib 300 mg daily
Drug: 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.
Other Name: MK-4827

Drug: 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.
Other Name: Afinitor




Primary Outcome Measures :
  1. Maximum tolerated dose [ Time Frame: 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 ]
    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).


Secondary Outcome Measures :
  1. 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 [ Time Frame: Every 12 weeks, study follow up could occur up to 24 months after study drug discontinuation ]
    To assess the toxicity of the combination of niraparib and everolimus in each cohort

  2. Response rate [ Time Frame: 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. ]
    To determine the response rate (according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 response criteria)


Other Outcome Measures:
  1. Toxicity of the combination in patients with certain molecular aberrations using molecular testing via Foundation Medicine tissue assay FoundationOne [ Time Frame: Molecular testing can take place at any time during the study if applicable, study follow up could occur up to 24 months after study drug discontinuation ]
    To assess whether patients with certain molecular aberrations, using Foundation Medicine's FoundationOne tissue assay and/or cell-free DNA (cfDNA) or circulating tumor cells (CTCs) responded more favorably to the combination

  2. Symptom occurrence as measured by the Therapy Related Symptoms Checklist (TRSC) [ Time Frame: Day one of each treatment cycle (each cycle is 28 days) and at the end of treatment visit (within 7 days of last dose) ]
    To describe symptom occurrence and health related quality of life as measured by the Therapy Related Symptoms Checklist (TRSC)

  3. Symptom occurrence as measured by the Health Related Quality of Life (HRQOL) - Linear Analogue Self Assessment (LASA) [ Time Frame: Day one of each treatment cycle (each cycle is 28 days) and at the end of treatment visit (within 7 days of last dose) ]
    To describe symptom occurrence and health related quality of life as measured by the Health Related Quality of Life (HRQOL) - Linear Analogue Self Assessment (LASA)

  4. Symptom severity as measured by the Therapy Related Symptoms Checklist (TRSC) [ Time Frame: Day one of each treatment cycle (each cycle is 28 days) and at the end of treatment visit (within 7 days of last dose) ]
    To describe symptom severity and health related quality of life as measured by the Therapy Related Symptoms Checklist (TRSC)

  5. Symptom severity as measured by the Health Related Quality of Life (HRQOL) - Linear Analogue Self Assessment (LASA) [ Time Frame: Day one of each treatment cycle (each cycle is 28 days) and at the end of treatment visit (within 7 days of last dose) ]
    To describe symptom severity and health related quality of life as measured by the Health Related Quality of Life (HRQOL) - Linear Analogue Self Assessment (LASA)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have ovarian or breast cancer and have failed at least 1 prior line of therapy
  • Patients must have measurable disease per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1. criteria OR per Gynecological Cancer Intergroup (GCIG) guidelines for incorporating Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 and CA125
  • 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) for 72 hours prior to admission and to continue its use during the study and for at least 90 days after the final dose
  • Male patients must agree to use an acceptable form of birth control from study Day 1 through at least 90 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 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 (poly adenosine diphosphate-ribose polymerase) PARP inhibitor or have participated in a study where any treatment arm included administration of a known (poly adenosine diphosphate-ribose polymerase) PARP inhibitor
  • Patients must not have a known hypersensitivity to the components of niraparib 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
  • Patient 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 receiving concomitant medications that prolong corrected QT interval (QTc)
  • 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, or any psychiatric disorder that prohibits obtaining informed consent
  • Patient must not have any known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)
  • Patient is a woman with a positive urine or 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03154281


Contacts
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Contact: Casey Williams, PharmD 605-322-3588 Casey.Williams@Avera.org

Locations
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United States, South Dakota
Avera Cancer Institute Recruiting
Sioux Falls, South Dakota, United States, 57105
Contact: Casey Williams, PharmD    605-322-3588    Casey.Williams@avera.org   
Sponsors and Collaborators
Avera McKennan Hospital & University Health Center
Investigators
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Principal Investigator: Casey Williams Avera Cancer Institute

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Responsible Party: Avera McKennan Hospital & University Health Center
ClinicalTrials.gov Identifier: NCT03154281     History of Changes
Other Study ID Numbers: TNE001
First Posted: May 16, 2017    Key Record Dates
Last Update Posted: July 24, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Avera McKennan Hospital & University Health Center:
Breast
Ovarian
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Sirolimus
Everolimus
Niraparib
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action