Clinical Trials /

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

NCT03154281

Description:

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.

Related Conditions:
  • Breast Carcinoma
  • Malignant Fallopian Tube Neoplasm
  • Malignant Ovarian Neoplasm
  • Malignant Peritoneal Neoplasm
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: TNE001
  • NCT ID: NCT03154281

Conditions

  • Breast Cancer
  • Ovarian Cancer

Interventions

DrugSynonymsArms
niraparibMK-4827Cohort 1
everolimusAfinitorCohort 1

Purpose

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

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort 1Experimental(each cycle is 28 days long) Everolimus 5mg daily on Mondays, Wednesdays, and Fridays Niraparib 100mg daily
  • niraparib
  • everolimus
Cohort 2Experimental(each cycle is 28 days long) Everolimus 5 mg daily on Mondays, Wednesdays, and Fridays Niraparib 200 mg daily
  • niraparib
  • everolimus
Cohort 3Experimental(each cycle is 28 days long) Everolimus 5 mg daily Niraparib 200 mg daily
  • niraparib
  • everolimus
Cohort 4Experimental(each cycle is 28 days long) Everolimus 5 mg daily Niraparib 300 mg daily
  • niraparib
  • everolimus

Eligibility Criteria

        Inclusion Criteria:

          1. 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

          2. Patients with breast cancer must have measurable disease per RECIST 1.1. criteria.
             Patients with ovarian cancer are eligible with or without measurable disease

          3. 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

          4. 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

          5. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of
             ≤2

          6. Patients must be ≥18 years of age

          7. 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

          8. Patient agrees to blood draws during screening and at the end of treatment for
             molecular and cytogenetic analysis

          9. Female patients of childbearing potential must have a negative serum pregnancy test
             (beta hCG) at Screening

         10. 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

         11. 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

         12. Patients must be able to understand the study procedures and agree to participate in
             the study by providing written informed consent

        Exclusion Criteria:

          1. Patients with HER2+ breast cancer measured by standard IHC or FISH testing

          2. Patients must not be simultaneously enrolled in any other interventional clinical
             trial

          3. 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

          4. 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

          5. Patients must not have had radiotherapy encompassing >20% of the bone marrow

          6. 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

          7. Patients must not have a known hypersensitivity to the components of niraparib,
             everolimus, rapamycin analogues, or the excipients

          8. Patients must not be immunocompromised (patients with splenectomy are allowed)

          9. Patients must not have had any known, persistent >Grade 2 toxicity from prior cancer
             therapy

         10. Patients must not have had any known, persistent (>4 weeks), ≥Grade 3 hematological
             toxicity or fatigue from prior cancer therapy

         11. Patients must not have received a transfusion (platelets or red blood cells) ≤4 weeks
             of the first dose of study treatment

         12. 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

         13. 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)

         14. Patients must not have known, symptomatic brain or leptomeningeal metastases

         15. 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

         16. Patients must not have any known history of myelodysplastic syndrome (MDS) or acute
             myeloid leukemia (AML)

         17. 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

         18. Patients with uncontrolled or poorly controlled hypertension

         19. 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)

         20. 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)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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

Measure: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
Safety Issue:
Description:To assess the toxicity of the combination of niraparib and everolimus in each cohort
Measure: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.
Safety Issue:
Description:To determine the response rate (according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 response criteria)

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Avera McKennan Hospital & University Health Center

Trial Keywords

  • Breast
  • Ovarian

Last Updated

June 12, 2020