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.
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.
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)
