This is a multi-institutional Phase I dose-escalation and dose-expansion trial for patients
with advanced, solid tumor malignancies who have pre-identified deleterious germline or
somatic mutations in the homologous recombination deoxyribonucleic acid (DNA) repair pathway
(HR deficient). The trial is designed to assess the efficacy and safety of niraparib plus
carboplatin in patients with evidence of HRD. The primary endpoint will be identifying the
recommended phase 2 dose (RP2D) and schedule of niraparib plus carboplatin, as well as
establishing the anti-tumor efficacy of niraparib plus carboplatin as determined by Response
Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.
This is a multi-institutional Phase I dose-escalation and dose-expansion trial for patients
with advanced, solid tumor malignancies who have pre-identified deleterious germline or
somatic mutations in the homologous recombination deoxyribonucleic acid (DNA) repair pathway
(HR deficient). The trial is designed to assess the efficacy and safety of niraparib plus
carboplatin in patients with evidence of HRD. The primary endpoint will be identifying the
recommended phase 2 dose (RP2D) and schedule of niraparib plus carboplatin, as well as
establishing the anti-tumor efficacy of niraparib plus carboplatin as determined by Response
Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.
Patients will be pre-identified from participating centers as having either a germline
deleterious mutation or tumor expression of a deleterious mutation in one of the genes listed
below, as determined by Next-generation DNA sequencing (NGS) only, completed prior to
enrollment in this protocol. Patients with advanced solid tumor malignancies with the
presence of somatic or germline deleterious mutation in a gene(s) critical to DNA repair
through homologous recombination, including but not limited to: ARID1A, ATM, ATRX, MRE11A,
NBN, PTEN, RAD50/51/51B, BARD1, BLM, BRCA1, BRCA2, BRIP1, FANCA/C/D2/E/F/G/L, PALB2, WRN,
CHEK2, CHEK1, BAP1, FAM175A, SLX4, MLL2 or XRCC, and who have an adequate performance status
(PS), bone marrow, hepatic, and renal function as well as biopsiable and measurable disease
will be screened for enrollment.
Appropriate patients will be enrolled in a 3+3 alternating dose escalating fashion, to a
maximum dose of niraparib of 300mg daily and a maximum dose of carboplatin area under the
curve (AUC) of 4. The 3+3 schema will be employed to insure safety and tolerability. However,
within any given cohort, a full contingent of 6 patients (assuming adequate tolerability)
will be enrolled to capture a sufficient number of patients and samples for pharmacodynamic
assessment of DNA damage.
Once the RP2D and schedule are identified, a Phase Ib expansion cohort of 20 additional
patients will be enrolled as a pilot subgroup to determine efficacy. Of the 20 patients in
this Phase Ib cohort, no more than 10 patients will have underlying breast cancer; and
additionally no more than 10 patients may harbor BRCA1 or BRCA2 mutations.
To assess the efficacy of poly (ADP-ribose) polymerase (PARP) inhibition and the extent of
DNA damage, patients will undergo serial tumor biopsies to measure DNA damage as quantified
by levels of ᵞH2AX and RAD51 foci formation, as well as an assessment of PARP inhibitory
activity. Tumor biopsies will also be used to assess the mechanisms of resistance to PARP
inhibitor-based therapy.
Assessment of safety including blood tests, clinic visits and exams will occur weekly at the
start of therapy, then will transition to every 3-week clinic visits and exams at the
beginning of cycle 4. For the Phase Ib portion, patients will undergo weekly lab work and
clinic visits for cycle 1 only. The researchers hypothesize that in this HR deficient patient
population, the addition of niraparib to carboplatin will lead to significant anti-tumor
responses with acceptable toxicities.
Inclusion Criteria:
- Patients PRE-identified as having either a germline deleterious mutation or tumor
expression of a deleterious mutation) as determined by Next-generation DNA sequencing
only, in at least one gene involved in DNA damage repair through homologous
recombination including but not limited to: ARID1A, ATM, ATRX, MRE11A, NBN, PTEN,
RAD50/51/51B, BARD1, BLM, BRCA1, BRCA2, BRIP1, FANCA/C/D2/E/F/G/L, PALB2, WRN, CHEK2,
CHEK1, BAP1, FAM175A, SLX4, MLL2 or XRCC.
- Patients with somatic mutations will be PRE-identified as having a homologous
recombination mutation based on NGS done in a CLIA certified, CAP tested and
bioinformatics-validated testing lab PRIOR to enrollment in this current protocol. The
testing may have been done at any time prior to enrollment. HOWEVER, if any patient
has had NGS testing more than 3 months prior to enrollment, or if there has been
intervening therapy, then a repeat NGS test must be done and the deleterious somatic
mutation must be re-identified for inclusion.
- The determination of a deleterious mutation must be supported in the documentation
included in the testing, and should include clinical, or pre-clinical literature to
support the finding that a specific mutation results in impaired function of the gene,
and thus impaired DNA repair through homologous recombination. Variants of unknown
significance will not be eligible.
- Patients with germline deleterious mutations may have been identified at any time
point prior to inclusion in the protocol and do NOT need to have this genetic testing
repeated regardless of time frame and intervening therapy.
- Advanced, solid tumor malignancy that is amenable to biopsy. Patient must consent to 4
mandatory biopsies during study
- Life expectancy of more than 3 months
- Age ≥ 18 years
- Measurable disease by RECIST v1.1 criteria (tumor ≥ 1 cm in longest diameter on axial
image on computed tomography (CT) or magnetic resonance imaging (MRI) and/or lymph
node(s) ≥ 1.5 cm in short axis on CT or MRI) on baseline imaging
- ECOG performance status (PS) of 0 to 1 (Table 10, Appendix A)
- Patients who have received and failed, or have been intolerant to, standard first line
therapies known to confer clinical benefit. Patients who refuse standard therapy would
also be eligible, as long as their refusal is documented.
- Patients with a standard 12-lead electrocardiogram (ECG) with the following parameters
at screening (defined as the mean of the triplicate ECGs):
1. QTc interval at screening < 481 msec
2. Resting heart rate 50-90bpm
- Adequate hepatic, bone marrow, and renal function at the time of enrollment:
- Bone Marrow: Absolute neutrophil count (ANC) ≥ 1,500/mm3; Platelets ≥ 100,000/mm3;
Hemoglobin ≥ 9.0 g/dL. Patients must be able to meet the criteria without transfusion
or receipt of colony stimulating factors within 2 weeks before obtaining sample
- Renal function: Serum creatinine ≤ 2.0 mg/dL OR creatinine clearance ≥ 50 mL/min/1.73
m2
- Hepatic function: aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
≤ 2.5 × the upper normal limit of institution's normal range. Total bilirubin ≤ 1.5 ×
the upper normal limit of institution's normal range. For subjects with liver
metastases, AST and ALT < 5 × the upper normal limit of institution's normal range,
and total bilirubin >1.5 - 3.0 x the upper normal limit of institution's normal range
are acceptable as long as there is no persistent nausea, vomiting, right upper
quadrant pain or tenderness, fever, rash, or eosinophilia
- Prothrombin Time (PT) and Partial Thromboplastin Time (PTT) must be ≤ 2 X the upper
limit of the institution's normal range and International Normalized Ratio (INR) < 2.
Subjects on anticoagulation (such as coumadin) will be permitted to enroll as long as the
INR is in the acceptable therapeutic range as determined by the investigator
- Patients may have received an unlimited number of prior therapies
- Patients must have fully recovered from all effects of surgery. Patients must have had
at least two weeks after minor surgery and four weeks after major surgery before
starting therapy. Minor procedures requiring conscious sedation such as endoscopies or
mediport placement may only require a 24-hour waiting period, but this must be
discussed with an investigator
- Women of childbearing potential must have a negative serum pregnancy test within 14
days prior to initiation of treatment and/or postmenopausal women must be amenorrheic
for at least 12 months to be considered of non-childbearing potential
- Patient is capable of swallowing pills whole
- Subject is capable of understanding and complying with parameters as outlined in the
protocol and able to sign and date the informed consent, approved by the IRB, prior to
the initiation of any screening or study-specific procedures
Exclusion Criteria:
- Prior disease progression while receiving platinum chemotherapy or platinum
chemotherapy within the last 6 months
- For patients who received platinum-based adjuvant chemotherapy, at least 6 months must
have passed between the last dose of platinum-based therapy and the development of
metastatic disease. For breast cancer patients, at least 12 months must have passed
between the last dose of platinum-based therapy and the development of metastatic
disease
- Prior PARP inhibitor-based therapy
- Known or suspected CNS metastases, unless at least one month has passed since last
local CNS therapy and there is no evidence for recurrent or progressive CNS disease on
follow up imaging. Participants may remain on steroids for CNS disease if they are
taking a stable dose
- Active severe infection, or known chronic infection with HIV or hepatitis B virus
(testing not required prior to enrollment)
- Patients with chronic Hepatitis C virus may be enrolled if there is no
clinical/laboratory evidence of cirrhosis AND the patient's liver function tests fall
within the parameters set in Section 3.2.8.3, Inclusion Criteria, Hepatic function
- Cardiovascular disease problems including unstable angina, therapy for
life-threatening ventricular arrhythmia, or myocardial infarction, stroke, or
congestive heart failure within the last 6 months. Additionally, patients must not
have QT prolongation greater than or equal to 481 milliseconds
- Life-threatening visceral disease or other severe concurrent disease that would, in
the investigator's judgment, cause unacceptable safety risks, contraindicate patient
participation in the clinical study or compromise compliance with the protocol (e.g.
chronic active hepatitis, active untreated or uncontrolled fungal, bacterial or viral
infections, etc.)
- Patient has impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of the study drugs (e.g., ulcerative diseases,
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel
resection)
- Presence of a psychiatric illness or social situation that would limit compliance with
study requirements
- Women who are pregnant or breastfeeding
- The subject 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). Questions regarding the inclusion of
individual subjects should be directed to the Principal Investigators, Dr. Isaacs and
Dr. Pishvaian.
- Clinically significant peripheral neuropathy at the time of enrollment (defined in the
NCI CTCAE v4.0) as grade 2 or greater neurosensory or neuromotor toxicity)
- 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 a known hypersensitivity to the components of niraparib or the
excipients
- 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 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 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)
