This study is a single-arm, open-label, phase 1/1b trial to determine the RP2D of neratinib
and niraparib when given in combination to patients with advanced solid tumors. The RP2D will
be identified during the phase 1 dose escalation portion of the study using a modified 3+3
design and evaluated in a phase 1b dose expansion cohort of up to 12 patients with
platinum-resistant ovarian cancer.
- Disease Characteristics
- Phase 1: Patients with advanced solid tumors, excluding primary CNS and prostate
tumors, that have progressed during or after treatment with approved therapies or for
which there is no standard effective therapy available or
- Phase 1b: Female patients with ovarian cancer who:
- Are platinum resistant (progressed within 6 months of finishing platinum therapy)
- Have received at least 2 prior lines of therapy and
- Do not have a BRCA germline mutation
- Measurable or evaluable disease by RECIST 1.1
- Age ≥ 18 years
- ECOG performance status 0 or 1
- Adequate bone marrow function as defined below:
- Absolute neutrophil count (ANC) ≥ 1,500/mm3
- Platelets ≥ 100,000/mm3 (untransfused)
- Hemoglobin ≥9 g/dL (untransfused)
- Adequate renal function as defined below:
- Serum creatinine ≤ 1.5 x upper limit of normal (ULN) for the laboratory OR
- Or actual creatinine clearance ≥ 30 mL/min (see Appendix 2 for the
Cockcroft-Gault formula for calculating creatinine clearance)
- Adequate hepatic function as defined below:
- Total bilirubin ≤ 1.5 x ULN for the laboratory OR direct bilirubin ≤ 1.0 x ULN
- Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x ULN (≤ 3x ULN
when liver metastases are present)
- Patients receiving corticosteroids may continue as long as their dose is stable for
least 4 weeks prior to initiating protocol therapy
- Patients must agree not to donate blood during the study or for 90 days after the last
dose of study treatment
- A woman of childbearing potential (WCBP) must have a documented negative serum
pregnancy test within 7 days prior to initiating study treatment and agree to abstain
from activities that could result in pregnancy from screening through 180 days after
the last dose of study treatment. Non Childbearing potential is defined as follows (by
other than medical reasons):
- ≥45 years of age and has not had menses for >1 year
- Patients who have been amenorrhoeic for <2 years without history of a
hysterectomy and oophorectomy must have a follicle stimulating hormone (FSH)
value in the postmenopausal range upon screening evaluation
- Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation.
Documented hysterectomy or oophorectomy must be confirmed with medical records of
the actual procedure or confirmed by an ultrasound. Tubal ligation must be
confirmed with medical records of the actual procedure, otherwise the patient
must be willing to use 2 adequate barrier methods throughout the study, starting
with the screening visit through 180 days after the last dose of study treatment.
Information must be captured appropriately within the site's source documents.
Note: Abstinence is acceptable if this is the established and preferred
contraception for the patient.
- Participant must agree to not breastfeed during the study or for 180 days after the
last dose of study treatment.
- Male participant agrees to use an adequate method of contraception starting with the
first dose of study treatment through 90 days after the last dose of study treatment.
Note: Abstinence is acceptable if this is the established and preferred contraception
for the patient.
- Ability to understand and the willingness to sign a written informed consent document
- Any investigational agent within 4 weeks, or within a time interval less than at least
5 half-lives of the investigational agent, whichever is shorter, prior to initiating
- Simultaneous enrollment in any other interventional clinical trial
- Active, uncontrolled diarrhea leading to dehydration or electrolyte disturbances not
controlled with oral repletion
- Serious (ie, grade ≥ 3) uncontrolled infection
- Major surgery ≤ 3 weeks prior to initiating study treatment and patient must have
recovered from any surgical effects.
- Radiation encompassing >20% of the bone marrow within 2 weeks, or any radiation
therapy within 1 week, prior to initiating study treatment.
- Transfusion of platelets or red blood cells ≤ 4 weeks prior to initiating study
- Receipt of colony-stimulating factors (e.g., granulocyte colony-stimulating factor
[GCSF], granulocyte macrophage colony- stimulating factor [GM-CSF], or recombinant
erythropoietin) within 4 weeks prior to initiating study treatment
- Known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)
- Known brain or leptomeningeal metastasis
- Diagnosis, detection, or treatment of another type of invasive cancer ≤ 2 years prior
to initiating study treatment
- Active or clinically significant cardiac disease including any of the following;
- Unstable angina (eg, angina symptoms at rest) or onset of angina within 3 months
prior to initiating study treatment
- Myocardial infarction diagnoses within 6 months prior to initiating study
- New York Heart Association (NYHA) class III or IV congestive heart failure
- Inability to swallow medication
- Known hypersensitivity to niraparib or neratinib components or excipients
- Known or suspected malabsorption condition or obstruction Note: Use of pancreatic
enzyme supplements is allowed to control malabsorption
- Inability to shift medications as follows:
- Antacids (eg, calcium carbonate): dose at least 3 hours after dosing with
- H2 receptor antagonists: dose must be taken at least 2 hours after or 10 hours
before dosing with neratinib
- Planned ongoing treatment with other drugs thought to potentially have adverse
interactions with either of the medications included in the study treatment:
- Proton pump inhibitors (PPIs).
- High-risk P-glycoprotein (P-gp) substrates (eg, digoxin, dabigatran).
- Strong or moderate CYP3A4 inhibitors and/or Strong or moderate CYP3A4 inducers.
Examples of clinical inhibitors and clinical inducers for P450-mediated
metabolism and classification of strong, moderate, and weak interactions are
available through the FDA website:
- If such medications have been used, patients must have discontinued these agents
≥ 2 weeks prior to initiating study treatment.
- Pregnancy or breastfeeding
- Medical, psychological, or social condition that, in the opinion of the investigator,
may increase the patient's risk or limit the patient's adherence with study