Ovarian Cancer Clinical Trial
Niraparib and Neratinib in Advanced Solid Tumors With Expansion Cohort in Advanced Ovarian Cancer
To determine the recommended phase 2 dose (RP2D) of niraparib and neratinib in combination in patients with advanced solid tumors during Phase 1. To evaluate clinical benefit (â‰¥4-month progression-free survival [PFS]) of niraparib and neratinib in patients with platinum-resistant ovarian cancer in Phase 1b.
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.
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) and
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 calculated
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 90 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 30 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.
Participant must agree to not donate sperm during the study or for 90 days after the last dose of study treatment
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 study treatment
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 treatment
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 treatment
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 neratinib
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). Must discontinue use 10 days prior to initiating study therapy.
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: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm
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 requirements
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