Niraparib and Neratinib in Advanced Solid Tumors With Expansion Cohort in Advanced Ovarian Cancer

Study Overview
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Brief Summary
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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 (≥4-month progression-free survival [PFS]) of niraparib and neratinib in patients with platinum-resistant ovarian cancer in Phase 1b.

Detailed Description
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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.

Official Title
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A Phase 1/1b Clinical Trial of Niraparib and Neratinib in Advanced Solid Tumors With an Expansion Cohort in Platinum-resistant Ovarian Cancer

Conditions
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Advanced Solid Tumor, Ovarian Cancer

Intervention / Treatment
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* Drug: Neratinib 160 mg
* Drug: Neratinib 200 mg
* Drug: Neratinib 240 mg
* Drug: Niraparib 100 mg
* Drug: Niraparib 200 mg
* Drug: Niraparib 300 mg
* Drug: Niraparib at RP2D
* Drug: Neratinib at RP2D


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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) 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 Exclusion Criteria: 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 Uncontrolled hypertension 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Dose escalation will proceed within each cohort. Phase 1b is the expansion cohort at the recommended phase 2 dose found in phase 1.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Level -1<br>Neratinib 160 mg and Niraparib 100 mg by mouth once daily for 28 day cycles. | Drug: Neratinib 160 mg<br>* Escalating doses to determine recommended phase 2 dose (RP2D)<br>Drug: Niraparib 100 mg<br>* Escalating doses to determine recommended phase 2 dose (RP2D)<br>|
| Experimental: Dose Level 1<br>Neratinib 160 mg and Niraparib 200 mg by mouth once daily for 28 day cycles. | Drug: Neratinib 160 mg<br>* Escalating doses to determine recommended phase 2 dose (RP2D)<br>Drug: Niraparib 200 mg<br>* Escalating doses to determine recommended phase 2 dose (RP2D)<br>|
| Experimental: Dose Level 2<br>Neratinib 200 mg and Niraparib 200 mg by mouth once daily for 28 day cycles. | Drug: Neratinib 200 mg<br>* Determined RP2D dose<br>Drug: Niraparib 200 mg<br>* Escalating doses to determine recommended phase 2 dose (RP2D)<br>|
| Experimental: Dose Level 3<br>Neratinib 240 mg and Niraparib 200 mg by mouth once daily for 28 day cycles. | Drug: Neratinib 240 mg<br>* Escalating doses to determine recommended phase 2 dose (RP2D)<br>Drug: Niraparib 200 mg<br>* Escalating doses to determine recommended phase 2 dose (RP2D)<br>|
| Experimental: Dose Level 4<br>Neratinib 240 mg and Niraparib 300 mg by mouth once daily for 28 day cycles. | Drug: Neratinib 240 mg<br>* Escalating doses to determine recommended phase 2 dose (RP2D)<br>Drug: Niraparib 300 mg<br>* Phase 1: Escalating doses to determine recommended phase 2 dose (RP2D)<br>|
| Experimental: Phase 1b: Platinum Resistant Expansion Cohort<br>This portion of the study provides for cohort expansion to observe for 4 month or greater progression-free survival in patients with platinum resistant ovarian cancer treated at the recommended phase 2 dose (RP2D) determined in Phase I. | Drug: Niraparib at RP2D<br>* Phase 1b: Determined dose<br>Drug: Neratinib at RP2D<br>* Phase 1b: Determined dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: To determine the Recommended phase 2 dose (RP2D) of niraparib and neratinib in 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. | 4 Months | 
| Phase 1b: To evaluate clinical benefit (≥4-month progression-free survival [PFS]) of niraparib and neratinib in patients with platinum-resistant ovarian cancer. | Phase 1b: To evaluate clinical benefit (≥4-month progression-free survival [PFS]) of niraparib and neratinib given at the RP2D to in patients with platinum-resistant ovarian cancer. To evaluate the clinical benefit, (defined as ≥4-month progression free survival (PFS), using Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria in patients with platinum-resistant ovarian cancer. | 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the frequency of adverse events (AEs) | To assess adverse events (AEs) characterized and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE V 5.0) to determine safety and toxicity of the combination of neratinib and niraparib | 5 months | 
| Preliminary efficacy (objective response rate [ORR]) of niraparib and neratinib in patients with advanced solid tumors. | To evaluate the objective response rate (ORR): The percentage of patients with objective response either partial response (PR) or complete response(CR), by analysis using RECIST 1.1 criteria | 5 years |