Onvansertib in Combination With Nanoliposomal Irinotecan, Leucovorin, and Fluorouracil for Second-Line Treatment of Participants With Metastatic Pancreatic Ductal Adenocarcinoma

Study Overview
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Brief Summary
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The main objective of this trial is to assess the efficacy of onvansertib in combination with nanoliposomal irinotecan (nal-IRI), leucovorin, and fluorouracil (5-FU) for treatment of participants with histologically confirmed metastatic pancreatic ductal adenocarcinoma (PDAC).

Official Title
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A Phase 2 Study of Onvansertib in Combination With Nanoliposomal Irinotecan, Leucovorin, and Fluorouracil for Second-Line Treatment of Patients With Metastatic Pancreatic Ductal Adenocarcinoma

Conditions
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Pancreatic Ductal Adenocarcinoma

Intervention / Treatment
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* Drug: Onvansertib
* Drug: Nanoliposomal irinotecan
* Drug: Leucovorin
* Drug: Fluorouracil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed metastatic PDAC Has received 1 prior gemcitabine-based chemotherapy as first line therapy for metastatic disease. Progression after completion of neoadjuvant or adjuvant therapy of < 6 months in duration is considered 1 line of therapy for metastatic disease Has measurable disease according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), defined as at least 1 lesion that can be accurately measured in at least 1 dimension (longest diameter to be recorded) as > 20 mm with conventional techniques or as > 10 mm with spiral computed tomography (CT) scan Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 Must be willing and able to undergo a tissue biopsy at screening; participants who, in the opinion of the investigator, do not have tissue that is accessible for biopsy are excepted from this criterion Women of childbearing potential: (defined as not post-menopausal for 12 months or no previous surgical sterilization) and fertile men must agree to use adequate contraception for the duration of study participation and for 4 months after the last dose of nal-IRI. Male subjects must agree to refrain from sperm donation during the study and for 4 months after the last dose of nal-IRI Ability to understand and the willingness to sign a written informed consent document. Signed informed consent form must be obtained prior to initiation of study evaluations and/or activities International Normalized Ratio (INR) < 1.5 unless on warfarin Participants with prior malignancy and who were treated with no evidence of active disease more than 2 years from initial diagnosis are eligible Age ≥ 18 years Participants must have adequate organ and bone marrow function Exclusion Criteria: Prior treatment with irinotecan, nal-IRI, or investigational PLK1 inhibitor Uncontrolled intercurrent illness including symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, and myocardial infarction within 3 months of initiation of therapy History of interstitial pneumonitis or interstitial lung disease Participants with microsatellite instability-high (MSI-H) tumors with no prior immune checkpoint inhibitor exposure Pregnancy or lactation Participant has active and uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy QT interval with Fridericia's correction (QTcF) > 470 milliseconds. The QTcF should be calculated as the arithmetic mean of the QTcF on triplicate electrocardiograms (ECGs). In the case of potentially correctible causes of QT prolongation, (eg, medications, hypokalemia), the triplicate ECG may be repeated once during Screening and that result may be used to determine eligibility Planned concomitant use of medications known to prolong the QT/QTc interval Participant has undergone major surgical resection within 4 weeks prior to enrollment Participant received radiotherapy, surgery, chemotherapy, or an investigational therapy within 2 weeks prior to study entry Participant has serious medical risk factors involving any of the major organ systems such that the investigator considers it unsafe for the participant to receive an experimental research drugs Serious psychiatric or medical conditions that could interfere with treatment Major bleeding in the last 4 weeks More than 1 prior chemotherapy regimen administered in the metastatic setting Unable or unwilling to swallow oral medication Use of strong CYP3A4 or UGT1A1 inhibitors or strong CYP3A4 inducers. Participants currently receiving these agents who are able to switch to alternate therapy are not excluded. Inhibitors should be stopped at least one week prior to the first dose of protocol therapy and inducers should be stopped at least two weeks prior to initiation of protocol therapy.

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Safety Lead-in: Onvansertib + nal-IRI + leucovorin + 5-FU<br>The first 3 participants will be administered onvansertib orally once a day at a dosing schedule of 12 mg/m^2 on Day 1 to Day 10 for two cycles, where each cycle is 2 weeks. Depending on the number of dose limiting toxicities (DLTs) experienced in the first 3 participants, additional participants may receive different dosing schedules, determining the dosing schedule to be used in the treatment period. Onvansertib will be administered in combination with 70 mg/m^2 nanoliposomal irinotecan (nal-IRI), 400 mg/m^2 leucovorin and 2400 mg/m^2 fluorouracil (5-FU). | Drug: Onvansertib<br>* Oral capsule<br>* Other names: PCM-075;Drug: Nanoliposomal irinotecan<br>* Intravenous infusion<br>* Other names: Nal-IRI;Drug: Leucovorin<br>* Intravenous infusion<br>Drug: Fluorouracil<br>* Intravenous infusion<br>* Other names: 5-FU;|
| Experimental: Treatment Period: Onvansertib + nal-IRI + leucovorin + 5-FU<br>Participants will be administered onvansertib at the dosing schedule selected based on the results of the safety lead-in, in cycles of 2 weeks. Onvansertib will be administered in combination with 70 mg/m^2 nanoliposomal irinotecan (nal-IRI), 400 mg/m^2 leucovorin and 2400 mg/m^2 fluorouracil (5-FU). | Drug: Onvansertib<br>* Oral capsule<br>* Other names: PCM-075;Drug: Nanoliposomal irinotecan<br>* Intravenous infusion<br>* Other names: Nal-IRI;Drug: Leucovorin<br>* Intravenous infusion<br>Drug: Fluorouracil<br>* Intravenous infusion<br>* Other names: 5-FU;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) |  | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experience a Treatment-emergent Adverse Event (TEAE) |  | Up to 2 years | 
| Duration of Response (DOR) |  | Up to 2 years | 
| Overall Response Rate (ORR) in Participants Who Receive At Least 2 Treatment Cycles | Each cycle is 2 weeks. | Up to 2 years | 
| Overall Survival (OS) |  | Up to 2 years | 
| Disease Control Rate (DCR) |  | Up to 2 years | 
| Reduction from Baseline in Serum CA19-9 Response |  | Baseline up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pancreatic Ductal Adenocarcinoma, Onvansertib, Nanoliposomal irinotecan, Leucovorin, Fluorouracil, PLK1, PLK Inhibitor