Onvansertib in Combination With NALIRIFOX for First Line Treatment of Advanced Pancreatic Cancer

A Phase 1b/2 Trial of Onvansertib in Combination With NALIRIFOX for First Line Treatment of Advanced Pancreatic Cancer

Pancreatic cancer is a deadly disease and will be the second leading cause of cancer related death behind lung cancer by 2030. Over 62,000 people are diagnosed each year in the United States with about 90% succumbing to the disease within 5 years. In the metastatic setting, NALIRIFOX, FOLFIRINOX and nab-paclitaxel-gemcitabine are standard treatment options in patients with good performance status (Eastern Cooperative Oncology Group [ECOG] 0/1). All three combinations have shown a survival advantage over previously standard gemcitabine-based therapy, with 11.1 months overall survival (OS) for NALIRIFOX/FOLFIRINOX and 8.7 months for nab-paclitaxel-gemcitabine versus 6.7 months for gemcitabine alone. There is an urgent need to improve treatment of patients with current and emerging therapeutic strategies.

KRAS is the most common oncogene mutated in pancreatic adenocarcinoma, and it is mutated in nearly all tumors. Mutant KRAS is essential for PDAC growth, where the constitutive activated RAS proteins contribute to tumorigenesis, treatment resistance, and metastases. Despite research and drug development efforts focused on KRAS, no effective RAS inhibitors have been approved for the treatment of pancreatic cancer with KRAS mutation. The poor prognosis of KRAS-mutated PDAC patients and the absence of KRAS-targeted therapies, highlight the urgency to develop novel therapies aimed at KRAS.

This study will investigate onvansertib (also known as PCM-075 and NMS-1286937) as the first PLK1-specific adenosine triphosphate competitive inhibitor administered by oral route to enter clinical trials with proven antitumor activity in different preclinical models.

Inclusion Criteria:

• Ability of participant to understand this study, and participant willingness to sign a written informed consent. Remote consenting will be allowed on a case-by-case basis, but will not replace in-person visits for labs/physical, etc.

• Males and females age ≥ 18 years

• ECOG Performance Status 0 - 1

• Measurable disease by RECIST 1.1

• Histologically or cytologically confirmed adenocarcinoma of the exocrine pancreas

• Locally advanced unresectable or metastatic disease who are treatment naive

• No previous systemic therapy in the metastatic setting

• Participant must be willing to submit archival tissue if available and sufficient - otherwise fresh biopsy collection will be performed at screening UNLESS it is deemed medically unsafe for the participant. If participant does not have archival tissue and is not able to undergo a fresh biopsy at this time, enrollment will be per the principal investigator's discretion

• Adequate organ function, defined as follows:

  • Leukocytes (White Blood Cell [WBC]) > 3 K/UL
  • Absolute Neutrophil Count >1.5K/UL
  • Platelets >100K/UL
  • Hemoglobin ≥ 9 g/dL(level must be maintained without transfusions)
  • Calculated creatinine clearance ≥ 50 mL/min using the Cockcroft-Gault equation
  • Total bilirubin ≤ 1.5 x ULN

• If known Gilbert's syndrome then discuss with principal investigator. Email documentation of discussion and approval will be saved and documented for source.

• Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x ULN unless liver metastases are present, in which case they must be ≤ 5 x ULN

• Women of child-bearing potential (WOCBP) and men with partners of child-bearing potential must agree to practice sexual abstinence or to use the forms of contraception listed in Child-Bearing Potential/Pregnancy section.

Exclusion Criteria:

• Simultaneously enrolled in any therapeutic clinical trial

• Current or anticipating use of other anti-neoplastic or investigational agents while participating in this study

• Diagnosed with a psychiatric illness or is in a social situation that would limit compliance with study requirements

• Is pregnant or breastfeeding

• Has a known allergic reaction to any excipient contained in the study drug formulation

• Active Grade 3 (per the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 5.027) or higher viral, bacterial, or fungal infection within 2 weeks prior to the first dose of study treatment.

• Patient has had major surgery within 4 weeks prior to enrollment

• Untreated or symptomatic brain metastasis

• Gastrointestinal (GI) disorder(s) that, in the opinion of the Investigator, would significantly impede the absorption of an oral agent (e.g., intestinal occlusion, active Crohn's disease, ulcerative colitis, extensive gastric and small intestine resection)

• Unable or unwilling to swallow study drug

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, clinically significant non-healing or healing wounds, symptomatic congestive heart failure (CHF) Class II or higher according to the New York Heart Association (NYHA) Functional Classification, unstable angina pectoris, clinically significant cardiac arrhythmia, significant pulmonary disease (shortness of breath at rest or mild exertion), uncontrolled infection

• Known active infection with HIV, with measurable viral titer, and/or active infection with hepatitis B or C (patients who have had a hepatitis B virus immunization are eligible)

• Known active infection with SARS-CoV-2 where symptoms are present

• Clinically significant ascites or pleural effusions

• Patients with a history of other malignancies except adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix or prostate, or other solid tumors curatively treated with no evidence of disease for > 2 years

• Any active disease condition that would render the protocol treatment dangerous or impair the ability of the patient to receive study drug per PI discretion.

• Any condition (e.g., psychological, geographical, etc.) that does not permit compliance with the protocol

• Treatment with any of the drugs listed in section with title; Prohibited or Restricted Concomitant Medications at the time of study treatment initiation. Planned concomitant use of medications known to prolong the QT/QTc interval according to institutional guidelines. Use of strong CYP3A4 or CYP2C19 inhibitors or strong CYP3A4 inducers. Patients currently receiving these agents who can be switched to alternate therapy are not excluded. Inhibitors should be stopped at least 1 week prior to the first dose of protocol therapy and inducers should be stopped at least 2 weeks prior to initiation of protocol therapy

• QT interval: Fridericia's correction (QTcF) > 470 milliseconds.

  • A single ECG is sufficient. Triplicate may be done per PI discretion. If triplicate ECG completed, the QTcF should be calculated as the arithmetic mean of the QTcF on triplicate ECGs. In the case of potentially correctible causes of QT prolongation that are readily corrected (e.g., medications, hypokalemia), the triplicate ECG may be repeated once during Screening and that result may be used to determine eligibility
  • Presence of risk factors for torsade de pointes, including family history of Long QT Syndrome or uncorrected hypokalemia