ONT01 and Gemcitabine/Nab-paclitaxel as Second Line Therapy for Metastatic Pancreatic Ductal Adenocarcinoma

Inclusion criteria

• Histologically or cytologically confirmed adenocarcinoma of the pancreas.
• Measurable or evaluable disease per RECIST 1.1.
• Previously treated with first-line systemic therapy for unresectable/advanced or metastatic PDAC and experienced progression or became intolerant to the therapy and is in need of another line of systemic therapy in the opinion of the investigator.
• At least 18 years of age.
• ECOG performance status ≤ 1.
• Adequate bone marrow and organ function as defined below:

• Absolute neutrophil count ≥ 1.5 K/cumm
• Platelets ≥ 100 K/cumm
• Hemoglobin ≥ 9.0 g/dL
• Total bilirubin ≤ 1.5 x IULN
• AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN, unless there are liver metastases in which case AST and ALT ≤ 5.0 x IULN
• Creatinine ≤ 1.5 x IULN or Creatinine clearance > 50 mL/min by Cockcroft-Gault
• The effects of ONT01 on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 120 days after last dose of ONT01 or 180 days after last dose of nab-paclitaxel/gemcitabine. Should a woman become pregnant or suspect she is pregnant while participating in this study or should a man suspect he has fathered a child, s/he must inform her treating physician immediately.
• Ability to understand and willingness to sign an IRB approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.

Exclusion criteria

• Received more than one line of treatment or received gemcitabine or nab-paclitaxel in the metastatic setting. Prior therapy in the adjuvant or neoadjuvant therapy will count as a line of treatment if progression occurred less than 6 months after the last dose of systemic therapy. The following exception applies:

• If treated in the adjuvant or neoadjuvant setting with systemic therapy and progression occurred greater than 6 months after last dose, the adjuvant or neoadjuvant systemic therapy may have included gemcitabine or nab-paclitaxel. If progression occurred within 6 months of the last dose of systemic therapy in the adjuvant or neoadjuvant setting, then that therapy must not have included gemcitabine or nab-paclitaxel.
• Current use or anticipated need for alternative, holistic, naturopathic, or botanical formulations used for the purpose of cancer treatment.
• Major surgery (defined as surgery that requires general anesthesia) within 28 days of C1D1 of ONT01 (phase I portion) or date of randomization (phase II portion).
• Chemotherapy, small molecular directed therapy, immunotherapy, and/or radiation therapy within 14 days of C1 of ONT01 (phase I portion) or date of randomization (phase II portion).
• History of other malignancy with the exception of 1) malignancies for which all treatment was completed at least 2 years before registration and the patient has no evidence of disease or 2) known indolent malignancies that do not require treatment and will likely not alter the course of treatment of metastatic PDAC (including but not limited to prostate adenocarcinoma Gleason 6 on surveillance, indolent follicular lymphoma on watch and wait surveillance, low risk CLL on surveillance, non-metastatic cutaneous basal cell or squamous cell carcinoma not requiring systemic therapy).
• History of allogeneic organ or stem cell transplant.
• Currently receiving any other investigational agents.
• Patients with known, untreated brain metastases. Patients with treated brain metastases are allowed if post-treatment brain-imaging after CNS-directed therapy shows no evidence of progression.
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to ONT01, gemcitabine, nab-paclitaxel, or other agents used in the study.
• Average QTc >470 msec on screening EKGs.
• Gastrointestinal condition which could prevent absorption of ONT01, or inability to digest ONT01, in the opinion of the PI or sub-investigator.
• Clinically significant peripheral neuropathy grade 2 or worse.
• Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative urine or serum pregnancy test within 7 days of C1D1 (phase I portion) or date of randomization (phase II portion).
• HIV-infected if not on effective anti-retroviral therapy with undetectable viral load for 6 months. Patients with HIV who are receiving effective anti-retroviral therapy and have had an undetectable viral load for at least 6 months are eligible. HIV testing not required in the absence of known history of infection.
• Evidence of chronic hepatitis B virus (HBV) that is detectable on suppressive therapy. Patients with evidence of chronic HBV infection with undetectable HBV viral load on suppressive therapy are eligible. HBV testing not required in the absence of known history of infection.
• History of hepatitis C virus (HCV) infection that has not been cured or that has a detectable viral load. Patients with a history of HCV that has been treated and cured are eligible. Patients with HCV infection who are currently on treatment and have an undetectable HCV viral load are eligible. HCV testing not required in the absence of known history of infection.
• Participants with active, known or suspected autoimmune disease. Participants with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, euthyroid participants with a history of Grave's disease (participants with suspected autoimmune thyroid disorders must be negative for thyroglobulin and thyroid peroxidase antibodies and thyroid stimulating immunoglobulin prior to first dose of study treatment), psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll after discussing with the Principal Investigator.
• Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days of C1D1 except for adrenal replacement steroid doses > 10 mg daily prednisone equivalent in the absence of active autoimmune disease. Note: treatment with a short course of steroids (< 5 days) up to 7 days prior to C1D1 (phase I portion) or date of randomization (phase II portion) is permitted. Inhaled intranasal, intra-articular, and topical steroid uses are permitted.
• Patients with known Gilbert's syndrome.