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 ormetastatic PDAC and experienced progression or became intolerant to the therapy andis 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 whichcase 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 contraceptionprior to study entry, for the duration of study participation, and for 120 daysafter 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 inthis study or should a man suspect he has fathered a child, s/he must inform hertreating physician immediately.

• Ability to understand and willingness to sign an IRB approved written informedconsent document. Legally authorized representatives may sign and give informedconsent on behalf of study participants.

Exclusion Criteria:

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

• If treated in the adjuvant or neoadjuvant setting with systemic therapy andprogression occurred greater than 6 months after last dose, the adjuvant orneoadjuvant systemic therapy may have included gemcitabine or nab-paclitaxel.If progression occurred within 6 months of the last dose of systemic therapy inthe adjuvant or neoadjuvant setting, then that therapy must not have includedgemcitabine or nab-paclitaxel.

• Current use or anticipated need for alternative, holistic, naturopathic, orbotanical formulations used for the purpose of cancer treatment.

• Major surgery (defined as surgery that requires general anesthesia) within 28 daysof C1D1 of ONT01 (phase I portion) or date of randomization (phase II portion).

• Chemotherapy, small molecular directed therapy, immunotherapy, and/or radiationtherapy 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 alltreatment was completed at least 2 years before registration and the patient has noevidence of disease or 2) known indolent malignancies that do not require treatmentand will likely not alter the course of treatment of metastatic PDAC (including butnot limited to prostate adenocarcinoma Gleason 6 on surveillance, indolentfollicular lymphoma on watch and wait surveillance, low risk CLL on surveillance,non-metastatic cutaneous basal cell or squamous cell carcinoma not requiringsystemic therapy).

• History of allogeneic organ or stem cell transplant.

• Currently receiving any other investigational agents.

• Patients with known, untreated brain metastases. Patients with treated brainmetastases are allowed if post-treatment brain-imaging after CNS-directed therapyshows no evidence of progression.

• A history of allergic reactions attributed to compounds of similar chemical orbiologic composition to ONT01, gemcitabine, nab-paclitaxel, or other agents used inthe study.

• Average QTc >470 msec on screening EKGs.

• Gastrointestinal condition which could prevent absorption of ONT01, or inability todigest 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 activeinfection, symptomatic congestive heart failure, unstable angina pectoris, orcardiac arrhythmia.

• Pregnant and/or breastfeeding. Women of childbearing potential must have a negativeurine or serum pregnancy test within 7 days of C1D1 (phase I portion) or date ofrandomization (phase II portion).

• HIV-infected if not on effective anti-retroviral therapy with undetectable viralload for 6 months. Patients with HIV who are receiving effective anti-retroviraltherapy 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 suppressivetherapy. Patients with evidence of chronic HBV infection with undetectable HBV viralload on suppressive therapy are eligible. HBV testing not required in the absence ofknown history of infection.

• History of hepatitis C virus (HCV) infection that has not been cured or that has adetectable viral load. Patients with a history of HCV that has been treated andcured are eligible. Patients with HCV infection who are currently on treatment andhave an undetectable HCV viral load are eligible. HCV testing not required in theabsence of known history of infection.

• Participants with active, known or suspected autoimmune disease. Participants withvitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmunecondition only requiring hormone replacement, euthyroid participants with a historyof Grave's disease (participants with suspected autoimmune thyroid disorders must benegative for thyroglobulin and thyroid peroxidase antibodies and thyroid stimulatingimmunoglobulin prior to first dose of study treatment), psoriasis not requiringsystemic treatment, or conditions not expected to recur in the absence of anexternal trigger are permitted to enroll after discussing with the PrincipalInvestigator.

• Participants with a condition requiring systemic treatment with eithercorticosteroids (> 10 mg daily prednisone or equivalent) or other immunosuppressivemedications within 14 days of C1D1 except for adrenal replacement steroid doses > 10mg 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. Inhaledintranasal, intra-articular, and topical steroid uses are permitted.

• Patients with known Gilbert's syndrome.