Study of 5-fluorouracil (5-FU), Nab®1-paclitaxel, Bevacizumab, Leucovorin, and Oxaliplatin in Patients With Metastatic Pancreatic Cancer

The purpose of this study is to learn about the safety and potential benefit of metronomic 5-fluorouracil in combination with nab®1-paclitaxel, bevacizumab, leucovorin, and oxaliplatin in treating patients with metastatic pancreatic adenocarcinoma.

The Phase 1 portion of the study is an open-label study enrolling subjects with metastatic pancreatic adenocarcinoma who have not previously received systemic chemotherapy at any time as treatment for pancreatic cancer (including adjuvant chemotherapy), except low dose chemotherapy administered as a radiosensitizer concomitant with radiotherapy and to determine the recommended Phase 2 dose (RP2D) and dose-limiting toxicities (DLTs) of metronomic 5-FU in combination with nab-paclitaxel, bevacizumab, leucovorin, and oxaliplatin in patients with metastatic pancreatic adenocarcinoma.

Subjects will be enrolled in cohorts of 6 subjects. There will be no dose escalation. Dose limiting toxicities will be assessed in cycle 1. If there is an incidence of ≥2 of 6 subjects experiencing a DLT, the dose will be de-escalated to the next lower dose. Based on the totality of the data, the investigators may advise the Sponsor to evaluate additional subjects at any of the dose levels. Upon Sponsor agreement, if additional subjects are enrolled at any dose level, DLT evaluation will occur at that same ratio (if ≥ 4 of 12 subjects, or ≥ 6 of 18 subjects experience a DLT, the dose will be de-escalated). Approximately 12-24 subjects will be enrolled in the Phase 1 portion of the study, dependent on the number of dose levels examined and the number of subjects enrolled at each dose level.

Safety will continuously be evaluated by incidence of Treatment Emergent Adverse Events (TEAEs) by the Medical Dictionary for Drug Regulatory Activities (MedDRA) and severity according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03 (v4.03).

The Phase 2 part of the study is to determine if the combination of metronomic 5-FU, nab-paclitaxel, bevacizumab, leucovorin, and oxaliplatin at the RP2D defined in Phase 1 achieves a clinically meaningful improvement in 1 year survival rate over the historical control. Approximately 60 subjects are planned to be enrolled in the Phase 2 portion of the study.

Subjects may remain on treatment until disease progression, unacceptable toxicity, withdrawal of consent, physician decision, or death. The anticipated duration of the study (including Phase 1, Phase 2 and follow-up) is approximately 4 years.

The Phase 1 portion of the study is an open-label study enrolling subjects with metastatic pancreatic adenocarcinoma who have not previously received systemic chemotherapy at any time as treatment for pancreatic cancer (including adjuvant chemotherapy), except low dose chemotherapy administered as a radiosensitizer concomitant with radiotherapy and to determine the recommended Phase 2 dose (RP2D) and dose-limiting toxicities (DLTs) of metronomic 5-FU in combination with nab-paclitaxel, bevacizumab, leucovorin, and oxaliplatin in patients with metastatic pancreatic adenocarcinoma.

Subjects will be enrolled in cohorts of 6 subjects. There will be no dose escalation. Dose limiting toxicities will be assessed in cycle 1. If there is an incidence of ≥2 of 6 subjects experiencing a DLT, the dose will be de-escalated to the next lower dose. Based on the totality of the data, the investigators may advise the Sponsor to evaluate additional subjects at any of the dose levels. Upon Sponsor agreement, if additional subjects are enrolled at any dose level, DLT evaluation will occur at that same ratio (if ≥ 4 of 12 subjects, or ≥ 6 of 18 subjects experience a DLT, the dose will be de-escalated). Approximately 12-24 subjects will be enrolled in the Phase 1 portion of the study, dependent on the number of dose levels examined and the number of subjects enrolled at each dose level.

Safety will continuously be evaluated by incidence of Treatment Emergent Adverse Events (TEAEs) by the Medical Dictionary for Drug Regulatory Activities (MedDRA) and severity according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03 (v4.03).

The Phase 2 part of the study is to determine if the combination of metronomic 5-FU, nab-paclitaxel, bevacizumab, leucovorin, and oxaliplatin at the RP2D defined in Phase 1 achieves a clinically meaningful improvement in 1 year survival rate over the historical control. Approximately 60 subjects are planned to be enrolled in the Phase 2 portion of the study.

Subjects may remain on treatment until disease progression, unacceptable toxicity, withdrawal of consent, physician decision, or death. The anticipated duration of the study (including Phase 1, Phase 2 and follow-up) is approximately 4 years.

Upon completion of the Phase 1 portion of the study, a decision not to proceed with the Phase 2 portion was taken by the Sponsor. The decision to terminate the study after Phase 1 was not based on any safety concerns that posed an unacceptable risk for this patient population and no safety issues have been identified.

Eligibility Criteria:
Inclusion Criteria:

A subject will be eligible for inclusion in this study only if all of the following criteria are met:

1. Male or female subject is between 18 and 65 years of age at the time of signing the Informed Consent Form (ICF).
2. Subject has definitive histologically or cytologically confirmed metastatic pancreatic adenocarcinoma.
3. Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1.
4. Subject has one or more tumors measurable by CT scan (or (MRI), if allergic to CT contrast media) as defined by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1.
5. Subject has the following blood counts / Hemoglobin (Hgb) at screening:

   * Absolute neutrophil count (ANC) ≥ 1.5 × 10\^9/L;
   * Platelet count ≥ 100,000/mm3 (100 × 10\^9/L);
   * Hgb ≥ LLN or 10 g/dL.
6. Subject has the following blood chemistry levels at screening:

   * AST (SGOT), ALT (SGPT) ≤ 2.5 x upper limit of normal range (ULN); if hepatic metastases present ≤ 5.0 x ULN
   * Total bilirubin ≤ 1.5 X ULN
   * Creatinine clearance ≥ 60 mL/min (by Cockroft-Gault)
   * Albumin ≥ 3.5 grams/dL7.
7. Females of childbearing potential (FOCBP) \[defined as a sexually mature woman who (1) have not undergone hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or (2) have not been naturally postmenopausal for at least 24 consecutive months (ie, has had menses at any time during the preceding 24 consecutive months)\] must:

   * Have a negative pregnancy test (β-human chorionic gonadotropin \[β -hCG\]) as verified by the study doctor within 72 hours prior to starting study therapy
   * Commit to complete abstinence from heterosexual contact, or agree to use medical doctor-approved contraception throughout the study without interruption; while receiving study medication and for at least 6 months following last dose of study IP.
8. Males must practice complete abstinence or agree to use a condom (even if he has undergone a successful vasectomy) during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 6 months following last dose of study IP.
9. Subject has no clinically significant abnormalities in urinalysis results at baseline.
10. Subject is able to adhere to the study visit schedule and other protocol requirements.
11. Subject understands the nature of the study, and has agreed to participate in the study, and has voluntarily signed the ICF prior to participation in any study-related activities.
12. Subject must consent to provide protocol-mandated tumor and blood samples for molecular analysis.
13. Subject is willing and able to adhere to the study visit schedule and other protocol requirements

Exclusion Criteria:

A subject will not be eligible for inclusion in this study if any of the following criteria apply:

1. Subject has received previous systemic chemotherapy or investigational therapy (other than that as a radiosensitizer concomitant with radiotherapy) for the treatment of pancreatic adenocarcinoma, including neo-adjuvant or adjuvant therapy.
2. Subject has known brain metastases unless previously treated and controlled for a minimum of 2 weeks prior to enrollment. Subject is not receiving corticosteroids with no evidence of cerebral edema.
3. Pre-existing peripheral neuropathy \> Grade 1
4. Subject with unstable stent.
5. History of malignancy in the last 3 years. Subjects with prior history of in situ cancer or basal or squamous cell skin cancer are eligible. Subjects with other malignancies are eligible if they were cured by surgery alone or surgery plus radiotherapy and have been continuously disease-free for at least 3 years.
6. Subject has active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy , defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment.
7. Subject has known historical or active infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C or subject receiving immunosuppressive or myelosuppressive medications that would, in the opinion of the Investigator, increase the risk of serious neutropenic complications.
8. Subject has undergone major surgery, other than diagnostic surgery (ie, surgery done to obtain a biopsy for diagnosis without removal of an organ), within 4 weeks prior to Day 1 of treatment in this study or surgical wound has not fully healed.
9. Subject has a history of allergy or hypersensitivity to any of the IP or any of their excipients, or the subject exhibits any of the events outlined in the Contraindications or Special Warnings and Precautions sections for and of the products' Summary of Product Characteristics or Prescribing Information.
10. History of connective tissue disorders (eg, lupus, scleroderma, arteritis nodosa).
11. Subject with a history of interstitial lung disease, history of slowly progressive dyspnea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis or multiple allergies that in the opinion of the Investigator may put them at increased risk of interstitial pneumonitis.
12. Subject with high cardiovascular risk, including, but not limited to:

    * uncontrolled hypertension
    * unstable angina
    * diagnosis of ischemic heart disease
    * heart disease of New York Heart Association functional classification ≥ 3 (see Appendix C)
    * prior history of hemorrhagic or thrombolytic stroke
    * prior exposure to anthracycline
    * history of peripheral artery disease (eg, claudication, Leo Buerger's disease)
    * any of the following within the prior 6 months
    * coronary stenting
    * myocardial infarction
    * coronary bypass surgery
13. Recent history of clinically significant hemoptysis.
14. Pregnant and nursing (lactating) women.
15. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
16. Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
17. Subject has any condition that confounds the ability to interpret data from the study.