A phase 1/2 multi-center investigation of nab-sirolimus (also known as ABI-009, nab-rapamycin) in combination with mFOLFOX6 and Bevacizumab as first-line therapy in patients with metastatic colorectal cancer

This study is a prospective phase 1/2, single arm, open-label, multi-institutional study to identify the RP2D and determine the efficacy and safety profile of nab-sirolimus administered as first-line therapy in combination with mFOLFOX6 and bevacizumab in patients with metastatic colorectal cancer.

Inclusion Criteria:

1. Patients with histologically confirmed advanced or metastatic colorectal cancers for whom chemotherapy is indicated.

2. Patients must not have had prior chemotherapy for advanced or metastatic disease. Patients could have received adjuvant chemotherapy or adjuvant chemo-radiotherapy.

3. Patients must have at least 1 measurable site of disease according to RECIST v1.1 that has not been previously irradiated. If the patient has had previous radiation to the marker lesion(s), there must be radiological evidence of progression since the radiation.

4. Eligible patients, 18 years or older, with Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2.

5. Patients must not have been previously treated with an mTOR inhibitor.

6. Adequate liver function:

   1. Total bilirubin ≤1.5 x upper limit of normal (ULN) mg/dL
   2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x ULN (<5 x ULN if the patient has liver metastases).

7. Adequate renal function:

   a. Serum creatinine ≤2 x ULN or creatinine clearance >50 cc/hr (Cockroft-Gault).

8. Adequate biological parameters:

   1. Absolute neutrophil count (ANC) ≥1.5 × 109/L
   2. Platelet count ≥100,000/mm3 (100 × 109/L)
   3. Hemoglobin ≥9 g/dL.

9. Fasting serum triglyceride ≤300 mg/dL; fasting serum cholesterol ≤350 mg/dL.

10. INR and PTT <1.5 x ULN (anticoagulation is allowed if target INR <1.5 on a stable dose of warfarin or on a stable dose of LMW heparin for >2 weeks at time of enrollment).

11. Minimum of 4 weeks since any major surgery, completion of radiation, or completion of all prior systemic anticancer therapy, and ≥6 months since adjuvant FOLFOX therapy (adequately recovered from the acute toxicities of any prior therapy, including neuropathy should be grade ≤1).

12. Male or non-pregnant and non-breast feeding female:

    • Females of child-bearing potential must agree to use effective contraception without interruption from 28 days prior to starting IP throughout 3 months after last dose of IP and have a negative serum pregnancy test (β -hCG) result at screening and agree to ongoing pregnancy testing during the course of the study, and after the end of study treatment. A second form of birth control is required even if she has had a tubal ligation.
    • Male patients must practice abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study and throughout 3 months after last dose of IP. A second form of birth control is required even if he has undergone a successful vasectomy.

13. Life expectancy of >3 months, as determined by the investigator.

14. Ability to understand and sign informed consent.

15. Willingness and ability to comply with scheduled visits, laboratory tests, and other study procedures.

Exclusion Criteria:

1. History of severe and uncontrolled allergic reactions to bevacizumab

2. Prior treatment with FOLFOX or bevacizumab within the preceding 4 weeks

3. Patients currently receiving or have received anticancer therapies within 4 weeks of the start of study treatment (including chemotherapy, radiation therapy, antibody based therapy, etc.)

4. Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or patients that may require major surgery during the course of the study

5. Chronic treatment with systemic steroids or another immunosuppressive agent; topical or inhaled corticosteroids are allowed

6. Recent infection requiring systemic anti-infective treatment that was completed ≤14 days prior to enrollment (with the exception of uncomplicated urinary tract infection or upper respiratory tract infection).

7. Patients who have any severe and/or uncontrolled medical or psychiatric conditions or other conditions that could affect their participation including:

   1. Known active uncontrolled or symptomatic central nervous system (CNS) metastases. A patient with controlled and asymptomatic CNS metastases may participate in this study. As such, the patient must have completed any prior treatment for CNS metastases ≥28 days (including radiotherapy and/or surgery) prior to start of treatment in this study and should not be receiving chronic corticosteroid therapy for the CNS metastases.
   2. Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤6 months prior to first study treatment, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease
   3. Pre-existing severely impaired lung function as defined as spirometry and DLCO that is 50% of the normal predicted value and/or O2 saturation that is 88% or less at rest on room air (Note: spirometry and PFTs not required to be performed unless clinically indicated).
   4. Uncontrolled diabetes as defined by fasting serum glucose >1.5x ULN or by HbA1c >8% despite adequate therapy.
   5. Any active (acute or chronic) or uncontrolled infection/ disorders.
   6. Nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with the study therapy. Note, controlled non-melanoma skin cancers, carcinoma in situ of the cervix, resected incidental prostate cancer, or other adequately treated carcinoma-in-situ may be eligible, after documented discussion with the sponsor / medical monitor.
   7. Known liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class C).

8. Patients with history of interstitial lung disease and/or pneumonitis, or pulmonary hypertension.

9. A known history of HIV seropositivity.

10. Active Hepatitis B or Hepatitis C. Note: A detailed assessment of Hepatitis B/C medical history and risk factors must be done at screening for all patients. HBV DNA and HCV RNA PCR testing are required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior HBV/HCV infection.

11. Patients with an active bleeding diathesis or on oral anti-vitamin K medication (except low dose Coumadin).

12. Use of strong inhibitors and inducers of CYP3A4 within the 14 days prior to receiving the first dose of ABI-009. Additionally, use of any known CYP3A4 substrates with narrow therapeutic window (such as fentanyl, alfentanil, astemizole, cisapride, dihydroergotamine, pimozide, quinidine, terfanide) within the 14 days prior to receiving the first dose of ABI-009.