A Phase 2 Trial of SCO-101 in Combination With FOLFIRI for Patients With Metastatic Colorectal Cancer (mCRC) With Acquired Resistance to FOLFIRI

This study evaluates the combination of SCO-101 to FOLFIRI for the treatment of metastatic colorectal cancer patients who have developed resistance to FOLFIRI treatment. The study is divided in two parts, where the first part evaluates the safety and toxicity of increasing doses of SCO-101 in combination with FOLFIRI at the same dose as the patient has previously developed resistance to. The second part of the study evaluates the safety and efficacy of the combination of FOLFIRI and SCO-101 at the dose level established in the first part.

This is a multi-center, open label, dose escalation, Phase 2 study of SCO-101 in combination with FOLFIRI in up to 50 mCRC patients. All patients included have previously had effect from treatment with FOLFIRI, but have now progressed (i.e. treatment failure due to acquired resistance).

FOLFIRI is a key anti-cancer chemotherapeutic combination in the treatment of several solid tumor cancers, e.g. colorectal cancer. Cancer resistance to FOLFIRI exposure is a well known phenomenon and can often be attributed to upregulation of cellular efflux pumps, e.g. ATP-Binding Cassette (ABC)G2 and ABCB1, involved in the efflux of the chemotherapeutic agents from the cancer cells and resulting in treatment failure.

SCO-101 is an inhibitor of ATP-Binding Cassette (ABC) efflux pumps and SRPK1 kinase which is responsible for phosphorylation of splicing factors, a key element involved in tumour growth.

The combination of SCO-101 with FOLFIRI is expected to inhibit the active efflux of chemotherapy molecules from the cancer cell thereby re-sensitizing it to the chemotherapeutic agents.

Eligibility Criteria:
Inclusion Criteria: Subjects are required to meet all of the following criteria for enrollment into the applicable stage (stage 1, stage 2 or stage 3) of the study:

1. Ability to understand and willingness to provide written informed consent before any trial-related activities.
2. Age 18 years or older.
3. Histologically verified colorectal adenocarcinoma.
4. Non-resectable mCRC in patients A. Stage 1 only: with or without known BRAF, KRAS or repair enzyme mutations. B. Stage 2 and stage 3 only: without known BRAF, KRAS or repair enzyme mutations
5. A. Stage 1 only: Documented progressive disease on FOLFIRI treatment regimen (with or without antiangiogenetic and EGFR inhibitory biological treatment).

   B. Stage 2 and stage 3 only: Documented progressive disease with a prior benefit (SD for more than 16 weeks, or CR or PR) on FOLFIRI treatment regimen (with or without antiangiogenetic and EGFR inhibitory biological treatment).
6. Maximum reduction of 33% in prior dose of FOLFIRI.
7. No indication for treatment with an oxaliplatin-containing treatment regimen. The patient may have received oxaliplatin treatment after treatment with FOLFIRI.
8. A. Stage 1 only: Evaluable disease by CT scan or MRI. B. Stage 2 and stage 3 only: Measurable disease by CT scan or MRI, according to RECIST. 1.1.
9. Performance status of ECOG ≤ 1.
10. Recovered to Grade 1 or less from prior surgery or acute toxicities of prior radiotherapy or treatment with cytotoxic or biologic agents.
11. ≥ 2 weeks must have elapsed since any prior surgery.
12. Adequate conditions as evidenced by the following clinical laboratory values:

    * Absolute neutrophils count (ANC) ≥ 1.5 x 109/L
    * Haemoglobin ≥ 6.0 mmol/L
    * Platelets ≥ 100 x 109 /L
    * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN\*
    * Total serum bilirubin ≤ 1.0 ULN\*\*
    * Alkaline phosphatase ≤ 2.5 x ULN\*
    * Creatinine ≤ 1.5 ULN
    * eGFR within normal limits.
    * Adequate blood clothing function as defined by the International Normalized Ratio (INR) ≤ 1.2;
13. Life expectancy equal to or longer than 3 months.
14. Sexually active males and females of child-producing potential must use highly effective contraception (intrauterine devices, hormonal contraceptives (contraceptive pills, implants, transdermal patches, hormonal vaginal devices or injections with prolonged release)) for the study duration and at least 6 months after the last dose of study drug.
15. Signed informed consent.

    * AST is not mandatory. In case of known liver metastases with ALT and AST ≤ 5 x ULN and/or alkaline phosphatase ≤ 5 x ULN: Patients who do not conform to the transaminase and/or alkaline phosphatase inclusion criteria, but who by the PI are considered in good PS and otherwise eligible for inclusion, and where the transaminase and/or alkaline phosphatase levels are considered elevated due to other reasons than deteriorated lever capacity, may be considered for inclusion based on conferred agreement between PI and sponsor.

      * Unconjugated bilirubin may be measured as the difference between total bilirubin and conjugated bilirubin.

Exclusion Criteria: Subjects meeting any of the following criteria will be excluded from enrollment:

1. Concurrent chemotherapy, radiotherapy, or other investigational drug except non-disease related conditions (e.g. insulin for diabetes) during study period.
2. Malabsorption syndrome or previous surgeries with resection of the stomach or small intestine, whereby absorption of SCO-101 may be affected. This includes patients with ileostomy.
3. Difficulty in swallowing tablets.
4. Clinical symptoms of CNS metastases requiring steroids.
5. Any active infection requiring parenteral or oral antibiotic treatment.
6. Known HIV positivity.
7. Known active hepatitis B or C.
8. Clinical significant (i.e. active) cardiovascular disease:

   * Stroke within ≤ 6 months prior to day 1
   * Transient ischemic attach (TIA) within ≤ 6 months prior to day 1
   * Myocardial infarction within ≤ 6 months prior to day 1
   * Unstable angina
   * New York Heart Association (NYHA) Grade II or greater congestive heart failure (CHF)
   * Serious cardiac arrhythmia requiring medication
9. Mental status is not fit for clinical study or CNS disease including symptomatic epilepsy.
10. Other medications or conditions that in the Investigator's opinion would contraindicate study participation of safety reasons or interfere with the interpretation of study results. Other severe medical conditions, including serious heart disease, unstable diabetes, uncontrolled hypercalcemia, clinically active infections or previous organ transplants. Participation in another clinical trial with experimental medication within 30 days prior to registration.
11. Known hypersensitivity to irinotecan, 5-FU or capecitabine
12. Pregnant women or women who are breastfeeding.