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

• ClinicalTrials.gov Identifier: NCT04247256
• Recruitment Status: Unknown
• First Posted: January 30, 2020
• Last Update Posted: March 2, 2022
• Sponsor: Scandion Oncology A/S
• Collaborator: TFS Trial Form Support
• Information provided by (Responsible Party): Scandion Oncology A/S

Tracking Information

• First Submitted Date: January 23, 2020
• First Posted Date: January 30, 2020
• Last Update Posted Date: March 2, 2022
• Actual Study Start Date: May 14, 2020
• Estimated Primary Completion Date: June 30, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 29, 2020)

• Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] of combination of SCO-101 and FOLFIRI [ Time Frame: 4 cycles (each cycle is 2 weeks) ]
  Safety and tolerability by assessing the number, frequency, and severity of adverse events (AEs) collected from the time of first treatment until four weeks after end of treatment to evaluate safety of SCO-101 in combination with FOLFIRI determined according to CTCAE version 5.0
• Maximum Tolerated Dose [ Time Frame: 1 cycle (each cycle is 2 weeks) ]
  Maximum tolerated dose (MTD) by evaluation of dose-limiting toxicities (DLTs) of SCO-101 in combination with FOLFIRI evaluated by CTCAE v. 5.0 (part 1 only)
• Objective Response Rate [ Time Frame: 4 cycles (each cycle is 2 weeks) ]
  Objective response rate (ORR) defined as CR and PR using the RECIST v. 1.1

Original Primary Outcome Measures (submitted: January 28, 2020)

• Safety and Toxicity of combination of SCO-101 and FOLFIRI [ Time Frame: 4 cycles (each cycle is 2 weeks) ]
  Safety and tolerability by assessing the number, frequency, and severity of adverse events (AEs) collected from the time of first treatment until four weeks after end of treatment to evaluate safety of SCO-101 in combination with FOLFIRI determined according to CTCAE version 5.0
• Maximum Tolerated Dose [ Time Frame: 1 cycle (each cycle is 2 weeks) ]
  Maximum tolerated dose (MTD) by evaluation of dose-limiting toxicities (DLTs) of SCO-101 in combination with FOLFIRI evaluated by CTCAE v. 5.0 (part 1 only)
• Objective Response Rate [ Time Frame: 4 cycles (each cycle is 2 weeks) ]
  Objective response rate (ORR) defined as CR and PR using the RECIST v. 1.1

Current Secondary Outcome Measures (submitted: January 28, 2020)

• Progression Free Survival (PFS) [ Time Frame: Start of treatment to first objective sign of progression, assessed up to 100 months ]
  Progression free survival (PFS) defined as time in months from the date of first study treatment to the date of disease progression or death from any cause, whichever comes first.
• Duration of Response [ Time Frame: From first response to progression, assessed up to 100 months ]
  Duration of response (from first response to progression)
• Duration of Response compared to prior Duration of response [ Time Frame: From first response to progression, assessed up to 100 months ]
  Duration of response (DOR) after administration of SCO-101 compared to DOR from patients initial FOLFIRI treatment regimen (without SCO-101).
• Overall Survival [ Time Frame: Up to 2 years ]
  Overall survival (OS) defined as time in months from the date of first study treatment to the date of death;
• Clinical Benefit Rate [ Time Frame: from benefit (CR, PR or SD > 16 weeks) to progression, assessed up to 100 months ]
  Clinical benefit rate (CBR) defined as the number of patients obtaining CR, PR, or SD > 16 weeks according to RECIST v.1.1.
• Pharmacokinetic profile of SCO-101 in combination with FOLFIRI [ Time Frame: First week of administration (study part 1 only) ]
  Pharmacokinetic profile of SCO-101 in blood samples
• ctDNA [ Time Frame: First 4 cycles of treatment (each cycle is 2 weeks) (study part 2 only) ]
  Change in ctDNA from baseline (prior first dose of SCO-101) until first CT scan
• Biomarker UGT1A1 [ Time Frame: Baseline (pre-treatment (all study parts)) ]
  Evaluation of Selected UGT1A1 polymorphism in a pre-treatment blood sample
• Biomarker IndiTreat(TM) [ Time Frame: Baseline (pre-treatment tumor biopsy (study part 2 only)) ]
  Efficacy of IndiTreat® to predict clinical response to SCO-101 treatment in combination with FOLFIRI from a tumor biopsy sample.
• Biomarkers ABCG2, ABCB1, SRPK1 [ Time Frame: Baseline (Pre-treatment biopsy (study part 2 only)) ]
  Efficacy of molecular biomarkers ABCB1/ABCG2/SRPK1 determined by immunohistochemistry to predict clinical response to SCO-101 treatment

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Phase 2 Trial of SCO-101 in Combination With FOLFIRI for Patients With Metastatic Colorectal Cancer (mCRC) With Acquired Resistance to FOLFIRI
• Official Title: An Open-label Phase II Prospective Clinical Trial to Investigate Safety, Tolerability, Maximum Tolerated Dose and Anti-tumor Effect for SCO-101 in Combination With FOLFIRI as a Safe and Efficient Treatment Modality in Metastatic or Advanced Colorectal Cancer (mCRC) Patients With Acquired FOLFIRI Resistant Cancer Disease.
• Brief Summary: 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.

Detailed Description

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.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:

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.

Cohorts of FOLFIRI-resistant mCRC patients will be treated with SCO-101 in combination with FOLFIRI . Patients to be enrolled should previously have had either complete response (CR), partial response (PR), or stable disease (SD) (>16 weeks) on FOLFIRI.

The study is separated in two parts. Part 1 is a dose escalation part with a standard 3+3 design, designed to evaluate the safety and toxicity of the combination of SCO-101 and FOLFIRI, and to identify the maximum tolerated dose (MTD). A maximum of 5 cohorts have been planned. Starting dose of SCO-101 is 150 mg (cohort 1) and maximum dose is 350 mg (cohort 5).

Part 2 is the efficacy part, where patients are treated with the MTD dose identified in the first part and evaluated for efficacy and safety of the combination SCO-101 plus FOLFIRI.

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Metastatic Colorectal Cancer

Intervention

• Drug: FOLFIRI Protocol
  FOLFIRI standard treatment on day 5 to 7 (both days included) of a 14 day period. repeated bi-weekly
• Drug: SCO-101
  Investigational Medicinal Product, oral tablet administered on day 1 to 6 (both days included) of a 14 day period. repeated bi-weekly

Study Arms

Experimental: Treatment arm

SCO-101 in combination with FOLFIRI

Interventions:

• Drug: FOLFIRI Protocol
• Drug: SCO-101

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: January 28, 2020): 35
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: June 30, 2022
• Estimated Primary Completion Date: June 30, 2022 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Denmark, Germany, Spain

Administrative Information

• NCT Number: NCT04247256
• Other Study ID Numbers: SCO101-001
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Scandion Oncology A/S
• Original Responsible Party: Same as current
• Current Study Sponsor: Scandion Oncology A/S
• Original Study Sponsor: Same as current
• Collaborators: TFS Trial Form Support

Investigators

• Principal Investigator: Jacob Hagen Vasehus Schou, MD; Herlev and Gentofte Hospital

• PRS Account: Scandion Oncology A/S
• Verification Date: December 2021