Overview
This is a Phase 2 randomized, open-label, two-part, multicenter study with a safety run-in to evaluate efficacy and safety of DKN-01 plus FOLFIRI/FOLFOX and bevacizumab versus standard of care (SOC) [FOLFIRI/FOLFOX and bevacizumab] as second-line treatment of advanced CRC patients.
Description
This is a Phase 2 randomized, open-label, two-part, multicenter study with a safety run-in to evaluate efficacy and safety of DKN-01 plus FOLFIRI/FOLFOX and bevacizumab versus standard of care (SOC) [FOLFIRI/FOLFOX and bevacizumab] as second-line treatment of advanced CRC patients.
In Parts A and B, approximately 200 evaluable adult advanced CRC patients with measurable disease (RECIST v1.1) who have radiographically progressed during or following 1 line of systemic treatment will be enrolled in the study.
The study consists of a Screening Period, a Treatment Period, a Safety Follow-up Period (SFUP) and a Long-Term Follow-up Period (LTFU). Patients will be followed in the SFUP for approximately 30 days (+7 days) after the last administration of study drug and then enter the LTFU period to be followed for survival and subsequent therapies. Additionally, patients that ended study treatment for a reason unrelated to progressive disease [PD] will also be followed for disease progression in the LTFU period.
Eligibility
Adult patients with advanced CRC with measurable disease (RECIST v1.1) who have
radiographically progressed during or following one line of systemic treatment will be
enrolled in the study.
Inclusion Criteria:
Patients meeting all of the following criteria will be considered eligible for study entry:
1. Disease progression following first-line systemic therapy with any
fluoropyrimidine-based regimen for advanced disease (except FOLFOXIRI, see exclusion
criteria).
• Patients may have received prior neoadjuvant or adjuvant therapy which could have
included irinotecan or oxaliplatin. If progression has occurred within 12 months from
last dose of neoadjuvant or adjuvant treatment, this regimen will be considered as the
one line of systemic therapy for advanced disease.
- If assigned to receive FOLFIRI, patient may have received no prior irinotecan as
part of first-line systemic therapy.
- If assigned to receive FOLFOX, patient may have received no prior oxaliplatin as
part of first line systemic therapy.
- Prior treatment with an anti-VEGF or anti-EGFR therapy is allowed as first-line
and/or maintenance systemic therapy.
2. Able to provide written informed consent for any study specific procedures.
3. One or more tumors measurable on radiographic imaging as defined by RECIST 1.1
4. Sufficient tumor tissue for mandatory pre-treatment evaluation (fresh biopsy
[preferred], or archived tissue block specimen).
5. ECOG performance status ≤1 within 7 days of first dose of study drug. Acceptable
liver, renal, hematologic, and coagulation function
6. Females of childbearing potential and male partners of female patients must agree to
use adequate contraception during the study and for 6 months after their last dose of
study drug
Exclusion Criteria:
Patients meeting any of the following criteria are not eligible for study entry:
1. Diagnosis of Microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR)
and/or BRAF V600E mutation positive colorectal cancer.
2. Prior therapy with an anti-DKK1, FOLFOXIRI, PD-1, anti-PD-L1, anti-PD-L-2 or any other
antibody or drug specifically targeting T-cell co-stimulation or coinhibitory
checkpoint.
3. Systemic anti-cancer therapy within 28 days prior to first dose of study drug.
4. Major surgery within 28 days prior to first dose of study drug.
5. Prior radiation therapy within 14 days prior to first dose of study drug.
6. Active leptomeningeal disease or uncontrolled brain metastases.
7. Any active cancer ≤ 2 years before first dose of study drug with the exception of
cancer for this study.
8. New York Heart Association Class III or IV cardiac disease, myocardial infarction
within the past 6 months, or unstable arrhythmia.
9. Fridericia-corrected QT interval (QTcF) > 470 msec (female) or history of congenital
long QT syndrome.
10. Active, uncontrolled bacterial, viral, or fungal infections, within 14 days of study
entry requiring systemic therapy.
11. Serious nonmalignant disease
12. Pregnant or nursing.
13. History of osteonecrosis of the hip or have evidence of structural bone abnormalities
in the proximal femur on MRI scan that are symptomatic and clinically significant.
14. Known osteoblastic bony metastasis.
15. Major surgery 28 days prior to study entry.
16. Prior radiation therapy within 14 days prior to study entry.
17. Significant allergy to a pharmaceutical therapy that, in the opinion of the
Investigator, poses an increased risk to the patient.
18. Active substance abuse.
19. Known dihydropyrimidine dehydrogenase deficiency.
20. Administration of a live vaccine within 28 days before first dose of study drug