Randomized Phase 2 Study of DKN-01 Plus FOLFIRI/FOLFOX and Bevacizumab Versus FOLFIRI/FOLFOX and Bevacizumab as Second-line Treatment of Advanced Colorectal Cancer (DeFianCe)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Leap Therapeutics Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

22 Dec 2023 → 3 Jul 2025

Decision date (initial)

2023-02-10

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Leap Therapeutics, Inc.

External identifiers

EU CT number

2022-501465-40-00

ClinicalTrials.gov

NCT05480306

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacogenomic, Safety, Efficacy, Pharmacokinetic, Pharmacodynamic

To assess whether the addition of DKN-01 to the combination of FOLFIRI/FOLFOX and bevacizumab improves progression-free survival (PFS) according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) as assessed by the Investigator in all patients with advanced colorectal cancer and in patients with left sided advanced colorectal cancer compared to standard of care (SOC) [FOLFIRI/FOLFOX and bevacizumab].

Secondary objectives 2

1. To estimate the objective response rate (ORR) according to the RECIST v1.1 as assessed by the Investigator, the duration of response (DoR) and overall survival (OS) in advanced CRC patients treated with DKN-01 in combination with FOLFIRI/FOLFOX and bevacizumab compared to SOC as a second-line therapy
2. To characterize the frequency of toxicity ≥Grade 3 treatment-related adverse events (TRAE) associated with each of the treatment arms.

Conditions and MedDRA coding

Colorectal Cancer

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. 1. Histologically proven diagnosis of advanced colorectal adenocarcinoma (by local laboratory and local clinical guidelines) with documented objective radiographic or symptomatic disease progression following first-line systemic therapy with any fluoropyrimidine-based regimen for advanced disease (except FOLFOXIRI, see exclusion #3). • 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 and can understand and agree to comply with the requirements of the study and the schedule of assessments
3. Age ≥18 years in North America or ≥19 years in the Republic of Korea on the day of signing the informed consent form
4. Presence of at least one measurable lesion assessed by CT and/or MRI according to RECIST 1.1. (A lesion in an area subjected to prior loco-regional therapy, including previous radiotherapy, is not considered measurable unless there has been demonstrated progression in the lesion since the therapy as defined by RECIST v1.1.)
5. Sufficient tumor tissue for mandatory pre-treatment evaluation (fresh biopsy [preferred], or archived tissue block specimen).
6. ECOG performance status ≤1 within 7 days of first dose of study drug
7. Acceptable liver function: a. Total bilirubin ≤1.5 times upper limit of normal (ULN) (if Gilbert’s disease present, then ≤3.0 times ULN is allowed). b. AST and ALT, ≤2.5 times ULN (if liver metastases are present, then ≤5 × ULN is allowed).
8. Acceptable renal function: a. Serum creatinine ≤1.5 × ULN or estimated glomerular filtration rate ≥30 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology Collaboration equation
9. Acceptable hematologic status (in the Republic of Korea patients must not have required blood transfusion or growth factor support within 14 days before sample collection at screening for the following): a. Absolute neutrophil count (ANC) ≥1.5 × 109/L. b. Platelets ≥100 × 109/L c. Hemoglobin ≥9 g/dL
10. Acceptable coagulation status: a. Prothrombin time/activated partial thromboplastin time ≤1.2 × ULN (unless receiving anticoagulation therapy, if receiving anticoagulation therapy, eligibility will be based upon international normalized ratio (INR), see (b) below. b. INR ≤1.5 (unless receiving anticoagulation therapy) If receiving anticoagulant: INR ≤3.0 and no active bleeding, (i.e., no clinically significant bleeding within 14 days prior to first dose of study drugs).
11. Females of childbearing potential must be willing to use a highly effective method of birth control for the duration of the study, and for at least 6 months after the last dose of study drugs and have a negative urine or serum pregnancy test within 7 days before first dose of study drugs
12. Non-sterile males must be willing to use a highly effective method of birth control for the duration of the study and for at least 6 months after the last dose of study drugs. Female partners of male patients should also use a highly effective form of contraception if they are of childbearing potential. a. A sterile male is defined as one for whom azoospermia has been previously demonstrated in a semen sample examination as definitive evidence of infertility. b. Males with known “low sperm counts” (consistent with “sub-fertility”) are not to be considered sterile for purposes of this study

Exclusion criteria 32

1. Microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) and/or BRAF V600E mutation positive colorectal cancer
2. Any active malignancy ≤2 years before first dose of study drug, with the exception of the specific cancer under investigation in this study and any locally recurring cancer that has been treated curatively (e.g., resected basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast).
3. Uncontrolled diabetes or >Grade 1 laboratory test abnormalities in potassium, sodium, or corrected calcium despite standard medical management or ≥Grade 3 hypoalbuminemia within 14 days before first dose of study drug
4. Uncontrolled arterial hypertension defined by blood pressure >150 mmHg systolic and/or 100 mmHg diastolic at rest despite appropriate medical therapy within 28 days before first dose of study drug.
5. Proteinuria, as demonstrated by >1.5 gram of protein in a 24-hour urine collection. All patients with ≥2+ protein on dipstick urianalysis at baseline must undergo 24-hr urine collection for protein.
6. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent drainage within 7 days prior to first dose of study drug (the cytological confirmation of any effusion is permitted).
7. Clinically significant anorexia (CTCAE ≥Grade 2) within 7 days prior to first dose of study drug.
8. Severe chronic or active infections requiring systemic antibacterial, antifungal, or antiviral therapy, including tuberculosis infection within 14 days of first dose of study drug.
9. Prior allogeneic stem cell transplantation or organ transplantation
10. Any of the following cardiovascular risk factors: a. Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily living within 28 days before first dose of study drug. b. Pulmonary embolism within 28 days before first dose of study drug. c. Any history of acute myocardial infarction within 6 months before first dose of study drug. d. Any history of heart failure meeting New York Heart Association Classification III or IV within 6 months before first dose of study drug. e. Any event of ventricular arrhythmia ≥Grade 2 in severity within 6 months before first dose of study drug. f. Any history of cerebrovascular accident, including transient ischemic attack, within 6 months before first dose of study drug. g. Clinically significant peripheral artery disease
11. Evidence of bleeding diathesis or significant coagulopathy
12. Prior therapy with an anti-DKK1 agent
13. Any episode of syncope or seizure within 28 days before first dose of study drug
14. Fridericia-corrected QT interval >470 msec (female) or >450 (male), or history of congenital long QT syndrome. Any ECG abnormality that in the opinion of the Investigator would preclude safe participation in the study; patients with pacemakers where QTc is not a reliable measure will require an evaluation by a cardiologist to exclude co-existing cardiac conditions which would prohibit safe participation in the study.
15. Known to be human immunodeficiency virus (HIV) positive unless HIV RNA is undetected, have hepatitis B surface antigen, or hepatitis C antibodies unless hepatitis C virus ribonucleic acid (RNA) is undetected/negative
16. Serious nonmalignant disease or other circumstance that could compromise protocol objectives or place the patient at risk in the opinion of the Investigator and/or the Sponsor
17. History of osteonecrosis of the hip or have evidence of structural bone abnormalities in the proximal femur on magnetic resonance imaging (MRI) scan that are symptomatic and clinically significant. Degenerative changes of the hip joint are not exclusionary. Screening of asymptomatic patients is not required
18. Known osteoblastic bony metastasis. Screening of asymptomatic patients without a history of metastatic bony lesions is not required
19. Serious psychiatric or medical conditions that could interfere with treatment
20. Toxicities (as a result of prior anticancer therapy) that have not recovered to baseline or stabilized, except for AEs not considered a likely safety risk (e.g., alopecia, neuropathy and specific laboratory abnormalities).
21. Administration of a live vaccine within 28 days before first dose of study drug. Note: Seasonal vaccines for influenza or COVID-19 vaccines are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and are not allowed
22. Prior therapy with FOLFOXIRI
23. Underlying medical conditions (including laboratory abnormalities) or alcohol or drug abuse or dependence that will be unfavorable for the administration of study drug, or affect the explanation of drug toxicity or AEs, or result in insufficient or impaired compliance with study conduct
24. Women who are pregnant or are breastfeeding
25. Concurrent participation in another therapeutic clinical study Note: Concurrent participation in observational or non-interventional studies is allowed. In addition, patients who have completed active treatment in a clinical study and are in the follow-up period can be enrolled in this study
26. Prior therapy with an anti-programmed cell death protein ligand-1 [PD-(L)1] or anti-programmed cell death protein ligand-2 (PD-L2) or any other antibody or drug specifically targeting T-cell co-stimulation or coinhibitory checkpoint pathways in any treatment setting (including adjuvant/neoadjuvant).
27. Systemic anti-cancer therapy within 28 days prior to first dose of study drug
28. Major surgery within 28 days prior to first dose of study drug
29. Treatment with radiation therapy within 14 days prior to first dose of study drug
30. Active leptomeningeal disease or uncontrolled brain metastases. Patients with equivocal findings or with confirmed brain metastases are eligible for the study provided that they are asymptomatic and radiologically stable without the need for corticosteroid treatment or seizure prophylaxis for ≥4 weeks before first dose of study drug.
31. History of gastrointestinal perforation and/or fistulae within 6 months prior to first dose of study drug, clinically significant bleeding from the gastrointestinal tract, or clinically significant bowel obstruction (CTCAE ≥Grade 2) within 28 days before first dose of study drug.
32. Known UGT1A1 deficiency

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression free survival (PFS), as determined by the Investigator per RECIST v1.1 of DKN-01 plus standard care (SOC) versus SOC in all patients with advanced colorectal cancer and in patients with left-sided advanced colorectal cancer.

Secondary endpoints 4

1. Objective response rate (ORR), as determined by the Investigator per RECIST v1.1 of DKN-01 plus SOC versus SOC
2. Duration of response (DoR), as determined by the Investigator per RECIST v1.1 of DKN-01 plus SOC versus SOC
3. Overall survival (OS) with DKN-01 plus SOC versus SOC.
4. Incidence of ≥Grade 3 related treatment-related adverse events (TRAEs)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Leap Therapeutics Inc.

Sponsor organisation

Leap Therapeutics Inc.

Address

47 Thorndike Street Suite B1-1

City

Cambridge

Postcode

02141-1799

Country

United States

Scientific contact point

Organisation

Leap Therapeutics Inc.

Contact name

Study Director

Public contact point

Organisation

Leap Therapeutics Inc.

Contact name

Study Director

Third parties 18

Locations

1 EU/EEA country · 5 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 18 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

10 submissions — initial application plus substantial / non-substantial modifications