A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of GS-6624 Combined with FOLFIRI as Second Line Treatment for Metastatic KRAS Mutant Colorectal Adenocarcinoma that Has Progressed Following a First Line Oxaliplatin- and Fluoropyrimidine-Containing Regimen.
This randomized Phase 2 study compares the additive efficacy of GS-6624 versus placebo in combination with FoLFiRi in subjects with metastatic KRaS mutant colorectal cancer. GS-6624 is a humanized igGB4B monoclonal antibody against human lysyl oxidase-like molecule 2 (LoXL2). There will be a screening period of up to 28 days to assess subject eligibility to enroll in the trial including confirmation of metastatic KRaS mutant colorectal adenocarcinoma. Computed tomography (CT) or magnetic resonance imaging (MRi) scans of the tumor will be required within 28 days of the first dose of GS-6624 or placebo to assess subject disease status prior to treatment. The treatment phase of this study will be
comprised of 2 sequential parts. Part a will be an open label treatment phase conducted in the first 10 eligible subjects and Part B will be a double-blind treatment phase conducted on the subsequent 255 subjects. The end of this trial
is defined as the date of the last study visit of the last study subject.
Subjects must meet all of the following inclusion criteria to be eligible for participation in
1. Subject has signed informed consent
2. KRAS mutated, histologically confirmed adenocarcinoma of the colon or rectum that is not amenable to complete surgical resection.
3. The subject must have received first-line combination therapy containing oxaliplatin,
and a fluoropyrimidine with or without bevacizumab for metastatic disease and must not be a candidate for further oxaliplatin, meeting one of the following criteria:
* Experienced radiographic disease progression during first-line therapy, or
* Experienced radiographic disease progression within 6 months after the last dose
of first-line therapy, or
* Discontinued part or all of first-line therapy due to toxicity and experienced
radiographic disease progression within 6 months after the last dose of first-line
* Experienced radiographic disease progression following first line therapy and not
be a candidate for therapy with additional oxaliplatin.
4. Stage IV disease.
5. ECOG 0-2.
6. Age > 18 years.
7. Estimated life expectancy > 3 months.
8. Measurable disease per RECIST (ver. 1.1), defined with all of following criteria:
1. Lesions accurately measured in at least 1 dimension
2. The longest diameter in the plane of measurement is to be recorded
3. A minimum size of 10 mm if CT slice thickness <= 5 mm; if thickness is > 5 mm then
the minimum size of measurable lesions should be twice slice thickness.
9. Women of childbearing potential must agree to use one medically approved (i.e.,
mechanical or pharmacological) contraceptive measure and have their partners agree to an additional barrier method of contraception for the duration of the study and for
90 days after the last administration of study drug.
10. Male subjects must agree to use protocol-recommended methods of contraception during heterosexual intercourse and avoid
sperm donation for the duration of this study and for 90 days after the last
administration of study drug.
11. Adequate hematologic function:
* neutrophils >= 1.5 x 109/L
* platelets >= 100 x 109/L
* hemoglobin >= 9 g/dL.
12. Coagulation: International Normalized Ratio (INR) <= 1.6 (unless receiving
anticoagulation therapy). Patients on full-dose anticoagulation must be on a stable
dose (minimum duration 14 days) of oral anticoagulant or low molecular weight
heparin. If receiving warfarin, the patient must have an INR <= 3.0 and no active
bleeding (ie, no bleeding within 14 days prior to first dose of study therapy).
13. Adequate hepatic function:
* Direct or total bilirubin <= 1.5 x upper limit of normal (ULN).
* ALT and AST <= 2.5x ULN, in case of liver metastases <= 5x ULN.
14. Serum creatinine <= 1.5x ULN or creatinine clearance >= 60 ml/minute as calculated by the Cockroft-Gault method
15. No major operations within 4 weeks prior to treatment start.
16. No relevant toxicities due to prior medical treatment at time of study entry.