A phase 1B study of dulanermin in combination with modified FOLFOX6 plus bevacizumab in patients with metastatic colorectal cancer.
OBJECTIVE
The study objectives were to evaluate the safety, tolerability, and preliminary efficacy of multiple doses of dulanermin in combination with modified FOLFOX6 and bevacizumab in previously untreated patients with locally advanced, recurrent, or metastatic colorectal cancer.


METHODS
A total of 23 patients received dulanermin at dosages of 4.5 or 9 mg/kg/d given on days 1 to 3 of each 14-day cycle along with standard dosing of modified FOLFOX6 plus bevacizumab. Dose-limiting toxicities, adverse events (AEs), maximum tolerated dose, and response according to Response Evaluation Criteria in Solid Tumors were assessed.


RESULTS
In the first cohort (3 patients given dulanermin at 4.5 mg/kg/d) and second cohort (6 patients given dulanermin at 9 mg/kg/day), no dose-limiting toxicities were observed. The subsequent 14 patients were treated with a dulanermin dosage of 9 mg/kg/d. Patients (N = 23) received 2 to 42 cycles of dulanermin (median 15). The most common grade 3 or 4 AEs were neutropenia (39%), hypertension (17%), peripheral neuropathy (17%), hand-foot syndrome (13%), and pulmonary embolism (13%). Three patients (13%) discontinued the study because of serious AEs. Overall, a best response of partial response was observed in 13 patients (57%) (9 confirmed, 4 unconfirmed), stable disease was observed in 7 patients (30%), and disease progression was observed in 3 patients (13%). The median progression-free survival was 9.9 months (95% confidence interval, 7.0-12.7).


CONCLUSIONS
Overall, the addition of dulanermin to first-line FOLFOX plus bevacizumab was well tolerated in patients with advanced colorectal cancer, with similar AEs that would be expected from FOLFOX plus bevacizumab. A randomized study is required to assess the clinical efficacy of dulanermin in this patient population.
David Geffen School of Medicine, University of California, Los Angeles, CA. Electronic address: zwainberg@mednet.ucla.edu.
Zev A
ZA
Wainberg
Wells A
WA
Messersmith
Parvin F
PF
Peddi
Amy V
AV
Kapp
Avi
A
Ashkenazi
Stephanie
S
Royer-Joo
Chia C
CC
Portera
Mark F
MF
Kozloff
D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage* / Q000009:adverse effects
D061067:Antibodies, Monoclonal, Humanized; D009944:Organoplatinum Compounds; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D000068258:Bevacizumab; D002955:Leucovorin; D005472:Fluorouracil
Apo2L/TRAIL; Apoptosis; Death receptor; Dulanermin; FOLFOX; Metastatic colorectal cancer