A first in man phase I trial of the oral immunomodulator, indoximod, combined with docetaxel in patients with metastatic solid tumors.

Abstract

BACKGROUND:

Indoleamine 2,3-dioxygenase (IDO) is an enzyme that tumors use to create a state of immunosuppression. Indoximod is an IDO pathway inhibitor. Preclinical studies demonstrated that indoximod combined with chemotherapy was synergistic in a mouse model of breast cancer. A phase I 3+3 trial was designed to study the combination of docetaxel and indoximod.

METHODS:

Docetaxel was administered at 60 mg/m2 intravenously every 3 weeks dose levels 1-4 and 75 mg/m2 for dose level 5. Indoximod was given at 300, 600, 1000, 2000, and 1200 mg PO twice daily continuously for levels 1-5, respectively. Serum drug levels were measured.

RESULTS:

Twenty-seven patients were treated, with 22 evaluable for response. DLTs included grade 3 dehydration (level 1), hypotension(level 4), mucositis (level 4) and grade 5 enterocolitis (level 2). Dose level 5 is the recommended phase II dose. The most frequent adverse events were fatigue (58.6%), anemia (51.7%), hyperglycemia (48.3%), infection (44.8%), and nausea (41.4%). There were 4 partial responses (2 breast, 1 NSCLC, 1 thymic tumor). No drug-drug interactions were noted.

CONCLUSIONS:

Docetaxel plus indoximod was well tolerated with no increase in expected toxicities or pharmacokinetic interactions. It was active in a pretreated population of patients with metastatic solid tumors.

• Authors: Hatem H Soliman, Erica Jackson, Tony Neuger, E Claire Dees, R Donald Harvey, Hyo Han, Roohi Ismail-Khan, Susan Minton, Nicholas N Vahanian, Charles Link, Daniel M Sullivan, Scott Antonia
• Journal: Oncotarget (Oncotarget) Vol. 5 Issue 18 Pg. 8136-46 (Sep 30 2014) ISSN: 1949-2553 [Electronic] United States
• PMID: 25327557 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Immunologic Factors
• Taxoids
• Docetaxel
• Tryptophan
• 1-methyltryptophan

Topics

• Administration, Intravenous
• Administration, Oral
• Adult
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, blood, pharmacokinetics, therapeutic use)
• Docetaxel
• Drug Administration Schedule
• Drug Monitoring
• Female
• Florida
• Humans
• Immunologic Factors (administration & dosage)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasm Metastasis
• Neoplasms (drug therapy, pathology)
• Taxoids (administration & dosage)
• Time Factors
• Treatment Outcome
• Tryptophan (administration & dosage, analogs & derivatives)