A phase I study of indoximod in patients with advanced malignancies.

Abstract

PURPOSE:

Indoximod is an oral inhibitor of the indoleamine 2,3-dioxygenase pathway, which causes tumor-mediated immunosuppression. Primary endpoints were maximum tolerated dose (MTD) and toxicity for indoximod in patients with advanced solid tumors. Secondary endpoints included response rates, pharmacokinetics, and immune correlates.

EXPERIMENTAL DESIGN:

Our 3+3 phase I trial comprised 10 dose levels (200, 300, 400, 600, and 800 mg once/day; 600, 800, 1200, 1600, and 2000 mg twice/day). Inclusion criteria were measurable metastatic solid malignancy, age ≥18 years, and adequate organ/marrow function. Exclusion criteria were chemotherapy ≤ 3 weeks prior, untreated brain metastases, autoimmune disease, or malabsorption.

RESULTS:

In 48 patients, MTD was not reached at 2000 mg twice/day. At 200 mg once/day, 3 patients previously treated with checkpoint inhibitors developed hypophysitis. Five patients showed stable disease >6 months. Indoximod plasma AUC and Cmax plateaued above 1200mg. Cmax (~12 μM at 2000 mg twice/day) occurred at 2.9 hours, and half-life was 10.5 hours. C reactive protein (CRP) levels increased across multiple dose levels.

CONCLUSIONS:

Indoximod was safe at doses up to 2000 mg orally twice/day. Best response was stable disease >6 months in 5 patients. Induction of hypophysitis, increased tumor antigen autoantibodies and CRP levels were observed.

• Authors: Hatem H Soliman, Susan E Minton, Hyo Sook Han, Roohi Ismail-Khan, Anthony Neuger, Fatema Khambati, David Noyes, Richard Lush, Alberto A Chiappori, John D Roberts, Charles Link, Nicholas N Vahanian, Mario Mautino, Howard Streicher, Daniel M Sullivan, Scott J Antonia
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 16 Pg. 22928-38 (Apr 19 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27008709 (Publication Type: Clinical Trial, Phase I, Journal Article)

Chemical References

• Antineoplastic Agents
• Indoleamine-Pyrrole 2,3,-Dioxygenase
• Tryptophan
• 1-methyltryptophan

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (administration & dosage, adverse effects)
• Dose-Response Relationship, Drug
• Female
• Humans
• Indoleamine-Pyrrole 2,3,-Dioxygenase (antagonists & inhibitors)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (drug therapy)
• Tryptophan (administration & dosage, adverse effects, analogs & derivatives)
• Young Adult