Study of IDO Inhibitor in Combination With Checkpoint Inhibitors for Adult Patients With Metastatic Melanoma

A Phase 1/2 Study of the Concomitant Administration of Indoximod Plus Immune Checkpoint Inhibitors for Adult Patients With Advanced or Metastatic Melanoma

To evaluate the preliminary efficacy of the established dose of indoximod in combination with immune checkpoint inhibition as measured by the best overall response rate (ORR) (complete response (CR) + partial response (PR))across both standard of care agents administered sequentially in patients with unresectable stage III or stage IV melanoma

Study Overview

• Status: Completed
• Conditions: Metastatic Melanoma; Stage IV Melanoma; Stage III Melanoma
• Intervention / Treatment: Drug: Indoximod; Drug: Ipilimumab; Drug: Pembrolizumab; Drug: Nivolumab

Detailed Description

The incidence of melanoma is increasing. Based upon data obtained between 2004 and 2006, the lifetime probability of developing melanoma in the United States is estimated to be 1 in 37 for men and 1 in 56 for women. In the United States, melanoma is the fifth leading cancer in men and the seventh in women. Locally confined, fully-resectable disease may be curable with current therapy; but Stage IV metastatic disease (or relapsed/recurrent disease) is highly refractory to therapy. Thus, experimental clinical trials provide an accepted treatment option for metastatic or relapsed/refractory melanoma.

The current study is designed as a prospective trial to evaluate the combination of indoximod and checkpoint inhibitors in adult patients with metastatic melanoma. Ipilimumab, pembrolizumab and nivolumab will be used at the recommended approved doses for this indication.

The current trial will be done in two phases: a Phase 1b dose escalation of indoximod in combination with ipilimumab, starting at half the recommended single-agent dose, to establish the recommended Phase 2 dose for the combination.

This will be followed by a three arm expansion study testing a fixed dose of indoximod (at the recommended Phase 2 dose) combined with standard-dose ipilimumab, pembrolizumab or nivolumab.

Treatment will be administered on an outpatient basis. No investigational or commercial cancer directed agents or therapies other than those described below may be administered.

Safety assessment will follow the guidelines provided in the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version.4.03.

Patients will be followed both clinically and radiographically starting 12 weeks after initiation of treatment then every 8 weeks for tumor evaluation. Post-treatment scans will be compared to the baseline scan and responses will be assessed based using mWHO and immune related response criteria (irRC) described by Wolchok et al. (Wolchok et al., 2009).

• Study Type: Interventional
• Enrollment (Actual): 131
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Augusta University
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospital and Clinics
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • New Mexico Cancer Center Alliance
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey Cancer Institue
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Unresectable Stage III or Stage IV melanoma.
• Patients must have measurable disease, defined as lesions that can be accurately measure in in 2 perpendicular diameters with at least one diameter > 20mm and the other >10mm on conventional CT or MRI or 10mm x 10 mm by spiral CT.
• No systemic treatment in the previous 28 days.
• Age ≥18 years. Because no dosing or adverse event data are currently available on the use of ipilimumab or indoximod in patients <18 years of age, children are excluded from this study.
• ECOG performance status ≤2 (Karnofsky ≥60% )
• Patients with known brain metastases will only be eligible after their tumors have been treated with definitive resection and/or radiotherapy and they are neurologically stable for at least 1 month off steroids.

Exclusion Criteria:

• Patients who have had molecular targeted therapy (including vemurafenib) or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
• Patients who have had prior therapy with immune checkpoint inhibition or or indoximod are excluded from the trial.
• Any other cancer, unless the patient has been disease-free for ≥5 years
• Patients with laboratory evidence of pancreatitis are excluded.
• Patients with autoimmune disease
• Chronic use of immune-suppressive drugs (ie, systemic corticosteroids used in the management of cancer or non-cancer related illnesses, eg, COPD).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Indoximod + Ipilimumab; Indoximod will be administered at 1200mg BID by mouth. Ipilimumab administered intravenously at 3 mg/kg every three weeks for a total of four doses. Indoximod and ipilimumab will be dosed concurrently. Indoximod will be dosed twice daily on all days of each 21 day cycles (segment 1). Ipilimumab will be dosed on the 1st day of each 21 day cycle for the first 4 cycles. Indoximod dosing will continue after all 4 doses of ipilimumab are administered (segment 2, 28-day cycles). Patients will continue until they experience disease progression or limiting toxicity.	Drug: Indoximod; Initial dose of 600mg BID by mouth with escalation planned to 1200mg BID by mouth Dose escalation: If 0 of the 3 subjects forming the first cohort experience RLT, 1200mg BID cohort will be enrolled; If 1 of the 3 subjects in any cohort experiences a RLT, then enrollment into that cohort will increase to a total of 6 subjects; If > 1 of the 3-6 subjects experience a RLT, then the MTD has been exceeded and further enrollment into the cohort will cease; If >1 subject at 600mg BID experiences a RLT, the dose will be de-escalated to 400mg BID. If >1 subject at this level experiences a RLT, one additional de-escalation to 200mg BID is allowed Dosing cycles are 21 days in length during the combination immunotherapy component (first 4 cycles) and 28 days during indoximod monotherapy. Patients will continue until they experience disease progression or limiting toxicity Phase 2 Treatment Plan (Cohort 2) Will receive fixed dose of indoximod determined in phase 1; Other Names: 1-methyl-D-tryptophan; D-1MT; Drug: Ipilimumab; Ipilimumab administered intravenously at 3 mg/kg every three weeks for a total of four doses.; Other Names: MDX-010; YERVOY; MDX-101
Experimental: Indoximod + Pembrolizumab; Indoximod will be administered at 1200mg BID by mouth. Pembrolizumab administered intravenously at 2 mg/kg every three weeks.	Drug: Indoximod; Initial dose of 600mg BID by mouth with escalation planned to 1200mg BID by mouth Dose escalation: If 0 of the 3 subjects forming the first cohort experience RLT, 1200mg BID cohort will be enrolled; If 1 of the 3 subjects in any cohort experiences a RLT, then enrollment into that cohort will increase to a total of 6 subjects; If > 1 of the 3-6 subjects experience a RLT, then the MTD has been exceeded and further enrollment into the cohort will cease; If >1 subject at 600mg BID experiences a RLT, the dose will be de-escalated to 400mg BID. If >1 subject at this level experiences a RLT, one additional de-escalation to 200mg BID is allowed Dosing cycles are 21 days in length during the combination immunotherapy component (first 4 cycles) and 28 days during indoximod monotherapy. Patients will continue until they experience disease progression or limiting toxicity Phase 2 Treatment Plan (Cohort 2) Will receive fixed dose of indoximod determined in phase 1; Other Names: 1-methyl-D-tryptophan; D-1MT; Drug: Pembrolizumab; Pembrolizumab administered intravenously at 2 mg/kg every three weeks.
Experimental: Indoximod + Nivolumab; Indoximod will be administered at 1200mg BID by mouth. Nivolumab administered intravenously at 240 mg every 2 weeks.	Drug: Indoximod; Initial dose of 600mg BID by mouth with escalation planned to 1200mg BID by mouth Dose escalation: If 0 of the 3 subjects forming the first cohort experience RLT, 1200mg BID cohort will be enrolled; If 1 of the 3 subjects in any cohort experiences a RLT, then enrollment into that cohort will increase to a total of 6 subjects; If > 1 of the 3-6 subjects experience a RLT, then the MTD has been exceeded and further enrollment into the cohort will cease; If >1 subject at 600mg BID experiences a RLT, the dose will be de-escalated to 400mg BID. If >1 subject at this level experiences a RLT, one additional de-escalation to 200mg BID is allowed Dosing cycles are 21 days in length during the combination immunotherapy component (first 4 cycles) and 28 days during indoximod monotherapy. Patients will continue until they experience disease progression or limiting toxicity Phase 2 Treatment Plan (Cohort 2) Will receive fixed dose of indoximod determined in phase 1; Other Names: 1-methyl-D-tryptophan; D-1MT; Drug: Nivolumab; Nivolumab administered intravenously at 240 mg every 2 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1 Regimen Limiting Toxicity of the Combination of Indoximod and Ipilimumab	Number subjects with at least one RLTs observed in each dose level.	6 weeks
Overall Response Rate	Phase 2 component: To evaluate the preliminary efficacy of the established dose of indoximod in combination with immune checkpoint inhibition as measured by the best overall response rate in patients with unresectable Stage III or Stage IV melanoma.	22 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Phase 2 component: Overall survival (OS) and 95% confidence interval	24 months
Progression Free Survival	Phase 2 component: Time to progression with the combination indoximod with checkpoint inhibitor. Progression will be evaluated in this study using Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1).	24 months
Disease Control Rate	Phase 2 component: Disease control rate (CR, PR or SD)	22 months

Collaborators and Investigators

• Sponsor: NewLink Genetics Corporation

Publications and helpful links

Helpful Links

• Study Sponsor Website

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2014
• Primary Completion (Actual): January 17, 2018
• Study Completion (Actual): July 3, 2019

Study Registration Dates

• First Submitted: February 25, 2014
• First Submitted That Met QC Criteria: February 25, 2014
• First Posted (Estimated): February 27, 2014

Study Record Updates

• Last Update Posted (Actual): May 29, 2026
• Last Update Submitted That Met QC Criteria: May 4, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Metastatic melanoma; unresectable; Stage III melanoma; Stage IV melanoma
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Skin Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Skin and Connective Tissue Diseases; Melanoma; Amino Acids, Peptides, and Proteins; Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Nivolumab; Ipilimumab; pembrolizumab; 1-methyltryptophan
• Other Study ID Numbers: NLG2103