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

NCT02073123 | Completed Phase 1

• 1 other identifier: NLG2103
• Study Type: interventional
• Target: 132
• Locations: 1 country
• Sites: 6

Brief Summary

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

Conditions

Metastatic Melanoma; Stage III Melanoma; Stage IV Melanoma

Keywords

Metastatic melanoma; Stage III melanoma; Stage IV melanoma; unresectable

Outcome Measures

Primary Outcomes (3)

• Overall Incidence of Adverse Events as a Measure of Safety and Tolerability

  Phase 1 component: Evaluate the safety (adverse events - type, incidence, severity, duration, causality and treatment intervention) of the combination of indoximod and ipilimumab when given concomitantly. The safety and tolerability ipilimumab followed by Indoximod will be assessed by listing the overall incidence of AEs. The AEs will be summarized and classified by body system and by treatment group. The type, incidence, severity, and causality of each AE, the duration of the event, and any required treatment interventions will be tabulated. Physical examination results will be presented in the patient data listings. The DLT will be listed per dose level and treatment along with overall frequencies. The data from the expansion part (Phase II) will be used for this part of safety and tolerability assessment.

  17 months

• Phase 2 Dosing

  Phase 1 component: To determine the recommended Phase 2 dose of indoximod in combination with ipilimumab in patients with unresectable melanoma. A minimum of nine patients will be treated depending on DLT. Each dose will be administered to a cohort of 3 patients. If 0 out of 3 or less than 2 out of 6 patients experienced a DLT at any given dose level, the dose escalation will proceed to the next dose level. The MTD is generally the largest dose level at which at most 1 out of 6 patients experiences a DLT. IF DLT is not reached at the highest dose level (1200mg twice daily), no further escalation will proceed and this dose level will be declared the recommended Phase II dose

  22 months

• 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 Outcomes (5)

• Number of Participants with Adverse Events as a Measure of Safety and Tolerability

  22 months

• Overall Survival

  24 months

• Mechanisms of activity/resistance to IDO/CTLA-4 inhibitor therapy

  24 months

• Progression Free Survival

  22 months

• Disease control rate

  22 months

Study Arms (3)

Indoximod + Ipilimumab

EXPERIMENTAL

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; Drug: Ipilimumab

Indoximod + Pembrolizumab

EXPERIMENTAL

Indoximod will be administered at 1200mg BID by mouth. Pembrolizumab administered intravenously at 2 mg/kg every three weeks.

Drug: Indoximod; Drug: Pembrolizumab

Indoximod + Nivolumab

EXPERIMENTAL

Indoximod will be administered at 1200mg BID by mouth. Nivolumab administered intravenously at 240 mg every 2 weeks.

Drug: Indoximod; Drug: Nivolumab

Interventions

Indoximod DRUG

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

Also known as: 1-methyl-D-tryptophan, D-1MT

Indoximod + Ipilimumab; Indoximod + Nivolumab; Indoximod + Pembrolizumab

Ipilimumab DRUG

Ipilimumab administered intravenously at 3 mg/kg every three weeks for a total of four doses.

Also known as: YERVOY, MDX-010, MDX-101

Indoximod + Ipilimumab

Nivolumab DRUG

Nivolumab administered intravenously at 240 mg every 2 weeks.

Indoximod + Nivolumab

Pembrolizumab DRUG

Pembrolizumab administered intravenously at 2 mg/kg every three weeks.

Indoximod + Pembrolizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• NewLink Genetics Corporation: lead

Study Sites (6)

Augusta University

Augusta, Georgia, 30912, United States

Location

University of Iowa Hospital and Clinics

Iowa City, Iowa, 52242, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

New Mexico Cancer Center Alliance

Albuquerque, New Mexico, 87106, United States

Location

Penn State Hershey Cancer Institue

Hershey, Pennsylvania, 17033, United States

Location

Huntsman Cancer Institute

Salt Lake City, Utah, 84112, United States

Location

MeSH Terms

Conditions

Melanoma

Interventions

1-methyltryptophan; Ipilimumab; Nivolumab; pembrolizumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 25, 2014
• First Posted: February 27, 2014
• Study Start: July 1, 2014
• Primary Completion: January 17, 2018
• Study Completion: July 3, 2019
• Last Updated: June 5, 2020

Record last verified: 2020-06

Locations

US (6)