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

NewLink Genetics

Status and phase

Completed

Phase 2

Phase 1

Conditions

Stage III Melanoma

Metastatic Melanoma

Stage IV Melanoma

Treatments

Drug: Pembrolizumab

Drug: Ipilimumab

Drug: Nivolumab

Drug: Indoximod

Study type

Interventional

Funder types

Industry

Identifiers

NCT02073123

NLG2103

Details and patient eligibility

About

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

Full 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).

Enrollment

132 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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).

Trial design

Primary purpose

Treatment

Allocation

Non-Randomized

Interventional model

Sequential Assignment

Masking

None (Open label)

132 participants in 3 patient groups

Indoximod + Ipilimumab

Experimental group

Description:

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.

Treatment:

Drug: Ipilimumab

Drug: Indoximod

Indoximod + Pembrolizumab

Experimental group

Description:

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

Treatment:

Drug: Pembrolizumab

Drug: Indoximod

Indoximod + Nivolumab

Experimental group