Study of IDO Inhibitor in Combination With Gemcitabine and Nab-Paclitaxel in Patients With Metastatic Pancreatic Cancer

Phase 1

Completed

• Conditions: Metastatic Pancreatic Adenocarcinoma; Metastatic Pancreatic Cancer
• Interventions: Drug: Nab-Paclitaxel; Drug: Gemcitabine; Drug: Indoximod

• Registration Number: NCT02077881
• Lead Sponsor: NewLink Genetics Corporation

Brief Summary

This phase I/II trial is designed to efficiently identify the regimen limiting toxicity (RLT) and recommended phase 2 dose (RP2D) for the combination of the immunotherapeutic agent indoximod when administered in combination with standard of care chemotherapy gemcitabine plus nab-paclitaxel in subjects with metastatic adenocarcinoma of the pancreas. All subjects will receive the same standard gemcitabine plus nab-paclitaxel regimen, plus indoximod in doses increasing from 600 mg twice daily to, potentially, 1200 mg twice daily.

Detailed Description

This is a Phase I/II trial designed to evaluate the combination of the immunotherapeutic agent indoximod and the standard of care chemotherapy gemcitabine plus nab-paclitaxel in subjects with metastatic adenocarcinoma of the pancreas. The phase 1 portion is designed to identify the regimen-limiting toxicity (RLT) and recommended phase 2 dose (RP2D) for the combination. The phase 2 portion of the study will evaluate the potential efficacy of this combination. All subjects will receive the standard 28-day gemcitabine plus nab-paclitaxel regimen. Twice daily oral indoximod will be administered concurrently in continuous 28 day cycles.

In the phase 1 portion, dose escalation of indoximod will begin at 600 mg twice a day and potentially escalate to 1200 mg twice a day. There will be no intra-subject dose escalation. Regimen-limiting toxicity will be considered as those toxicities related to indoximod that significantly limit the administration of the backbone chemotherapy gemcitabine plus nab-paclitaxel. The period for determination of dose-limiting toxicities will be the initial 28 days of treatment. The recommended phase 2 dose will include an assessment of toxicities that occur at later time points.

Once a RP2D is determined, the phase 2 portion of the study will be initiated. In both phase 1 and phase 2, every 2 cycles subjects will have repeat imaging to assess response. Corollary biomarkers will be assessed at the same interval as will PET-CT after the 1st 8 week cycle. Up to 18 patients will be enrolled in the phase 1 portion of the study and 80 patients will be enrolled in the phase 2 portion.

Study Timeline

• Study First Submitted: 2014-02-28
• Study First Submitted QC: 2014-02-28
• Study First Posted: 2014-03-04
• Study Start: 2014-08
• Primary Completion: 2018-01-17
• Disposition First Submitted: 2018-06-29
• Disposition First Submitted QC: 2018-06-29
• Disposition First Posted: 2018-07-05
• Study Completion: 2018-10-17
• Status Verified: 2020-05
• Last Update Submitted: 2020-05-26
• Last Update Posted: 2020-05-28

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 157

Inclusion Criteria

• Patient has definitive histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas. Patients with islet cell or neuroendocrine neoplasms are excluded.
• Initial diagnosis of metastatic disease must have occurred ≤8 weeks prior to entry in the study.
• Patient has one or more metastatic tumors measurable per RECIST 1.1 by CT scan ≤4 weeks prior to entry into the study
• Male or non-pregnant and non-lactating female, and ≥18 years of age.
• Patients must have received no previous radiotherapy, surgery, chemotherapy or investigational therapy for the treatment of metastatic disease.
• Prior treatment with gemcitabine and/or nab-paclitaxel in the adjuvant setting is allowed, provided at least 6 months have elapsed since completion of the last dose and no lingering toxicities are present.
• Patients cannot have received any other immunomodulatory therapies (including vaccines) as treatment for this or any other cancer.
• Patient has a Karnofsky performance status (KPS) ≥ 70.
• Patients should be asymptomatic for jaundice prior to Day 1.

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Exclusion Criteria

• Patients may not be receiving (or received prior to enrollment) any other investigational agents for metastatic disease.
• Patient has known brain metastases,
• Patient has only locally advanced disease.
• Lymph node only metastases even if considered M1 disease by official staging criteria.
• History of malignancy in the last 3 years. Patients with prior history of in situ cancer or basal or squamous cell skin cancer are eligible. Patients with other malignancies are eligible if they were cured by surgery alone or surgery plus radiotherapy and have been continuously disease-free for at least 3 years.
• Patients with any active autoimmune disease
• Patient has undergone major surgery, other than diagnostic surgery (ie, surgery done to obtain a biopsy for diagnosis without removal of an organ), within 4 weeks prior to Day 1 of treatment in this study.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Indoximod and Gemcitabine + Nab-paclitaxel	Indoximod	Phase 1 portion: Participants to receive indoximod (600mg, 100mg, or 1200mg according to their assigned dose cohort) PO BID for 28 days concurrently with IV Nab-paclitaxel 125 mg/m\^2 followed by gemcitabine 1000 mg/m\^2 weekly for 3 weeks with one week rest. Each cycle is 28 days. Patients will continue until they experience disease progression or significant toxicity. Phase 2 portion: Once a RP2D is determined, treatment will commence with oral indoximod concurrent with the first backbone chemotherapy cycle.Patients will receive gemcitabine plus nab-paclitaxel on a standard 4 week cycle schedule. Oral indoximod will continue throughout.
Indoximod and Gemcitabine + Nab-paclitaxel	Gemcitabine	Phase 1 portion: Participants to receive indoximod (600mg, 100mg, or 1200mg according to their assigned dose cohort) PO BID for 28 days concurrently with IV Nab-paclitaxel 125 mg/m\^2 followed by gemcitabine 1000 mg/m\^2 weekly for 3 weeks with one week rest. Each cycle is 28 days. Patients will continue until they experience disease progression or significant toxicity. Phase 2 portion: Once a RP2D is determined, treatment will commence with oral indoximod concurrent with the first backbone chemotherapy cycle.Patients will receive gemcitabine plus nab-paclitaxel on a standard 4 week cycle schedule. Oral indoximod will continue throughout.
Indoximod and Gemcitabine + Nab-paclitaxel	Nab-Paclitaxel	Phase 1 portion: Participants to receive indoximod (600mg, 100mg, or 1200mg according to their assigned dose cohort) PO BID for 28 days concurrently with IV Nab-paclitaxel 125 mg/m\^2 followed by gemcitabine 1000 mg/m\^2 weekly for 3 weeks with one week rest. Each cycle is 28 days. Patients will continue until they experience disease progression or significant toxicity. Phase 2 portion: Once a RP2D is determined, treatment will commence with oral indoximod concurrent with the first backbone chemotherapy cycle.Patients will receive gemcitabine plus nab-paclitaxel on a standard 4 week cycle schedule. Oral indoximod will continue throughout.

Primary Outcome Measures

Name	Time	Method
Phase 2 Dosing	10 months	Phase 1 component: To determine recommended phase 2 dose of indoximod when administered with a standard of care chemotherapy backbone consisting of gemcitabine plus nab-paclitaxel.
Overall Survival	22 months	Phase 2 component: To evaluate efficacy as determined by overall survival (OS) in patients with metastatic adenocarcinoma of the pancreas.
Regimen Limiting Toxicity	10 months	Phase 1 component: To identify the regimen limiting toxicity (RLT) for the combination of the immunotherapeutic agent indoximod when administered in combination with standard of care chemotherapy gemcitabine plus nab-paclitaxel in subjects with metastatic adenocarcinoma of the pancreas.; RLT will be considered as only grade 3 and 4 toxicities that are attributable to the test agent and result in the delay of the administration of the backbone chemotherapy, gemcitabine plus nab-paclitaxel.

Secondary Outcome Measures

Name	Time	Method
Biomarker Response	22 months	A secondary objective is to examine biomarker responses of gemcitabine and nab-paclitaxel with indoximod through the evaluation of serum for biomarkers of IDO activity (kynurenine and tryptophan), before and after initiation of therapy through specimen collection at protocol specified timepoints.
Response Rate	22 months	To determine the response rate of the combination indoximod with gemcitabine plus nab-paclitaxel. Imaging assessments to be performed at protocol-specified time points and evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1).
Time to Progression of Disease	22 months	To determine the time to progression with the combination indoximod with gemcitabine plus nab-paclitaxel. Progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1).

Trial Locations

Locations (11)

University of Kentucy; 🇺🇸 Lexington, Kentucky, United States

Greenville Health Systems; 🇺🇸 Greenville, South Carolina, United States

Augusta University; 🇺🇸 Augusta, Georgia, United States

Stanford University; 🇺🇸 Palo Alto, California, United States

University of Vermont Medical Center; 🇺🇸 Burlington, Vermont, United States

Huntsman Cancer Center; 🇺🇸 Salt Lake City, Utah, United States

Washington University in St. Louis; 🇺🇸 Saint Louis, Missouri, United States

The Vally Hospital; 🇺🇸 Paramus, New Jersey, United States

Gibbs Cancer Center and Research Institute; 🇺🇸 Spartanburg, South Carolina, United States

The West Clinic; 🇺🇸 Memphis, Tennessee, United States

University of Pittsburgh Medical Center; 🇺🇸 Pittsburgh, Pennsylvania, United States