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

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ClinicalTrials.gov Identifier: NCT02077881
Recruitment Status : Active, not recruiting
First Posted : March 4, 2014
Last Update Posted : July 4, 2018
Sponsor:
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Metastatic Pancreatic Adenocarcinoma Metastatic Pancreatic Cancer Drug: Nab-Paclitaxel Drug: Gemcitabine Drug: Indoximod Phase 1 Phase 2

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 Type : Interventional  (Clinical Trial)
Actual Enrollment : 157 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Study of Indoximod in Combination With Gemcitabine and Nab-Paclitaxel in Patients With Metastatic Adenocarcinoma of the Pancreas
Actual Study Start Date : August 2014
Actual Primary Completion Date : January 17, 2018
Estimated Study Completion Date : October 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Indoximod and Gemcitabine + 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.

Drug: Nab-Paclitaxel
Nab-Paclitaxel 125 mg/m^2 given intravenously over 30-40 minutes for 3 weeks (days 1, 8 and 15) with 1 week rest. Patients will continue until they experience disease progression or significant toxicity.
Other Names:
  • Abraxane
  • Paclitaxel

Drug: Gemcitabine
Gemcitabine 1000 mg/m^2 given intravenously over 30 minutes for 3 weeks (days 1, 8 and 15) with 1 week rest. Patients will continue until they experience disease progression or significant toxicity.
Other Name: Gemzar

Drug: Indoximod

Indoximod will be administered in escalating doses. Initial dosing will be 600 mg BID by mouth with escalation planned to 1200 mg BID by mouth

Indoximod in the form of 200 mg capsules will be given (3, 5, and 6 capsules depending on the escalated dose). Indoximod should be taken with water by mouth one hour before breakfast and one hour prior to dinner. The medication should be taken twice daily for 28 days each cycle. Patients will continue until they experience disease progression or toxicity.

Other Names:
  • 1-methyl-D-tryptophan
  • D-1MT




Primary Outcome Measures :
  1. Phase 2 Dosing [ Time Frame: 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.


  2. Regimen Limiting Toxicity [ Time Frame: 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.


  3. Overall Survival [ Time Frame: 22 months ]

    Phase 2 component:

    To evaluate efficacy as determined by overall survival (OS) in patients with metastatic adenocarcinoma of the pancreas.



Secondary Outcome Measures :
  1. Biomarker Response [ Time Frame: 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.

  2. Response Rate [ Time Frame: 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).

  3. Time to Progression of Disease [ Time Frame: 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).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02077881


Locations
United States, California
Stanford University
Palo Alto, California, United States, 94304
United States, Georgia
Augusta University
Augusta, Georgia, United States, 30912
United States, Kentucky
University of Kentucy
Lexington, Kentucky, United States, 40536
United States, Missouri
Washington University in St. Louis
Saint Louis, Missouri, United States, 63110
United States, New Jersey
The Vally Hospital
Paramus, New Jersey, United States, 07652
United States, Pennsylvania
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States, 15232
United States, South Carolina
Greenville Health Systems
Greenville, South Carolina, United States, 29605
Gibbs Cancer Center and Research Institute
Spartanburg, South Carolina, United States, 29303
United States, Tennessee
The West Clinic
Memphis, Tennessee, United States, 38120
United States, Utah
Huntsman Cancer Center
Salt Lake City, Utah, United States, 84112
United States, Vermont
University of Vermont Medical Center
Burlington, Vermont, United States, 05401
Sponsors and Collaborators
NewLink Genetics Corporation

Additional Information:
Responsible Party: NewLink Genetics Corporation
ClinicalTrials.gov Identifier: NCT02077881     History of Changes
Other Study ID Numbers: NLG2104
First Posted: March 4, 2014    Key Record Dates
Last Update Posted: July 4, 2018
Last Verified: June 2018

Keywords provided by NewLink Genetics Corporation:
metastatic
metastasis
Pancreatic
Pancreas
Cancer
adenocarcinoma

Additional relevant MeSH terms:
Adenocarcinoma
Pancreatic Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Paclitaxel
Gemcitabine
Albumin-Bound Paclitaxel
Tryptophan
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs