Epacadostat and Pembrolizumab in Treating Patients with Imatinib-Refractory Advanced Gastrointestinal Stromal Tumors That Cannot Be Removed by Surgery

Status: Active

Description

This phase II trial studies how epacadostat and pembrolizumab work in treating patients with gastrointestinal stromal tumors that have spread to other places in the body and do not respond to imatinib or that cannot be removed by surgery. Epacadostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Giving epacadostat and pembrolizumab may work better in treating patients with gastrointestinal stromal tumors.

Eligibility Criteria

Inclusion Criteria

  • Histologically confirmed diagnosis of GIST
  • Unresectable or metastatic GIST
  • Allowable prior therapies: * Subjects must have had clinical or radiographic progression on imatinib; those who were taken off of imatinib for intolerance must have progressed on at least one other tyrosine kinase inhibitor (TKI) * Subjects must have received >= 1 prior systemic therapy (including imatinib); a maximum of 4 prior therapies for metastatic disease are allowed
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1
  • Life expectance of >= 3 months
  • Absolute neutrophil count >= 1.5 x 10^9/L within 28 days of treatment initiation and must be independent of hematopoietic growth factor support
  • Platelets >= 100 x 10^9/L within 28 days of treatment initiation and must be independent of hematopoietic growth factor support
  • Hemoglobin >= 9 g/dL (transfusion is acceptable to meet this criteria) within 28 days of treatment initiation and must be independent of hematopoietic growth factor support
  • Serum creatinine =< 1.5 x institutional upper limit of normal (ULN) OR calculated creatinine clearance >= 50 mL/min for subjects with creatinine levels > 1.5 x institutional ULN within 28 days of treatment initiation and must be independent of hematopoietic growth factor support
  • Aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase =< 2.5 x ULN, or =< 5 x ULN in subjects with liver metastases within 28 days of treatment initiation and must be independent of hematopoietic growth factor support
  • Total bilirubin =< 1.5 x ULN within 28 days of treatment initiation and must be independent of hematopoietic growth factor support * Note: patients with hyperbilirubinemia clinically consistent with an inherited disorder of bilirubin metabolism (eg, Gilbert syndrome) will be eligible at the discretion of the principal investigator
  • International normalized ratio (INR) or prothrombin time (PT) < 1.5 x ULN unless subject is receiving anticoagulation therapy as long as PT or INR is within therapeutic range of intended use of anticoagulant within 28 days of treatment initiation and must be independent of hematopoietic growth factor support
  • Activated partial thromboplastin time (aPTT) < 1.5 x ULN unless subject is receiving anticoagulant therapy, as long as partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants within 28 days of treatment initiation and must be independent of hematopoietic growth factor support
  • Presence of baseline measurable disease by RECIST v1.1 for solid tumors, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
  • Female subjects of childbearing potential (defined as women who have not undergone surgical sterilization with a hysterectomy and/or bilateral oophorectomy, and are not postmenopausal [defined as >= 12 months of amenorrhea]) must have a negative pregnancy test at screening and must agree to use adequate contraception (complete abstinence, or two methods of birth control) prior to study entry and until at least 4 months after the last dose of study treatment; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
  • Fertile men must also agree to use adequate contraception (2 barrier methods or abstinence) during the study and for up to 4 months after the last dose of study drug
  • All subjects must agree to pre- and on-treatment tumor biopsies; subjects in whom biopsy is technically not feasible or in whom would result in unacceptable risk, in the opinion of the investigator, may be exempted from the biopsy requirement with discussion with the principal investigator; use of outside archived tumor tissue for a baseline biopsy is not permitted
  • Willingness and ability to provide written informed consent prior to any study-related procedures and to comply with all study requirements

Exclusion Criteria

  • Treatment with chemotherapy (not including tyrosine kinase inhibitors) or radiotherapy within 4 weeks (6 weeks from nitrosoureas or mitomycin C), or treatment with monoclonal antibody therapy within 4 weeks prior to start of study treatment * Note: no minimum washout period is required for tyrosine kinase inhibitor therapy (eg, imatinib or sunitinib)
  • Patients must have recovered from adverse events (greater than grade 1) due to prior anticancer therapy, except for stable chronic toxicities such as alopecia
  • Participation in any other clinical study with investigational drug received within 28 days or 5 half lives (whichever is longer) before first dose
  • Subjects who have received prior anti-PD-1 or anti-PD-L1 antibody, or an IDO inhibitor; subjects who have received experimental vaccines or other immune therapies should be discussed with the principal investigator to confirm eligibility
  • Any prior >= grade 3 immune-related adverse event (irAE) while receiving immunotherapy, or any unresolved irAE > grade 1
  • Subjects receiving immunologically based treatment for any reason, including chronic steroids or prednisone (at dose > 10 mg/day of prednisone) within 14 day prior to first study treatment; inhaled or topical steroids or systemic steroids (at dose =< 10 mg/day of prednisone) is permitted
  • Subjects with any active or inactive autoimmune process (eg, rheumatoid arthritis, moderate or severe psoriasis, multiple sclerosis, inflammatory bowel disease) or who are receiving systemic therapy for an autoimmune disease; exceptions include vitiligo, hypothyroidism controlled on hormone replacement, type I diabetes, Grave’s disease, adrenal insufficiency on stable replacement doses of steroids (prednisone =< 10 mg/day or equivalent), or with principal investigator approval
  • No prior organ allograft or allogenic bone marrow transplantation
  • History of (noninfectious) pneumonitis that require steroids or current pneumonitis
  • A diagnosis of another active malignancy with the following exceptions: basal or squamous cell carcinoma of the skin, in-situ carcinoma of the cervix, isolated elevation of prostate-specific antigen, indolent secondary malignancies not requiring active therapy, or with the approval of the principal investigator; subjects with a completely treated prior malignancy and no evidence of disease for >= 2 years are eligible
  • Subjects with known active hepatitis B (HBV) or hepatitis C (HCV) infection as defined by the following (hepatitis screening studies are required): * Positive test for hepatitis B surface antigen * Positive test for hepatitis C antibody and/ or hepatitis C quantitative viral load (Note: subjects with a positive hepatitis C antibody and negative quantitative hepatitis C polymerase chain reaction [PCR] viral load are eligible)
  • Subjects with a known history of human immunodeficiency virus (HIV), including patients with controlled disease on antiretroviral therapy; HIV testing is not required as part of screening for this study
  • Subjects receiving monoamine oxidase (MAO) inhibitors within 21 days of study enrollment (epacadostat increases serotonin levels, theoretically increasing the risk of serotonin syndrome, although this has not been reported in any ongoing clinical studies to date)
  • Any history of serotonin syndrome (SS) after receiving 1 or more serotonergic drugs
  • Current pregnancy or breast feeding; pregnant women are excluded from this study; breastfeeding should be discontinued in all female subjects
  • Receipt of live attenuated vaccines (including, but not limited to: intranasal influenza vaccine [FluMist], measles, mumps, rubella, chicken pox, yellow fever, rabies, Bacillus Calmette-Guerin [BCG], and typhoid vaccine) within 30 days before the first dose of study treatment
  • Concurrent use of any medication that is an inhibitor of UGT1A9 during the screening or treatment period
  • Major surgical procedure or significant traumatic injury within 14 days of initiating study drug or anticipation of the need for major surgery during the study
  • Inability to swallow capsules, or refractory nausea and vomiting, malabsorption, an external biliary shunt, or significant bowel resection that would preclude adequate absorption
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, active liver disease, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • History of current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, or interfere with the subject’s participation for the full duration of the study
  • Known allergy or reaction to any component of either study drug formulation

Locations & Contacts

Michigan

Ann Arbor
University of Michigan Comprehensive Cancer Center
Status: Active
Contact: Rashmi Chugh
Phone: 734-647-8902
Email: rashmim@med.umich.edu

New York

New York
NYP / Columbia University Medical Center / Herbert Irving Comprehensive Cancer Center
Status: Active
Contact: Richard D. Carvajal
Phone: 646-317-6354
Email: rdc2150@cumc.columbia.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To assess the efficacy of combined indoleamine 2,3-dioxygenase (IDO) and PD-1 inhibition in a single arm phase II trial of epacadostat and pembrolizumab in patients with advanced imatinib-refractory gastrointestinal stromal tumor (GIST), using a primary endpoint of overall response rate using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria.

SECONDARY OBJECTIVES:

I. To evaluate the progression free survival (PFS) of patients with advanced GIST treated with epacadostat and pembrolizumab using RECIST v1.1 criteria.

II. To evaluate the overall survival (OS) of patients with advanced GIST treated with epacadostat and pembrolizumab.

III. To evaluate response rate using Choi criteria.

IV. To evaluate the safety and tolerability of combined epacadostat and pembrolizumab treatment in the advanced GIST population.

EXPLORATORY OBJECTIVES:

I. To correlate the effect of IDO inhibition with response to therapy by evaluating baseline and on-treatment serum samples for tryptophan metabolite levels.

II. To characterize the effect of combined therapy with IDO and PD-1 inhibition on T-cell subsets by evaluating baseline and on-treatment tumor samples for changes in the T-effector to T-regulator cell ratio using immunohistochemistry.

III. To characterize the relationship between PD-L1 status and response to combined IDO and PD-1 inhibition.

OUTLINE:

Patients receive epacadostat orally (PO) twice daily (BID) on days 1- 21 and pembrolizumab intravenously (IV) over 30 minutes on day 1. Courses repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 and 90 days and then every 12 weeks thereafter.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
NYP / Columbia University Medical Center / Herbert Irving Comprehensive Cancer Center

Principal Investigator
Richard D. Carvajal

Trial IDs

Primary ID AAAR1581
Secondary IDs NCI-2017-02061
Clinicaltrials.gov ID NCT03291054