Advanced Solid Tumor, Non-small Cell Lung Cancer (NSCLC)
Conditions
Keywords
epacadostat, sirolimus
Brief summary
This is a small phase I study with dose escalation and dose expansion cohorts. The former cohort will need up to 12 subjects with advanced solid tumor to define feasibility and recommended phase 2 dose (RP2D); the latter up to 10 subjects to further define safety. Study subjects will be adults with advanced solid tumor (dose escalation) and advanced non-small cell lung cancer (NSCLC) who progressed on at least one first-line systemic therapy (dose expansion).
Detailed description
Indoleamine 2,3 dioxygenase-1 (IDO1) is a target of cancer immunotherapy. Epacadostat (INCB24360) is an oral IDO1 inhibitor. IDO1 activation blocks T-cell activation, enhances T-cell apoptosis and promotes the differentiation of naïve T cells to regulatory T cells (Tregs). Preclinical findings suggest that IDO1 is critical for cancers to evade immune surveillance and can be exploited for cancer immunotherapy. Sirolimus is an oral Mammalian Target Of Rapamycin (mTOR) inhibitor. Protein Kinase B mTOR pathway has been considered one of major signaling cascade downstream of receptor kinases in human cells. Its activation in human cancer cells prompted scientists to develop its inhibitors. Preclinical findings found that sirolimus can enhance activity of anti-Programmed Death-1 (PD-1) antibody by suppressing Programmed Death Ligand-1 (PD-L1) expression in human lung cancer models. Sirolimus is also known to suppress function of Tregs which contribute to immune evasion in cancer. Other research groups also reported that autophagy is essential for Thymus cell/lymphocyte (T-cell) -mediated apoptosis which can be enhanced by AKT/mTOR/Phosphoinositide 3-kinase (PI3K) inhibitors. These studies indicate that autophagy is essential for T-cell mediated apoptosis signaling. Because autophagy is at least partially down-regulated by mTOR, mTOR inhibitors such as sirolimus can be used to pharmacologically induce autophagy. Overall, these findings suggest that activation of mTOR and resultant suppression of autophagy play a critical role in resistance of IDO1 inhibitor. There is a clear unmet need for patients with advanced NSCLC whose median survival is approximately one year. Those who progressed on both standard first-line chemotherapy and second line anti-PD-1 inhibitor do not have any standard therapeutic option. Novel therapeutic strategy needs to develop for this population. The IDO1 inhibitor epacadostat is currently being investigated in clinical trials in combination with various agents. However, these existing studies do not consider that mTOR and/or autophagy are key mechanisms of its resistance despite the abovementioned background information. The purpose of this phase I study is to test the combination of sirolimus with the IDO1 inhibitor in order to overcome potential resistance mechanisms associated with the use of IDO1.
Interventions
DRUGEpacadostat
Epacadostat tablet: 100mg or 300mg
DRUGsirolimus
Sirolimus tablet: 1mg, 2mg, 3mg, or 6mg
Sponsors
University of Kansas Medical Center
Chao Huang
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
For the Dose Escalation cohort: Traditional 3+3 dose escalation design. For the Dose Expansion cohort: Once recommended phase two dose (RP2D) is defined by the PI, a total of 10 NSCLC patients who meet eligibility will be enrolled in the dose expansion cohort. If RP2D is not defined for any reason, the study will be terminated.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Participants must meet all of the inclusion criteria to participate in this study. * Ability to understand and the willingness to sign a written informed consent. * Prior treatment with at least one line of systemic therapy. * Dose escalation: subjects with advanced and unresectable solid tumor who progressed on at least one line of systemic therapy, and no approved therapy or standard therapy with demonstrated clinical benefit exists; and all subjects with T790M mutation positive NSCLC have progressed on osimertinib. \*Note - Disease measurability is not required for dose escalation. * Dose expansion: subjects with metastatic or recurrent NSCLC who progressed on at least one line of systemic therapy for metastatic or recurrent disease, which must include anti PD-1 or PD-L1 inhibitor, and must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and accessible tumor for biopsy. Molecular status of Epidermal Growth Factor Receptor (EGFR) and Anaplastic Lymphoma Kinase (ALK) must have been assessed for nonsquamous NSCLC. Those with activating EGFR mutation or ALK gene arrangement must have progressed on at least one kinase inhibitor. * Age ≥ 18 years. * Eastern Cooperative Oncology Group (ECOG) Performance Status #0-2. * Adequate organ and marrow function as defined below: * Leukocytes ≥ 3,000/mcL * Absolute neutrophil count ≥ 1,500/microliter (mcL) * Platelets ≥ 100,000/mcL * Hemoglobin ≥ 9 grams per deciliter (g/dL) * Total bilirubin within normal institutional limits * Aspartate Aminotransferase (AST) Serum Glutamic Oxaloacetic Transaminase (SGOT) ≤ 2.5 X institutional upper limit of normal (ULN) * Alanine Aminotransferase (ALT) Serum Glutamic Pyruvic Transaminase (SPGT) ≤ 2.5 X ULN * Alkaline Phosphatase Level (ALP) ≤ 2.5 X ULN * Serum creatinine ≤ 1.5 X ULN or Creatinine Clearance (CrCl) ≥ 50ml/min * Note: Subjects with bone metastasis and no liver metastasis on screening image may enroll if ALP is \<5 X ULN. Subjects with liver metastasis may enroll if all of AST/ALT/ALP are \<5 X ULN. However, subjects with extensive liver metastasis occupying more than 50% of liver parenchyma will be excluded. * 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. * Women of child-bearing potential and men with partners of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. * A woman of child-bearing potential is any female (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: * Has not undergone a hysterectomy or bilateral oophorectomy; or * Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)
Exclusion criteria
Participants meeting any of the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of treatment-emergent adverse events. | 28 days | Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 will be used to measure incidence of treatment-emergent adverse events. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall response response in subjects with NSCLC (dose expansion cohort) | up to 12 months | Subjects will be assessed every 8 weeks by radiologic imaging to monitor disease status. |
| Disease control rate (DCR) >40% in subjects with NSCLC (dose expansion cohort) | 2 months | Subjects will be assessed at Week 8 by radiologic imaging to monitor disease status. |
| Median progression free survival (mPFS) >3 months in subjects with NSCLC (dose expansion cohort) | up to 12 months | Subjects will be assessed every 8 weeks by radiologic imaging to monitor disease status. |
| Median Overall Survival (mOS) > 6 months in subjects with NSCLC (dose expansion cohort) | up to 12 months | Subjects will be assessed every 8 weeks by radiologic imaging to monitor disease status. |
Countries
United States
Outcome results
None listed