Epacadostat (INCB24360) in Combination With Sirolimus in Advanced Malignancy

NCT03217669 | Unknown Phase 1 DMC FDA Drug

• 1 other identifier: IIT-2016-Epacadostat+SIRO
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 2

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).

Conditions

Advanced Solid Tumor; Non-small Cell Lung Cancer (NSCLC)

Keywords

epacadostat; sirolimus

Outcome Measures

Primary Outcomes (1)

• Incidence of treatment-emergent adverse events.

  Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 will be used to measure incidence of treatment-emergent adverse events.

  28 days

Secondary Outcomes (4)

• Overall response response in subjects with NSCLC (dose expansion cohort)

  up to 12 months

• Disease control rate (DCR) >40% in subjects with NSCLC (dose expansion cohort)

  2 months

• Median progression free survival (mPFS) >3 months in subjects with NSCLC (dose expansion cohort)

  up to 12 months

• Median Overall Survival (mOS) > 6 months in subjects with NSCLC (dose expansion cohort)

  up to 12 months

Study Arms (2)

Sirolimus/Epacadostat Dose Escalation

EXPERIMENTAL

Traditional 3 + 3 dose escalation design. Starting doses: sirolimus 3milligrams (mg) loading/1mg maintenance and epacadostat 300mg twice daily (BID). If 0 in 3 subjects develops dose limiting toxicity (DLT), next 3 subjects will be treated at dose level 2 (DL2): sirolimus 6mg loading/2mg maintenance and epacadostat 300mg BID. If 1 subject in dose level 1 (DL1) develops DLT, 3 additional subjects will be enrolled in DL1. If 2 or more subjects in a total of 6 subjects, or 2 or more subjects in the initial 3 subjects develop DLT, the next 3 subjects will be treated at dose level -1 (DL-1): 3mg loading/1mg sirolimus + epacadostat 100mg BID. If only 1 subject in a total of 6 develops DLT, dose escalation to DL2 will be made for the next 3 subjects. Same algorithm will apply to DL2 except no further dose escalation/de-escalation will be made. Sirolimus lead-in phase: loading dose on day -7 and maintenance dose starting day -6. On Cycle 1 Day 1, epacadostat 300mg BID will be added.

Drug: Epacadostat; Drug: sirolimus

Sirolimus/Epacadostat Dose Expansion

EXPERIMENTAL

Once recommended phase 2 dose (RP2D) is defined, a total of 10 non-small cell lung cancer (NSCLC) patients who meet eligibility will be enrolled in the dose expansion cohort. Treatment will be sirolimus RP2D once daily and epacadostat RP2D twice daily (BID). Sirolimus lead-in phase: loading dose on day -7 and maintenance dose starting day -6. On Cycle 1 Day 1, epacadostat 300mg BID will be added.

Drug: Epacadostat; Drug: sirolimus

Interventions

Epacadostat DRUG

Epacadostat tablet: 100mg or 300mg

Also known as: INCB24360

Sirolimus/Epacadostat Dose Escalation; Sirolimus/Epacadostat Dose Expansion

sirolimus DRUG

Sirolimus tablet: 1mg, 2mg, 3mg, or 6mg

Also known as: rapamycin, rapamune

Sirolimus/Epacadostat Dose Escalation; Sirolimus/Epacadostat Dose Expansion

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• Current or anticipated use of other investigational agents while participating in this study.
• Participation in any other study in which receipt of an investigational study drug occurred within 28 days or 5 half-lives (whichever is longer) before first dose.
• Subjects who have received an IDO inhibitor. Subjects who have received other immune checkpoint inhibitors (e.g. anti-PD-1, anti-PD-L1, and any other treatment targeting T-cell) will be permitted. Subjects who have received experimental vaccines or other immune therapies should be discussed with the Principal Investigator (PI) to confirm eligibility.
• Subjects who have received sirolimus, everolimus, temsirolimus, or any other agent for current malignancy that theoretically targets Phosphoinositide 3-kinase (PI3K), AKT and / or mTOR.
• Any prior ≥ Grade 3 immune-related adverse event (irAE) while receiving immunotherapy, including anti-Cytotoxic T-Lymphocyte antigen 4 (CTLA-4) and anti-PD-1/PD-L1 treatment, or any unresolved irAE\>Grade 1.
• \*Note: Previous immune-related ocular toxicity of any grade is excluded.
• Subjects who are receiving an immunosuppressive treatment for any reason, including chronic use of systemic steroid or prednisone equivalent at doses ≥ 10 milligrams per day (mg/day) within 14 days prior to the first dose of study treatment. Use of inhaled or topical steroids or systemic corticosteroids \< 10 mg is permitted.
• Subjects who have had prior radiotherapy within 2 weeks of therapy. Subjects must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis.
• Patient has received chemotherapy within 3 weeks prior to entering the study or has not recovered sufficiently (i.e., greater than grade 1. PI will judge patient recovery status) from adverse events due to agents administered more than 3 weeks earlier. Exceptions are stable chronic toxicities not expected to resolve, such as peripheral neurotoxicity, alopecia, and fatigue.
• Prior monoclonal antibody within 4 weeks before study Day 1 or not recovered (≤ Grade 1 or at baseline) from AEs due to agents administered more than 4 weeks earlier. Exception to this rule would be use of denosumab.
• Brain metastases: Symptomatic, unstable, or disease requiring use of steroid treatment.
• Subjects with any active or inactive autoimmune process (eg, rheumatoid arthritis, moderate or severe psoriasis, multiple sclerosis, inflammatory bowel disease, etc.) or who are receiving systemic therapy for an autoimmune or inflammatory disease.
• \*Exceptions include subjects with vitiligo, hypothyroidism stable on hormone replacement, controlled asthma, Type I diabetes, Graves' disease, Hashimoto's disease, or with PI approval.
• Evidence of or any history of interstitial lung disease or active, noninfectious pneumonitis including symptomatic and/or pneumonitis requiring treatment.
• Hepatitis B virus (HBV) or hepatitis C virus (HCV) viremia or at risk for HBV reactivation. Hepatitis B virus deoxyribonucleic acid (DNA) and testing for HCV ribonucleic acid (RNA) must be undetectable. At risk for HBV reactivation is defined as hepatitis B surface antigen positive

Sponsors & Collaborators

• Chao Huang: lead
• University of Kansas Medical Center: collaborator

Study Sites (2)

Clinical Research Center

Fairway, Kansas, 66208, United States

Location

The University of Kansas Cancer Center

Westwood, Kansas, 66205, United States

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

epacadostat; Sirolimus

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Study Officials

• Chao Huang, MD

  KUMC

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Medical Doctor

Model Details: 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.

Study Record Dates

• First Submitted: July 12, 2017
• First Posted: July 14, 2017
• Study Start: February 22, 2018
• Primary Completion: April 1, 2024
• Study Completion: August 1, 2025
• Last Updated: May 3, 2023

Record last verified: 2023-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)