Epacadostat in Combination With Pembrolizumab and Azacitidine in Subjects With Metastatic Colorectal Cancer

NCT03182894 | Withdrawn Phase 1 DMC FDA Drug

• 1 other identifier: UPCI 16-123
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

Trial Design This is an open label, single-arm, phase IB/II trial to evaluate the safety, tolerability and anti-tumor efficacy of epacadostat (INCB024360) in combination with pembrolizumab (MK-3475) plus azacitidine in patients with chemo-refractory MSS mCRC. The phase 1B portion of the study will evaluate the safety, tolerability and RP2D of epacadostat (INCB024360) in combination with pembrolizumab plus azacitidine in subjects with chemo-refractory MSS mCRC without any further standard treatment options. The phase 2 portion of the study will evaluate the efficacy and safety of epacadostat (INCB024360) in combination with pembrolizumab plus azacitidine in subjects with chemo-refractory MSS mCRC without any further standard treatment options. In both phase IB and phase 2 portions, patients will receive the combination of azacitidine, pembrolizumab and epacadostat (INCB024360) for the first 18 cycles (Cycles 1-18). Beginning with Cycle 19 through Cycle 35, patients will receive the combination of pembrolizumab and epacadostat (INCB024360).

Conditions

Metastatic Colorectal Cancer

Keywords

chemo-refractory; pembrolizumab; epacadostat; azacitidine; recommended phase 2 dose (RP2D); microsatellite-stable (MSS) Metastatic Colorectal Cancer

Outcome Measures

Primary Outcomes (2)

• Phase lB: Recommended phase 2 dose (RP2D) of epacadostat (INCB024360) plus pembrolizumab plus azacitidine

  Recommended phase 2 dose (RP2D) of epacadostat (INCB024360) in combination with pembrolizumab plus azacitidine in subjects with chemo-refractory microsatellite-stable (MSS) mCRC without any further standard treatment options.

  Up to 12 months

• Phase ll: Objective Response Rate (ORR)

  The proportion of patients with the best response of complete response (CR), or partial response (PR) by RECIST1.1 criteria.

  Up to 18 months

Secondary Outcomes (3)

• Progression-free survival (PFS)

  Up to 18 months

• Duration of response (DoR)

  Up to 18 months

• Overall survival (OS)

  Up to 18 months

Study Arms (1)

Epacadostat + Pembrolizumab + Azacitidine

EXPERIMENTAL

Oral Epacadostat (INCB024360) (50, 100, or 300 mg twice per day,on days 1-21 of each cycle, every 21 days) in combination with Pembrolizumab (MK-3475) (200 mg IV on days 1 of each cycle, every 21 days) and Azacitidine (VIDAZA) (100 mg SQ daily on days 1-5 of each cycle, every 21 days)

Drug: Epacadostat (INCB024360) in Combination with Pembrolizumab (MK-3475) and Azacitidine (VIDAZA)

Interventions

Epacadostat (INCB024360) in Combination with Pembrolizumab (MK-3475) and Azacitidine (VIDAZA) DRUG

Oral Epacadostat (INCB024360) (50, 100, or 300 mg twice per day,on days 1-21 of each cycle, every 21 days) in combination with Pembrolizumab (MK-3475) (200 mg IV on days 1 of each cycle, every 21 days) and Azacitidine (VIDAZA) (100 mg SQ daily on days 1-5 of each cycle, every 21 days)

Epacadostat + Pembrolizumab + Azacitidine

Eligibility Criteria

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

You may qualify if:

• Be willing and able to provide written informed consent/assent for the trial.
• Be at least 18 years of age on day of signing informed consent.
• The diagnosis of microsatellite-stable (MSS) mCRC will be based on histologic or cytologic confirmation. The histologic or cytologic confirmation of MSS status will be based on CLIA-certified immunohistochemistry (IHC) or PCR assay.
• Have mCRC that has been previously treated with currently approved standard therapies, including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy.
• Have measurable disease based on RECIST1.1.
• At least 1 of the tumor sites must be amenable to core needle biopsy and this may not be the site of disease used to measure antitumor response.
• Have a performance status of 0 or 1 on the ECOG Performance Scale.
• Life expectancy of at least 12 weeks.
• Demonstrate adequate organ function as defined in Table 1 (Section 3.1.9), all screening labs should be performed within 14 days of treatment initiation.
• Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Female subjects of childbearing potential (Section 5.7.2) must be willing to use an adequate method of contraception as outlined in Section 5.7.2 - Contraception, for the course of the study through 120 days after the last dose of study medication.
• Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
• Male subjects of childbearing potential (Section 5.7.2) must agree to use an adequate method of contraception as outlined in Section 5.7.2- Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy.
• Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject

You may not qualify if:

• Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in doses exceeding 10mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
• Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
• Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
• Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
• Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
• Has extensive metastatic tumor burden in the liver (\> 30% of liver volume) with serum albumin \<3.0 g/dL.
• Has known renal tubular acidosis with serum bicarbonate \<20 mEq/L.
• Has a known hypersensitivity to azacitidine or mannitol.
• Has a known history of active TB (Bacillus Tuberculosis)
• Hypersensitivity to pembrolizumab or epacadostat (INCB024360) or any of their excipients.
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment.
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.

Sponsors & Collaborators

• James J Lee: lead
• Incyte Corporation: collaborator
• Merck Sharp & Dohme LLC: collaborator

Study Sites (1)

UPMC Hillman Cancer Center

Pittsburgh, Pennsylvania, 15232, United States

Location

MeSH Terms

Conditions

Colorectal Neoplasms; Spinocerebellar Degenerations

Interventions

epacadostat; pembrolizumab; Azacitidine

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Cerebellar Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Spinal Cord Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• James J Lee, MD, PhD

  University of Pittsburgh

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: June 7, 2017
• First Posted: June 9, 2017
• Study Start: September 30, 2018
• Primary Completion: July 30, 2019
• Study Completion: July 30, 2020
• Last Updated: August 28, 2018

Record last verified: 2018-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)