Epacadostat + Chemoradiation for Rectal Cancer

Recruiting at 2 trial locations

Overseen By Katrina S. Pedersen

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Washington University School of Medicine

Must not be taking: Warfarin, MAOIs, others

Disqualifiers: Other cancer, Metastatic disease, Autoimmune, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 11

49 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this research study is to evaluate epacadostat when given with routine radiation therapy and chemotherapy (capecitabine and oxaliplatin) to treat rectal cancer before routine surgery is performed to remove the tumor.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are currently on warfarin (a blood thinner) or certain drugs that can cause serotonin syndrome. If you stop warfarin and your blood levels are normal, you can join without a waiting period.

What data supports the effectiveness of the drug Epacadostat when used with chemoradiation for rectal cancer?

Research shows that blocking IDO1, which Epacadostat does, can make colorectal cancer cells more sensitive to radiation, potentially improving treatment outcomes. Additionally, IDO1 inhibition may help protect normal tissues from radiation damage, reducing side effects. ^{1 2 3 4 5}

How is the drug Epacadostat combined with chemoradiation unique for treating rectal cancer?

Epacadostat is an IDO inhibitor, which means it works by blocking an enzyme that helps cancer cells evade the immune system. This approach is different from traditional chemoradiation treatments that primarily focus on directly killing cancer cells, making it a novel addition to rectal cancer therapy. ^{6 7 8 9 10}

Research Team

Moh'd Khusman, M.D.

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

This trial is for adults with newly diagnosed locally advanced rectal cancer who are planning to receive neoadjuvant radiation and chemotherapy. Participants must be in good physical condition (ECOG ≤ 1), have normal organ and bone marrow function, agree to use contraception, and not have had previous cancer treatments or certain other medical conditions.

Inclusion Criteria

- Absolute neutrophil count ≥ 1,500/mcl

- Platelets ≥ 100,000/mcl

- Hemoglobin > 9 g/dL

Exclusion Criteria

I have not received any live vaccines in the last 30 days.

I do not have lung inflammation or disease that needed treatment.

Currently receiving any other investigational agents

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation

Participants receive short-course pelvic radiation therapy (SCRT) for 1 week

1 week

5 visits (in-person)

Chemotherapy

Participants receive neoadjuvant chemotherapy with CAPOX or FOLFOX for 18 weeks

18 weeks

6 cycles of 21 days each

Surgery

Surgery to remove the tumor is performed approximately 4-6 weeks after chemotherapy

4-6 weeks after chemotherapy

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Epacadostat

Trial Overview The study tests epacadostat combined with CAPOX chemotherapy and short-course radiation before surgery for rectal cancer. It aims to see if this combination improves outcomes compared to the standard preoperative treatment.

Participant Groups

Group I: Phase II Treatment Cohort: Epacadostat + SCRT + Chemotherapy + Surgery Experimental Treatment 4 Interventions

* Epacadostat 400 mg BID 1st day of radiation therapy and continuing for \~28 days, until biopsy (with the exception of patients enrolling to dose expansion and starting on epacadostat with neoadjuvant chemotherapy prior to approval of post-sIRB A2) * Preoperative therapy approximately 20-24 weeks of chemoradiation: * Week 1: SCRT, typically 5 Gy x 5 fractions over 1 week, with epacadostat 400 mg BID starting on D1 of SCRT * Weeks 2-4: Epacadostat monotherapy 400 mg BID \& continued for a minimum of 21 days, until the day prior to chemotherapy * For patients enrolled at Washington University and Dana Farber Cancer Institute ONLY, tumor biopsy between the end of RT and prior to initiation of chemotherapy. Tumor biopsy target of between Days 15-28 * Weeks 3-6: 4-5 weeks after completion of SCRT \& after completion of approximately 21-35 days of epacadostat, SOC neoadjuvant chemotherapy of CAPOX or FOLFOX will be initiated * Surgery will occur approximately 4-6 weeks after chemotherapy

Group II: Dose Escalation Cohort (Phase I): Epacadostat + SCRT + Chemotherapy + Surgery Experimental Treatment 3 Interventions

* Epacadostat at the designated dose level starting on the 1st day of radiation therapy and continuing throughout chemotherapy until the day of surgery. * Standard of care preoperative therapy will consist of a total of approximately 20-24 weeks of short-course pelvic radiation and chemotherapy: * Cycle 0 Days 1-7(Week 1): Short-course pelvic radiation therapy (SCRT), 5 fractions over 1 week * Cycle 0 Days 8-21 or 8-28 (Weeks 2-4): Treatment break for 2 to 3 weeks; for patients enrolled at Washington University and Dana Farber only, tumor biopsy will be obtained between the end of RT and prior to chemotherapy (target Days 14-28) * Cycles 1-6: (6) 21-day cycles of CAPOX for a total of 18 weeks. CAPOX is typically capecitabine at 1000 mg/m\^2 PO BID (days 1-14 of each cycle) and oxaliplatin 130 mg/m\^2 IV Q3W. * Surgery will follow approximately 4 to 6 weeks after completion of CAPOX

Group III: Phase II Biomarker Cohort: SCRT + Chemotherapy + Surgery Active Control 3 Interventions

Washington University and Dana Farber only: Patients enrolled to this cohort will not receive epacadostat. Patients will undergo standard of care preoperative therapy consisting of approximately 20 to 24 weeks of chemoradiation. All treatment will be administered in this cohort as per institutional standard. The expected schedule for these patients will consist of 1 week of short-course pelvic radiation therapy, followed by a treatment break, followed by neoadjuvant chemotherapy. Approximately 4 to 6 weeks after completion of neoadjuvant chemotherapy, patients may undergo surgery. Tumor biopsy may occur at screening and after completion of RT, prior to starting neoadjuvant chemotherapy.

Epacadostat is already approved in United States for the following indications:

Approved in United States as Epacadostat for:

• None approved; Orphan designation for stage IIB-IV melanoma

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Incyte Corporation

Industry Sponsor

Trials

408

Recruited

66,800+

Steven Stein

Incyte Corporation

Chief Medical Officer since 2015

MD from University of Witwatersrand

Hervé Hoppenot

Incyte Corporation

Chief Executive Officer since 2014

MBA from ESSEC Business School

Findings from Research

Inhibition of the IDO1 pathway using the drug epacadostat enhances the effectiveness of radiotherapy in colorectal cancer by increasing radiation sensitivity and promoting immune responses in the tumor microenvironment.

Blocking IDO1 not only improves the response to radiation treatment but also protects normal intestinal tissue from radiation damage, suggesting a dual benefit of IDO1 inhibitors in reducing side effects while enhancing cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interferon-Induced IDO1 Mediates Radiation Resistance and Is a Therapeutic Target in Colorectal Cancer. Chen, B., Alvarado, DM., Iticovici, M., et al.[2020]

In a phase I study involving 52 patients with advanced solid tumors, epacadostat, an IDO1 inhibitor, was generally well tolerated and achieved significant reductions in plasma kynurenine levels, indicating effective inhibition of IDO1 activity at doses of 100 mg BID and above.

Although no objective tumor responses were observed, 7 out of 52 patients experienced stable disease for at least 16 weeks, suggesting potential for further investigation in combination with other immunomodulatory therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-Human Phase I Study of the Oral Inhibitor of Indoleamine 2,3-Dioxygenase-1 Epacadostat (INCB024360) in Patients with Advanced Solid Malignancies. Beatty, GL., O'Dwyer, PJ., Clark, J., et al.[2022]

In a phase II study involving 30 patients with advanced sarcoma, the combination of epacadostat (an IDO1 inhibitor) and pembrolizumab showed limited antitumor activity, with a best objective response rate of only 3.3%.

The treatment was well tolerated, with 23% of patients experiencing grade 3 treatment-related adverse events, but no significant changes in tumor expression of PD-L1 or IDO1 were observed, suggesting that the IDO1 inhibition may not have been sufficient.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II Study of Epacadostat and Pembrolizumab in Patients with Advanced Sarcoma. Kelly, CM., Qin, LX., Whiting, KA., et al.[2023]

First-generation IDO1 inhibitors like epacadostat showed disappointing results in clinical trials, particularly when combined with anti-PD-1 therapies, indicating a need for more effective treatments.

Newer IDO1 inhibitors that displace the heme group from the IDO1 enzyme demonstrate higher potency and selectivity, suggesting they could be a promising advancement in cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in the discovery and development of selective heme-displacing IDO1 inhibitors. Sun, L.[2021]

A new compound, referred to as compound 3, has shown superior inhibitory potency against the IDO1 enzyme compared to the existing IDO1 inhibitor epacadostat, indicating its potential as a more effective treatment in oncology immunotherapy.

Compound 3 also demonstrated improved pharmacokinetic properties, including better oral exposure and bioavailability, while maintaining comparable antitumor efficacy in preclinical models, suggesting it could be a promising lead for developing more effective IDO1 inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design, synthesis, biological evaluation of urea substituted 1,2,5-oxadiazole-3-carboximidamides as novel indoleamine 2,3-dioxygenase-1 (IDO1) inhibitors. Ye, K., Wang, K., Wang, T., et al.[2023]

Elevated levels of cIAP1 and cIAP2 in patients with stage III colorectal cancer are linked to poor outcomes and may contribute to resistance against 5-fluorouracil (5FU) chemotherapy, highlighting their potential as biomarkers for prognosis.

The IAP antagonist tolinapant shows promise in enhancing the effectiveness of FOLFOX chemotherapy by inducing apoptosis in colorectal cancer cells, suggesting a potential new treatment strategy for patients with high cIAP1/2 expression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Positioning of the IAP Antagonist Tolinapant (ASTX660) in Colorectal Cancer. Crawford, N., Stott, KJ., Sessler, T., et al.[2022]

The IAP antagonist Birinapant enhances the effectiveness of oxaliplatin/5-fluorouracil (5-FU) chemotherapy specifically in colorectal cancer cell lines of the CMS1 subtype, promoting apoptosis through sustained activation of caspases.

In CMS2 cell lines, Birinapant can restore extrinsic apoptosis signaling when combined with inflammatory signals like TNFα, indicating that molecular subtyping of colorectal cancer may help tailor treatments with IAP antagonists.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular subtype-specific responses of colon cancer cells to the SMAC mimetic Birinapant. Fichtner, M., Bozkurt, E., Salvucci, M., et al.[2022]

The smac mimetic JP-1201 significantly enhances the effectiveness of ionizing radiation in treating radioresistant HT-29 colorectal cancer cells, leading to a 46% reduction in tumor load in mice when combined with radiation therapy.

JP-1201 works by promoting apoptosis (cell death) through increased levels of cleaved PARP-1 and reducing the inhibitor XIAP, while also impairing the cancer cells' ability to repair DNA damage, which is crucial for their survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro and in vivo radiosensitization of colorectal cancer HT-29 cells by the smac mimetic JP-1201. Huerta, S., Gao, X., Livingston, EH., et al.[2019]

In a nonrandomized phase II trial involving 259 patients with stage II or III rectal cancer, adding modified FOLFOX6 chemotherapy after chemoradiotherapy improved disease-free survival rates, indicating a potential benefit in treatment outcomes.

The study found that the number of chemotherapy cycles received was linked to better survival outcomes, suggesting that neoadjuvant consolidation chemotherapy not only enhances the likelihood of a complete pathological response but also improves overall treatment compliance and long-term survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Consolidation mFOLFOX6 Chemotherapy After Chemoradiotherapy Improves Survival in Patients With Locally Advanced Rectal Cancer: Final Results of a Multicenter Phase II Trial. Marco, MR., Zhou, L., Patil, S., et al.[2019]

Neoadjuvant chemoradiation, particularly with fluorouracil (5-FU) plus radiation, is now the preferred treatment for stage II/III rectal cancer, showing lower local relapse rates and better safety compared to postoperative treatments.

Capecitabine (Xeloda) plus radiation has been found to be as effective as 5-FU plus radiation, making it a viable alternative, while combinations with oxaliplatin or irinotecan show promise for improved outcomes and warrant further investigation in larger studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant chemoradiation for rectal cancer: is more better? Patel, A., Puthillath, A., Yang, G., et al.[2018]

References

1. United States pubmed.ncbi.nlm.nih.gov

Interferon-Induced IDO1 Mediates Radiation Resistance and Is a Therapeutic Target in Colorectal Cancer. [2020]

2. United States pubmed.ncbi.nlm.nih.gov

First-in-Human Phase I Study of the Oral Inhibitor of Indoleamine 2,3-Dioxygenase-1 Epacadostat (INCB024360) in Patients with Advanced Solid Malignancies. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

A Phase II Study of Epacadostat and Pembrolizumab in Patients with Advanced Sarcoma. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Advances in the discovery and development of selective heme-displacing IDO1 inhibitors. [2021]

5. France pubmed.ncbi.nlm.nih.gov

Design, synthesis, biological evaluation of urea substituted 1,2,5-oxadiazole-3-carboximidamides as novel indoleamine 2,3-dioxygenase-1 (IDO1) inhibitors. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Clinical Positioning of the IAP Antagonist Tolinapant (ASTX660) in Colorectal Cancer. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Molecular subtype-specific responses of colon cancer cells to the SMAC mimetic Birinapant. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

In vitro and in vivo radiosensitization of colorectal cancer HT-29 cells by the smac mimetic JP-1201. [2019]

9. United States pubmed.ncbi.nlm.nih.gov

Consolidation mFOLFOX6 Chemotherapy After Chemoradiotherapy Improves Survival in Patients With Locally Advanced Rectal Cancer: Final Results of a Multicenter Phase II Trial. [2019]

10. United States pubmed.ncbi.nlm.nih.gov

Neoadjuvant chemoradiation for rectal cancer: is more better? [2018]