Epacadostat + Chemoradiation for Rectal Cancer
Recruiting in Palo Alto (17 mi)
+3 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Washington University School of Medicine
Must not be taking: Warfarin, MAOIs, others
Disqualifiers: Other cancer, Metastatic disease, Autoimmune, others
No Placebo Group
Approved in 1 Jurisdiction
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.
12345How 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.
678910Eligibility 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
+12 more
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
+19 more
Trial 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
Participant Groups
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.
3Treatment groups
Experimental Treatment
Active Control
Group I: Phase II Treatment Cohort: Epacadostat + SCRT + Chemotherapy + SurgeryExperimental Treatment4 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 + SurgeryExperimental Treatment3 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 + SurgeryActive Control3 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Washington University School of MedicineSaint Louis, MO
University of California IrvineOrange, CA
Dana Farber Cancer InstituteBoston, MA
University of California Irvine - Chao Family Comprehensive Cancer CenterOrange, CA
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Who Is Running the Clinical Trial?
Washington University School of MedicineLead Sponsor
National Cancer Institute (NCI)Collaborator
Incyte CorporationIndustry Sponsor
References
Interferon-Induced IDO1 Mediates Radiation Resistance and Is a Therapeutic Target in Colorectal Cancer. [2020]Colorectal cancer is a major cause of mortality worldwide. Chemotherapy and radiation remain standard treatment for locally advanced disease, with current immune-targeting therapies applying to only a small subset of patients. Expression of the immuno-oncology target indoleamine 2,3 dioxygenase 1 (IDO1) is associated with poor colorectal cancer clinical outcomes but is understudied as a potential treatment target. In this study, we examined the interaction between the IDO1 pathway and radiotherapy in colorectal cancer. We used human and mouse colorectal cancer cell lines, organoids, mouse syngeneic colorectal cancer tumor graft models, and colorectal cancer tissues from patients who received radiotherapy. IDO1 activity was blocked using the clinical IDO1 inhibitor epacadostat and by genetic disruption. We found that radiation induced IDO1 overexpression in colorectal cancer through type I and II IFN signaling. IDO1 enzymatic activity directly influenced colorectal cancer radiation sensitivity. IDO1 inhibition sensitized colorectal cancer to radiation-induced cell death, whereas the IDO1 metabolite kynurenine promoted radioprotection. IDO1 inhibition also potentiated Th1 cytokines and myeloid cell-modulating factors in the tumor microenvironment and promoted an abscopal effect on tumors outside the radiation field. Conversely, IDO1 blockade protected the normal small intestinal epithelium from radiation toxicity and accelerated recovery from radiation-induced weight loss, indicating a role in limiting side effects. These data demonstrated that IDO1 inhibition potentiates radiotherapy effectiveness in colorectal cancer. The findings also provide rationale and mechanistic insight for the study of IDO1 inhibitors as adjuvant therapy to radiation in patients with locally advanced sporadic and colitis-associated colorectal cancer.
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]Purpose: Indoleamine 2,3-dioxygenase-1 (IDO1) catalyzes the degradation of tryptophan to N-formyl-kynurenine. Overexpressed in many solid malignancies, IDO1 can promote tumor escape from host immunosurveillance. This first-in-human phase I study investigated the maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics, and antitumor activity of epacadostat (INCB024360), a potent and selective inhibitor of IDO1.Experimental Design: Fifty-two patients with advanced solid malignancies were treated with epacadostat [50 mg once daily or 50, 100, 300, 400, 500, 600, or 700 mg twice daily (BID)] in a dose-escalation 3 + 3 design and evaluated in 28-day cycles. Treatment was continued until disease progression or unacceptable toxicity.Results: One dose-limiting toxicity (DLT) occurred at the dose of 300 mg BID (grade 3, radiation pneumonitis); another DLT occurred at 400 mg BID (grade 3, fatigue). The most common adverse events in >20% of patients overall were fatigue, nausea, decreased appetite, vomiting, constipation, abdominal pain, diarrhea, dyspnea, back pain, and cough. Treatment produced significant dose-dependent reductions in plasma kynurenine levels and in the plasma kynurenine/tryptophan ratio at all doses and in all patients. Near maximal changes were observed at doses of ≥100 mg BID with >80% to 90% inhibition of IDO1 achieved throughout the dosing period. Although no objective responses were detected, stable disease lasting ≥16 weeks was observed in 7 of 52 patients.Conclusions: Epacadostat was generally well tolerated, effectively normalized kynurenine levels, and produced maximal inhibition of IDO1 activity at doses of ≥100 mg BID. Studies investigating epacadostat in combination with other immunomodulatory drugs are ongoing. Clin Cancer Res; 23(13); 3269-76. ©2017 AACR.
A Phase II Study of Epacadostat and Pembrolizumab in Patients with Advanced Sarcoma. [2023]Epacadostat, an indole 2,3 dioxygenase 1 (IDO1) inhibitor, proposed to shift the tumor microenvironment toward an immune-stimulated state, showed early promise in melanoma but has not been studied in sarcoma. This study combined epacadostat with pembrolizumab, which has modest activity in select sarcoma subtypes.
Advances in the discovery and development of selective heme-displacing IDO1 inhibitors. [2021]Indoleamine 2,3-dioxygenase 1 (IDO1) has been considered as an attractive intracellular target for the development of small-molecule cancer immunotherapy. Results in human clinical studies indicated that the first-generation IDO1 inhibitor epacadostat lacked anticancer activity when combined with the anti-PD-1 antibody pembrolizumab. Epacadostat inhibits IDO1 activity by forming a tertiary IDO1-heme-inhibitor complex. Recently, IDO1 inhibitors capable of displacing the heme group to form a binary high-affinity complex have been discovered and investigated in humans.
Design, synthesis, biological evaluation of urea substituted 1,2,5-oxadiazole-3-carboximidamides as novel indoleamine 2,3-dioxygenase-1 (IDO1) inhibitors. [2023]Indoleamine 2,3-dioxygenase-1 (IDO1) has been considered as an attractive target for oncology immunotherapy due to its immunosuppressive effects on the tumor microenvironment. The most advanced IDO1 inhibitor epacadostat in combination with anti-PD-1 antibody failed to show desirable objective response. Epacadostat is now reevaluated in phase III clinical trials, but its pharmacokinetic (PK) properties are unsatisfactory. To further unravel the antitumor efficacy of IDO1 inhibitors, we designed a series of epacadostat analogues by introducing various urea-containing side chains. In particular, the most active compound 3 showed superior inhibitory potency against recombinant hIDO1 and hIDO1 in HeLa cells induced by interferon γ (IFNγ) relative to epacadostat (3, biochemical hIDO1 IC50 = 67.4 nM, HeLa hIDO1 IC50 = 17.6 nM; epacadostat, biochemical hIDO1 IC50 = 75.9 nM, HeLa hIDO1 IC50 = 20.6 nM). Moreover, compound 3 exhibited improved physicochemical properties and rat PK profile with better oral exposure and bioavailability compared with epacadostat. Importantly, this compound exhibited comparable antitumor efficacy with epacadostat in LLC syngeneic xenograft models. Hence, compound 3 represents a promising lead compound for discovery of more effective IDO1 inhibitors.
Clinical Positioning of the IAP Antagonist Tolinapant (ASTX660) in Colorectal Cancer. [2022]Inhibitors of apoptosis proteins (IAPs) are intracellular proteins, with important roles in regulating cell death, inflammation, and immunity. Here, we examined the clinical and therapeutic relevance of IAPs in colorectal cancer. We found that elevated expression of cIAP1 and cIAP2 (but not XIAP) significantly correlated with poor prognosis in patients with microsatellite stable (MSS) stage III colorectal cancer treated with 5-fluorouracil (5FU)-based adjuvant chemotherapy, suggesting their involvement in promoting chemoresistance. A novel IAP antagonist tolinapant (ASTX660) potently and rapidly downregulated cIAP1 in colorectal cancer models, demonstrating its robust on-target efficacy. In cells co-cultured with TNFα to mimic an inflammatory tumor microenvironment, tolinapant induced caspase-8-dependent apoptosis in colorectal cancer cell line models; however, the extent of apoptosis was limited because of inhibition by the caspase-8 paralogs FLIP and, unexpectedly, caspase-10. Importantly, tolinapant-induced apoptosis was augmented by FOLFOX in human colorectal cancer and murine organoid models in vitro and in vivo, due (at least in part) to FOLFOX-induced downregulation of class I histone deacetylases (HDAC), leading to acetylation of the FLIP-binding partner Ku70 and downregulation of FLIP. Moreover, the effects of FOLFOX could be phenocopied using the clinically relevant class I HDAC inhibitor, entinostat, which also induced acetylation of Ku70 and FLIP downregulation. Further analyses revealed that caspase-8 knockout RIPK3-positive colorectal cancer models were sensitive to tolinapant-induced necroptosis, an effect that could be exploited in caspase-8-proficient models using the clinically relevant caspase inhibitor emricasan. Our study provides evidence for immediate clinical exploration of tolinapant in combination with FOLFOX in poor prognosis MSS colorectal cancer with elevated cIAP1/2 expression.
Molecular subtype-specific responses of colon cancer cells to the SMAC mimetic Birinapant. [2022]Colorectal cancer is a molecularly heterogeneous disease. Responses to genotoxic chemotherapy in the adjuvant or palliative setting vary greatly between patients, and colorectal cancer cells often resist chemotherapy by evading apoptosis. Antagonists of an inhibitor of apoptosis proteins (IAPs) can restore defective apoptosis signaling by degrading cIAP1 and cIAP2 proteins and by inhibition of XIAP. Due to the multiple molecular mechanisms-of-action of these targets, responses to IAP antagonist may differ between molecularly distinct colon cancer cells. In this study, responses to the IAP antagonist Birinapant and oxaliplatin/5-fluorouracil (5-FU) were investigated in 14 colon cancer cell lines, representing the consensus molecular subtypes (CMS). Treatment with Birinapant alone did not result in a substantial increase in apoptotic cells in this cell line panel. Annexin-V/PI assays quantified by flow cytometry and high-content screening showed that Birinapant increased responses of CMS1 and partially CMS3 cell lines to oxaliplatin/5-FU, whereas CMS2 cells were not effectively sensitized. FRET-based imaging of caspase-8 and -3 activation validated these differences at the single-cell level, with CMS1 cells displaying sustained activation of caspase-8-like activity during Birinapant and oxaliplatin/5-FU co-treatment, ultimately activating the intrinsic mitochondrial apoptosis pathway. In CMS2 cell lines, Birinapant exhibited synergistic effects in combination with TNFα, suggesting that Birinapant can restore extrinsic apoptosis signaling in the context of inflammatory signals in this subtype. To explore this further, we co-cultured CMS2 and CMS1 colon cancer cells with peripheral blood mononuclear cells. We observed increased cell death during Birinapant single treatment in these co-cultures, which was abrogated by anti-TNFα-neutralizing antibodies. Collectively, our study demonstrates that IAP inhibition is a promising modulator of response to oxaliplatin/5-FU in colorectal cancers of the CMS1 subtype, and may show promise as in the CMS2 subtype, suggesting that molecular subtyping may aid as a patient stratification tool for IAP antagonists in this disease.
In vitro and in vivo radiosensitization of colorectal cancer HT-29 cells by the smac mimetic JP-1201. [2019]The response to neoadjuvant chemoradiation in rectal cancer is variable and unpredictable. Resistance to chemoradiation has been directly correlated with the levels of the inhibitors of apoptosis (IAPs) in several malignancies. Because smac-DIABLO is a pro-apoptotic gene product that directly inhibits the activity of the IAPs, molecules with similar activity might radiosensitize rectal tumors with phenotypes that express high levels of IAPs. This study was undertaken to assess the radiosensitizing properties of the smac mimetic JP-1201 in radioresistant HT-29 colorectal cancer cells in vitro and established xenografts in SCID mice.
Consolidation mFOLFOX6 Chemotherapy After Chemoradiotherapy Improves Survival in Patients With Locally Advanced Rectal Cancer: Final Results of a Multicenter Phase II Trial. [2019]Adding modified FOLFOX6 (folinic acid, fluorouracil, and oxaliplatin) after chemoradiotherapy and lengthening the chemoradiotherapy-to-surgery interval is associated with an increase in the proportion of rectal cancer patients with a pathological complete response.
Neoadjuvant chemoradiation for rectal cancer: is more better? [2018]Neoadjuvant chemoradiation is now considered the clear preferable adjuvant standard of care in the management of stage II/III rectal cancer. Neoadjuvant fluorouracil (5-FU) plus radiation results in a decrease in local relapse rates and a favorable toxicity profile in comparison with postoperative adjuvant 5-FU plus radiation therapy. Recent nonrandomized comparative studies have shown that capecitabine (Xeloda) plus radiation result in downstaging and pathologic complete responses equivalent to those of 5-FU plus radiation, making this combination an acceptable alternative neoadjuvant treatment. The addition of oxaliplatin (Eloxatin) or irinotecan (Camptosar) to 5-FU or capecitabine concurrently with radiation therapy appears to result in more favorable pathologic responses in phase I/II trials. These combinations should be investigated further in larger phase III studies before they are endorsed in the routine neoadjuvant treatment of rectal cancer. This article will review the progress of chemoradiation over the past 2 decades, current standards of care, and investigational treatments in the neoadjuvant treatment of rectal cancer.