JANUS: Testing the Addition of an Anti-Cancer Drug, Irinotecan, to the Standard Chemotherapy Treatment (FOLFOX) After Long-Course Radiation Therapy for Advanced-Stage Rectal Cancers to Improve the Rate of Complete Response and Long-Term Rates of Organ Preservation

Sponsor

Alliance for Clinical Trials in Oncology (Other)

Overall Status

Recruiting

CT.gov ID

NCT05610163

Collaborator

National Cancer Institute (NCI) (NIH)

312

Enrollment

Locations

Arms

116.8

Anticipated Duration (Months)

156

Patients Per Site

1.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase II trial compares the effect of irinotecan versus oxaliplatin after long-course chemoradiation in patients with stage II-III rectal cancer. Combination chemotherapy drugs, such as FOLFIRINOX (fluorouracil, irinotecan, leucovorin, and oxaliplatin), FOLFOX (leucovorin, fluorouracil, oxaliplatin, and irinotecan ), and CAPOX (capecitabin and oxaliplatin) work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. FOLFOX or CAPOX are used after chemoradiation as usual treatment for rectal cancer. Giving FOLFIRINOX after chemoradiation may increase the response rate and lead to higher rates of clinical complete response (with a chance of avoiding surgery) compared to FOLFOX or CAPOX after chemoradiation in patients with locally advanced rectal cancer.

Condition or Disease	Intervention/Treatment	Phase
Locally Advanced Rectal Carcinoma Stage II Rectal Cancer AJCC v8 Stage III Rectal Cancer AJCC v8	Drug: Capecitabine Drug: 5-fluorouracil Drug: Leucovorin calcium Drug: Irinotecan Drug: Oxaliplatin Radiation: Long Course Chemoradiotherapy Procedure: Computed Tomography Procedure: Magnetic Resonance Imaging Procedure: Sigmoidoscopy Procedure: biopsy	Phase 2

Detailed Description

PRIMARY OBJECTIVE:

To evaluate and compare the clinical complete response (cCR) rates in patients with locally advanced rectal cancer treated with neoadjuvant long-course neoadjuvant radiotherapy (LCRT) followed by neoadjuvant modified fluorouracil, irinotecan, leucovorin, and oxaliplatin (mFOLFIRINOX) versus neoadjuvant LCRT followed by neoadjuvant modified leucovorin , fluorouracil, and oxaliplatin (mFOLFOX6).

SECONDARY OBJECTIVES:

To evaluate and compare organ-preservation-time (OPT) between two treatment arms.
To evaluate and compare the disease-free survival (DFS) time between the two treatment arms.
To evaluate and compare time to distant metastasis between two treatment arms.
To evaluate and compare overall survival (OS) between two treatment arms. V. To evaluate and compare toxicity profiles of total neoadjuvant therapy (TNT) between two treatment arms.

EXPLORATORY OBJECTIVE:

Evaluation of circulating tumor deoxyribonucleic acid (ctDNA) kinetics during neoadjuvant therapy & surveillance and to correlate with radiographic, pathologic, and clinical outcomes.

OUTLINE: Patients are randomized to 1 of 2 arms.

GROUP I: Patients receive long-course chemoradiation therapy on study and then receive either: FOLFOX regimen consisting of leucovorin intravenously (IV), fluorouracil IV, and oxaliplatin IV or CAPOX consisting of capecitabine orally (PO), and oxaliplatin IV on study. Patients undergo computed tomography (CT) scan, magnetic resonance imaging (MRI), and biospecimen collection throughout the trial. Patients also undergo sigmoidoscopy throughout the trial and biopsy during screening.

GROUP II: Patients receive long-course chemoradiation therapy on study and then receive FOLFIRINOX regimen consisting of leucovorin IV, fluorouracil IV, irinotecan IV, and oxaliplatin IV on study. Patients undergo CT scan, MRI scan, and blood specimen collection throughout the trial. Patients undergo sigmoidoscopy throughout the trial and biopsy during screening.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

312 participants

Allocation:

Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

The Janus Rectal Cancer Trial: A Randomized Phase II Trial Testing The Efficacy of Triplet Versus Doublet Chemotherapy to Achieve Clinical Complete Response in Patients With Locally Advanced Rectal Cancer

Actual Study Start Date :

Dec 8, 2022

Anticipated Primary Completion Date :

Sep 1, 2024

Anticipated Study Completion Date :

Sep 1, 2032

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Group I (LCRT, FOLFOX or CAPOX) Patients receive long-course chemoradiation therapy on study and then receive either: FOLFOX regimen consisting of leucovorin IV, fluorouracil IV, and oxaliplatin IV or CAPOX consisting of capecitabine PO, and oxaliplatin IV on study. Patients undergo CT scan, MRI, and biospecimen collection throughout the trial. Patients also undergo sigmoidoscopy throughout the trial and biopsy during screening.	Drug: Capecitabine Given PO Drug: 5-fluorouracil Given IV Drug: Leucovorin calcium Given IV Drug: Oxaliplatin Given IV Radiation: Long Course Chemoradiotherapy Receive LCRT Procedure: Computed Tomography undergo CT Procedure: Magnetic Resonance Imaging undergo MRI Procedure: Sigmoidoscopy undergo sigmoidoscopy Procedure: biopsy undergo biopsy
Experimental: Group II (LCRT, FOLFIRINOX) Patients receive long-course chemoradiation therapy on study and then receive FOLFIRINOX regimen consisting of leucovorin IV, fluorouracil IV, irinotecan IV, and oxaliplatin IV on study. Patients undergo CT scan, MRI scan, and blood specimen collection throughout the trial. Patients undergo sigmoidoscopy throughout the trial and biopsy during screening.	Drug: Capecitabine Given PO Drug: 5-fluorouracil Given IV Drug: Leucovorin calcium Given IV Drug: Irinotecan Given IV Drug: Oxaliplatin Given IV Radiation: Long Course Chemoradiotherapy Receive LCRT Procedure: Computed Tomography undergo CT Procedure: Magnetic Resonance Imaging undergo MRI Procedure: Sigmoidoscopy undergo sigmoidoscopy Procedure: biopsy undergo biopsy

Arm

Intervention/Treatment

Active Comparator: Group I (LCRT, FOLFOX or CAPOX)

Patients receive long-course chemoradiation therapy on study and then receive either: FOLFOX regimen consisting of leucovorin IV, fluorouracil IV, and oxaliplatin IV or CAPOX consisting of capecitabine PO, and oxaliplatin IV on study. Patients undergo CT scan, MRI, and biospecimen collection throughout the trial. Patients also undergo sigmoidoscopy throughout the trial and biopsy during screening.

Drug: Capecitabine

Given PO

Drug: 5-fluorouracil

Given IV

Drug: Leucovorin calcium

Given IV

Drug: Oxaliplatin

Given IV

Radiation: Long Course Chemoradiotherapy

Receive LCRT

Procedure: Computed Tomography

undergo CT

Procedure: Magnetic Resonance Imaging

undergo MRI

Procedure: Sigmoidoscopy

undergo sigmoidoscopy

Procedure: biopsy

undergo biopsy

Experimental: Group II (LCRT, FOLFIRINOX)

Patients receive long-course chemoradiation therapy on study and then receive FOLFIRINOX regimen consisting of leucovorin IV, fluorouracil IV, irinotecan IV, and oxaliplatin IV on study. Patients undergo CT scan, MRI scan, and blood specimen collection throughout the trial. Patients undergo sigmoidoscopy throughout the trial and biopsy during screening.

Drug: Capecitabine

Given PO

Drug: 5-fluorouracil

Given IV

Drug: Leucovorin calcium

Given IV

Drug: Irinotecan

Given IV

Drug: Oxaliplatin

Given IV

Radiation: Long Course Chemoradiotherapy

Receive LCRT

Procedure: Computed Tomography

undergo CT

Procedure: Magnetic Resonance Imaging

undergo MRI

Procedure: Sigmoidoscopy

undergo sigmoidoscopy

Procedure: biopsy

undergo biopsy

Outcome Measures

Primary Outcome Measures

Clincal Complete Response (cCR) Rates [Up to 5 years]
efined as the number of patients who achieved cCR at the end of total neoadjuvant therapy (TNT) divided by number of patients included in the analysis population. This endpoint will be assessed within 8-12 weeks after completion of TNT. If there is a cCR, then the patient will be counted in the numerator. If there is a near-complete response (nCR) then a re-evaluation within 4-8 weeks will be performed. If the tumor has evolved to a cCR, then the patient will be counted in the numerator. Otherwise, the patient will be deemed as NOT achieving cCR status. divided by number of patients included in the analysis population.

Secondary Outcome Measures

Disease-free survival (DFS) rate [rom date of randomization, assessed up to 5 years]
Defined as the time from date of randomization to the date of first occurrence of the following events: death due to all causes, tumor that recurs locally after an R0 total mesorectal excision (TME), tumor that regrows after an initial apparent clinical and radiological CR and cannot be surgically removed with an R0 TME, and M1 disease diagnosed at any point after the initiation of treatment.
Organ-preservation-time (OPT) [From date of randomization, assessed up to 5 years]
Defined as time from the date of randomization to the date of the first occurrence of the following events: TME performed or attempted, tumor that regrows after an initial apparent clinical and radiological complete response (CR), and death due to all causes.
Time to distant metastasis (TDM) [From the date of randomization to the date of first documented distant metastasis, assessed up to 5 years]
Will be estimated, in each arm, using the method of Kaplan-Meier and compared by a stratified Cox regression model.
Overall survival (OS) [From the date of randomization to the date of death due to all causes, assessed up to 5 years]
Will be estimated, in each arm, using the method of Kaplan-Meier and compared by a stratified Cox regression model.
Incidence of adverse events (AEs) [Up to 5 years]
Defined as the proportion of patients experienced at least one Grade 3, Grade 4, or Grade 5 of each type of AE. The overall adverse event rates for grade 3 or higher adverse events will be compared between two treatment groups using Chi-square test (or Fisher's exact test if the data in the contingency table is sparse).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Stage: Clinical stage II or III rectal adenocarcinoma defined as T4N0 or any T with node positive disease (any T, N+); also T3N0 requiring abdominal perineal resection (APR) or coloanal anastomosis
Tumor site: Rectum; =< 12cm from the anal verge
No prior systemic chemotherapy, targeted therapy, or immunotherapy; or radiation therapy administered as treatment for colorectal cancer within the past 5 years is allowed
Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects

Therefore, for women of childbearing potential only, a negative pregnancy test (urine or serum according to institutional guidelines) done =< 14 days prior to registration is required. Female subjects agree to use highly effective contraception combined with an additional barrier method (e.g, diaphragm, with a spermicide) while on study and for >= 9 months after last dose of study drug, and the same criteria are applicable to male subjects if they have a partner of childbirth potential. Male subject agrees to use a condom and not donate sperm while in this study and for >= 6 months after the last treatment

Age >= 18 years
Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (or Karnofsky >= 60%)
Absolute neutrophil count (ANC) >= 1,500/mm^3
Platelet count >= 100,000/mm
Creatinine =< 1.5 x upper limit of normal (ULN) OR calculated (calc.) creatinine clearance >= 50 mL/min

Total bilirubin =< 1.5 x upper limit of normal (ULN)
Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN)
No upper rectal tumors (distal margin of tumor > 12 cm from the anal verge)
No recurrent rectal cancer; prior transanal excision, prior distal sigmoid cancer with a low anastomosis
No known mismatch repair deficient rectal adenocarcinoma
Human immunodeficiency virus HIV-infected patients on effective anti-retro viral therapy with undetectable viral load within 6 months are eligible for this trial
Patients with known history or current symptoms of cardiac disease, or history of treatment with cardio toxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification1. To be eligible for this trial, patients should be class 2B or better
Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this study. Patients on strong CYP3A4 inhibitors must discontinue the drug for 14 days prior to registration on the study * Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 14 days prior to the start of study treatment