NEOadjuvant Chemotherapy Only Compared With Standard Treatment for Locally Advanced Rectal Cancer (NEOLAR)

NEOadjuvant Chemotherapy Only Compared With Standard Treatment for Locally Advanced Rectal Cancer: a Randomized Phase II Trial

The main clinical hypothesis is that compared to radio-chemotherapy for low and mid rectal tumors or surgery for high rectal tumors neoadjuvant chemotherapy reduces the rate of distant relapse without increasing the rate of local relapse.

The aim of the present study is to compare long term and short term outcomes in rectal cancer patients undergoing standard treatment (radio-chemotherapy/surgery) or experimental neoadjuvant chemotherapy/surgery Furthermore, early surgical and medical complications, the functional outcome, toxicity and quality of life (QoL) may be improved if radiotherapy can be avoided.

Exploratory analyses are planned in order to find potential predictive markers for selecting patients to either radio-chemotherapy/surgery or neoadjuvant combination chemotherapy/surgery.

Study Overview

• Status: Recruiting
• Conditions: Intestinal Neoplasms; Colorectal Cancer; Rectal Cancer; Rectal Neoplasms; Colorectal Neoplasm; Chemotherapy Effect; Intestinal Disease
• Intervention / Treatment: Drug: Capecitabine; Drug: FOLFOX regimen (oxaliplatin/leucovorin/5FU); Drug: CAPOX (oxaliplatin/capecitabine)

Detailed Description

The standard treatment of locally advanced but resectable cancer in the middle or lower rectum is preoperative radio-chemotherapy and in the upper part initial surgery. The clinical benefit from radio-chemotherapy is primarily through a reduction in local relapse but the treatment is associated with acute toxicity and long term functional dysfunction. Subsequently, it is important to select patients with high risk of local relapse. Intense systemic combination chemotherapy reduces the risk of distant relapse and increases survival in the postoperative setting. The biological rationale is eradication of micrometastases and hence it may be anticipated that earlier, i.e. neoadjuvant, combination therapy may improve systemic control.

• Study Type: Interventional
• Enrollment (Anticipated): 124
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Ismail Gögenur, MD; Phone Number: +45 26336426; Email: igo@regionsjaelland.dk
• Study Contact Backup: Name: Lars Henrik Jensen, MD

Study Locations

• Denmark
  • Vejle, Denmark
    • Recruiting
    • Vejle Hospital
    • Contact: Lars Henrik Jensen, MD PhD; Email: lars.henrik.jensen@rsyd.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adenocarcinoma of the rectum with the lower boarder within 15 cm from the anal verge
• Locally advanced tumor based on imaging
• T3 tumors within 10 cm from the anal verge fulfilling the criteria for preoperative radio-chemotherapy according to Danish Colorectal Cancer Group (DCCG) guidelines
• T3c or T4 tumors 10-15 cm from the anal verge
• Deemed resectable at the multidisciplinary team (MDT) conference
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Age at least 18 years
• Adequate bone marrow, liver and renal function allowing systemic chemotherapy
• Absolute neutrophil count ≥1.5x109/l and thrombocytes ≥ 100x109/l.
• Bilirubin ≤ 1.5 x upper normal value and alanine aminotransferase ≤ 3 x upper normal value
• Calculated or measured renal glomerular filtration rate at least 30 mL/min
• Anticonception for fertile women and for male patients with a fertile partner. Intrauterine device, vasectomy of a female subject's male partner or hormonal contraceptive are acceptable
• Written and orally informed consent

Exclusion Criteria:

• Distant metastasis
• Invasive ingrowth into other organs
• Incapacity, frailty, disability and comorbidity to a degree that according to the investigator is not compatible with combination chemotherapy
• Previous radiotherapy to the pelvis
• Previous treatment with 5FU or oxaliplatin
• Surgery within two weeks
• Neuropathy NCI grade > 1
• Other malignant tumor within 5 years except non-melanoma skin cancer or carcinoma in situ cervicis uteri
• Pregnant (positive pregnancy test) or breast feeding women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: A, capecitabine; Radiochemotherapy with 50.4 Gy in 28 fractions concomitantly with chemotherapy	Drug: Capecitabine; Radio-chemotherapy with 50.4 Gy in 28 fractions to tumor and regional lymph nodes concomitantly with capecitabine 825 mg/m2 b.i.d
Experimental: B, FOLFOX or CAPOX; Neoadjuvant chemotherapy with CAPOX (oxaliplatin/capecitabine) or FOLFOX regimen (oxaliplatin/leucovorin/5FU), according to institutional practice	Drug: FOLFOX regimen (oxaliplatin/leucovorin/5FU); Six cycles: Oxaliplatin 85 mg/m2 day 1, leucovorin 400 mg/m2 day 1, 5FU 400 mg/m2 bolus day 1 and 5FU 2400 mg/ m2 over 46-48 hours day 1-3, repeated every two weeks.; Other Names: FOLFOX (oxaliplatin/leucovorin/5FU); Drug: CAPOX (oxaliplatin/capecitabine); Four cycles: Oxaliplatin 130 mg/m2 day 1 and capecitabine 1000 mg/m2 b.i.d. days 1-14, repeated every 3 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease free survival	All patients will be evaluated with CT and MRI scans and clinically every 6 months for 2 years and annually until the number of events is reached and the trial is stopped (max 5 years)	5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	All patients will be evaluated with CT and MRI scans and clinically every 6 months for 2 years and annually for maximum 5 years	5 years
Local relapse	Defined to be within the pelvis. Any relapse should be verified by biopsy	5 years
Distant relapse	Defined to be outside the pelvis. Any relapse should be verified by biopsy	5 years
Early toxicity	Evaluated using CTCEA (Common Terminology Criteria for Adverse Events) version 4.	5 years
Late toxicity	Evaluated using CTCEA version 4.	5 years
Functional outcome	Measured with LARS questionnaire	5 years
Quality of life (QoL)	Measured with EORTC QoL questionnaire	5 years

Collaborators and Investigators

• Sponsor: Zealand University Hospital
• Investigators: Study Chair: Ismail Gögenur, MD, Department of Surgery, ZUH; Principal Investigator: Lars Henrik Jensen, MD, Vejle Hospital

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2017
• Primary Completion (Anticipated): December 31, 2018
• Study Completion (Anticipated): December 31, 2024

Study Registration Dates

• First Submitted: September 7, 2017
• First Submitted That Met QC Criteria: September 8, 2017
• First Posted (Actual): September 12, 2017

Study Record Updates

• Last Update Posted (Actual): September 28, 2017
• Last Update Submitted That Met QC Criteria: September 26, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Keywords: chemotherapy; Neoadjuvant chemotherapy,; locally advanced rectal cancer,; CAPOX (oxaliplatin/capecitabine); FOLFOX (oxaliplatin/leucovorin/5FU)
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Rectal Diseases; Neoplasms; Colorectal Neoplasms; Rectal Neoplasms; Intestinal Diseases; Intestinal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Protective Agents; Micronutrients; Vitamins; Antidotes; Vitamin B Complex; Capecitabine; Oxaliplatin; Leucovorin; Levoleucovorin
• Other Study ID Numbers: S-20160158

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No