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Short Course Radiation Therapy Followed by Pre-operative Chemotherapy and Surgery in High-risk Rectal Cancer (LARCT-US)

Primary Purpose

Rectal Cancer

Status

Recruiting

Phase

Phase 2

Locations

Sweden

Study Type

Interventional

Intervention

radiotherapy, capecitabine, oxaliplatin

About this trial

This is an interventional treatment trial for Rectal Cancer focused on measuring rectal cancer, high risk, total neoadjuvant treatment

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

• Histological proof of newly diagnosed primary adenocarcinoma of the rectum
- Locally advanced tumour fulfilling at least one of the following criteria on pelvic MRI indicating high risk of failing locally and/or systemically (T4b, i.e. overgrowth to an adjacent organ or structure like the prostate, urinary bladder, uterus, sacrum, pelvic floor or side-wall (according to TNM version 7), cT4a, i.e. peritoneal involvement, extramural vascular invasion (EMVI+). N2, i.e. four or more lymph nodes in the mesorectum showing morphological signs on MRI indicating metastatic disease. Four or more nodes, whether enlarged or not, with a rounded, homogeneous appearance is thus not sufficient. Positive MRF, i.e. tumour or lymph node < 1 mm from the mesorectal fascia. Enlarged lateral nodes, > 1 cm (lat LN+).

Exclusion Criteria:

Extensive growth into cranial part of the sacrum (above S3) or the lumbosacral nerve roots indicating that surgery will never be possible even if substantial tumour down-sizing is seen.
Presence of metastatic disease or recurrent rectal tumour. Familial Adenomatosis Polyposis coli (FAP), Hereditary Non-Polyposis Colorectal Cancer (HNPCC), active Crohn's disease or active ulcerative Colitis.
Concomitant malignancies, except for adequately treated basocellular carcinoma of the skin or in situ carcinoma of the cervix uteri. Subjects with prior malignancies must be disease-free for at least 5 years.
Known DPD deficiency.
Any contraindications to MRI (e.g. patients with pacemakers).
Medical or psychiatric conditions that compromise the patient's ability to give informed consent.
Concurrent uncontrolled medical conditions.
Any investigational treatment for rectal cancer within the past month.
Pregnancy or breast feeding.
Patients with known malabsorption syndromes or a lack of physical integrity of the upper gastrointestinal tract.
Clinically significant (i.e. active) cardiac disease (e.g. congestive heart failure, symptomatic coronary artery disease and cardiac dysrhythmia, e.g. atrial fibrillation, even if controlled with medication) or myocardial infarction within the past 12 months.
Patients with symptoms of peripheral neuropathy.

Sites / Locations

Akademiska sjukhusetRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

LARCT-US

Arm Description

Short Course Radiation Therapy (5 x 5 Gy in 1 week, scRT) followed by 4 cycles of Pre-operative Chemotherapy using capecitabine and oxaliplatin (CAPOX) and Surgery in High-risk Rectal Cancer

Outcomes

Primary Outcome Measures

Pathological complete response (pCR) rate and clinical complete response (cCR) rate

pCR assessed at pathological examination of the surgical specimen, cCR at clinical and radiological (MRI) examination

Secondary Outcome Measures

Disease-free survival

non-radical surgery, recurrence or death within 3 years

Neoadjuvant rectal score (NAR score)

Score from 0 - 100, where 0 is best

Incidence of Treatment-Emergent Adverse Events

CTCAE v 4.0

Long-term Adverse Events

CTCAE v 4.0

Full Information

NCT ID

NCT03729687

First Posted

October 10, 2018

Last Updated

October 31, 2018

Sponsor

Uppsala University

Collaborators

Swedish Cancer Society

1. Study Identification

Unique Protocol Identification Number

NCT03729687

Brief Title

Short Course Radiation Therapy Followed by Pre-operative Chemotherapy and Surgery in High-risk Rectal Cancer

Acronym

LARCT-US

Official Title

Phase II of Short Course Radiation Therapy Followed by Pre-operative Chemotherapy and Surgery in Primary High-risk Rectal Cancer

Study Type

Interventional

2. Study Status

Record Verification Date

October 2018

Overall Recruitment Status

Recruiting

Study Start Date

July 4, 2016 (Actual)

Primary Completion Date

June 30, 2020 (Anticipated)

Study Completion Date

June 30, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Uppsala University

Collaborators

Swedish Cancer Society

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

5. Study Description

Brief Summary

Patients with a primary rectal cancer without detectable distant metastasis who after locoregional therapy only, meaning preoperative radio(chemo)therapy plus surgery have at least a 40% risk of not having a CRM negative resection or a recurrence, local or distant, within three years will be treated with the short course 5 x 5 Gy radiation scheme followed by four cycles of combination chemotherapy (capecitabine and oxaliplatin) and TME surgery

Detailed Description

The multicentre, multinational RAPIDO (Rectal cancer And Pre-operative Induction therapy followed by Dedicated Operation, EudraCT number 2010-023957-12) closed patient entry in June 2016 after having randomised the planned number of 920 patients. In the study, patients were randomised to conventional chemoradiotherapy (CRT) to 50 Gy with capecitabine followed by surgery or to short-course radiotherapy (scRT, 5 x 5 Gy), 6 cycles of oxaliplatin-capecitabine (CAPOX) followed by surgery. In the CRT arm, adjuvant chemotherapy with 8 cycles of CAPOX was optional. At the time of closure of the RAPIDO study, it was discussed in Uppsala whether CRT should be the reference treatment for these high-risk rectal cancers, the experimental treatment or an alternative. Influenced by a Polish study reported by Bujko et al in 2016 with a similar design comparing CRT with scRT followed by 3 cycles of FOLFOX), it was decided that the reference treatment for patient with primary rectal cancer at high risk of failing either locally or systemically should be scRT followed by 4 cycles of CAPOX and surgery. This regimen, identical to the experimental arm in a Chinese trial (Stellar trial (ClinicalTrials.gov NCT02533271), preliminarily revealing promising pCR rates has since then been the reference treatment for patients having the same inclusion criteria as in the RAPIDO trial. Other centres in Sweden have also decided to use this regimen as reference treatment. A formal protocol is written and approved.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Rectal Cancer

Keywords

rectal cancer, high risk, total neoadjuvant treatment

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Model Description

Treatment with short-course radiotherapy (scRT) followed by 4 cycles of CAPOX chemotherapy and surgery in locally advanced rectal cancer while waiting for the results of the randomized phase III RAPIDO trial

Masking

None (Open Label)

Allocation

N/A

Enrollment

100 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

LARCT-US

Arm Type

Experimental

Arm Description

Short Course Radiation Therapy (5 x 5 Gy in 1 week, scRT) followed by 4 cycles of Pre-operative Chemotherapy using capecitabine and oxaliplatin (CAPOX) and Surgery in High-risk Rectal Cancer

Intervention Type

Combination Product

Intervention Name(s)

radiotherapy, capecitabine, oxaliplatin

Intervention Description

5x5 Gy radiotherapy in 1 week, 4 cycles of CAPOX (capecitabine 1000 mg/m2 x2 d 1-14, oxaliplatin 130 mg/m2 d 1 every third week), surgery

Primary Outcome Measure Information:

Title

Pathological complete response (pCR) rate and clinical complete response (cCR) rate

Description

pCR assessed at pathological examination of the surgical specimen, cCR at clinical and radiological (MRI) examination

Time Frame

pCR assessed directly after surgery and cCR 12 months after end of treatment if no surgery is performed (cCR)]

Secondary Outcome Measure Information:

Title

Disease-free survival

Description

non-radical surgery, recurrence or death within 3 years

Time Frame

3 years

Title

Neoadjuvant rectal score (NAR score)

Description

Score from 0 - 100, where 0 is best

Time Frame

After surgery when the patological examination of the surgical specimen is completed

Title

Incidence of Treatment-Emergent Adverse Events

Description

CTCAE v 4.0

Time Frame

within 60 days after end of treatment

Title

Long-term Adverse Events

Description

CTCAE v 4.0

Time Frame

4 years after end of treatment

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: • Histological proof of newly diagnosed primary adenocarcinoma of the rectum Locally advanced tumour fulfilling at least one of the following criteria on pelvic MRI indicating high risk of failing locally and/or systemically (T4b, i.e. overgrowth to an adjacent organ or structure like the prostate, urinary bladder, uterus, sacrum, pelvic floor or side-wall (according to TNM version 7), cT4a, i.e. peritoneal involvement, extramural vascular invasion (EMVI+). N2, i.e. four or more lymph nodes in the mesorectum showing morphological signs on MRI indicating metastatic disease. Four or more nodes, whether enlarged or not, with a rounded, homogeneous appearance is thus not sufficient. Positive MRF, i.e. tumour or lymph node < 1 mm from the mesorectal fascia. Enlarged lateral nodes, > 1 cm (lat LN+). Exclusion Criteria: Extensive growth into cranial part of the sacrum (above S3) or the lumbosacral nerve roots indicating that surgery will never be possible even if substantial tumour down-sizing is seen. Presence of metastatic disease or recurrent rectal tumour. Familial Adenomatosis Polyposis coli (FAP), Hereditary Non-Polyposis Colorectal Cancer (HNPCC), active Crohn's disease or active ulcerative Colitis. Concomitant malignancies, except for adequately treated basocellular carcinoma of the skin or in situ carcinoma of the cervix uteri. Subjects with prior malignancies must be disease-free for at least 5 years. Known DPD deficiency. Any contraindications to MRI (e.g. patients with pacemakers). Medical or psychiatric conditions that compromise the patient's ability to give informed consent. Concurrent uncontrolled medical conditions. Any investigational treatment for rectal cancer within the past month. Pregnancy or breast feeding. Patients with known malabsorption syndromes or a lack of physical integrity of the upper gastrointestinal tract. Clinically significant (i.e. active) cardiac disease (e.g. congestive heart failure, symptomatic coronary artery disease and cardiac dysrhythmia, e.g. atrial fibrillation, even if controlled with medication) or myocardial infarction within the past 12 months. Patients with symptoms of peripheral neuropathy.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Bengt Glimelius, MD, PhD

Phone

+46 70 6112432

bengt.glimelius@igp.uu.se

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Bengt Glimelius, MD,PhD

Organizational Affiliation

Uppsala University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Akademiska sjukhuset

City

Uppsala

ZIP/Postal Code

S-75185

Country

Sweden

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Calin Radu, MD,PhD

Phone

+46 18 6110000

calin.radu@akademiska.se

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

23742033

Citation

Nilsson PJ, van Etten B, Hospers GA, Pahlman L, van de Velde CJ, Beets-Tan RG, Blomqvist L, Beukema JC, Kapiteijn E, Marijnen CA, Nagtegaal ID, Wiggers T, Glimelius B. Short-course radiotherapy followed by neo-adjuvant chemotherapy in locally advanced rectal cancer--the RAPIDO trial. BMC Cancer. 2013 Jun 7;13:279. doi: 10.1186/1471-2407-13-279.

Results Reference

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PubMed Identifier

26884592

Citation

Bujko K, Wyrwicz L, Rutkowski A, Malinowska M, Pietrzak L, Krynski J, Michalski W, Oledzki J, Kusnierz J, Zajac L, Bednarczyk M, Szczepkowski M, Tarnowski W, Kosakowska E, Zwolinski J, Winiarek M, Wisniowska K, Partycki M, Beczkowska K, Polkowski W, Stylinski R, Wierzbicki R, Bury P, Jankiewicz M, Paprota K, Lewicka M, Cisel B, Skorzewska M, Mielko J, Bebenek M, Maciejczyk A, Kapturkiewicz B, Dybko A, Hajac L, Wojnar A, Lesniak T, Zygulska J, Jantner D, Chudyba E, Zegarski W, Las-Jankowska M, Jankowski M, Kolodziejski L, Radkowski A, Zelazowska-Omiotek U, Czeremszynska B, Kepka L, Kolb-Sielecki J, Toczko Z, Fedorowicz Z, Dziki A, Danek A, Nawrocki G, Sopylo R, Markiewicz W, Kedzierawski P, Wydmanski J; Polish Colorectal Study Group. Long-course oxaliplatin-based preoperative chemoradiation versus 5 x 5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer: results of a randomized phase III study. Ann Oncol. 2016 May;27(5):834-42. doi: 10.1093/annonc/mdw062. Epub 2016 Feb 15.

Results Reference

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Short Course Radiation Therapy Followed by Pre-operative Chemotherapy and Surgery in High-risk Rectal Cancer

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