Avelumab With Chemoradiation in Locally Advanced Rectal Cancer

NCT03299660 | Completed Phase 2 DMC

• 1 other identifier: AveRec
• Study Type: interventional
• Target: 37
• Locations: 1 country
• Sites: 7

Brief Summary

This trial is investigating the inclusion of avelumab post long-course chemo-radiotherapy in patients with resectable locally advanced rectal cancer. It is hypothesised that this may enhance the pathological and imaging response rates whilst potentially reducing the relapse rates. Participants will receive standard long course chemoradiotherapy (LCCRT) treatment with radiotherapy and 5-fluorouracil (5 FU)/Capecitabine for 6 weeks, this then followed by 4 cycles of Avelumab and then surgical resection. The trial will measure disease response just prior to surgery and participants will be followed up for a minimum of 18 months (from study entry) and up to 42 months.

Conditions

Rectal Cancer

Outcome Measures

Primary Outcomes (1)

• Pathological Response rate

  To investigate the role of PD-L1 blockade for rectal cancer following neoadjuvant LCCRT, prior to definitive surgical resection, in terms pathological response rates. Assessed by tumour regression grade in resected rectal cancers post LCCRT at the time of definitive surgery: according to Ryan et al

  At time of resection i.e.16 -18 weeks post commencement of treatment

Secondary Outcomes (4)

• Response as per structural imaging

  At 8 weeks post LCCRT

• Overall FDG PET response

  At 8 weeks post LCCRT

• Define toxicity during administration of PDL1 inhibitor and post-surgery

  From consent until 4 weeks post surgery

• Determine rate of downstaging

  At time of surgical resection

Study Arms (1)

Avelumab

EXPERIMENTAL

Long course chemoradiotherapy (LCCRT) comprised of 50.4 Gy radiotherapy in conjunction with 5FU (225mg/m2/day continuous infusion)/Capecitabine (825 mg/m2 BID on RT days) over 5. 5 weeks, followed by 4 cycles of Avelumab. This is then followed up with surgical resection

Drug: Avelumab; Drug: 5 Fluorouracil; Drug: Capecitabine Pill; Radiation: Radiotherapy; Procedure: Surgical Resection

Interventions

Avelumab DRUG

Avelumab 10 mg/Kg every 2 weeks for 4 cycles post LCCRT

Also known as: MSB0010718C

Avelumab

5 Fluorouracil DRUG

5FU continuous infusion 225mg/m2/day during radiotherapy

Avelumab

Capecitabine Pill DRUG

Can be administered in place of 5FU infusion. Dose = 825 mg/m2 twice a day on each day of radiotherapy

Avelumab

Radiotherapy RADIATION

50.4 Gy in 28 fractions delivered over 5.5 weeks as 5 fractions/week

Avelumab

Surgical Resection PROCEDURE

Surgical resection of tumour mass post radiotherapy and chemotherapy

Avelumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female aged ≥ 18 years at screening
• Patients with histologically confirmed rectal adenocarcinoma clinical stage T3bN1-N2M0, T3c/dN0-N2M0, T4N0-N2M0 (see Appendix 1),1 as defined by pelvic MRI
• Planned to receive neoadjuvant long course chemoradiotherapy (50.4 Gy, with infusional 5FU or capecitabine) followed by curative total mesorectal excision plus abdomino-perineal resection or anterior resection
• Lower border of tumour must be within 12 cm from anal verge
• Measurable disease by RECIST1.12
• ECOG Performance Status 0-1
• Patients must be willing to provide fresh (where possible) and archival tumour tissue samples for translational studies at specified time points
• Adequate organ function
• Absolute neutrophil count ≥1.5 x 109/L
• Platelet count ≥100 x 109/L
• Haemoglobin ≥ 90 g/L (may have been transfused)
• Creatinine ≤ 1.5 x upper normal limit OR measured creatinine clearance ≥ 50 mL/minute
• Total bilirubin ≤ 1.5 x upper normal limit
• AST/ALT ≤ 2.5 x upper normal limit
• Female patients of childbearing potential must have a negative urine or serum pregnancy test at screening

You may not qualify if:

• Patients with disease outside the pelvis
• Prior pelvic radiotherapy
• Participation in another interventional clinical trial within 30 days of registration (participation in observational studies are permitted)
• Concurrent anti-cancer treatment
• Concurrent treatment with a non-permitted drug (Section 8.3.2)
• Major surgery for any reason within 4 weeks of registration (except defunctioning stoma creation with the patient having fully recovered from this procedure)
• Current use of immunosuppressive medication. Except for the following: (a) intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); (b). Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; (c). Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication); (d) Short-term administration of systemic steroids (that is, for allergic reactions or the management of irAEs) is allowed while on study.
• Note: Patients receiving bisphosphonate or denosumab are eligible
• Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible
• Active or history of immunodeficiencies
• Has received prior therapy with an anti-PD1, anti-PDL1, anti-PDL2 or anti-CTLA-4 agents
• Has clinically significant (that is, active) cardiovascular disease: cerebral vascular accident / stroke (\< 6 months prior to registration), myocardial infarction (\< 6 months prior to registration), unstable angina, congestive heart failure (New York Heart Association Classification Class ≥ II), or serious cardiac arrhythmia requiring medication.
• Has an active infection requiring systemic therapy
• Other severe acute or chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behaviour; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study
• Prior malignancies within 3 years of registration (with the exception of non- melanomatous skin cancer)

Sponsors & Collaborators

• Peter MacCallum Cancer Centre, Australia: lead

Study Sites (7)

Prince of Wales Hospital

Randwick, New South Wales, 2031, Australia

Location

Royal North Shore

St Leonards, New South Wales, 2065, Australia

Location

Box Hill Hospital

Box Hill, Victoria, 3128, Australia

Location

Cabrini Hospital

Malvern, Victoria, 3144, Australia

Location

Peter MacCallum Cancer Centre

Melbourne, Victoria, 3002, Australia

Location

Monash Health

Melbourne, Victoria, Australia

Location

Alfred Hospital

Prahran, Victoria, 3000, Australia

Location

MeSH Terms

Conditions

Rectal Neoplasms

Interventions

avelumab; Fluorouracil; Capecitabine; Radiotherapy

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Therapeutics

Study Officials

• Michael Michael, A/Prof

  Peter MacCallum Cancer Centre, Australia

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: All participants will receive standard LCCRT treatment followed by 4 cycles of Avelumab followed by surgical resection

Study Record Dates

• First Submitted: September 24, 2017
• First Posted: October 3, 2017
• Study Start: April 30, 2018
• Primary Completion: February 28, 2023
• Study Completion: February 28, 2023
• Last Updated: March 16, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share

Locations

AU (7)