Rectal Cancer
Conditions
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.
Interventions
DRUGAvelumab
Avelumab 10 mg/Kg every 2 weeks for 4 cycles post LCCRT
DRUG5 Fluorouracil
5FU continuous infusion 225mg/m2/day during radiotherapy
Can be administered in place of 5FU infusion. Dose = 825 mg/m2 twice a day on each day of radiotherapy
RADIATIONRadiotherapy
50.4 Gy in 28 fractions delivered over 5.5 weeks as 5 fractions/week
PROCEDURESurgical Resection
Surgical resection of tumour mass post radiotherapy and chemotherapy
Sponsors
Peter MacCallum Cancer Centre, Australia
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
All participants will receive standard LCCRT treatment followed by 4 cycles of Avelumab followed by surgical resection
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female aged ≥ 18 years at screening 2. Patients with histologically confirmed rectal adenocarcinoma clinical stage T3bN1-N2M0, T3c/dN0-N2M0, T4N0-N2M0 (see Appendix 1),1 as defined by pelvic MRI 3. 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 4. Lower border of tumour must be within 12 cm from anal verge 5. Measurable disease by RECIST1.12 6. ECOG Performance Status 0-1 7. Patients must be willing to provide fresh (where possible) and archival tumour tissue samples for translational studies at specified time points 8. Adequate organ function 1. Absolute neutrophil count ≥1.5 x 109/L 2. Platelet count ≥100 x 109/L 3. Haemoglobin ≥ 90 g/L (may have been transfused) 4. Creatinine ≤ 1.5 x upper normal limit OR measured creatinine clearance ≥ 50 mL/minute 5. Total bilirubin ≤ 1.5 x upper normal limit 6. AST/ALT ≤ 2.5 x upper normal limit 9. Female patients of childbearing potential must have a negative urine or serum pregnancy test at screening 10. Both male and female patients should be willing to use highly effective contraception (that is, methods with a failure rate of less than 1% per year) if the risk of conception exists 11. Has provided written informed consent for the trial 12. Agrees to comply with trial therapy or trial-related investigations and evaluations
Exclusion criteria
1. Patients with disease outside the pelvis 2. Prior pelvic radiotherapy 3. Participation in another interventional clinical trial within 30 days of registration (participation in observational studies are permitted) 4. Concurrent anti-cancer treatment 5. Concurrent treatment with a non-permitted drug (Section 8.3.2) 6. Major surgery for any reason within 4 weeks of registration (except defunctioning stoma creation with the patient having fully recovered from this procedure) 7. 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 8. 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 9. Active or history of immunodeficiencies 10. Has received prior therapy with an anti-PD1, anti-PDL1, anti-PDL2 or anti-CTLA-4 agents 11. 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. 12. Has an active infection requiring systemic therapy 13. 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 14. Prior malignancies within 3 years of registration (with the exception of non- melanomatous skin cancer) 15. Prior organ transplantation, including allogeneic stem-cell transplantation 16. A known history of testing positive for HIV or known acquired immunodeficiency syndrome (AIDS) 17. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test is positive) 18. Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (CTCAE v4.03 grade ≥ 3) 19. Is pregnant or lactating 20. Vaccination within 4 weeks of registration and while on trials is prohibited except for administration of inactivated vaccines 21. Known deficiency of dihydropyrimidine dehydrogenase
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathological Response rate | At time of resection i.e.16 -18 weeks post commencement of treatment | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Response as per structural imaging | At 8 weeks post LCCRT | Describe radiological response rate based on Pelvic MRI post PD-L1 blockade as per RECIST 1.1 |
| Overall FDG PET response | At 8 weeks post LCCRT | Describe FDG-PET response rate post PDL1 blockade as per PERCIST |
| Define toxicity during administration of PDL1 inhibitor and post-surgery | From consent until 4 weeks post surgery | Worst grade AE's and SAE's CTCAE version 4.03 |
| Determine rate of downstaging | At time of surgical resection | Patients will be considered downstaged if the pathologic T or N stage at surgery assessment is lower than the initial radiological stage. |
Countries
Australia
Outcome results
None listed