Avelumab With Chemoradiation in Locally Advanced Rectal Cancer

Phase II Trial PD-L1/PD-1 Blockade Avelumab (MSB0010718C) With Chemoradiotherapy for Locally Advanced Resectable Rectal Cancer

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.

Study Overview

• Status: Completed
• Conditions: Rectal Cancer
• Intervention / Treatment: Drug: Avelumab; Drug: 5 Fluorouracil; Drug: Capecitabine Pill; Radiation: Radiotherapy; Procedure: Surgical Resection

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Randwick, New South Wales, Australia, 2031
      • Prince of Wales Hospital
    • St Leonards, New South Wales, Australia, 2065
      • Royal North Shore
  • Victoria
    • Box hill, Victoria, Australia, 3128
      • Box Hill Hospital
    • Malvern, Victoria, Australia, 3144
      • Cabrini Hospital
    • Melbourne, Victoria, Australia, 3002
      • Peter Maccallum Cancer Centre
    • Melbourne, Victoria, Australia
      • Monash Health
    • Prahran, Victoria, Australia, 3000
      • Alfred Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Avelumab; 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; Avelumab 10 mg/Kg every 2 weeks for 4 cycles post LCCRT; Other Names: MSB0010718C; Drug: 5 Fluorouracil; 5FU continuous infusion 225mg/m2/day during radiotherapy; Drug: Capecitabine Pill; Can be administered in place of 5FU infusion. Dose = 825 mg/m2 twice a day on each day of radiotherapy; Radiation: Radiotherapy; 50.4 Gy in 28 fractions delivered over 5.5 weeks as 5 fractions/week; Procedure: Surgical Resection; Surgical resection of tumour mass post radiotherapy and chemotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response as per structural imaging	Describe radiological response rate based on Pelvic MRI post PD-L1 blockade as per RECIST 1.1	At 8 weeks post LCCRT
Overall FDG PET response	Describe FDG-PET response rate post PDL1 blockade as per PERCIST	At 8 weeks post LCCRT
Define toxicity during administration of PDL1 inhibitor and post-surgery	Worst grade AE's and SAE's CTCAE version 4.03	From consent until 4 weeks post surgery
Determine rate of downstaging	Patients will be considered downstaged if the pathologic T or N stage at surgery assessment is lower than the initial radiological stage.	At time of surgical resection

Collaborators and Investigators

• Sponsor: Peter MacCallum Cancer Centre, Australia

Study record dates

Study Major Dates

• Study Start (Actual): April 30, 2018
• Primary Completion (Actual): February 28, 2023
• Study Completion (Actual): February 28, 2023

Study Registration Dates

• First Submitted: September 24, 2017
• First Submitted That Met QC Criteria: October 1, 2017
• First Posted (Actual): October 3, 2017

Study Record Updates

• Last Update Posted (Actual): March 16, 2023
• Last Update Submitted That Met QC Criteria: March 14, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Fluorouracil; Capecitabine; Avelumab
• Other Study ID Numbers: AveRec

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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