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Avelumab With Chemoradiation in Locally Advanced Rectal Cancer

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ClinicalTrials.gov Identifier: NCT03299660
Recruitment Status : Recruiting
First Posted : October 3, 2017
Last Update Posted : May 14, 2020
Sponsor:
Information provided by (Responsible Party):
Peter MacCallum Cancer Centre, Australia

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.

Condition or disease Intervention/treatment Phase
Rectal Cancer Drug: Avelumab Drug: 5 Fluorouracil Drug: Capecitabine Pill Radiation: Radiotherapy Procedure: Surgical Resection Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: All participants will receive standard LCCRT treatment followed by 4 cycles of Avelumab followed by surgical resection
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Trial PD-L1/PD-1 Blockade Avelumab (MSB0010718C) With Chemoradiotherapy for Locally Advanced Resectable Rectal Cancer
Actual Study Start Date : April 30, 2018
Estimated Primary Completion Date : February 1, 2022
Estimated Study Completion Date : April 1, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Avelumab

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 Name: 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




Primary Outcome Measures :
  1. Pathological Response rate [ Time Frame: 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 Outcome Measures :
  1. Response as per structural imaging [ Time Frame: At 8 weeks post LCCRT ]
    Describe radiological response rate based on Pelvic MRI post PD-L1 blockade as per RECIST 1.1

  2. Overall FDG PET response [ Time Frame: At 8 weeks post LCCRT ]
    Describe FDG-PET response rate post PDL1 blockade as per PERCIST

  3. Define toxicity during administration of PDL1 inhibitor and post-surgery [ Time Frame: From consent until 4 weeks post surgery ]
    Worst grade AE's and SAE's CTCAE version 4.03

  4. Determine rate of downstaging [ Time Frame: 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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03299660


Contacts
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Contact: Michael Michael, A/Prof +61385597860 Michael.Michael@petermac.org
Contact: Maria Farrell +61386697533 Maria.Farrell@petermac.org

Locations
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Australia, Victoria
Peter MacCallum Cancer Centre Recruiting
Melbourne, Victoria, Australia, 3002
Contact: Michael Michael, A/Prof    +61385597860    michael.michael@petermac.org   
Sponsors and Collaborators
Peter MacCallum Cancer Centre, Australia
Investigators
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Principal Investigator: Michael Michael, A/Prof Peter MacCallum Cancer Centre, Australia
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Responsible Party: Peter MacCallum Cancer Centre, Australia
ClinicalTrials.gov Identifier: NCT03299660    
Other Study ID Numbers: AveRec
First Posted: October 3, 2017    Key Record Dates
Last Update Posted: May 14, 2020
Last Verified: December 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Rectal Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Rectal Diseases
Fluorouracil
Capecitabine
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs