Colon Rectal CancerPhase 2AVANANCT03854799
Immunotherapy In Locally Advanced Rectal Cancer
A Phase 2 study testing Avelumab, Capecitabine and EXTERNAL---BEAM IRRADIATION 50.4 GY in people with Colon Rectal Cancer, run by Gruppo Oncologico del Nord-Ovest at 1 site in Italy.
Trial summary
Preoperative CTRT is considered the standard of care in the management of LARC. Preoperative CTRT approach results in significant tumor downstaging and local control with a complete pathological response rate of about 15% even if additional therapeutic strategies should be explored to improve outcomes, expecially for… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Colon Rectal Cancer
- What is being tested?
- Avelumab, Capecitabine and EXTERNAL---BEAM IRRADIATION 50.4 GY
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 101 participants
- Where
- 1 siteItaly
- Study dates
- 1 Apr 2019to 30 Sep 2023
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Written informed consent to study procedures.
- Histologically proven diagnosis of rectal adenocarcinoma
- Locally advanced, resectable disease defined by the presence of at least one of the following features:
- cN+ (with the definition of a clinically positive lymph node being any node ≥ 1 cm)
- cT4
- high risk cT3 (according to magnetic resonance imaging [MRI] criteria): tumour extending to within 1 mm of or beyond the mesorectal fascia (ie, circumferential radial margin threatened or involved); lower third (≤ 6 cm from the anal verge); tumour extending 5 mm or more into perirectal fat
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- Distal tumor margin at < 12 cm from the anal verge
- No evidence of metastatic disease by computed tomography (CT) scan of the chest and abdomen and total body FDG-PET/CT scan
- Tumor must be amenable to curative resection (curative resection can include pelvic exenteration)
- No history of invasive rectal malignancy, regardless of disease-free interval
- No other rectal cancers (i.e., sarcoma, lymphoma, carcinoid, squamous cell carcinoma, or cloacogenic carcinoma) or synchronous colon cancer
- No clear indication of involvement of the pelvic side walls by imaging
- Age ≥ 18 years
- Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1
- Life expectancy of at least 5 years (excluding diagnosis of cancer)
- Hematopoietic: absolute neutrophil count ≥ 1,500/mm3; platelet count ≥ 100,000/mm3; haemoglobin level ≥ 9 g/dL
- Hepatic: total bilirubin ≤ 1.5 times upper limit of normal (ULN); alkaline phosphatase ≤ 2 times ULN; AST and ALT ≤ 2.5 times ULN [Note: *If AST>ULN, serologic testing for Hepatitis B and C must be negative]
- Renal: creatinine clearance ³ 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method); no renal disease that would preclude study treatment or follow-up
- Available tumor samples at baseline (archival biopsy) and after chemoradiotheraphy + avelumab
- Male subjects with female partners of childbearing potential must be willing to use adequate contraception as outlined in Section 5.5 - Contraception, starting with the first dose of study therapy through 180 days after the last dose of treatment Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
- Women of childbearing potential must have a negative blood or urine pregnancy test at the baseline visit
- Female subjects of childbearing potential must be willing to use an adequate method of contraception as outlined in Section 5.5 - Contraception, for the course of the study starting with the first dose of study therapy through 180 days after the last dose of treatment Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
- Will and ability to comply with the protocol.
Who cannot join
- Previous therapy with any antibody or drug targeting T cell coregulatory proteins, or immunosuppressive agents
- Previous pelvic RT
- Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible
- Any of the following in the 6 months prior to treatment start: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, congestive heart failure (≥ New York Heart Association Classification Class II), cerebrovascular accident/strock, transient ischemic attack, serious cardiac arhythmia requiring medication or symptomatic pulmonary embolism
- Uncontrolled coagulopathy
- Active infection requiring systemic therapy
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- Current use of immunosuppressive medication, EXCEPT for the following: a. Intranasal, inhaled, topical steroids, or local steroids 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)
- Prior organ transplantation including allogenic stem-cell transplantation
- Active tubercolosis
- Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
- 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 positive)
- Vaccination within 4 weeks of the first dose of avelumab and while on trials is prohibited except for administration of inactivated vaccines
- Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v4.03 Grade ≥ 3)
- Pregnant female patients, breastfeeding female patients, and male patients able to father children and female patients of childbearing potential who are unwilling or unable to use 2 highly effective methods of contraception as outlined in the protocol for the duration of the study
- Lack of upper gastrointestinal tract integrity or malabsorption syndrome; immune colitis; active inflammatory bowel disease (i.e., patients requiring current medical interventions or who are symptomatic)
- Patients with prior malignancies (with the exception of rectal cancer), including invasive colon cancer, are eligible provided they have been disease-free for ≥ 5 years and are deemed by their physician to be at low risk for recurrence
- Other malignancy within the past 5 years with the exception of effectively treated squamous cell or basal cell skin cancer, melanoma in situ, carcinoma in situ of the cervix, or carcinoma in situ of the colon or rectum
- Other severe acute or chronic medical conditions including immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; 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
- Any concomitant drugs contraindicated for use with the trial drugs according to the product information of the pharmaceutical companies.
- Pregnant or lactating women. Women of childbearing potential with either a positive or no pregnancy test at baseline. Postmenopausal women must have been amenorrheic for at least 12 months to be considered of non-childbearing potential. Sexually active males and females (of childbearing potential) unwilling to practice contraception during the study and until 180 days after the last trial treatment.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Phase II Study Of Preoperative Chemoradiotherapy Plus Avelumab In Patients With Locally Advanced Rectal Cancer
Preoperative CTRT is considered the standard of care in the management of LARC. Preoperative CTRT approach results in significant tumor downstaging and local control with a complete pathological response rate of about 15% even if additional therapeutic strategies should be explored to improve outcomes, expecially for T4 cancers.
Immunotherapy with PD-1/PD-L1 immunocheckpoint blockade (ICB), turned out a breakthrough in cancer treatment among different tumor types, including CRC. An ICB strategy could lead up to a 40% of response in metastatic CRC with deficient mismatch repair (MMR) status. Unfortunately, the activity of ICBs in MMR proficient mCRC is extremely low but it might be improved using immunomodulatory strategies as demonstrated by Bendell et al.
Read more
In this context, the role of RT in revert the tolerance to a low neoantigen-burden (such as in MMR proficient CRCs) by the induction of antigen release from the tumour and activation of dendritic cells leading to a CD8+ T lymphocyte-mediated anticancer immune response has been widely elucidated. Moreover, antineoplastic agents can be exploited to target other crucial cellular effectors of immunosuppressive tumor microenvironment (i.e. regulatory T cells and myeloid-derived suppressor cells).
In line with these evidences, Hecht et al. have recently reported that in rectal cancer patients, neoadjuvant CTRT increases PD-L1 expression in tumor cells, strongly suggesting a neoadjuvant combinatory strategy with RT and PD-1/PD-L1 pathway blockade. The integration of immunotherapy in the neoadjuvant setting (instead of adjuvant one) for the management of LARC is also supported by preclinical findings showing that in metastatic breast cancer mice models, neoadjuvant immunotherapy is superior in inducing long-term survivors, compared with adjuvant strategy with a greater magnitude of tumor-specific T cell expansion in neoadjuvant treated mice and a better anti-tumor T cell-mediated immune response.
On the basis of such considerations, there is a strong biological and clinical rationale for testing the addition of avelumab, an anti-PD-L1 moab, to capecitabine-based CTRT in patients with technically resectable, LARC. The aim of this strategy is to lead to significant improvements of pCR and, ultimately, patients' survival.
- Conditions
- Colon Rectal Cancer
- Being tested
- Avelumab, Capecitabine, EXTERNAL---BEAM IRRADIATION 50.4 GY
- Medical subject headings
- Colonic Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AvelumabDrug
Eligible patients will receive:
CHEMORADIOTHERAPY PLUS AVELUMAB:
- CAPECITABINE 825 mg/sqm/bid p.o. 5 days/week
- EXTERNAL-BEAM IRRADIATION 50.4 GY in 28 fractions over 5.5 weeks
- AVELUMAB 10 mg/Kg ev over 1 hour every 2 weeks at days 1, 14, 28, 42, 56, 70
Surgery with TME must be performed at week 8-10 after the end of CTRT. The final choice of surgical procedure (ie, abdominoperineal surgery or anterior resection) is at the surgeon's discretion.
CapecitabineDrug
Eligible patients will receive:
CHEMORADIOTHERAPY PLUS AVELUMAB:
- CAPECITABINE 825 mg/sqm/bid p.o. 5 days/week
- EXTERNAL-BEAM IRRADIATION 50.4 GY in 28 fractions over 5.5 weeks
- AVELUMAB 10 mg/Kg ev over 1 hour every 2 weeks at days 1, 14, 28, 42, 56, 70
Surgery with TME must be performed at week 8-10 after the end of CTRT. The final choice of surgical procedure (ie, abdominoperineal surgery or anterior resection) is at the surgeon's discretion.
EXTERNAL---BEAM IRRADIATION 50.4 GYRadiation
Surgery with TME must be performed at week 8-10 after the end of CTRT. The final choice of surgical procedure (ie, abdominoperineal surgery or anterior resection) is at the surgeon's discretion.
| Study group | Role | What they receive |
|---|---|---|
| CHEMORADIOTHERAPY PLUS AVELUMAB | Experimental | CHEMORADIOTHERAPY PLUS AVELUMAB:
CAPECITABINE 825 mg/sqm/bid p.o. 5 days/week EXTERNAL-BEAM IRRADIATION 50.4 GY in 28 fractions over 5.5 weeks AVELUMAB 10 mg/Kg ev over 1 hour every 2 weeks at days 1, 14, 28, 42, 56, 70 Receives: Drug: Avelumab; Drug: Capecitabine; Radiation: EXTERNAL---BEAM IRRADIATION 50.4 GY |
What is being measured
The primary outcome is the main question the study is designed to answer.
The primary objective of this trial is to evaluate the rate of complete pathologic response (pCR)
pCR rate is defined as the percentage of patients, relative to the total of enrolled subjects,achieving complete histological regression with no available tumor cells yT0N0
Measured: 24 months
Secondary outcomes (4)
R0 resection rate
is defined as the percentage of patients, relative to the total of enrolled subjects, undergoing R0 resection of primary tumour
Measured: 24 months
Tumor downstaging
is defined as reduction of at least one level in T or N staging between the baseline MRI and histopathological staging, without evidence of upstaging or disease progression.
Measured: 24 months
Local recurrence
is defined as an intrapelvic recurrence following a primary rectal cancer resection, with or without distal metastasis.
Measured: 24 months
Sphincter preservation rate
is defined as the percentage of patients undergoing sphincter-sparing surgery.
Measured: 24 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Feb 2019
- Study start1 Apr 2019
- Primary completion15 Feb 2021
- Study completion30 Sep 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Colon Rectal CancerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 101 participants (actual)
Sponsor and investigators
- Lead sponsor
- Gruppo Oncologico del Nord-Ovest
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03854799
- Sponsor's protocol ID
- 2017-003582-10
- Other IDs
- 2017
- Acronym
- AVANA
- Status last verified
- Oct 2023
- First submitted
- 12 Feb 2019
- Last updated
- 19 Oct 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 19 Oct 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase II Study Of Preoperative Chemoradiotherapy Plus Avelumab In Patients With Locally Advanced Rectal Cancer
- ClinicalTrials.gov ID
- NCT03854799
- Acronym / sponsor ID
- AVANA / 2017-003582-10
- Conditions
- Colon Rectal Cancer
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 101 participants (actual)
- Lead sponsor
- Gruppo Oncologico del Nord-OvestUniversity, hospital or other
- Study start
- 1 Apr 2019 (actual)
- Primary completion
- 15 Feb 2021 (actual)
- Study completion
- 30 Sep 2023 (actual)
- First posted
- 26 Feb 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Preoperative CTRT is considered the standard of care in the management of LARC. Preoperative CTRT approach results in significant tumor downstaging and local control with a complete pathological response rate of about 15% even if additional therapeutic strategies should be explored to improve outcomes, expecially for T4 cancers.
Immunotherapy with PD-1/PD-L1 immunocheckpoint blockade (ICB), turned out a breakthrough in cancer treatment among different tumor types, including CRC. An ICB strategy could lead up to a 40% of response in metastatic CRC with deficient mismatch repair (MMR) status. Unfortunately, the activity of ICBs in MMR proficient mCRC is extremely low but it might be improved using immunomodulatory strategies as demonstrated by Bendell et al.
In this context, the role of RT in revert the tolerance to a low neoantigen-burden (such as in MMR proficient CRCs) by the induction of antigen release from the tumour and activation of dendritic cells leading to a CD8+ T lymphocyte-mediated anticancer immune response has been widely elucidated. Moreover, antineoplastic agents can be exploited to target other crucial cellular effectors of immunosuppressive tumor microenvironment (i.e. regulatory T cells and myeloid-derived suppressor cells).
In line with these evidences, Hecht et al. have recently reported that in rectal cancer patients, neoadjuvant CTRT increases PD-L1 expression in tumor cells, strongly suggesting a neoadjuvant combinatory strategy with RT and PD-1/PD-L1 pathway blockade. The integration of immunotherapy in the neoadjuvant setting (instead of adjuvant one) for the management of LARC is also supported by preclinical findings showing that in metastatic breast cancer mice models, neoadjuvant immunotherapy is superior in inducing long-term survivors, compared with adjuvant strategy with a greater magnitude of tumor-specific T cell expansion in neoadjuvant treated mice and a better anti-tumor T cell-mediated immune response.
On the basis of such considerations, there is a strong biological and clinical rationale for testing the addition of avelumab, an anti-PD-L1 moab, to capecitabine-based CTRT in patients with technically resectable, LARC. The aim of this strategy is to lead to significant improvements of pCR and, ultimately, patients' survival.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| CHEMORADIOTHERAPY PLUS AVELUMAB | Experimental | Drug: Avelumab, Drug: Capecitabine, Radiation: EXTERNAL---BEAM IRRADIATION 50.4 GYCHEMORADIOTHERAPY PLUS AVELUMAB: CAPECITABINE 825 mg/sqm/bid p.o. 5 days/week EXTERNAL-BEAM IRRADIATION 50.4 GY in 28 fractions over 5.5 weeks AVELUMAB 10 mg/Kg ev over 1 hour every 2 weeks at days 1, 14, 28, 42, 56, 70 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (23 listed)
- Written informed consent to study procedures.
- Histologically proven diagnosis of rectal adenocarcinoma
- Locally advanced, resectable disease defined by the presence of at least one of the following features:
- Distal tumor margin at < 12 cm from the anal verge
- No evidence of metastatic disease by computed tomography (CT) scan of the chest and abdomen and total body FDG-PET/CT scan
Key exclusion criteria (20 listed)
- Previous therapy with any antibody or drug targeting T cell coregulatory proteins, or immunosuppressive agents
- Previous pelvic RT
- Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible
- Any of the following in the 6 months prior to treatment start: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, congestive heart failure (≥ New York Heart Association Classification Class II), cerebrovascular accident/strock, transient ischemic attack, serious cardiac arhythmia requiring medication or symptomatic pulmonary embolism
- Uncontrolled coagulopathy
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AvelumabEligible patients will receive: CHEMORADIOTHERAPY PLUS AVELUMAB: * CAPECITABINE 825 mg/sqm/bid p.o. 5 days/week * EXTERNAL-BEAM IRRADIATION 50.4 GY in 28 fractions over 5.5 weeks * AVELUMAB 10 mg/Kg ev over 1 hour every 2 weeks at days 1, 14, 28, 42, 56, 70 Surgery with TME must be performed at week 8-10 after the end of CTRT. The final choice of surgical procedure (ie, abdominoperineal surgery or anterior resection) is at the surgeon's discretion. | Drug | CHEMORADIOTHERAPY PLUS AVELUMAB |
| CapecitabineEligible patients will receive: CHEMORADIOTHERAPY PLUS AVELUMAB: * CAPECITABINE 825 mg/sqm/bid p.o. 5 days/week * EXTERNAL-BEAM IRRADIATION 50.4 GY in 28 fractions over 5.5 weeks * AVELUMAB 10 mg/Kg ev over 1 hour every 2 weeks at days 1, 14, 28, 42, 56, 70 Surgery with TME must be performed at week 8-10 after the end of CTRT. The final choice of surgical procedure (ie, abdominoperineal surgery or anterior resection) is at the surgeon's discretion. | Drug | CHEMORADIOTHERAPY PLUS AVELUMAB |
| EXTERNAL---BEAM IRRADIATION 50.4 GYSurgery with TME must be performed at week 8-10 after the end of CTRT. The final choice of surgical procedure (ie, abdominoperineal surgery or anterior resection) is at the surgeon's discretion. | Radiation | CHEMORADIOTHERAPY PLUS AVELUMAB |
Primary outcome
The primary objective of this trial is to evaluate the rate of complete pathologic response (pCR)
Time frame: 24 months
pCR rate is defined as the percentage of patients, relative to the total of enrolled subjects,achieving complete histological regression with no available tumor cells yT0N0
4 secondary outcomes
R0 resection rate
Time frame: 24 months
Tumor downstaging
Time frame: 24 months
Local recurrence
Time frame: 24 months
Sphincter preservation rate
Time frame: 24 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Oct 2023.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Avelumab, Capecitabine and EXTERNAL---BEAM IRRADIATION 50.4 GY in people with Colon Rectal Cancer, run by Gruppo Oncologico del Nord-Ovest at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 23 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Oct 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The primary objective of this trial is to evaluate the rate of complete pathologic response (pCR) (time frame: 24 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Oct 2023.