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Capecitabine Plus Concomitant Radiation Therapy Followed by Durvalumab as Preoperative Treatment in Rectal Cancer (PANDORA)

Primary Purpose

RECTAL CANCER

Status
Recruiting
Phase
Phase 2
Locations
Italy
Study Type
Interventional
Intervention
Capecitabine
Radiotherapy
Durvalumab
Sponsored by
AUSL Romagna Rimini
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for RECTAL CANCER

Eligibility Criteria

18 Years - 100 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria

  1. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and Data Privacy Directive obtained from the patient/legal representative prior to performing any protocol- related procedures, including screening evaluations.
  2. Age > 18 years at time of study entry.
  3. Eastern Cooperative Oncology Group (ECOG) 0 or 1.
  4. Histological diagnosis of adenocarcinoma of rectum.
  5. Clinical stage 2-3 rectal adenocarcinoma, cT3/4N0/M0 or Tx N1-2/M0, assessed by thorax abdomen pelvis with contrast Computed tomography (CT) scan, pelvi Magnetic resonance imaging (MRI) scan, pancolonscopy.
  6. Able to swallow oral medication.
  7. Body weight >30kg.
  8. Adequate normal organ and marrow function as defined below:

    1. Haemoglobin ≥9.0 g/dL - Absolute neutrophil count (ANC) > 1500 per mm3
    2. Platelet count >100.000 per mm3
    3. Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology), who will be allowed only in consultation with their physician.
    4. AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal
    5. Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976).
  9. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre- menopausal patients. Women of childbaring potential or male patients with a female partner of childbearing potential must agree to use at least 1 highly effective method of contraception from the time of screening throughout the total duration of the drug treatment and the drug washout period (90 days after the last dose of durvalumab monotherapy) as detailed in section 7.1. Women will be considered post-menopausal if they have been amenorrhoeic for 12 months without an alternative medical cause. The following age-specific requirements apply:

    1. Women <50 years of age would be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post- menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
    2. Women ≥50 years of age would be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
  10. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up. 11. Must have a life expectancy of at least 12 weeks.

Exclusion Criteria:

  1. Previous treatment for local advanced rectum cancer.
  2. Concurrent enrolment in another clinical study unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study. 3. Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab.
  3. History of hypersensitivity to fluorouracil.
  4. Known Dihydropyrimidine dehydrogenase (DPD) deficiency.
  5. History of another primary malignancy except for:

    1. Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of study drug and of low potential risk for recurrence
    2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease - Adequately treated carcinoma in situ without evidence of disease e.g., cervical cancer in situ
  6. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. The following are exceptions to this criterion:

    1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
    2. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
    3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
  7. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
  8. Major surgical procedure within 28 days prior to the first dose of treatment.
  9. History of allogenic organ transplantation.
  10. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:

    1. Patients with vitiligo or alopecia
    2. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement - Any chronic skin condition that does not require systemic therapy
    3. Patients without active disease in the last 5 years may be included but only after consultation with the study physician
    4. Patients with celiac disease controlled by diet alone
  11. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
  12. History of leptomeningeal carcinomatosis.
  13. History of active primary immunodeficiency.
  14. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
  15. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.
  16. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ highly effective birth control from screening to 90 days after the last dose of durvalumab monotherapy.
  17. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
  18. Judgment by the investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements.
  19. Patients unable to follow the Protocol procedures and to sign the informed consent. In the case of patients' incapable of giving informed consent, it must be provided and signed by guardians or legal representative. Patients incapable must also sign the agreement to the extent that they are able to do so.

Sites / Locations

  • Ospedale Degli Infermi Uo OncologiaRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

CAPECITABINE + concomitant RT + Durvalumab

Arm Description

After careful staging, patients will be initiated to a standard concomitant chemoradiation therapy with 825 mg/m2 twice daily capecitabine every day for 5 weeks and 5040 cGy radiotherapy for 5 days per week for 5 weeks. At the end of treatment patients will undergo a lesion biopsy. One week after the end of CT/RT patients will be treated with 1500 mg IV Q4W durvalumab for 3 administrations. From week 9 to 10 after neoadjuvant therapy will be performed re-staging with CT and MRI scan. Surgery will be performed at week 10-12 from the end of CT/RT and the surgical piece will be analyzed

Outcomes

Primary Outcome Measures

Pathological complete response (pCR) rate after durvalumab treatment
The primary end point will be assessed by means of the proportion of patients having complete pathological response pCR after durvalumab treatment. Corresponding two-sided 95% confidence intervals (CIs) will be computed.

Secondary Outcome Measures

The clinical complete remission rate (cCR) after durvalumab treatment
The secondary endpoints are the clinical complete remission rate (cCR) after durvalumab treatment, before surgery. The secondary end point will be assessed by means of the proportion of patients having complete remission rate (cCR) after durvalumab treatment. Corresponding two-sided 95% confidence intervals (CIs) will be computed.
Disease-free survival (DSF)
The disease-free survival will be evaluated during a follow up of 5 years. . DFS will be estimated by using Kaplan-Meier approach

Full Information

First Posted
August 30, 2019
Last Updated
May 29, 2023
Sponsor
AUSL Romagna Rimini
Collaborators
AstraZeneca, Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori
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1. Study Identification

Unique Protocol Identification Number
NCT04083365
Brief Title
Capecitabine Plus Concomitant Radiation Therapy Followed by Durvalumab as Preoperative Treatment in Rectal Cancer
Acronym
PANDORA
Official Title
A Phase II Study of Capecitabine Plus Concomitant Radiotion Therapy Followed by Durvalumab (MEDI4736) as Preoperative Treatment in Rectal Cancer.
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
January 1, 2020 (Actual)
Primary Completion Date
November 30, 2022 (Actual)
Study Completion Date
August 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
AUSL Romagna Rimini
Collaborators
AstraZeneca, Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
This is a prospective phase II, open label, single arm, multi-centre study to evaluate activity of an innovative sequence on capecitabine plus concomitant radiation therapy followed by durvalumab in patients with operable rectal cancer. The enrollment period will be of 12 months. Eligible patients will be initiated to a standard concomitant chemoradiation therapy for 5 weeks. One week after the end of CT/RT patients will be treated with durvalumab for 3 administrations. Patient will undergo surgery after 10-12 weeks from the end of CT/RT and the surgical piece will be analyzed. After surgery patients will be followed up for 5 years, according to clinical practice.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
RECTAL CANCER

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
100 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
CAPECITABINE + concomitant RT + Durvalumab
Arm Type
Experimental
Arm Description
After careful staging, patients will be initiated to a standard concomitant chemoradiation therapy with 825 mg/m2 twice daily capecitabine every day for 5 weeks and 5040 cGy radiotherapy for 5 days per week for 5 weeks. At the end of treatment patients will undergo a lesion biopsy. One week after the end of CT/RT patients will be treated with 1500 mg IV Q4W durvalumab for 3 administrations. From week 9 to 10 after neoadjuvant therapy will be performed re-staging with CT and MRI scan. Surgery will be performed at week 10-12 from the end of CT/RT and the surgical piece will be analyzed
Intervention Type
Drug
Intervention Name(s)
Capecitabine
Intervention Description
chemoradiation therapy with 825 mg/m2 twice daily capecitabine every day for 5 weeks
Intervention Type
Drug
Intervention Name(s)
Radiotherapy
Intervention Description
5040 cGy radiotherapy for 5 days per week for 5 weeks
Intervention Type
Drug
Intervention Name(s)
Durvalumab
Intervention Description
One week after the end of CT/RT patients will be treated with 1500 mg IV Q4W durvalumab for 3 administrations
Primary Outcome Measure Information:
Title
Pathological complete response (pCR) rate after durvalumab treatment
Description
The primary end point will be assessed by means of the proportion of patients having complete pathological response pCR after durvalumab treatment. Corresponding two-sided 95% confidence intervals (CIs) will be computed.
Time Frame
36 months
Secondary Outcome Measure Information:
Title
The clinical complete remission rate (cCR) after durvalumab treatment
Description
The secondary endpoints are the clinical complete remission rate (cCR) after durvalumab treatment, before surgery. The secondary end point will be assessed by means of the proportion of patients having complete remission rate (cCR) after durvalumab treatment. Corresponding two-sided 95% confidence intervals (CIs) will be computed.
Time Frame
36 months
Title
Disease-free survival (DSF)
Description
The disease-free survival will be evaluated during a follow up of 5 years. . DFS will be estimated by using Kaplan-Meier approach
Time Frame
60 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
100 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and Data Privacy Directive obtained from the patient/legal representative prior to performing any protocol- related procedures, including screening evaluations. Age > 18 years at time of study entry. Eastern Cooperative Oncology Group (ECOG) 0 or 1. Histological diagnosis of adenocarcinoma of rectum. Clinical stage 2-3 rectal adenocarcinoma, cT3/4N0/M0 or Tx N1-2/M0, assessed by thorax abdomen pelvis with contrast Computed tomography (CT) scan, pelvi Magnetic resonance imaging (MRI) scan, pancolonscopy. Able to swallow oral medication. Body weight >30kg. Adequate normal organ and marrow function as defined below: Haemoglobin ≥9.0 g/dL - Absolute neutrophil count (ANC) > 1500 per mm3 Platelet count >100.000 per mm3 Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology), who will be allowed only in consultation with their physician. AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976). Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre- menopausal patients. Women of childbaring potential or male patients with a female partner of childbearing potential must agree to use at least 1 highly effective method of contraception from the time of screening throughout the total duration of the drug treatment and the drug washout period (90 days after the last dose of durvalumab monotherapy) as detailed in section 7.1. Women will be considered post-menopausal if they have been amenorrhoeic for 12 months without an alternative medical cause. The following age-specific requirements apply: Women <50 years of age would be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post- menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy). Women ≥50 years of age would be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up. 11. Must have a life expectancy of at least 12 weeks. Exclusion Criteria: Previous treatment for local advanced rectum cancer. Concurrent enrolment in another clinical study unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study. 3. Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab. History of hypersensitivity to fluorouracil. Known Dihydropyrimidine dehydrogenase (DPD) deficiency. History of another primary malignancy except for: Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of study drug and of low potential risk for recurrence Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease - Adequately treated carcinoma in situ without evidence of disease e.g., cervical cancer in situ Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. The following are exceptions to this criterion: Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection) Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable. Major surgical procedure within 28 days prior to the first dose of treatment. History of allogenic organ transplantation. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion: Patients with vitiligo or alopecia Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement - Any chronic skin condition that does not require systemic therapy Patients without active disease in the last 5 years may be included but only after consultation with the study physician Patients with celiac disease controlled by diet alone Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent History of leptomeningeal carcinomatosis. History of active primary immunodeficiency. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ highly effective birth control from screening to 90 days after the last dose of durvalumab monotherapy. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients. Judgment by the investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements. Patients unable to follow the Protocol procedures and to sign the informed consent. In the case of patients' incapable of giving informed consent, it must be provided and signed by guardians or legal representative. Patients incapable must also sign the agreement to the extent that they are able to do so.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
STEFANO TAMBERI
Phone
0546601193
Email
stefano.tamberi@auslromagna.it
Facility Information:
Facility Name
Ospedale Degli Infermi Uo Oncologia
City
Faenza
ZIP/Postal Code
48018
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
STEFANO TAMBERI
Email
stefano.tamberi@auslromagna.it

12. IPD Sharing Statement

Learn more about this trial

Capecitabine Plus Concomitant Radiation Therapy Followed by Durvalumab as Preoperative Treatment in Rectal Cancer

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