| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the lower end of the large bowel. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10038038 |
| E.1.2 | Term | Rectal cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary objectives:
(1) Evaluate the efficacy of durvalumab in combination with either short course radiotherapy or long course chemoradiation followed by FOLFOX chemotherapy. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives:
(1) Evaluate safety and tolerability of durvalumab in combination with long course chemoradiotherapy as comparted to short course radiotherapy followed by FOLFOX.
(2) Evaluate the efficacy of durvalumab in priming an immune response when administered in combination with either short course radiotherapy or long course chemoradiation followed by FOLFOX chemotherapy.
(3) Evaluate the efficacy of durvalumab in combination with either short course radiotherapy or long course chemoradiation followed by FOLFOX chemotherapy.
(4) Evaluate long term outcome at 36 months
(5) Evaluate the requirement for permanent colostomy.
(6) Evaluate the ability for patients to undergo radical surgical resection post neo-adjuvant treatment.
(7) Ability to deliver neo-adjuvant radiotherapy or chemoradiation.
(8) Evaluate the surgical morbidity following this neo-adjuvant treatment schedule
(9) To measure quality of life of patients receiving this treatment.
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|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion criteria:
1.Be willing and able to provide written informed consent for the trial.
2.Willingness to comply with scheduled visits, treatment plans and laboratory tests and other trial procedures including willingness to provide repeated biopsy samples of tumour via flexible sigmoidoscopy.
3.Age 16 or over on the day of signing informed consent.
4.Histologically confirmed non-metastatic, locally advanced rectal adenocarcinoma deemed appropriate for radical treatment.
5.Non-metastatic disease confirmed with CT of chest/abdomen and pelvis. Note: Suspicious extramesorectal lymph nodes identified on initial staging investigations are not considered an exclusion criteria if the local MDT deem these resectable at and would treat patients with curative intent.
6.The rectal tumour must have at least one of the following high risk criteria on MRI scan:
• cT3b+ OR
• EMVI positive, OR
• Primary tumour or morphologically malignant lymph node at 1mm or less from the mesorectal fascia or beyond the mesorectal fasica OR
• Low rectal tumour and the consensus of the multi-disciplinary meeting is that abdomino-perineal excision would be required for sufficient surgical management.
7.ECOG performance status 0-1 (see Appendix 2)
8.No contra-indication to treatment with pelvic radiotherapy. For example, no pre-existing condition which would deter radiotherapy, e.g.Table of, fistulas, severe ulcerative colitis (particularly subjects currently taking sulphasalazine), Crohn’s disease, prior adhesions.
9.Primary disease which can be encompassed within a radical radiotherapy treatment volume.
10.Adequate haematological and biochemical function as indicated below. These measurements should be performed within 7 days prior to randomisation:
- Absolute neutrophil count > 1.5 x 10-9/L.
- Platelets ≥100 x109/l.
- Haemoglobin ≥90 g/l. Transfusion is acceptable if necessary to increase haemoglobin levels.
- Coagulation International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.
- Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.
- Renal Creatinine OR Measured or calculated a creatinine clearance* (GFR can also be used in place of creatinine or CrCl) ≤1.5 X upper limit of normal (ULN) OR ≥660 mL/min for subject with creatinine levels > 1.5 X institutional ULN.
*Creatinine clearance should be calculated per institutional standard.
- Bilirubin <1.5 x upper limit of normal (ULN) except for unconjugated hyperbilirubinemia in patients who have Gilbert’s syndrome. In this case direct bilirubin must be ≤ ULN for subjects with total bilirubin levels > 1.5 ULN.
- AST and ALT ≤ 2.5 X ULN.
- Albumin ≥ 2.5 g/dL.
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|
| E.4 | Principal exclusion criteria |
Exclusion criteria:
1.Patients with DPD deficiency (any degree).
2.Unable to have MRI assessment
3.Patient weight less than or equal to 30kg.
4.Previous pelvic radiotherapy
5.Metastatic disease defined by CT (includes resectable metastases).
6.Previous treatment with immunotherapy including but not limited to anti-PD-1, anti-PD-L1, anti-PD-L2 or anti-CTLA4 agents, interferon or anti-IL2 for the treatment of malignancy.
7.Previous treatment with chemotherapy for the treatment of current malignancy or treatment with chemotherapy within the last 5 years for a separate malignancy (unless that malignancy was treated squamous/basal cell skin cancer, treated early stage cervical cancer or treated/biochemically stable, organ confined prostate cancer).
8.History of a separate malignancy in the last 5 years (other than treated squamous/basal cell skin cancer, treated early stage cervical cancer or treated/biochemically stable, organ confined prostate cancer).
9.Pregnant or lactating females or males unwilling to use a highly effective method of contraception. Women of childbearing potential, and men with female partners of childbearing potential, must agree to use adequate contraceptive measures for the duration of the study and for 6 months after the completion of study treatment.
10. Major surgery within 28 days prior to trial entry
11. Prolongation of corrected QT (QTc) interval to >470 msec when electrolyte balance is normal.
12. Recent occurrence (within 3-6 months) of a major thromboembolic event, such as pulmonary embolism or proximal deep vein thrombosis, unless stable on (2 weeks) therapeutic anticoagulation (aspirin <325 mg daily or low-molecular-weight heparin [LMWH]). Subjects with a history of clinically non-significant thromboembolic events, not requiring anticoagulation, are allowed on study.
13.Active inflammatory bowel disease affecting the colon and rectum based on previous endoscopy and defined by ongoing drug treatment.
14. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., levothyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
15. Patients with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
16. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisolone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial drug.
17. Has a history of (non-infectious) interstitial pneumonia or pneumonitis that required steroids or current pneumonitis.
18. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
19.Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
20.Has received a live vaccine within 30 days prior to the first dose of trial drug.
21.Any patients receiving treatment with brivudine, sorivudine and analogues or patients who have not stopped these drugs at least 4 weeks prior to start of study treatment
22.Any patient with severe diarrhoea (defined as ≥ grade 3 diarrhoea despite maximum supportive measures and exclusion of underlying infection)
23.Known hypersensitivity for any component of any study drug
24.Administration of any investigational drug within 28 days or 5 half-lives, whichever is longer, prior to receiving the first dose of trial treatment.
25.Uncontrolled CHF, or history of MI, unstable angina, stroke, or transient ischemia within previous 6 months.
26.Patients with known malabsorption or inability to comply with oral medication
27.Human immunodeficiency virus (HIV1/2).
28.Hepatitis B or Hepatitis C.
29.Receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Includes prior organ transplantation including allogenic stem-cell transplant.
30.Known history of active TB. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of patients achieving a complete clinical response (CCR) or a complete pathological response at 6 months. In each arm, treatment would be considered to be effective if >30% of patients exhibit complete clinical or pathological response. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 6 months following initiation of treatment. |
|
| E.5.2 | Secondary end point(s) |
(1) Objective: Evaluate safety and tolerability of durvalumab in combination with long course chemoradiotherapy as compared to short course radiotherapy followed by FOLFOX.
Endpoint: Occurrence of Grade 3-5 treatment-emergent adverse events and treatment-related adverse events.
(2) Objective: Evaluate the efficacy of durvalumab in priming an immune response when administered in combination with either short course radiotherapy or long course chemoradiotherapy followed by FOLFOX chemotherapy.
Endpoint: Presence of a moderate-high grade CD3+ T cell infiltrate on rectal tumour biopsy during treatment. In each arm, treatment would be considered to be effective if a mod-high grade CD3+ infiltrates are seen at any time point after commencing treatment in 40% of patients.
(3) Objective: Evaluate the efficacy of durvalumab in combination with either short course radiotherapy or long course chemoradiotherapy followed by FOLFOX chemotherapy.
Endpoint:
(a) In patients who do not achieve a cCR, the proportion of patients with a NAR score <8.
(b) Proportion of patients achieving MRI-confirmed complete tumour regression (using ESGAR template)
(c) Proportion of patients achieving MRI-confirmed near complete tumour regression (using ESGAR template)
(d) Proportion of patients achieving MRI-confirmed downstaging in T stage
(4) Objective: Evaluate long term outcome at 36 months
Endpoints:
(a) Proportion of patients with local regrowth after a cCR.
(b) Overall survival at 36 months.
(c) Recurrence free survival at 36 months.
(5) Objective: Evaluate the requirement for permanent colostomy.
Endpoint: Proportion of patients who have a permanent colostomy.
(6) Objective: Evaluate the ability for patients to undergo radical surgical resection post neo-adjuvant treatment.
Endpoint: Proportion of patients who proceed to surgery (or who have a complete clinical response and go onto the deferred surgery pathway).
(7) Objective: Ability to deliver neo-adjuvant radiotherapy or chemoradiotherapy.
Endpoint: Proportion of patients receiving at least 4 fractions of short course RT or 20 fractions of long course RT. For those patients having long course chemoradiotherapy the proportion of patients receiving 80% or greater of the planned capecitabine dose will also be evaluated.
(8) Objective: Evaluate the surgical morbidity following this neo-adjuvant treatment schedule
Endpoint: In patients undergoing surgical resection, Clavien-Dindo grading of complications will be performed. Proportion of patients with Grade 3-5 complications
(9) Objective: To measure quality of life of patients receiving this treatment.
Endpoint: Patient Reported Outcome Measures (PROMS) through the use of EORTC QLQ30, EORTC CR29 and EQ5D. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
(1) During neo-adjuvant treatment and for up to at least 30 days after the last dose of CTIMP.
(2) As measured on biopsy samples taken at week 2 and 6 during neoadjuvant treatment and at the end of treatment
(3)(a) Post-surgery
(b) Post treatment MRI
(c) Post treatment MRI
(d) Post treatment MRI
(4)(a) Any time during follow up
(b) 36 months (post randomisation)
(c) 36 months (post randomisation)
(5) After surgery until end of follow up
(6) End of treatment (approximately week 15-18)
(7) End of treatment (approximately week 15-18)
(8) Post-surgery
(9) Time-points for QoL: Baseline and months 3, 6, 12, 18, 24 and 30
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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