| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally advanced (stage IIIA/B, T3/T4, any N,M0) anal cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 10061424 |
| E.1.2 | Term | Anal 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Pembrolizumab, a new drug, is a monoclonal antibody that enhances the body’s immune response to cancer cells by acting on a receptor on the surface of T-cells. This receptor is called Programmed Death-1 (PD-1). The CORINTH study aims to see whether this new drug, pembrolizumab, can be added safely to standard chemoradiotherapy. We will explore how safe the combination is and how well tolerated it is for patients with stage T3/4 anal cancer. |
|
| E.2.2 | Secondary objectives of the trial |
1. We will assess the feasibility of combining pembrolizumab (an immune checkpoint inhibitor) with standard chemoradiotherapy in patients with locally advanced T3/4 anal cancer. We will use a series of sequential cohorts of 6 patients where in each cohort pembrolizumab will be introduced earlier in the patient’s chemoradiation. We will be looking at study eligibility, recruitment, planned treatment in terms of adherence to trial protocol and treatment retention in each cohort.
2. Using a series of sequential cohorts of 6 patients where in each cohort pembrolizumab (an immune checkpoint inhibitor) will be introduced earlier in the patient’s chemoradiation, we will evaluate clinical response rates (disappearance of all signs of cancer in response to treatment) of the different schedules of exposure of pembrolizumab in CRT in patients with locally advanced T3/4 anal cancer. We want to assess if the addition of pembrolizumab offers at least a similar clinical complete response as that of |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| CORINTH translational study will generate samples from all cohorts to explore potential predictive and prognostic biomarkers for combination immuno-chemoradiation in anal cancer. The study will explore the association between clinical response and pharmacodynamic characteristics of peripheral blood and additional tumour tissue genomic biomarkers which may be relevant to the alteration the immune environment, both locally and systemically, in treated patients. The characterization of this evolving immune status over time during treatment will inform how future combinations should be optimized, both within this clinical context and with other immunotherapy combinations with RT/CRT. |
|
| E.3 | Principal inclusion criteria |
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide written informed consent/assent for the trial.
2. Age 18 years or over on day of signing informed consent.
3. Histologically proven Squamous Cell Cancer of Anus (SCCA) Stage IIIA/B (T3/4, +/- any N, M0) anal cancer or highly suspicious and confirmed by the MDT
4. Be willing to provide tissue sample either archival or repeat biopsy to be tested for HPV and p16.
5. Have a performance status of 0 or 1 on the ECOG Performance Scale.
6. Demonstrate adequate organ function performed within 10 days of treatment initiation.
a. Haematological: Absolute neutrophil count (ANC) ≥1.5 x 109/L, Platelets ≥100 x 109/L, Haemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within 7 days of assessment)
b. 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).
c. Renal: Serum creatinine ≤1.5 X upper limit of normal (ULN) OR Measured or
calculated creatinine clearance (GFR can also be used in place of creatinine
or CrCl) ≥60 mL/min for subject with creatinine levels > 1.5 X institutional
ULN
d. Hepatic Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for
subjects with total bilirubin levels > 1.5 ULN
7. Female subject of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
8. Female subjects of childbearing potential must be willing to use an adequate method of contraception as outlined in Section 15.9 – Contraception and pregnancy, for the course of the study through 120 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
9. Male subjects of childbearing potential must agree to use an adequate method of contraception as outlined in Section 15.9- Contraception and pregnancy, starting with the first dose of study therapy through 120 days after the last dose of study therapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
|
|
| E.4 | Principal exclusion criteria |
The subject must be excluded from participating in the trial if the subject:
1. Has malignant tumour of non-epithelial origin (sarcoma)
2. Has any metastatic disease
3. Is unsuitable for radical CRT for whatever reason
4. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
5. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Patients on long-term physiological doses of steroid (¬<10mg prednisolone or equivalent) are eligible.
6. Has a known history of active TB (Bacillus Tuberculosis)
7. Hypersensitivity to pembrolizumab or any of its excipients.
8. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
9. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
a. Note: Subjects with ≤ Grade 2 neuropathy are an exception to this
criterion and may qualify for the study.
b. Note: If subject received major surgery, they must have recovered
adequately from the toxicity and/or complications from the intervention prior
to starting therapy.
10. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer or previous VIN (vulval intra-epithelial neoplasia) or vulval cancer adequately treated, or previous adequately treated breast cancer / DCIS > 5 years ago.
11. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
12. Has known history of, or any evidence of active, non-infectious pneumonitis.
13. Has an active infection requiring systemic therapy.
14. 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.
15. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
16. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
17. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
18. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)
19. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g. HCV RNA is detected). Testing only required if patient has a history of either of these.
20. Has received a live vaccine within 30 days of planned start of study therapy. (Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.)
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Safety and tolerability of a combination of different schedules of exposure to pembrolizumab, an immune checkpoint inhibitor, concomitantly with standard CRT in patients with locally advanced T3/4 anal cancer by assessing AEs / SAEs and extent of protocol adherence by study population. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Mandatory safety visit at 30 days post chemo-radiotherapy
Early toxicity check 6 weeks post chemo-radiotherapy
Later toxicity check at 12 weeks post chemo-radiotherapy
Late toxicity assessment 6, 9 and 12 months post treatment |
|
| E.5.2 | Secondary end point(s) |
1.Feasibility of combining pembrolizumab, an immune checkpoint inhibitor, with standard CRT at different schedules in patients with locally advanced T3/4 anal cancer as measured by:
a.Adherence to protocol treatment, as assessed by numbers of patients receiving per protocol treatment, dose delays, treatment reductions, treatment discontinuation and documenting the reasons for delays or discontinuation for each patient.
b.Retention as assessed by the proportion of patients withdrawing from protocol treatment and number of patients lost to follow-up with documentation of reasons in each case.
c.Recruitment rate as assessed by the number of days study is open for recruitment, the number of patients screened, the number of screened patients not recruited and why and the number (proportion) of patients recruited.
d.Study eligibility as assessed by the number of patients eligible and ineligible at screening and reasons for ineligibility.
2.Clinical response assessment as measured by RECIST v 1.1 (MRI) for the overall response rate (ORR) at 3 and 6 months post-CRT and 12 months follow up.
3.Patient-reported outcomes (PRO) using the PRO-CTCAE tool during CRT, pembrolizumab monotherapy and 6 post CRT and 12 months follow-up to assess symptomatic toxicity both acute and late.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
A statistical analysis plan will be developed before the earliest toxicity check 30 days post CRT.
No interim analysis is planned for this study.
Efficacy Analysis: Clinical response assessment as measured by RECIST v 1.1 (MRI) for the overall response rate (ORR) at 3 months and 6 months post-CRT and at 12 months follow up.
Patient Reported Outcomes Analysis: Patient reported outcomes will be measured by the PRO-CTCAE tool during CRT, pembrolizumab monotherapy and 6 and 12 months follow-up. |
|
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Safety and tolerability Feasibility |
|
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 1 |
| 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
|
| The end of the trial is defined as the date of final data capture to meet the trial endpoints. Date of final data capture is defined as the act of entering the final data onto the trial database. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
Print
