| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Untreated Stage II/III dMMR/MSI-H locally advanced rectal 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 | 21.0 | | E.1.2 | Level | PT | | E.1.2 | Classification code | 10038049 | | E.1.2 | Term | Rectal cancer stage II | | E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) | |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 | | E.1.2 | Level | PT | | E.1.2 | Classification code | 10038050 | | E.1.2 | Term | Rectal cancer stage III | | 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 | | - To estimate the efficacy of dostarlimab in participants with Stage II/III (locally advanced) dMMR/MSI-H rectal cancer that has not been previously treated | |
| E.2.2 | Secondary objectives of the trial | - To further estimate the efficacy of dostarlimab in participants with Stage II/III (locally advanced) dMMR/MSI-H rectal cancer that has not been previously treated
- To assess the safety and tolerability of dostarlimab in participants with Stage II/III (locally advanced), dMMR/MSI-H rectal cancer that has not been previously treated
- To describe the PK of dostarlimab in participants with Stage II/III (locally advanced), dMMR/MSI-H rectal cancer that has not been previously treated
- To determine the immunogenicity of dostarlimab in participants with Stage II/III (locally advanced), dMMR/MSI-H rectal cancer that has not been previously treated | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | Inclusion criteria
Inclusion criteria (Prescreening Period)
A Prescreening Period will only be available at sites/countries where
local dMMR/MSI-H testing is not available. The Prescreening Period is
not required for participants whose dMMR/MSI-H status has been previously determined. Prior to Screening, participants without must meet the Prescreening criteria below. To be eligible for participation in the study, participants must meet the full inclusion and exclusion criteria presented in Section 5.1.2 and Section 5.2, respectively, after completing the Prescreening Period.
Age
1. Is at least 18 years of age (or the local legal age of consent) at the
time of signing the ICF.
Type of participant and disease characteristics
1. Has histologically confirmed Stage II to III (T3-T4, N0, or T any, N+),
locally advanced rectal adenocarcinoma.
2. Has radiologically and endoscopically evaluable disease.
Inclusion criteria (Screening Period)Participants are eligible to be
included in the study only if all the following criteria apply:
Age
1. Is at least 18 years of age (or the local legal age of consent) at the
time of signing the ICF.
2. Has histologically confirmed Stage II to III (T3-T4, N0, or T any, N+),
locally advanced rectal adenocarcinoma.
3. Has radiologically and endoscopically evaluable disease.
4. Has a tumor demonstrating the presence of either:
a. dMMR status; MMR status must be assessed by IHC for MMR protein expression (MLH1, MSH2, MSH6, PMS2) where loss of 1 or more proteins indicates MMR; MMR status may be determined either locally or by the central reference laboratory; or
b. MSI-H phenotype as determined by polymerase chain reaction or by tissue next generation sequencing; MSI-H may be determined locally.
NOTE: Participants who are known to have Lynch syndrome and have
been found to carry a specific germline mutation in an MMR gene (MLH1, MSH2, MSH6, PMS2,or EPCAM) may be eligible to participate.
5. Has an archival FFPE tissue sample that must be available and
submitted to the central reference laboratory for testing at Screening. If no archival tissue is available, a fresh baseline biopsy will be required.
8. Has an ECOG performance status of 0 or 1.
9. Has adequate organ function, as defined in Table 8. (NOTE: A
complete blood count test should be obtained without transfusion or
receipt of colony-stimulating factors within 2 weeks of obtaining the
sample.)
For a full list of Inclusion criteria please refer to the Study Protocol
Section 5.1 Inclusion Criteria | |
| E.4 | Principal exclusion criteria | Exclusion criteria
Participants are excluded from the study if any of the following criteria apply:
Medical conditions
1. Has distant metastatic disease.
2. Has received prior radiation therapy, systemic therapy, or surgery for management of rectal cancer. Note: Endoscopy guided biopsy is not considered surgery.
3. Has a tumor that, in the investigator's judgment, is causing symptomatic bowel obstruction or otherwise requires urgent/emergent local intervention.
4. Has a known additional malignancy that progressed or required active treatment within the past 2 years. Exceptions include adequately treated superficial skin cancers, superficial bladder cancers, and other in situ cancers.
5. Is immunocompromised in the opinion of the investigator.
6. Has an active autoimmune disease that has required systemic
treatment in the past 2 years (i.e., with use of disease-modifying agents, corticosteroids, orimmunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
8. Has experienced any of the following with prior immunotherapy: any irAE of Grade ≥3, immune-related severe neurologic events of any grade (e.g., myasthenic syndrome/myasthenia gravis, encephalitis, Guillain- Barré Syndrome, or transverse myelitis), exfoliative dermatitis of any grade (Stevens-Johnson Syndrome, toxic epidermal necrolysis, or DRESS syndrome), or myocarditis of any grade. Non-clinically significant laboratory abnormalities are not exclusionary.
9. Has undergone any major surgical procedure, open biopsy, or experienced significant traumatic injury within 28 days prior to
enrollment.
15. Is receiving immunosuppressive medication.
16. Has received systemic corticosteroids (>10 mg daily prednisone or
equivalent) within 7 days of first dose of study intervention. Use of
inhaled steroids, local injection of steroids, topical steroids, and
steroidal eye drops are allowed.
18. Has received or plans to receive an organ or stem cell transplant that uses donor stem cells (allogeneic stem cell transplant).
For a full list of Exclusion criteria please refer to the Study Protocol
Section 5.2 | |
| E.5 End points |
| E.5.1 | Primary end point(s) | | - cCR12 as assessed by ICR, defined as maintenance of cCR for 12 months. The 12-month period starts from the first disease assessment after last dose of study intervention that demonstrates cCR by ICR. | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | | - cCR12 as assessed by ICR, defined as maintenance of cCR for 12 months. The 12-month period starts from the first disease assessment after last dose of study intervention that demonstrates cCR by ICR. | |
| E.5.2 | Secondary end point(s) | • cCR24 as assessed by ICR, defined as maintenance of cCR for 24
months. The 24-month period starts from the first disease assessment after last dose of study intervention that
demonstrates cCR by ICR.
• cCR36 as assessed by ICR, defined as maintenance of cCR for 36
months. The 36-month period starts from the first
disease assessment after last dose of study intervention that
demonstrates cCR by ICR.
• EFS3 as assessed by investigator assessment, defined as remaining
alive and free of 1) disease progression precluding
surgery, 2) local recurrence, and 3) distant recurrence, as assessed by
investigator at 3 years from the first dose of study intervention.
• EFS by investigator assessment defined as time from the date of first dose of study intervention to any of the following events:
1) progression of disease that precludes surgery, 2) local recurrence, 3) distant recurrence (all as assessed by the investigator), or 4) death due to any cause
• cCR12 by investigator assessment
• cCR24 by investigator assessment
• cCR36 by investigator assessment
• ORR by ICR, defined as achieving a PR, nCR, or cCR at PIDA
or at least 4 weeks but no longer than 8 weeks after PIDA for
participants with nCR or iCR (PIDA 2)
• ORR at PIDA by investigator assessment
• Organ preservation rate at 3 years, defined as not undergoing TME,
either as primary management or for local recurrence, or
who did not have a permanent colostomy created, at any time up to 3
years
• DSS, Disease-Specific Survival, defined as time from the date of first
dose of study intervention to death due to disease under
study
• DSS5, defined as not dying due to disease under study at 5 years from the first dose of study intervention
• OS, defined as time from first dose of study intervention to death from any cause
• OS5, defined as being alive at 5 years from first dose of study
intervention
Frequency and severity of AEs, SAEs, irAEs, and AEs leading to death or discontinuation of study intervention
Serum concentrations and PK parameters (C-EOI and Ctrough) for
dostarlimab Incidence of ADA against dostarlimab | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | • cCR24 as assessed by ICR, defined as maintenance of cCR for 24
months. The 24-month period starts from the first
disease assessment after last dose of study intervention that
demonstrates cCR by ICR.
• cCR36 as assessed by ICR, defined as maintenance of cCR for 36
months. The 36-month period starts from the first
disease assessment after last dose of study intervention that
demonstrates cCR by ICR.
• EFS3 as assessed by investigator assessment, defined as remaining
alive and free of 1) disease progression precluding
surgery, 2) local recurrence, and 3) distant recurrence, as assessed by
investigator at 3 years from the first dose of study
intervention. | |
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | Yes |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 23 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned | | Canada | | Japan | | Korea, Republic of | | United Kingdom | | United States | | France | | Germany | | Italy | | Netherlands | | Spain | |
| 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 | 6 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 18 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 18 |
