This study has been transitioned to CTIS with ID 2023-509583-22-00 check the CTIS register for the current data. Primary objective:To estimate the efficacy of dostarlimab in participants with Stage II/III (locally advanced) dMMR/MSI-H rectal cancer…
ID
Source
Brief title
Condition
- Malignant and unspecified neoplasms gastrointestinal NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
cCR12 (complete clinical response) as assessed by ICR (independent central
review), 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.
Secondary outcome
• 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 an 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
Background summary
The widely accepted standard of care SOC in the United States and Europe for
locally advanced rectal cancer is neoadjuvant therapy followed by surgery and
adjuvant chemotherapy. However, there is an evolving body of literature
supporting treatment with both concurrent chemoradiotherapy and chemotherapy in
the neoadjuvant setting.
Unfortunately, chemo- and radiotherapy for locally advanced rectal cancer
results in significant morbidity for patients, including bowel, urinary, and
sexual dysfunction; secondary malignancy; infertility; and substantially
impaired quality of life.
Results from clinical studies in various tumor types have demonstrated that
anti-PD-1 antibodies, including dostarlimab, are effective in metastatic dMMR
tumors regardless of tissue of origin.
Studies of immunotherapy in early-stage dMMR/MSI-H colon cancer provide further
support to the use of immunotherapy in this population.
The purpose of this study is to investigate dostarlimab monotherapy in
participants with locally advanced mismatch-repair deficient
(dMMR)/microsatellite instability-high (MSI H) rectal cancer who have received
no prior treatment.
Study objective
This study has been transitioned to CTIS with ID 2023-509583-22-00 check the CTIS register for the current data.
Primary objective:
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
Secondary Objectives:
- 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
Study design
All participants will complete a Screening Period of up to 28 days to assess
eligibility. Eligible participants who have pathologically confirmed,
previously untreated locally advanced rectal cancer that is dMMR/MSI-H (as
assessed by local testing) will enroll in the Intervention Period and be
treated with dostarlimab 500 mg intravenously every 3 weeks for 9 cycles,
although study intervention can be discontinued early in the event of disease
progression or intolerable toxicity. Pharmacokinetic and immunogenicity
samples will be obtained from all participants at certain time points. Safety
evaluation will include collection of treatment-emergent adverse events,
clinical laboratory assessments, electrocardiograms, Eastern Cooperative
Oncology Group (ECOG) performance status, physical examinations, concomitant
medications, and vital signs.
At any point during study intervention administration, if the participant has
evidence of disease progression, they will be transitioned to standard of care
therapy, which will be selected at the investigator*s discretion. Details of
the selected subsequent anticancer therapy, response, and survival outcomes of
these participants will be collected. Any participants achieving complete
clinical response prior to the end of the Intervention Period will continue to
receive study intervention .
Following completion of the Intervention Period, participants will undergo the
post intervention disease assessment, including endoscopy, rectal MRI, and CT
CAP. These assessments will be reviewed to determine clinical response.
Treatment decisions will be made based upon the investigator*s assessment of
clinical response.
If the participant meets criteria for clinical response, they will begin the
non-operative management period. If the participant has any response less than
a clinical response, they will proceed to standard of care therapy.
Intervention
Dostarlimab 500 mg intravenously every 3 weeks for 9 cycles
Study burden and risks
These side effects are considered very common in patients who took dostarlimab
(may affect more than 1 in 10 people):
• Decrease in the number of red blood cells that carry oxygen. Low red blood
cells count may make you feel tired or short of breath and symptoms may require
a blood transfusion (Anaemia)
• Underactive thyroid gland (Hypothyroidism)
• Feeling sick to the stomach (Nausea)
• Vomiting
• Frequent watery stools (Diarrhoea)
• Itchy skin (Pruritus)
• Rash
• Fever (Pyrexia)
• Increased levels of substances in the blood produced by the liver which may
be a sign of liver injury (AST increased; ALT increased) (Transaminases
increased)
These side effects are considered common in patients who took dostarlimab (may
affect up to 1 in 10 people):
• Decreased production of adrenal hormones resulting in possible weakness
and/or low blood pressure (Adrenal insufficiency)
• Overactive thyroid gland (Hyperthyroidism)
• Inflammation of the lungs which can cause shortness of breath and difficulty
breathing (Pneumonitis)
• Inflammation of the pancreas causing pain in the upper abdomen. This could
become severe and cause nausea and vomiting, fever and rapid heart rate
(Pancreatitis)
• Inflammation of the colon that can cause stomach pain or diarrhoea (Colitis)
• Muscle pain (Myalgia)
• Chills
These side effects are considered uncommon in patients who took dostarlimab
(may affect up to 1 in 100 people):
• Destruction of red blood cells which can cause tiredness, dizziness, yellow
skin or fast heart rate (Autoimmune haemolytic anaemia)
• Inflammation of the thyroid gland (Thyroiditis)
• Pituitary gland inflammation (Hypophysitis)
• Severe high blood sugar due to uncontrolled diabetes (Diabetic Ketoacidosis)
• Diabetes requiring insulin (Type 1 Diabetes Mellitus)
• Inflammation in the brain (encephalitis)
• Inflammation of the eye which can cause redness, blurred vision or vision
loss (Uveitis)
• Inflammation of the heart muscle (myocarditis)
• Inflammation of the Liver (Hepatitis)
• Muscle pain involving several muscles (Polymyalgia rheumatica)
• Kidney inflammation (Nephritis)
• Myasthenia gravis
• Immune-mediated arthritis
• Inflammation of the lining of the stomach (Gastritis)
• Inflammation of the food pipe (Esophagitis)
• Inflammation of the small intestine (Enteritis)
• Inflammation of blood vessels in the gastrointestinal tract (Vasculitis
gastrointestinal)
• Inflammation of the muscle which can cause weakness, swelling and pain
(Myositis)
• Inflammation throughout the whole body leading to high or low temperatures,
low blood pressure, increased heart rate, increased rate of breathing and low
or high white blood cell count (Systemic Inflammatory Response Syndrome)
• Infusion-related reactions which can occur within 24 hours after receiving an
intravenous infusion, or which can be delayed for up to about 2 weeks.
Infusion-related reactions may include dizziness or fainting, flushing, rash,
fever, chills, shortness of breath, increased or decreased blood pressure,
increased heart rate, swelling of the lips, tongue or face, feeling sick to
your stomach, back pain or pain at the site of infusion. Although
infusion-related reactions are usually reversible, they can be severe or life
threatening. (Infusion related reactions)
There are rare but serious immune-related adverse events which have been seen
when dostarlimab was used alone or in combination with other medicines:
• Overactive immune-system cells which damage body tissues and organs leading
to signs of uncontrolled fever, enlarged spleen, low blood count and liver test
abnormalities. This disease can be fatal. (Hemophagocytic Lymphohistiocytosis)
• A neurological disorder where the immune system attacks part of the
peripheral nervous system that can cause tingling in the feet and hands, pain,
muscle weakness, and problems with coordination (Guillain-Barre syndrome).
Risks of measurements:
- Blood draw: pain, bruising, irritation, or redness from the needle, fainting/
feeling faint may occur. In rare cases, an infection and/or swelling and
redness along a vein may occur.
- ECG: skin irritation from the patches.
- CT Scan: exposure to radiation (total of 171 mSv) and possible allergic
reaction to the contrast dye (mild to to severe (such as breathing difficulties
and shock)). There is a risk that the injection of dyes may cause pain,
swelling, bruising, irritation, or redness at the site. In rare cases, an
infection may occur.
- Biopsy during endoscopy: discomfort, feeling faint, local mild pain, pressure
or pain from the needle, soreness, or tenderness at the biopsy site, swelling
or redness, and scarring at the biopsy site. In rare cases, an infection may
occur.
Risks related to the expected outcome of treatment:
Dostarlimab is still experimental for people who have rectal cancer. In
another, ongoing clinical trial that is testing dostarlimab in patients living
with early-stage rectal cancer, it has been shown that dostarlimab has helped
the patients with the ability to delay surgery and chemotherapy and radiation
for an extended amount of time. However, there is a risk that treatment during
this study does not lead to the desired cancer remission. In that case, the
patient will receive the standard of care consisting of chemotherapy, radiation
and/or surgery.
Van Asch van Wijckstraat 55H
Amersfoort 3811 LP
NL
Van Asch van Wijckstraat 55H
Amersfoort 3811 LP
NL
Listed location countries
Age
Inclusion criteria
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 dMMR; 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
ECPAM) 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.
6. A female participant is eligible to participate if she is not pregnant or
breastfeeding, and if a woman of child bearing potential (WOCBP), is using a
contraceptive method that is highly effective
7. Has an ECOG performance status of 0 or 1.
8. Has adequate organ function, as defined in Table 8 of the protocol.
Exclusion criteria
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, see protocol 5.2.1. item 6 for details.
7. Is unable to undergo MRI.
8. Has experienced any of the following with prior immunotherapy: see protocol
5.1.1. item 8 for details
9. Has undergone any major surgical procedure, open biopsy, or experienced
significant traumatic injury within 28 days prior to enrollment.
10. Has any history of interstitial lung disease or pneumonitis.
11. Has cirrhosis or current unstable liver or biliary disease per investigator
assessment, see protocol 5.2.1. item 11 for details.
12. Has a history or current evidence of any medical condition, therapy, or
laboratory abnormality that might confound the study results, interfere with
participation for the full duration of the study intervention, or indicate it
is not in the best interest of the participant to participate, in the opinion
of the investigator.
13. Has a history of or evidence of cardiac abnormalities such as serious,
uncontrolled cardiac arrhythmia or clinically significant ECG abnormalities
within the 6 months prior to enrollment, see protocol 5.2.1. item 14 for
details.
14. Is receiving any other anticancer or experimental therapy, see protocol
5.2.1. item 15 for details.
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, see protocol
5.2.1. item 17 for details.
17. Has received any live vaccine within 30 days prior to enrollment. see
protocol 5.2.1. item 18 for details.
18. Has received or plans to receive an organ or stem cell transplant that uses
donor stem cells (allogeneic stem cell transplant)
19. Has documented presence of HBsAg at Screening, a positive HCV antibody test
result at Screening , a positive HCV RNA test result at Screening ,
20. a known history of HIV infection, see protocol 5.2.1. item 19, 20, 21 & 22
for details.
For a detailed list of Exclusion Criteria please refer to the protocol section
5.2.1.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| Other | 219369 |
| EU-CTR | CTIS2023-509583-22-00 |
| EudraCT | EUCTR2022-003289-18-NL |
| CCMO | NL83464.100.22 |