IRB Study Number 24-278
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
To evaluate the efficacy of peri-operative dostarlimab compared with SOC in participants with untreated T4N0 or Stage III (resectable), dMMR/MSI-H colon cancer.
Secondary Objectives
To evaluate the efficacy of neo-adjuvant dostarlimab in participants with untreated T4N0 or Stage III (resectable), dMMR/MSI-H colon cancer.
To estimate the difference in OS for participants treated with perioperative dostarlimab compared with SOC in participants with untreated T4N0 or Stage III (resectable), dMMR/MSI-H colon cancer.
To evaluate the efficacy of peri-operative dostarlimab compared with SOC in participants with untreated T4N0 or Stage III (resectable), dMMR/MSI-H colon cancer.
To assess the safety and tolerability of dostarlimab compared with SOC in participants with untreated T4N0 or Stage III (resectable), dMMR/MSI-H colon cancer.
To describe the PK of dostarlimab in participants with untreated T4N0 or Stage III (resectable), dMMR/MSI-H colon cancer.
To determine the immunogenicity of dostarlimab in participants with untreated T4N0 or Stage III (resectable), dMMR/MSI-H colon cancer.
Inclusion Criteria
5.1.1. Age
- Is at least 18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place) at the time of signing the ICF.
5.1.2. Type of Participant and Disease Characteristics
Has untreated pathologically confirmed colon adenocarcinoma.
Has resectable colon adenocarcinoma defined as clinically T4N0 or Stage III.
Has radiologically evaluable disease.
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 PCR or by tissue NGS; MSI-H determined by local laboratory. 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 gene may be eligible to participate.
- Provides a tumor tissue sample obtained at the time of or after the initial diagnosis of colon cancer. Although a fresh tumor tissue sample obtained during screening is preferred, an archival tumor specimen (≤6 months old) is acceptable. Tissue biopsy is required. Cytological specimens such as fine needle aspirates or cell blocks are not acceptable.
5.1.3. Sex and Contraceptive/Barrier Requirements
- Is willing to use adequate contraception.
− Contraceptive use by male and female participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
a. Male Participants (only those randomized to the Control Arm):
Male participants are eligible to participate if they agree to the following during the study intervention period and for at least 180 days, after the last dose of chemotherapy, or longer if required by local label or regulations.
• Refrain from donating sperm
PLUS, either:
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent. OR
• Must agree to use contraception/barrier as detailed below o Agree to use a male condom and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak when having sexual intercourse with a WOCBP who is not currently pregnant.
o Agree to use a male condom when engaging in any activity that allows for passage of ejacul*te to another person.
b. Female participants (ALL female participants regardless of randomization):
• A female participant is eligible to participate if she is not pregnant or breastfeeding, and 1 of the following conditions applies:
o Is a WONCBP as defined in the protocol. OR
o Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency, as described in the protocol, during the study intervention period and for at least 120 days after the last dose of dostarlimab.
o For female participants who are randomized to receive chemotherapy, the duration of contraceptive use should be consistent with local label requirements e.g., oxaliplatin requires contraception in females for 9 months in the USPI and 4 months in the SmPC after the last dose; capecitabine requires contraception in females for 6 months after the last dose.
o The investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated) in relationship to the first dose of study intervention.
• A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours before the first dose of study intervention.
• If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
• Additional requirements for pregnancy testing during and after study intervention will be provided in the protocol.
• The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
• If a participant does not receive study treatment, contraception is not required.
5.1.4. Informed Consent
- Can provide a signed informed consent as described in the protocol, including compliance with the requirements and restrictions listed in the ICF and in this protocol.
5.1.5. Performance Status and Organ Function
Has an ECOG- PS of 0 or 1.
Has adequate organ function, as defined in Table 6. (NOTE: A complete blood count test should be obtained without transfusion or receipt of colony stimulating factors within 2 weeks of obtaining the sample). NOTE: Eligibility should be determined using laboratory results obtained during the Screening Period. In situations where laboratory results are outside the permitted range, the investigator may opt to retest the participant and the subsequent within range screening result may be used to confirm eligibility.
Exclusion Criteria
5.2.1. Medical Conditions
Has distant metastatic disease.
Has received prior medical therapy (chemotherapy, immunotherapy, biologic, or targeted therapy), radiation therapy or surgery for management of colon cancer.
Has a tumor that, in the investigator’s judgment is causing symptomatic bowel obstruction or otherwise requires urgent/emergent surgery.
Has, in the investigator’s opinion, a tumor that is not amenable to surgery or has any other contraindication to surgery.
Has a known additional malignancy that progressed or required active treatment within the past 2 years. Exceptions include adequately treated superficial nonmelanoma skin cancers, superficial bladder cancers, and other in situ cancers.
Is immunocompromised in the opinion of the investigator.
Has an 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) is not considered a form of systemic treatment.
Has experienced any of the following with prior immunotherapy: any irAE ≥ Grade 3, immune-mediated severe neurologic events of any-grade (e.g., myasthenic syndrome/myasthenia gravis, encephalitis, Guillain-Barré Syndrome, or transverse myelitis), exfoliative dermatitis of any grade (SJS, TEN, or DRESS syndrome), or myocarditis of any grade. Non-clinically significant laboratory abnormalities are not exclusionary.
Has undergone any major surgical procedure, open biopsy, or experienced significant traumatic injury within 28 days prior to enrollment. (Note: implantation of an infusion port or catheter, polypectomy, or colonoscopy-guided biopsy are not exclusionary).
Has any history of interstitial lung disease or pneumonitis.
Has cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal/gastric varices, or persistent jaundice. NOTE: Stable non-cirrhotic chronic liver disease (including Gilbert’s syndrome or asymptomatic gallstones) is acceptable if participant otherwise meets entry criteria.
Has a history or current evidence of any medical condition, therapy, or laboratory abnormality that might confound the study results, interfere with their 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.
Has a history of allogenic stem cell or organ transplantation.
Has a history of congenital long QT syndrome.
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, including:
a. Second degree (Type II) or third-degree atrioventricular block.
b. Cardiomyopathy, myocarditis, myocardial infraction, acute coronary syndromes (including unstable angina pectoris), coronary angioplasty, stenting, or bypass grafting.
c. Symptomatic pericarditis.
5.2.2. Prior/Concomitant Therapy
Is receiving any other anticancer or experimental therapy. No other experimental therapies (including but not limited to chemotherapy, radiation, hormonal treatment, antibody therapy, immunotherapy, gene therapy, vaccine therapy, or other experimental drugs) of any kind are permitted while the participant is receiving study intervention.
Is receiving immunosuppressive medication.
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.
Has received any live vaccine within 30 days of enrollment. Vaccination against COVID-19 using vaccines that are authorized via the appropriate regulatory mechanisms (e.g., Emergency Use Authorization, Conditional Marketing Authorization, or Marketing Authorization Application) are not exclusionary. Note: mRNA and adenoviral-based COVID-19 vaccines are considered non-live. If a COVID-19 vaccine is administered at any time, the date of COVID-19 vaccination must be entered in the eCRF.
5.2.3. Diagnostic Assessments and Other Criteria
Has documented presence of HBsAg at Screening or within 3 months prior to randomization. Participants with a negative HBsAg and positive HBcAb result are eligible only if HBV DNA is negative.
Has a positive HCV antibody test result at Screening Visit or within 3 months prior to randomization. NOTE: Participants with a positive HCV antibody test result due to prior resolved disease can be enrolled, only if a confirmatory negative HCV RNA test is obtained.
Has a positive HCV RNA test result at Screening Visit or within 3 months prior to randomisation. NOTE: The HCV RNA test is optional and participants with negative HCV antibody test are not required to undergo HCV RNA testing as well.
Is considered, in investigator’s opinion, a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease, or active infection requiring systemic therapy. Specific examples include but are not limited to uncontrolled major seizure disorder; unstable spinal cord compression; superior vena cava syndrome; or any psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study (including obtaining informed consent).
Has known history of HIV infection, with the exception of participants who are positive for HIV and meet all of the following criteria:
a. Is receiving a stable regimen of HAART
b. If a concurrent opportunistic infection, the participant will be on a stable dose of treatment and well-controlled (antibiotic and/or antifungal)
c. Has a CD4 count above 200 cells/mcL and an undetectable HIV viral load on standard PCR-based tests.
Is pregnant, breastfeeding, or expecting to conceive children within the projected duration of the study, starting with the Screening Visit through 9 months after the last dose of study intervention (Note: duration of contraceptive use after last dose of chemotherapy may be longer than 270 days in order to comply with local requirements and local approved product labels) after the last dose of study intervention.
Has a history of severe allergic and/or anaphylactic reactions to chimeric, human or humanized antibodies, fusion proteins, or known allergies to dostarlimab, or its excipients, or any components of FOLFOX or CAPEOX.
Has any other condition that would exclude the patient from chemotherapy with FOLFOX or CAPEOX.
