A Phase 2, open label, randomized study of neoadjuvant dostarlimab plus CAPEOX versus CAPEOX in participants with previously untreated T4N0 or Stage III MMRp/ MSS colon cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Glaxosmithkline Research & Development Limited

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06], Diseases [C] - Neoplasms [C04]

Trial duration

27 Nov 2024 → ongoing

Decision date (initial)

2024-11-07

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

GlaxoSmithKline Research & Development Limited, UK

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To assess the efficacy of neoadjuvant dostarlimab in combination with CAPEOX versus CAPEOX in participants with T4N0 or Stage III MMRp/MSS colon cancer.
To assess the safety and tolerability of neoadjuvant dostarlimab in combination with CAPEOX versus CAPEOX in participants with T4N0 or Stage III MMRp/MSS colon cancer

Secondary objectives 2

1. To assess the feasibility of neoadjuvant dostarlimab in combination with CAPEOX versus CAPEOX in participants with T4N0 or Stage III MMRp/MSS colon cancer
2. To assess the efficacy of neoadjuvant dostarlimab in combination with CAPEOX versus CAPEOX in participants with T4N0 or Stage III MMRp/MSS colon cancer

Conditions and MedDRA coding

MMRp/ MSS colon cancer

Study design 1 period

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-002463-PIP01-18

Plan to share IPD

Yes

IPD plan description

Qualified researchers may request access to anonymized individual patient-level data (IPD) and related study documents of the eligible studies via the Data Sharing Portal. Details on GSK's data sharing criteria can be found at: Sharing Clinical Trial Data’ on the GSK Study Register (www.gsk-studyregister.com). IPD Sharing Access Criteria: Anonymized IPD is shared with researchers whose proposals are approved by an Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension may be granted, when justified, for up to 6 months. IPD Sharing Time Frame: Anonymized IPD will be made available within 6 months of publication of primary, key secondary and safety results for studies in product with approved indication(s) or asset(s) with development terminated across all indications.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. 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.
2. Has untreated pathologically confirmed colon adenocarcinoma.
3. Has resectable colon adenocarcinoma defined as clinically T4N0 or Stage III.
4. Has a tumor demonstrating the presence of either: a. MMR status: MMR status must be assessed by IHC for MMR protein expression (MLH1, MSH2, MSH6, PMS2) where all proteins are present indicates MMRp; MMR status may be determined local laboratory; or b. MSS or MSI-L phenotype as determined by PCR or by tissue NGS, determined by local laboratory.
5. Provides fresh tumor tissue obtained during either the pre-screening or screening period via colonoscopy performed per procedure manual. Tissue biopsy is required.
6. Is willing to use adequate contraception male and/or female participants. − Contraceptive use by male and/or female participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. − Male participants: 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 ejaculate to another person. − 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: − Is a WONCBP as defined in the protocol OR − 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 180 days after the last dose of NAT. − 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.
7. Is capable of giving signed informed consent as described in protocol, including compliance with the requirements and restrictions listed in the ICF and in this protocol.
8. Has an ECOG-PS of 0 or 1.
9. Has adequate organ function as defined in protocol.

Exclusion criteria 33

1. Has distant metastatic disease.
2. Has received prior medical therapy (chemotherapy, immunotherapy, biologic, or targeted therapy), radiation therapy or surgery for management of colon cancer.
3. Has a tumor that, in the investigator’s judgment is causing symptomatic bowel obstruction or otherwise requires or required urgent/emergent surgery.
4. Has, in the investigator’s opinion, a tumor that is not amenable to surgery or has any other contraindication to surgery.
5. 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.
6. Is immunocompromised in the opinion of the investigator.
7. 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.
8. Has experienced any of the following with prior immunotherapy: any imAE ≥ 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.
9. Has undergone any major surgical procedure, open biopsy, or experienced significant traumatic injury, or has not recovered from such within 35 days prior to randomization.
10. Has any history of interstitial lung disease or immune-related pneumonitis.
11. 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.
12. Has a history of allogenic stem cell or organ transplantation.
13. Has known complete dihydropyrimidine hydrogenase (DPD) deficiency.
14. Has a history of congenital long QT syndrome.
15. 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).
16. 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 randomization, including: − Second degree (Type II) or third-degree atrioventricular block. − Cardiomyopathy, myocarditis, myocardial infraction, acute coronary syndromes (including unstable angina pectoris), coronary angioplasty, stenting, or bypass grafting. − Symptomatic pericarditis.
17. Has an ALT value >2.5x ULN.
18. Has a total bilirubin value >1.5x ULN.
19. 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.
20. Has documented presence of HBsAg at screening or within 3 months prior to thefirst dose of study intervention. Participants with a negative HBsAg and positive HBcAb result are eligible only if HBV DNA is negative.
21. Has a positive HCV antibody test result at screening or within 3 months prior to thefirst dose of study intervention.
22. Has a positive HCV RNA test result at screening or within 3 months prior to the first dose of study intervention.
23. Has received treatment with an investigational agent within [4 weeks] of the firstdose of study intervention.
24. Is receiving immunosuppressive medication.
25. 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.
26. Has previously received any therapies for their colon cancer.
27. Has received any live vaccine within 30 days of randomization. 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.
28. Is currently enrolled or has participated in any other clinical study involving an investigational study intervention or any other type of interventional medical research within 35 days, or less than 5 times the half-life of the most recent therapy prior to study Day 1, whichever is shorter.
29. Has a known HIV infection AND meets at least 1 of the following criteria: a. Has documented evidence of plasma HIV-1 RNA ³50 c/mL within 3 months prior to or at screening. In the 3 to 12 months prior to screening, plasma HIV-1 RNA levels consistently <50 c/mL are required for enrolment; if multiple instances of plasma HIV-1 RNA values ³50 c/mL occurred in the 3 to 12 months prior to screening, the participant is not eligible for enrolment unless, per the investigator’s assessment, the elevations were neither persistent nor associated with antiretroviral resistance; OR b. Has not had CD4 cell counts measured in the past 12 months (i.e., at least 2 separate measurements taken a minimum of 28 days apart, 1 of which must be conducted at screening); OR c. Has had any CD4 cell count values ≤200 cells/mm3 in the past 12 months; OR d. Has had 1 or more changes in their combination antiretroviral therapy regimen (except for switches as allowed per details provided in (Section 10.9 [Appendix 9] or has received an antiretroviral therapy regimen that is inconsistent with locally recommended guidelines during the 3 months prior to screening; OR e. Has received treatment with an HIV-1 immunotherapeutic vaccine within 90 days of screening.
30. Is pregnant or breastfeeding
31. Is unable to adhere to the protocol-defined SoA, including requirements for the Safety and Survival Follow-up Period of the study.
32. 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 CAPEOX.
33. Has any other condition that would exclude the participant from chemotherapy with CAPEOX.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Proportion of participants with major pathological response determined by local assessment with protocol specific training/methods, defined as≤10% RVT.
2. Frequency and severity of treatment emergent AEs, SAEs, imAEs, and AEs leading to death or discontinuation of study intervention.

Secondary endpoints 2

1. Proportion of participants for whom primary tumour resection is not excluded by either: o Disease progression precluding surgery. o Treatment related toxicity that results in the participant not being suitable for surgery.
2. Proportion of participants with pathological response determined by local assessment in the following categories: o Complete pathologic response (cPR) (0% RVT) o Major pathological response excluding cPR (>0% & ≤10% RVT) o Partial pathologic response (>10% & ≤50% RVT) o Negligible pathologic response (>50% RVT)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 11

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Glaxosmithkline Research & Development Limited

Sponsor organisation

Glaxosmithkline Research & Development Limited

Address

G S K House, 980 Great West Road 980 Great West Road

City

Brentford

Postcode

TW8 9GS

Country

United Kingdom

Scientific contact point

Organisation

Glaxosmithkline Research & Development Limited

Contact name

EU GSK Clinical Trials Call Center

Public contact point

Organisation

Glaxosmithkline Research & Development Limited

Contact name

EU GSK Clinical Trials Call Center

Third parties 7

Locations

3 EU/EEA countries · 24 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 56 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

10 submissions — initial application plus substantial / non-substantial modifications