Pembrolizumab in Mmr-Proficient Metastatic Colorectal Cancer Pharmacologically Primed to Trigger Dynamic Hypermutation Status - the Arethusa Trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ifom Istituto Fondazione Di Oncologia Molecolare Ets In Breve Ifom Ets

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

9 Jan 2025 → 9 Jan 2025

Decision date (initial)

2025-01-09

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

MSD

External identifiers

EU CT number

2024-518526-33-01

EudraCT number

2018-001441-14

ClinicalTrials.gov

NCT03519412

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy

To assess the objective response rate of pembrolizumab in metastatic MMR proficient, extended RAS mutated CRC patients who have failed standard therapies, with MGMT-negative tumors treated with TMZ, given with the intent of increasing the mutational load of their tumors (cohort P).

Secondary objectives 4

1. To assess the objective response rate in MMR deficient patients (cohort D) identified during the MMR screening.
2. To assess the Progression Free Survival (PFS) and Overall Survival (OS) both P and D cohorts patients.
3. To assess the safety and tolerability of pembrolizumab after TMZ-priming therapy (cohort P).
4. To assess the safety and tolerability of pembrolizumab (cohort D).

Conditions and MedDRA coding

Metastatic colorectal cancer

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 26

1. SCREENING Phase: Histologically confirmed diagnosis of metastatic colorectal cancer.
2. SCREENING Phase: Documented RAS extended mutations in the archival sample (cohort P only).
3. SCREENING Phase: ECOG performance status 0-1.
4. SCREENING Phase: SCREENING phase informed consent signed.
5. SCREENING Phase: Understanding and accepting the need for undergoing two tumor biopsies if eligible for PRIMING Phase.
6. SCREENING Phase: Age ≥ 18 years.
7. SCREENING Phase: Availability of all diagnostic FFPE blocks (primary tumor and or metastases), or at least 20 slides (primary tumor and/or metastases). Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides.
8. SCREENING Phase: Normal organ functions.
9. PRIMING Phase: Fulfilment of all the SCREENING inclusion criteria.
10. PRIMING Phase: PRIMING informed consent signed.
11. PRIMING Phase: Confirming the willingness to undergo two tumor biopsies.
12. PRIMING Phase: Acceptance that, if the mutational load determination is unfeasible for technical reasons (not enough tissue, substandard test performance, etc.), access to TRIAL phase will not be possible.
13. PRIMING Phase: Imaging documented failure of previous standard CRC therapies including fluoropyrimidine, oxaliplatin, irinotecan plus or minus antiangiogenics agents (Bevacizumab, Aflibercept, Regorafenib, others).
14. PRIMING Phase: At least one measurable tumor lesion as per RECIST v1.1. Lesions in previously irradiated areas or those that have received other loco-regional therapies (i.e. percutaneous ablation) should not be considered measurable unless there is clear documented evidence of progression of the lesion since therapy. Imaging must be performed maximum within 28 days prior to enrolment.
15. PRIMING Phase: ECOG performance status 0 or 1.
16. PRIMING Phase: Following results in the SCREENING Phase tests: 1. Proficient MMR status assessed by IHC or MSI-Low status defined by PCR (Bethesda panel); 2. Negative score for the MGMT protein expression IHC test; 3. Positive score for the MGMT promoter methylation performed on Tissue.
17. PRIMING Phase: Normal organ functions.
18. TRIAL Phase: Fulfilment of all the SCREENING inclusion criteria and Deficient MMR status (IHC) or MSI-High status (PCR) (cohort D only).
19. TRIAL Phase: Fulfilment of all the SCREENING and PRIMING inclusion criteria (cohort P only).
20. TRIAL Phase: TRIAL Phase informed consent signed (both cohorts).
21. TRIAL Phase: Imaging documented PD to TMZ (cohort P only).
22. TRIAL Phase: A mutational load value > 20 mutations/MB at TMZ-ML assay (cohort P only).
23. TRIAL Phase: Imaging documented failure of previous standard CRC therapies including fluoropyrimidine, oxaliplatin, irinotecan plus or minus targeted agents (Bevacizumab, Aflibercept, Regorafenib, Cetuximab, Panitumumab, others) (cohort D only).
24. TRIAL Phase: At least one measurable tumor lesion as per RECIST v1.1. Lesions in previously irradiated areas or those that have received other loco-regional therapies (i.e. percutaneous ablation) should not be considered measurable unless there is clear documented evidence of progression of the lesion since therapy. Imaging must be performed maximum within 28 days prior to enrolment (both cohorts).
25. TRIAL Phase: Woman with childbearing potential should complete a pregnancy test and be willing to use highly effective contraceptive methods (both cohorts).
26. TRIAL Phase: Normal organ functions. Blood specimens must be collected within 10 days prior to the start of study treatment (both cohorts).

Exclusion criteria 20

1. A woman of child bearing potential who has a positive serum pregnancy test within 72 hours prior to allocation.
2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
3. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks [could consider shorter interval for kinase inhibitors or other short half-life drugs] prior to enrollment. a. Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible. b. Note: If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.
4. Has received prior radiotherapy within 2 weeks of start of study treatment (with Pembrolizumab). Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1- week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non- CNS disease.
5. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
6. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment. Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
7. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
8. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
9. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
10. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
11. Has severe hypersensitivity (≥Grade 3) to temozolomide and/or any of its excipients.
12. 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 (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
13. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
14. Has an active infection requiring systemic therapy.
15. Has a known history of Human Immunodeficiency Virus (HIV). Note: No HIV testing is required.
16. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
17. Has a known history of active TB (Bacillus Tuberculosis).
18. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
19. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
20. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. To assess the objective response rate of pembrolizumab in metastatic MMR proficient, extended RAS mutated CRC patients who have failed standard therapies, with MGMT-negative tumors treated with TMZ, given with the intent of increasing the mutational load of their tumors (cohort P).

Secondary endpoints 4

1. To assess the objective response rate in MMR deficient patients (cohort D) identified during the MMR screening.
2. To assess the Progression Free Survival (PFS) and Overall Survival (OS) both P and D cohorts patients.
3. To assess the safety and tolerability of pembrolizumab after TMZ-priming therapy (cohort P).
4. To assess the safety and tolerability of pembrolizumab (cohort D).

Investigational products

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

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ifom Istituto Fondazione Di Oncologia Molecolare Ets In Breve Ifom Ets

Sponsor organisation

Ifom Istituto Fondazione Di Oncologia Molecolare Ets In Breve Ifom Ets

Address

Via Adamello 16

City

Milan

Postcode

20139

Country

Italy

Scientific contact point

Organisation

Ifom Istituto Fondazione Di Oncologia Molecolare Ets In Breve Ifom Ets

Contact name

Silvia Marsoni

Public contact point

Organisation

Ifom Istituto Fondazione Di Oncologia Molecolare Ets In Breve Ifom Ets

Contact name

Silvia Marsoni

Locations

1 EU/EEA country · 4 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 6 files

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

Application history

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