Pembrolizumab in MMR-Proficient Metastatic Colorectal Cancer Pharmacologically Primed to Trigger Hypermutation Status

• Register: ClinicalTrials.gov
• Last refreshed on: 9 October 2023
• Main ID: NCT03519412
• Date of registration: 26/04/2018
• Prospective Registration: Yes
• Primary sponsor: IFOM ETS - The AIRC Institute of Molecular Oncology
• Public title: Pembrolizumab in MMR-Proficient Metastatic Colorectal Cancer Pharmacologically Primed to Trigger Hypermutation Status ARETHUSA
• Scientific title: Pembrolizumab in MMR-Proficient Metastatic Colorectal Cancer Pharmacologically Primed to Trigger Dynamic Hypermutation Status
• Date of first enrolment: January 23, 2019
• Target sample size: 102
• Recruitment status: Active, not recruiting
• URL: https://clinicaltrials.gov/ct2/show/NCT03519412
• Study type: Interventional
• Study design: Allocation: Non-Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 2

Countries of recruitment

Italy

Contacts

• Name: Salvatore Siena, MD
• Affiliation: Grande ospedale metropolitano Niguarda

• Name: Andrea Sartore bianchi, MD
• Affiliation: Grande ospedale metropolitano Niguarda

• Name: Silvia Marsoni, MD
• Affiliation: IFOM (Istituto FIRC di Oncologia Molecolare)

Key inclusion & exclusion criteria

Inclusion Criteria:

Entry criteria for SCREENING Phase

1. Histologically confirmed diagnosis of metastatic colorectal cancer.

2. Documented RAS extended mutations in the archival sample (cohort P only).

3. ECOG performance status 0-1.

4. SCREENING phase informed consent signed.

5. Understanding and accepting the need for undergoing two tumor biopsies if eligible for
PRIMING Phase.

6. Age = 18 years.

7. 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. Normal organ functions.

Entry Criteria for PRIMING Phase

1. Fulfilment of all the SCREENING inclusion criteria;

2. PRIMING informed consent signed;

3. Confirming the willingness to undergo two tumor biopsies,

4. 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.

5. Imaging documented failure of previous standard CRC therapies including
fluoropyrimidine, oxaliplatin, irinotecan plus or minus antiangiogenics agents
(Bevacizumab, Aflibercept, Regorafenib, others).

6. 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.

7. ECOG performance status 0 or 1;

8. Following results in the SCREENING Phase tests:

- Proficient MMR status assessed by IHC or MSI-Low status defined by PCR (Bethesda
panel);

- Negative score for the MGMT protein expression IHC test;

- Positive score for the MGMT promoter methylation performed on Tissue.

9. Women with childbearing potential should complete a pregnancy test and be willing to
use highly effective contraceptive methods.

10. Normal organ functions.

Entry Criteria for TRIAL Phase

1. 1. Fulfilment of all the SCREENING inclusion criteria and Deficient MMR status (IHC)
or MSI-High status (PCR) (cohort D only).

2. Fulfilment of all the SCREENING and PRIMING inclusion criteria (cohort P only).

3. TRIAL Phase informed consent signed (both cohorts).

4. Imaging documented PD to TMZ (cohort P only).

5. A mutational load value > 20 mutations/MB at TMZ-ML assay (cohort P only).

6. 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).

7. 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).

8. Woman with childbearing potential should complete a pregnancy test and be willing to
use highly effective contraceptive methods (both cohorts).

9. Normal organ functions. Blood specimens must be collected within 10 days prior to the
start of study treatment (both cohorts).

Exclusion Criteria:

1. A woman of child bearing potential who has a positive urine pregnancy test within 72
hours prior to allocation (see Appendix 3). If the urine test is positive or cannot be
confirmed as negative, a serum pregnancy test will be required.

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 allocation.

1. 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.

2. 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.

a. 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


Age minimum: 18 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Colorectal Neoplasms

Microsatellite Instability

Intervention(s)

Biological: pembrolizumab (treatment)

Drug: temozolomide (induction),

Primary Outcome(s)

Overall response rate (ORR) [Time Frame: Tumor assessments every 8-9 weeks from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months]

Secondary Outcome(s)

Safety and Tolerability [Time Frame: assessments every 3 weeks from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months]

Overall Survival [Time Frame: assessments every 8-9 weeks from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months]

Progression Free Survival [Time Frame: assessments every 8-9 weeks from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months]

Secondary ID(s)

2018-001441-14

IFOM-CPT002/2018/PO001

Source(s) of Monetary Support

Please refer to primary and secondary sponsors