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

NCT03519412 | Completed Phase 2 Results

• 3 other identifiers: IFOM-CPT002/2018/PO0012024-518526-33-012018-001441-14
• Study Type: interventional
• Target: 107
• Locations: 1 country
• Sites: 4

Brief Summary

In this study, MMRd metastatic colorectal cancer (mCRC) patients who failed standard therapies will undergo treatment with pembrolizumab, while RAS-extended mutated MMR-proficient mCRC patients will be tested for o6-methylguanine-DNA-methyltransferase (MGMT) expression (IHC) and then for MGMT promoter methylation. MGMT IHC-negative, promoter methylation positive patients will be treated with temozolomide (TMZ). Patients progressing under temozolomide will be tested for tumor mutational burden (TMB) and proceed to pembrolizumab if TMB is \> 20 mutations/Mb. The primary study hypothesis is that tumors with acquired resistance to temozolomide become hypermutated and are sensitive to pembrolizumab.

Conditions

Colorectal Neoplasms; Microsatellite Instability

Keywords

DNA Mismatch Repair; Pembrolizumab

Outcome Measures

Primary Outcomes (1)

• Overall Response Rate (ORR)

  Overall response rate (ORR) to pembrolizumab according to RECIST v1.1. An objective response is defined as either a CR or PR assessed by RECIST v1.1 at the discretion of the local investigator.

  Tumor assessments every 8-9 weeks from date of enrollment (in Trial Phase of the study) until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months.

Secondary Outcomes (4)

• Overall Response Rate (ORR)

  Tumor assessments every 8-9 weeks from date of enrollment (in Trial Phase of the study) 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 (PFS)

  From the date of treatment initiation with pembrolizumab to the date of first documented progression or date of death from any cause, whichever came first, up to maximum 72 months.

• Overall Survival (OS)

  Every 8-12 weeks from date of treatment initiation with pembrolizumab to the date of death due to any cause (up to maximum 72 months). A participant who has not died will be censored at last known date alive.

• Safety and Tolerability

  From the time the first dose of study medication (either pembrolizumab or temozolomide) is administered until 30 days following discontinuation of study treatment.

Study Arms (2)

MMR-proficient (MMRp)

EXPERIMENTAL

MGMT-IHC-negative, MGMT promoter methylation-positive patient population is selected for treatment with temozolomide (induction) orally until disease progression or unacceptable toxicity whichever comes first, followed by pembrolizumab IV if Tumor Mutational Burden post Temozolomide is \> 20 Muts/Mb

Drug: temozolomide (induction),; Biological: pembrolizumab (treatment)

MMR-deficient (MMRd)

OTHER

Patients receive Pembrolizumab (treatment) IV until disease progression or unacceptable toxicity or 35 cycles, whichever comes first

Biological: pembrolizumab (treatment)

Interventions

temozolomide (induction), DRUG

temozolomide is administered to MGMT promoter methylation-positive MMRp patients orally, once daily, at the dose of 150-200 mg/m2/day for 5 consecutive days of each treatment cycle A treatment cycle will comprise 5 days of temozolomide administration (Day 1 to 5) followed by 23 days of rest for a total of 28 days (4 weeks) period (dose-schedule: 150 mg/m2 day 1-5 q28),until disease progression or unacceptable toxicity whichever comes first.

Also known as: methazolastone, Temodal, Temodar

MMR-proficient (MMRp)

pembrolizumab (treatment) BIOLOGICAL

pembrolizumab is administered to MGMT-IHC-negative, MGMT promoter methylation-positive MMRp patients with TMB\>20 Mut/Mb after Temozolomide treatment, and to MMRd. Patients receive pembrolizumab IV , 200 mg Q3W, Day 1 of each 3 week cycle for maximum 35 cycles, until disease progression or unacceptable toxicity whichever comes first.

Also known as: Keytruda, Lambrolizumab, MK-3475, SCH 900475

MMR-deficient (MMRd); MMR-proficient (MMRp)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Entry criteria for SCREENING Phase
• Histologically confirmed diagnosis of metastatic colorectal cancer.
• Documented RAS extended mutations in the archival sample (cohort P only).
• ECOG performance status 0-1.
• SCREENING phase informed consent signed.
• Understanding and accepting the need for undergoing two tumor biopsies if eligible for PRIMING Phase.
• Age ≥ 18 years.
• 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.
• Normal organ functions.
• Entry Criteria for PRIMING Phase
• PRIMING informed consent signed;
• Confirming the willingness to undergo two tumor biopsies,
• 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.
• Imaging documented failure of previous standard CRC therapies including fluoropyrimidine, oxaliplatin, irinotecan plus or minus antiangiogenics agents (Bevacizumab, Aflibercept, Regorafenib, others).
• 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.

You may not qualify if:

• 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.
• 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).
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiological 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.
• Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
• Has severe hypersensitivity (≥Grade 3) to temozolomide and/or any of its excipients.
• 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.

Sponsors & Collaborators

• IFOM ETS - The AIRC Institute of Molecular Oncology: lead

Study Sites (4)

Grande Ospedale Metropolitano Niguarda

Milan, Italy

Location

Istituto Europeo di Oncologia

Milan, Italy

Location

Istituto Nazionale Tumori di Milano

Milan, Italy

Location

Istituto Clinico Humanitas

Rozzano, Italy

Location

Related Publications (8)

• Amatu A, Sartore-Bianchi A, Moutinho C, Belotti A, Bencardino K, Chirico G, Cassingena A, Rusconi F, Esposito A, Nichelatti M, Esteller M, Siena S. Promoter CpG island hypermethylation of the DNA repair enzyme MGMT predicts clinical response to dacarbazine in a phase II study for metastatic colorectal cancer. Clin Cancer Res. 2013 Apr 15;19(8):2265-72. doi: 10.1158/1078-0432.CCR-12-3518. Epub 2013 Feb 19.

  PMID: 23422094 BACKGROUND

• Amatu A, Barault L, Moutinho C, Cassingena A, Bencardino K, Ghezzi S, Palmeri L, Bonazzina E, Tosi F, Ricotta R, Cipani T, Crivori P, Gatto R, Chirico G, Marrapese G, Truini M, Bardelli A, Esteller M, Di Nicolantonio F, Sartore-Bianchi A, Siena S. Tumor MGMT promoter hypermethylation changes over time limit temozolomide efficacy in a phase II trial for metastatic colorectal cancer. Ann Oncol. 2016 Jun;27(6):1062-1067. doi: 10.1093/annonc/mdw071. Epub 2016 Feb 24.

  PMID: 26916096 BACKGROUND

• Barault L, Amatu A, Bleeker FE, Moutinho C, Falcomata C, Fiano V, Cassingena A, Siravegna G, Milione M, Cassoni P, De Braud F, Ruda R, Soffietti R, Venesio T, Bardelli A, Wesseling P, de Witt Hamer P, Pietrantonio F, Siena S, Esteller M, Sartore-Bianchi A, Di Nicolantonio F. Digital PCR quantification of MGMT methylation refines prediction of clinical benefit from alkylating agents in glioblastoma and metastatic colorectal cancer. Ann Oncol. 2015 Sep;26(9):1994-1999. doi: 10.1093/annonc/mdv272. Epub 2015 Jun 25.

  PMID: 26113646 BACKGROUND

• Bardelli A, Cahill DP, Lederer G, Speicher MR, Kinzler KW, Vogelstein B, Lengauer C. Carcinogen-specific induction of genetic instability. Proc Natl Acad Sci U S A. 2001 May 8;98(10):5770-5. doi: 10.1073/pnas.081082898. Epub 2001 Apr 10.

  PMID: 11296254 BACKGROUND

• Germano G, Lamba S, Rospo G, Barault L, Magri A, Maione F, Russo M, Crisafulli G, Bartolini A, Lerda G, Siravegna G, Mussolin B, Frapolli R, Montone M, Morano F, de Braud F, Amirouchene-Angelozzi N, Marsoni S, D'Incalci M, Orlandi A, Giraudo E, Sartore-Bianchi A, Siena S, Pietrantonio F, Di Nicolantonio F, Bardelli A. Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth. Nature. 2017 Dec 7;552(7683):116-120. doi: 10.1038/nature24673. Epub 2017 Nov 29.

  PMID: 29186113 BACKGROUND

• Macagno M, Pessei V, Congiusta N, Lazzari L, Bellomo SE, Idrees F, Cavaliere A, Pietrantonio F, Raimondi A, Gusmaroli E, Zampino MG, Gervaso L, Ciardiello D, Mondello G, Santoro A, Personeni N, Bonoldi E, Aquilano MC, Valtorta E, Siena S, Sartore-Bianchi A, Amatu A, Bonazzina EF, Bencardino KB, Serini G, Marsoni S, Barault L, Di Nicolantonio F, Maione F. A Comparative Study of Methyl-BEAMing and Droplet Digital PCR for MGMT Gene Promoter Hypermethylation Detection. Diagnostics (Basel). 2024 Nov 5;14(22):2467. doi: 10.3390/diagnostics14222467.

  PMID: 39594133 RESULT

• Crisafulli G, Sartore-Bianchi A, Lazzari L, Pietrantonio F, Amatu A, Macagno M, Barault L, Cassingena A, Bartolini A, Luraghi P, Mauri G, Battuello P, Personeni N, Zampino MG, Pessei V, Vitiello PP, Tosi F, Idotta L, Morano F, Valtorta E, Bonoldi E, Germano G, Di Nicolantonio F, Marsoni S, Siena S, Bardelli A. Temozolomide Treatment Alters Mismatch Repair and Boosts Mutational Burden in Tumor and Blood of Colorectal Cancer Patients. Cancer Discov. 2022 Jul 6;12(7):1656-1675. doi: 10.1158/2159-8290.CD-21-1434.

  PMID: 35522273 RESULT

• Willis JA, Overman MJ. Inducing Hypermutability to Promote Anti-PD-1 Therapy Response. Cancer Discov. 2022 Jul 6;12(7):1612-1614. doi: 10.1158/2159-8290.CD-22-0492.

  PMID: 35791694 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms; Microsatellite Instability

Interventions

Temozolomide; Neoadjuvant Therapy; pembrolizumab; Therapeutics

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Genomic Instability; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Combined Modality Therapy

Results Point of Contact

• Title: Luca Lazzari
• Organization: IFOM ETS - The AIRC Institute of Molecular Oncology

luca.lazzari@ifom.eu

+39 02 57430 3799

Study Officials

• Salvatore Siena, MD

  Grande ospedale metropolitano Niguarda

  STUDY CHAIR

• Silvia Marsoni, MD

  IFOM (Istituto FIRC di Oncologia Molecolare)

  STUDY DIRECTOR

• Andrea Sartore bianchi, MD

  Grande ospedale metropolitano Niguarda

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 26, 2018
• First Posted: May 9, 2018
• Study Start: January 23, 2019
• Primary Completion: January 8, 2025
• Study Completion: January 8, 2025
• Last Updated: March 3, 2026
• Results First Posted: March 3, 2026

Record last verified: 2026-03

Locations

IT (4)