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Trial record 1 of 1 for:    NCT03519412
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Pembrolizumab in MMR-Proficient Metastatic Colorectal Cancer Pharmacologically Primed to Trigger Hypermutation Status (ARETHUSA)

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ClinicalTrials.gov Identifier: NCT03519412
Recruitment Status : Recruiting
First Posted : May 9, 2018
Last Update Posted : November 8, 2019
Sponsor:
Information provided by (Responsible Party):
IFOM, The FIRC Institute of Molecular Oncology

Brief Summary:
In this study, metastatic colorectal cancer (CRC) patients with RAS-extended mutations will be tested for MMR-deficiency. MMRd patients who failed standard therapies will undergo treatment with pembrolizumab while MMR-proficient 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.

Condition or disease Intervention/treatment Phase
Colorectal Neoplasms Microsatellite Instability Drug: temozolomide (induction), Biological: pembrolizumab (treatment) Phase 2

Detailed Description:

Arethusa consists of three different phases - SCREENING Phase, PRIMING phase, and TRIAL Phase.

  • SCREENING PHASE: RAS-mutated metastatic CRC patients are tested for MMR status. MMR-Deficient (MMR-D) patients proceed directly to TRIAL Phase and are treated with pembrolizumab. MMR-Proficient (MMR-P) patients are further tested for O6-methylguanine-DNA methyltransferase (MGMT) expression by immunohistochemistry and promoter methylation analysis. MGMT negative patients proceed to PRIMING phase. MGMT positive patients go off-study.
  • PRIMING PHASE: MMR-P MGMT-negative patients who have failed standard therapies receive TMZ therapy until progression. At PD (disease progression) patients are biopsied to determine the tumor mutational burden (TMB). Patients with TMB < 20 mutations/megabase go off-study. Patients with TMB >20 mutations/megabase, proceed to trial phase.
  • TRIAL PHASE: Eligible patients are treated with pembrolizumab until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 348 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pembrolizumab in MMR-Proficient Metastatic Colorectal Cancer Pharmacologically Primed to Trigger Dynamic Hypermutation Status
Actual Study Start Date : January 23, 2019
Estimated Primary Completion Date : February 2022
Estimated Study Completion Date : June 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: MMR-proficient (MMRp)
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),
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.
Other Names:
  • methazolastone
  • Temodal
  • Temodar

Biological: pembrolizumab (treatment)
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.
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

MMR-deficient (MMRd)
Patients receive Pembrolizumab (treatment) IV until disease progression or unacceptable toxicity or 35 cycles, whichever comes first
Biological: pembrolizumab (treatment)
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.
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475




Primary Outcome Measures :
  1. 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 ]
    Overall response rate (ORR) to pembrolizumab according to RECIST v1.1 and iRECIST


Secondary Outcome Measures :
  1. 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 ]
    Progression Free Survival in MMRp pembrolizumab treated patients

  2. 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 ]
    Overall Survival in MMRp pembrolizumab treated patients

  3. 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 ]
    Safety and Tolerability according to CTCAE version 4.03



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
  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. 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 antiangiogenics agents (Bevacizumab, Aflibercept, Regorafenib, 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 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.
  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..

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03519412


Contacts
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Contact: Paolo Luraghi, PhD +3902574303799 paolo.luraghi@ifom.eu
Contact: Luca Lazzari, PhD +3902574303799 luca.lazzari@ifom.eu

Locations
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Italy
Grande Ospedale Metropolitano Niguarda Recruiting
Milano, Italy
Contact: Andrea Sartore Bianchi, MD         
Istituto Europeo di Oncologia Recruiting
Milano, Italy
Contact: Maria Giulia Zampino         
Istituto Nazionale Tumori di Milano Recruiting
Milano, Italy
Contact: Filippo Pietrantonio, MD         
Istituto Clinico Humanitas Recruiting
Rozzano, Italy
Contact: Nicola Personeni, MD         
Sponsors and Collaborators
IFOM, The FIRC Institute of Molecular Oncology
Investigators
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Study Chair: Salvatore Siena, MD Grande ospedale metropolitano Niguarda
Study Director: Silvia Marsoni, MD IFOM (Istituto FIRC di Oncologia Molecolare)
Principal Investigator: Andrea Sartore bianchi, MD Grande ospedale metropolitano Niguarda

Publications:

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Responsible Party: IFOM, The FIRC Institute of Molecular Oncology
ClinicalTrials.gov Identifier: NCT03519412     History of Changes
Other Study ID Numbers: IFOM-CPT002/2018/PO001
2018-001441-14 ( EudraCT Number )
First Posted: May 9, 2018    Key Record Dates
Last Update Posted: November 8, 2019
Last Verified: March 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by IFOM, The FIRC Institute of Molecular Oncology:
DNA Mismatch Repair
Pembrolizumab
Additional relevant MeSH terms:
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Colorectal Neoplasms
Microsatellite Instability
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
Pembrolizumab
Temozolomide
Antineoplastic Agents, Immunological
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action