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Identification and Treatment Of Micrometastatic Disease in Stage III Colon Cancer

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ClinicalTrials.gov Identifier: NCT03803553
Recruitment Status : Not yet recruiting
First Posted : January 14, 2019
Last Update Posted : January 14, 2019
Sponsor:
Collaborator:
Stand Up To Cancer
Information provided by (Responsible Party):
Aparna Parikh, Massachusetts General Hospital

Brief Summary:

This research study is comparing two standard of care treatment options based on blood test results for participants who have metastatic colorectal cancer.

The names of the potential treatments involved in this study are:

  • Active surveillance
  • FOLFIRI treatment

Condition or disease Intervention/treatment Phase
Metastatic Colorectal Cancer Stage III Colorectal Cancer Drug: FOLFIRI Protocol Other: ACTIVE SURVEILLANCE Phase 3

Detailed Description:

The FDA (the U.S. Food and Drug Administration) has approved FOLFIRI, comprised of Irinotecan, Leucovorin, and 5-Fluorouracil, as a treatment option for metastatic colorectal cancer in the Stage IV setting.

  • After diagnosis and surgical removal of tumors, individuals with metastatic colorectal cancer commonly receive what is called adjuvant chemotherapy treatment, commonly utilizing treatment plans called FOLFOX, CAPOX, or therapy with 5-Fluorouracil.
  • If all the cancer is not killed, the investigators may be able to detect tumor in the blood called circulating tumor DNA (ctDNA). This is genetic material unique to metastatic colorectal cancer that may be present in the blood stream, and it can be identified through a ctDNA blood test. If ctDNA is present in the blood stream, it is commonly called micro-metastatic disease (meaning disease that can't be seen detected by CT scans but may be there in the blood). Cancer researchers believe that ctDNA in the blood stream may be an indicator that cancer is more likely to recur.
  • After initial adjuvant chemotherapy, it is standard for individuals to begin active surveillance, where they do not receive further treatment but instead undergo frequent tumor imaging scans to see if their cancer is stable, growing, or coming back. The investigators plan to see if additional therapy, where FOLFIRI (comprised of Irinotecan, Leucovorin, and 5-Fluorouracil) is administered can decrease recurrence. Typically, FOLFIRI is given when the disease is visibly recurrent.

However, in this research study, the investigators are

  • determining whether there are differences in cancer recurrence in ctDNA positive participants treated with additional therapy versus put on active surveillance.
  • determining whether there are differences in health in ctDNA positive participants treated with additional therapy versus put on active surveillance.
  • examining whether patients who undergo further therapy experience changes in the ctDNA levels.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 400 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Early Identification and Treatment of Occult Metastatic Disease in Stage III Colon Cancer
Estimated Study Start Date : February 1, 2019
Estimated Primary Completion Date : February 1, 2021
Estimated Study Completion Date : February 1, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: ctDNA-POSITIVE: FOLFIRI Protocol

Pre-screening evaluation, including tumor assessment, tumor sequencing and blood tests. If these tests show that the participant is eligible to participate in the research study . The participant will be randomized into1 of 3 groups : ctDNA-Positive: Folfiri or ctDNA-Positive: Active Surveillance or ctDNA Negative: Active Surveillance

- ctDNA-POSITIVE: FOLFIRI Protocol

  • FOLFIRI chemotherapy via intravenous infusion ( on days 1-3 of each cycle. Cycle is 14 days long. This will occur for up to 12 cycles (24 weeks).
  • infusions will consist of the drugs
  • 5-Fluorouracil
  • Irinotecan
  • Leucovorin
Drug: FOLFIRI Protocol
FOLFIRI, a cycle will be two weeks (14 days) long, with FOLFIRI administered on Days 1-3. Participants will receive up to 12 two-week cycles (for a total of 24 weeks) of FOLFIRI chemotherapy.
Other Name: FOLinic acid-Fluorouracil-IRInotecan regimen

Active Comparator: ctDNA-POSITIVE: ACTIVE SURVEILLANCE

Pre-screening evaluation, including tumor assessment, tumor sequencing and blood tests. If these tests show that the participant is eligible to participate in the research study . The participant will be randomized into1 of 3 groups : ctDNA-Positive: Folfiri or ctDNA-Positive: Active Surveillance or ctDNA Negative: Active Surveillance

-- Active surveillance.

  • Observation and monitoring with imaging (every 3 months), tumor markers, and ctDNA draws every 1 month for the initial 6 months.
  • After 6 months, followed with ctDNA, tumor markers, and scans every 3 months for the first 3 years and every 6 months thereafter.

Additional scans and tumor markers will be at the discretion of the clinician. .

Other: ACTIVE SURVEILLANCE
Will be followed with observation and monitoring with imaging, tumor markers, and ctDNA collections

Active Comparator: ctDNA-NEGATIVE: ACTIVE SURVEILLANCE

Pre-screening evaluation, including tumor assessment, tumor sequencing and blood tests. If these tests show that the participant is eligible to participate in the research study . The participant will be randomized into1 of 3 groups : ctDNA-Positive: Folfiri or ctDNA-Positive: Active Surveillance or ctDNA Negative: Active Surveillance

- Observation and monitoring with imaging, tumor markers, and ctDNA collections every 3 months for the first 3 years and every 6 months thereafter.

Additional scans and tumor markers will be at the discretion of the clinician

Other: ACTIVE SURVEILLANCE
Will be followed with observation and monitoring with imaging, tumor markers, and ctDNA collections




Primary Outcome Measures :
  1. Disease-free survival (DFS) [ Time Frame: 5 years ]
    Disease-free survival (DFS) between ctDNA-positive patients treated treated with additional adjuvant therapy and ctDNA-positive patients who are untreated

  2. Clearance rate of ctDNA [ Time Frame: 7 Months ]
    Compare the clearance rate of ctDNA in ctDNA-positive patients between patients treated with additional adjuvant therapy and those who are untreated


Secondary Outcome Measures :
  1. Overall Survival (OS) Rate [ Time Frame: 5 years ]
    Overall survival (OS) between ctDNA-positive patients treated with additional adjuvant therapy and ctDNA-positive patients who are untreated



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:

  • Participants must have histologically confirmed resected Stage III adenocarcinoma of colorectal. Any T [Tx, T1, T2, T3, or T4-], N1-2MO; included NC.
  • Patient must have completed resected disease. In patients with tumor adherent to adjacent structures, en block RO resection must be documented.
  • Entire tumor must be in the colon (rectal involvement is excluded)
  • Patients must have a plan to receive or must be receiving standard adjuvant chemotherapy per the discretion of the treating physician. Standard therapy includes FOLFOX, CAPOX, or therapy with 5FU analog alone will be permitted if it constitutes appropriate standard therapy in the opinion of the treating physician.
  • Pre-screening must begin prior to or within the first 3 months of starting adjuvant treatment.
  • Patients must have a CT scan 3-6 weeks after completion of adjuvant therapy to confirm no radiographic evidence of disease
  • Patients must not have had prior neoadjuvant chemotherapy.
  • Age ≥18 years.
  • ECOG performance status ≤1
  • Life expectancy of greater than 3 months
  • Participants must have normal organ and marrow function as defined below:

    • leukocytes ≥3,000/mcL
    • absolute neutrophil count ≥1,500/mcL
    • platelets ≥100,000/mcL
    • total bilirubin within normal institutional limits
    • AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal creatinine within normal institutional limits

      --- OR

    • creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels above institutional normal.
  • Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 6 months after the last dose of investigational drug.
  • Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG).
  • Women must not be breastfeeding
  • Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year.
  • Women who are not of childbearing potential, ie, who are postmenopausal or surgically sterile as well as azoospermic men, do not require contraception
  • Must have documentation of microsatellite status. Immunohistochemistry (IHC) is acceptable as is PCR. Presence of deficient (d) DNA mismatch repair (dMMR) may be assessed by IHC for MMR protein expression (MLH1, MSH2, MSH6, PMS2) where loss of one or more proteins indicated dMMR. This may be done locally per local standards.
  • Patients must have sufficient tumor tissue available for molecular profiling, defined as at least 10 x 5 micron sections of FFPE tumor tissue or the equivalent.
  • Patients must have a detectable mutation on molecular profiling to be followed as per guidelines below.

    -- Tumor Sequencing:

    • DNA extracted from formalin-fixed or frozen primary tumor tissue will need to be sequenced to identify somatic mutations across all or a subset of the coding regions for at least 50 genes. Patients must have at least 1 mutation identified on tumor sequencing that is covered by the ctDNA assay. Tumor sequencing will be performed at Memorial Sloan Kettering by IMPACT.

      -- Circulating tumor DNA (ctDNA) analysis:

    • DNA extracted from plasma will be assessed for the presence of mutations. Testing may be performed using digital PCR or next-generation sequencing but must be able to reliably identify genomic alterations (excluding copy number changes or fusions) at or below a minimum allele frequency of 0.2%. If initial ctDNA assay fails to meet minimum coverage levels patients will be excluded from the study. Testing must be performed by ACCESS- Memorial Sloan Kettering Molecular Genetics Laboratory, New York, NY.

      -- Definition of ctDNA positive:

    • In order to be eligible for the ctDNA positive cohort, patient must be ctDNA positive following adjuvant therapy. ctDNA positive will be defined as positive if at least one mutation is shared between the tumor and ctDNA sequence. The mutation(s) of interest can be assessed as changes at the nucleotide or protein level (i.e. KRAS c.35G>A vs. KRAS G12D).
  • The effects on the developing human fetus are unknown. For this reason and because 5FU, Capecitabine, Oxaliplatin, Irinotecan, and Leucovorin are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion of any of the study drug administration.
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Patients who are receiving additional investigational therapy or on another investigational protocol
  • Patients who have confirmed metastatic disease.
  • Patients who are unable to get any standard adjuvant therapy
  • Patient who have received more than 3 months of standard adjuvant therapy at the time of potential study entry
  • Patients who are MSI-high are excluded
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  • Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 6 months for woman and 6 months for men, after the last dose of trial treatment.
  • Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin and squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
  • Has an active infection requiring systemic therapy

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): NCT03803553


Contacts
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Contact: Aparna Parikh, MD 617-724-4000 Aparna.Parikh@MGH.HARVARD.EDU

Locations
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United States, Massachusetts
Massachusetts General Hospital Not yet recruiting
Boston, Massachusetts, United States, 02115
Contact: Aparna Parikh, MD       aparna.parikh@mgh.harvard.edu   
Principal Investigator: Aparna Parikh, MD         
Dana Farber Cancer Institute Not yet recruiting
Boston, Massachusetts, United States, 02215
Contact: Marios Giannakis, MD       MGIANNAKIS@PARTNERS.ORG   
Principal Investigator: Marios Giannakis, MD         
Sponsors and Collaborators
Massachusetts General Hospital
Stand Up To Cancer
Investigators
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Principal Investigator: Aparna Parikh, MD Massachusetts General Hospital

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Responsible Party: Aparna Parikh, Principal Investigator, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT03803553     History of Changes
Other Study ID Numbers: 18-397
First Posted: January 14, 2019    Key Record Dates
Last Update Posted: January 14, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: Data can be shared no earlier than 1 year following the date of publication
Access Criteria: MGH - Contact the Partners Innovations team at http://www.partners.org/innovation

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Aparna Parikh, Massachusetts General Hospital:
Metastatic colorectal cancer
Stage III Colorectal Cancer
Additional relevant MeSH terms:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Leucovorin
Irinotecan
Camptothecin
Fluorouracil
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antimetabolites
Antimetabolites, Antineoplastic
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Phytogenic
Antidotes
Protective Agents
Vitamin B Complex
Vitamins