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Metastatic Colorectal CancerPhase 2NCT03668431

Dabrafenib + Trametinib + PDR001 In Colorectal Cancer

A Phase 2 study testing Dabrafenib, Trametinib and PDR001 in people with Metastatic Colorectal Cancer, run by Massachusetts General Hospital at 2 sites in United States.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial summary

This research study is studying a combination of drugs as a possible treatment for metastatic colorectal cancer characterized by BRAF V600E mutation. The names of the study drugs involved in this study are: Dabrafenib Trametinib PDR001 Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Metastatic Colorectal Cancer
What is being tested?
Dabrafenib, Trametinib and PDR001
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
25 participants
Where
2 sitesUnited States
Study dates
15 Oct 2018to 1 Dec 2022
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Participants must have histologically or cytologically confirmed metastatic colorectal cancer and a documented BRAF V600E mutation by a CLIA-certified laboratory test and must be wild-type for KRAS and NRAS.
  • Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥20 mm with conventional techniques or as ≥10 mm with spiral CT scan, MRI, or calipers by clinical exam. See Section 11 for the evaluation of measurable disease.
  • Patients may have received prior chemotherapy, prior anti-EGFR therapy, prior BRAF or MEK inhibitor, or prior immunotherapy (e.g. anti-PD1/PD-L1). Patients will also be allowed without prior treatments. If patient has been treated in the past, they must be at least 4 weeks since prior chemotherapy or radiation therapy.
  • Age ≥ 18 years
  • ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)
  • Life expectancy of greater than 3 months
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  • 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.
  • PT/INR <1.5 x ULN and PTT <1.5 ULN
  • Albumin > 2.5 g/dl
  • Patients must meet eligibility criteria on C1D1.
  • LVEF > LLN by ECHO or MUGA
  • The effects of trametinib, dabrafenib and PDR001 on the developing human fetus are unknown. For this reason and because these agents may 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 4 months after completion of treatment.
  • Ability to understand and the willingness to sign a written informed consent document.
  • Subjects must avoid consumption of grapefruit, Seville oranges or products containing the juice of each during the entire study and preferably 7 days before the first dose of study medications, due to potential CYP3A4 interaction with the study medications. Orange juice is allowed.

Who cannot join

  • Participants who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
  • Participants who are receiving any other investigational agents.
  • Participants with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to of trametinib, dabrafenib or PDR001.
  • Participants receiving any medications or substances that are strong inhibitors or inducers of CYP3A4 are ineligible but once on treatment must be used with caution. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the Physicians' Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
  • 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.
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  • Pregnant women are excluded from this study because trametinib, dabrafenib or PDR001 have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with trametinib, dabrafenib or PDR001 breastfeeding should be discontinued if the mother is treated with trametinib, dabrafenib or PDR001.
  • HIV-positive participants on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with trametinib, dabrafenib or PDR001. In addition, these participants are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated.
  • Active known or suspected autoimmune disease or a documented history of autoimmune disease, including ulcerative colitis and Crohn's disease (Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll).
  • Systemic chronic steroid therapy (≥ 10mg/day prednisone or equivalent) or any immunosuppressive therapy 7 days prior to planned date for first dose of study treatment. Topical, inhaled, nasal and ophthalmic steroids are allowed.
  • Current pneumonitis or interstitial lung disease.
  • History of organ transplant requiring use of immunosuppressive medication.
  • Taken an investigational drug ≤ 28 days or ≤ 5 half-lives (minimum 14 days) prior to start of study treatment, whichever is shorter.
  • Current use of a prohibited medication.
  • Malignant disease, other than that being treated in this study. Exceptions to this exclusion include the following: malignancies that were treated curatively and have not recurred within 2 years prior to study treatment; completely resected basal cell and squamous cell skin cancers and any completely resected carcinoma in situ.
  • Active infection requiring systemic antibiotic therapy within 2 weeks prior to start of study treatment.
  • Subjects with active Hepatitis B infection (HbsAg positive) will be excluded. Note: Subjects with antecedent of Hepatitis B (anti-HBc positive, HbsAg and HBV-DNA negative) are eligible.
  • Subjects with positive test for hepatitis C ribonucleic acid (HCV RNA) Note: Subjects in whom HCV infection resolved spontaneously (positive HCV antibodies without detectable HCV-RNA) or those that achieved a sustained virological response after antiviral treatment and show absence of detectable HCV RNA ≥ 6 months (with the use of IFN-free regimes) or ≥ 12 months (with the use of IFN-based regimes) after cessation of antiviral treatment are eligible.
  • Any medical condition that would, in the investigator's judgment, prevent the subject's participation in the clinical study due to safety concerns, compliance with clinical study procedures or interpretation of study results.
  • Use of any live vaccines against infectious diseases within 4 weeks of initiation of study treatment
  • Uncorrectable electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), long QT syndrome or taking medicinal products known to prolong the QT interval
  • Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO).
  • A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy including:
  • Presence of predisposing factors to RVO or central serous retinopathy (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes); or
  • Visible retinal pathology as assessed by ophthalmic examination that is considered a risk factor for RVO or central serous retinopathy such as:
  • Evidence of new optic disc cupping;
  • Evidence of new visual field defects on automated perimetry;
  • Intraocular pressure >21 mmHg as measured by tonometry.
  • Cardiac or cardiac repolarization abnormality, including any of the following:
  • History or current diagnosis of cardiac disease indicating significant risk of safety for subjects participating in the study such as uncontrolled or significant cardiac disease, including any of the following:
  • Recent (within last 6 months) myocardial infarction (MI)
  • Unstable angina (within last 6 months),
  • Uncontrolled congestive heart failure (CHF)
  • Clinically significant (symptomatic) cardiac arrhythmias (e.g., sustained ventricular tachycardia, and clinically significant second or third degree atrioventricular [AV] block without a pacemaker).

Trial locations and contacts

2 sites in 1 country.

Ryan Corcoran, MD contact

(617) 724-4000

rbcorcoran@partners.org

United States2 sites, 2 recruiting

  • Massachusetts General Hosital Cancer Center

    Boston, Massachusetts, 02114

    Ryan Corcoran, MD, 617-724-4000

    Ryan Corcoran, MD

    Recruiting

  • Dana Farber Cancer Institite

    Boston, Massachusetts, 02215

    Marios Giannakis, MD, 617-632-3000, MGIANNAKIS@PARTNERS.ORG

    Marios Giannakis, MD

    Recruiting

Other trials in United States

About this study

Official title: A Phase 2 Study of Dabrafenib and Trametinib in Combination With PDR001 in Patients With BRAFV600E Metastatic Colorectal Cancer

This research study is studying a combination of drugs as a possible treatment for metastatic colorectal cancer characterized by BRAF V600E mutation.

The names of the study drugs involved in this study are:

  • Dabrafenib
  • Trametinib
  • PDR001
Read the detailed description
  • This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug combination to learn whether the drug combination works in treating a specific disease. "Investigational" means that the drug combination is being studied.
  • The FDA (the U.S. Food and Drug Administration) has not approved PDR001 as a treatment for any disease.
  • The FDA has not approved dabrafenib and trametinib for your specific disease but it has been approved for other uses, whether alone as single agents, or given together as in this study.
  • This research study is studying a combination of drugs as a possible treatment for metastatic colorectal cancer characterized by BRAF V600E mutation.
  • All humans have a gene called BRAF which is responsible for sending signals to proteins called B-Raf inside of cells that help them grow. In some metastatic colorectal patients, this gene mutates and causes cancer cells to grow in uncontrolled ways. --- Dabrafenib is a drug that is thought to inhibit the mutant BRAF activity, which may serve to slow or stop cell growth of metastatic colon cancer.
  • Mitogen-activated protein kinase (MAPK) is a pathway that helps to activate the BRAF mutated genes. The MAPK pathway is commonly found to be overactivated in BRAF mutated tumor cells. MEK (which refers to MAPK/ERK Kinase) enzymes are essential to the activity of the MAPK pathway.
  • Trametinib inhibits the MEK enzymes in order to shut down the MAPK pathway, thus blocking the pathway that helps the cancer cells grow uncontrollably.
  • PDR001 is a drug which binds to PD1 on immune cells and is believed to block binding of PD-L1 and PD-L2. PD-L1/PDL1 and PD-L2/PDL2 are often used by cancer cells and to escape the power of the body's immune system so that they cannot be fought. By blocking that binding of the molecules, the body's immune system may reach and fight the cancer cells. Researchers are hoping that administration of all three of these drugs may help anti-cancer activities work together to slow or stop the cancer growth and may help your own immune system damage or destroy the existing cancer cells.
Being tested
Dabrafenib, Trametinib, PDR001
Keywords
Metastatic colorectal cancer
Medical subject headings
Colorectal Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • DabrafenibDrug

    Also called Tafinlar®

    Dabrafenib will be taken twice a day for 28 consecutive days

    .

  • TrametinibDrug

    Also called Mekinist®

    Trametinib will be taken once a day for 28 consecutive days

  • PDR001Drug

    PDR001 will be administered IV every 28 days

Study groups in NCT03668431
Study groupRoleWhat they receive
PDR001, Dabrafenib, TrametinibExperimentalPatients who fulfill eligibility criteria will be entered into the trial to receive PDR001, Dabrafenib, Trametinib. Treatment will be administered on an outpatient basis. After the screening procedures confirm participation in the research study: * Dabrafenib will be taken twice a day for 28 consecutive days * Trametinib will be taken once a day for 28 consecutive days * PDR001 will be administered IV every 28 days.
Receives: Drug: Dabrafenib; Drug: Trametinib; Drug: PDR001

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Overall Response Rate

    The participants best overall response will be assessed using RECIST 1.1 criteria

    • Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.
    • Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
    • Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).
    • Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

    Measured: From the start of the treatment until disease progression/recurrence, up to approximately 5 years

  2. Number of participants with grade 3, 4 and 5 adverse events

    Adverse Events will be assessed using Common Terminology Criteria for Adverse Events (CTCAE 4)

    Measured: From the start of treatment until 30 days after the last dose of a study drug, up to approximately 5 years

Secondary outcomes (5)

  1. Progression Free Survival

    Progression free survival is measured from the date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause. Progression will be assessed using RECIST 1.1 Criteria.

    Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).

    Measured: From the date of randomization until disease progression or death due to any cause, up to approximately 5 years

  2. Disease Control Rate

    The number of participants that achieve either a Complete Response (CR), Partial Response (PR), or Stable Disease (SD) per RECIST 1.1 Criteria.

    • Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.
    • Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
    • Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

    Measured: From the start of the treatment until disease progression/recurrence, up to approximately 5 years

  3. Duration of Response

    The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started, or death due to any cause. Participants without events reported are censored at the last disease evaluation). Response is assessed using RECIST 1.1 Criteria.

    Measured: From the first documented response until the time of disease progression, up to approximately 5 years

  4. Overall Survival

    Overall Survival (OS) is defined as the time from randomization (or registration) to death due to any cause, or censored at date last known alive.

    Measured: From the date of randomization until the time of death, up to approximately 10 years

  5. Mechanisms of response and resistance to dabrafenib, trametinib, and PDR001

    Using multiplexed immune IF and RNAseq, assess the change in immune microenvironment between pre-treatment and day 15 on-treatment biopsies Using serial cfDNA analyses, monitor response and define mechanisms of resistance to this therapy.

    Measured: Pre treatment and day 15

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted12 Sep 2018
  2. Study start15 Oct 2018
  3. Primary completion1 Sep 2022 (estimated)
  4. Study completion1 Dec 2022 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
25 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03668431
Sponsor's protocol ID
18-144
Status last verified
Jun 2022
First submitted
11 Sep 2018
Last updated
27 Jun 2022
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Tian J, Chen JH, Chao SX, Pelka K, Giannakis M, Hess J, Burke K, Jorgji V, Sindurakar P, Braverman J, Mehta A, Oka T, Huang M, Lieb D, Spurrell M, Allen JN, Abrams TA, Clark JW, Enzinger AC, Enzinger PC, Klempner SJ, McCleary NJ, Meyerhardt JA, Ryan DP, Yurgelun MB, Kanter K, Van Seventer EE, Baiev I, Chi G, Jarnagin J, Bradford WB, Wong E, Michel AG, Fetter IJ, Siravegna G, Gemma AJ, Sharpe A, Demehri S, Leary R, Campbell CD, Yilmaz O, Getz GA, Parikh AR, Hacohen N, Corcoran RB. Combined PD-1, BRAF and MEK inhibition in BRAFV600E colorectal cancer: a phase 2 trial. Nat Med. 2023 Feb;29(2):458-466. doi: 10.1038/s41591-022-02181-8. Epub 2023 Jan 26.

    PubMed 36702949

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Dabrafenib, Trametinib and PDR001 in people with Metastatic Colorectal Cancer, run by Massachusetts General Hospital at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 21 inclusion and 34 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 27 Jun 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

Contact Ryan Corcoran, MD ((617) 724-4000, rbcorcoran@partners.org), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Overall Response Rate (time frame: From the start of the treatment until disease progression/recurrence, up to approximately 5 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03668431, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Jun 2022.

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