Clinical Trials /

Dabrafenib + Trametinib + PDR001 In Colorectal Cancer

NCT03668431

Description:

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

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Dabrafenib + Trametinib + PDR001 In Colorectal Cancer
  • Official Title: A Phase 2 Study of Dabrafenib and Trametinib in Combination With PDR001 in Patients With BRAFV600E Metastatic Colorectal Cancer

Clinical Trial IDs

  • ORG STUDY ID: 18-144
  • NCT ID: NCT03668431

Conditions

  • Metastatic Colorectal Cancer

Interventions

DrugSynonymsArms
DabrafenibTafinlar®PDR001, Dabrafenib, Trametinib
TrametinibMekinist®PDR001, Dabrafenib, Trametinib
PDR001PDR001, Dabrafenib, Trametinib

Purpose

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

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.
    

Trial Arms

NameTypeDescriptionInterventions
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.
  • Dabrafenib
  • Trametinib
  • PDR001

Eligibility Criteria

        Inclusion Criteria:

          -  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

          -  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.

          -  Exclusion Criteria

          -  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.

          -  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).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate
Time Frame:From the start of the treatment until disease progression/recurrence, up to approximately 5 years
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Progression Free Survival
Time Frame:From the date of randomization until disease progression or death due to any cause, up to approximately 5 years
Safety Issue:
Description: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).
Measure:Disease Control Rate
Time Frame:From the start of the treatment until disease progression/recurrence, up to approximately 5 years
Safety Issue:
Description: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.
Measure:Duration of Response
Time Frame:From the first documented response until the time of disease progression, up to approximately 5 years
Safety Issue:
Description: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.
Measure:Overall Survival
Time Frame:From the date of randomization until the time of death, up to approximately 10 years
Safety Issue:
Description: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.
Measure:Mechanisms of response and resistance to dabrafenib, trametinib, and PDR001
Time Frame:Pre treatment and day 15
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Massachusetts General Hospital

Trial Keywords

  • Metastatic colorectal cancer

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