Dabrafenib, Trametinib, and Spartalizumab in Treating Patients with BRAFV600E Mutant Metastatic Colorectal Cancer
- Participants must have histologically or cytologically confirmed metastatic colorectal cancer and a documented BRAF V600E mutation by a Clinical Laboratory Improvement Act (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 computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam.
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%).
- Life expectancy of greater than 3 months.
- Leukocytes >= 3,000/mcL.
- Absolute neutrophil count >= 1,500/mcL.
- Platelets >= 100,000/mcL.
- Total bilirubin within normal institutional limits.
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal.
- Creatinine =< institutional upper limit of normal OR creatinine clearance >= 60 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal.
- Prothrombin time (PT)/institutional normalized ratio (INR) < 1.5 x upper limit of normal (ULN) and partial thromboplastin time (PTT) < 1.5 ULN.
- Albumin > 2.5 g/dl.
- Patients must meet eligibility criteria on course 1 day 1 (C1D1).
- Left ventricular ejection fraction (LVEF) > lower limit of normal (LLN) by echocardiogram (ECHO) or multigated acquisition (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.
- Any major surgery, extensive radiotherapy (> 15 days of treatment), chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 21 days prior to first dose of study treatment and/or chemotherapy without the potential for delayed toxicity within 14 days prior to first dose of study treatment. Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of study drug(s)and during the study.
- Participants who are receiving any other investigational agents.
- Patients 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. Exception: Patients will be allowed on study if they have brain metastases that have been treated and have been stable for at least 2 months.
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to of trametinib, dabrafenib or PDR001.
- Patients with history of prior treatment with MEK, BRAF, or anti-PD-1/PD-L1 monoclonal antibodies are not eligible.
- 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.
- Human immunodeficiency virus (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 (>= 10 mg/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.
- 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 (hepatitis B surface antigen [HbsAg] positive) will be excluded. * Note: Subjects with antecedent of hepatitis B (anti-hepatitis B core [HBc] positive, HbsAg and hepatitis B virus [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 interferon [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).
I. To assess antitumor activity of the combination of dabrafenib, trametinib, and spartalizumab (PDR001) in patients with BRAFV600E metastatic colorectal cancer.
II. To assess safety of dabrafenib, trametinib, and PDR001 in patients with BRAFV600E metastatic colorectal cancer.
SECONDARY (EXPLORATORY) OBJECTIVES:
I. To evaluate clinical response of dabrafenib, trametinib, and PDR001.
II. To describe mechanisms of response and resistance to dabrafenib, trametinib, and PDR001.
Patients receive dabrafenib orally (PO) twice daily (BID) on days 1-28, trametinib PO once daily (QD) on days 1-28, and spartalizumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 and 150 days, and every 12 weeks.
Trial Phase Phase II
Trial Type Treatment
Dana-Farber Harvard Cancer Center
Ryan Bruce Corcoran
- Primary ID 18-144
- Secondary IDs NCI-2018-02374
- Clinicaltrials.gov ID NCT03668431