A randomized, double-blind, placebo-controlled, phase III study comparing the combination of PDR001, dabrafenib and trametinib versus placebo, dabrafenib and trametinib in previously untreated patients with unresectable or metastatic BRAF V600 mutant melanoma
There are 3 parts to this study. The goal of Part 1 of this clinical research study (called "Safety Run-In") is to find the recommended dosing schedule of PDR001 when given with Tafinlar (dabrafenib) and Mekinist (trametinib) in patients with melanoma. The goal of Part 2 of this study (called "Biomarker Study") is to understand the effects of the combination of PDR001, dabrafenib, and trametinib. Researchers also want to study the biomarkers in patients receiving the study drugs. Biomarkers are found in the blood/tissue and may be related to your reaction to the study drugs. The goal of Part 3 of this study (called "Randomized") is to learn if the recommended dosing schedule of PDR001 found in Part 1 can help control melanoma when given in combination with dabrafenib and trametinib. In Part 3 of the study, PDR001 will be compared to a placebo. A placebo is not a drug. It looks like the study drug but is not designed to treat any disease or illness. It is designed to be compared with a study drug to learn if the study drug has any real effect.
Disease Group: Melanoma and other malignant neoplasms of skin
Treatment Agent: Dabrafenib,PDR001,Trametinib
Treatment Location: Both at MDACC & and Other Sites
IRB Review and Approval Date: 08/02/2017
Recruitment Status: Open
Projected Accrual: 538
1) (Part 1): ECOG performance status </= 1
2) (Part 1): Aspartate transaminase (AST) < 2.5× ULN and Alanine transaminase (ALT) < 2.5× ULN
3) (Part 2): ECOG performance status </= 2
4) (Part 2): A total of at least two cutaneous or subcutaneous lesions or nodal lesions for tumor sample collection. Lesions situated in a previously irradiated area, or an area subject to other locoregional therapy (e.g. intralesional injections) cannot be considered for sample collection.
5) (Part 3): ECOG performance status </= 2
6) All Subjects: >/= 18 years of at the time of informed consent
7) Written informed consent must be obtained prior to any screening procedures
8) Histologically confirmed, unresectable or metastatic melanoma (stage IIIC or IV)
9) BRAF V600 mutation positive melanoma as assessed locally, or if local BRAF testing is unavailable, at a Novartis designated central reference laboratory
10) Measurable disease per RECIST 1.1
11) Treatment-related toxicities (except alopecia) must = Grade 1 at the time of randomization according to CTCAE version 4.03
12) An adequate amount of tumor tissue (archived tumor tissue, or new biopsy if archived tissue is not available) must be available at the time of enrollment for central validation of BRAF V600 mutation and biomarker assessments
13) Subject has adequate bone marrow and organ function as defined by the following laboratory values without continuous supportive treatment (such as blood transfusion, coagulation factors and/or platelet infusion, or red/white blood cell growth factor administration) as assessed by laboratory for eligibility: Hematological: Absolute neutrophil count >/= 1.5 × 109/L Platelet count >/= 100 × 109/L Hemoglobin >/= 9 g/dL
14) contd from #13: Coagulation: PT/INR and PTT </= 1.5 x ULN. Subjects receiving anticoagulation treatment may be allowed to participate with INR established within the therapeutic range prior to randomization Renal: Serum creatinine < 1.5 mg/dL Hepatic: Total bilirubin </= 1.5 x ULN except for subjects with Gilbert’s syndrome who may only be included if the total bilirubin is </= 3.0 × ULN or direct bilirubin </= 1.5 × ULN
15) contd. from #14: Aspartate transaminase (AST) < 2.5 × ULN, except for subjects with liver metastasis, who are only included if the AST is < 5 × ULN Alanine transaminase (ALT) < 2.5 × ULN, except for subjects with liver metastasis, who are only included if the ALT is < 5 × ULN Albumin >/= 2.5 g/dL
16) Left ventricular ejection fraction (LVEF) >/=lower limit of institutional normal (LLN) as assessed by echocardiogram (ECHO) or multigated acquisition (MUGA) scan
17) Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels
18) 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.
1) (Part 1): Any history of CNS metastases
2) (Part 2) and (Part 3): Clinically active cerebral melanoma metastasis. Subjects with up to three cerebral metastases are eligible, if all lesions are stable and have been definitively treated with stereotactic radiation therapy, surgery or gamma knife therapy with no evidence of disease progression prior to enrollment as assessed by two consecutive assessments >/= 6 weeks apart and have not required steroids for at least >/= 4 weeks prior to enrollment (physiological doses of corticosteroids are allowed).
3) All Subjects: Subjects with uveal or mucosal melanoma
4) Prior systemic anti-cancer treatment (e.g., checkpoint inhibitors, targeted therapy [e.g. BRAF and/or MEK inhibitors], chemotherapy, biologic therapy, tumor vaccine therapy, or any systemic investigational treatment) for unresectable or metastatic melanoma.
5) Prior loco-regional treatment with intralesional therapy (e.g. talimogene laherparepvec) for unresectable or metastatic melanoma in the last 6 month prior to start of study treatment.
6) Prior neoadjuvant and/or adjuvant therapy for melanoma completed less than 6 months prior to start of study treatment (e.g., targeted therapy, immunotherapy [e.g. interferon], biochemotherapy, tumor vaccine).
7) Radiation therapy </= 4 weeks prior to start of study treatment (palliative radiotherapy to bone lesions allowed </= 2 weeks prior to start of study treatment).
8) Major surgery, open biopsy, or significant traumatic injury </= 2 weeks prior to start of study treatment. Minor surgical procedures should be completed 7 days prior to start of study treatment.
9) 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).
10) 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.
11) Current pneumonitis or interstitial lung disease.
12) History of organ transplant requiring use of immunosuppressive medication.
13) Taken an investigational drug </= 28 days or </= 5 half-lives (minimum 14 days) prior to start of study treatment, whichever is shorter.
14) History of severe hypersensitivity reactions to other monoclonal antibodies, which in the opinion of the investigator may pose an increased risk of serious infusion reaction.
15) Current use of a prohibited medication.
16) 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.
17) Active infection requiring systemic antibiotic therapy within 2 weeks prior to start of study treatment.
18) Known history of testing positive for Human Immunodeficiency Virus (HIV) infection. For Germany only: testing positive for HIV during screening using a local test.
19) 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.
20) 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
21) 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.
22) Use of any live vaccines against infectious diseases within 4 weeks of initiation of study treatment.
23) Uncorrectable electrolyte abnormalities (e.g. hypokalemia, hypomagnesemia, hypocalcemia), long QT syndrome or taking medicinal products known to prolong the QT interval.
24) Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO).
25) Pregnant or nursing (lactating) women confirmed by a positive hCG laboratory test within 72 hours prior to initiating study treatment. Note: Low levels of hCG may also be considered a tumor marker, therefore if low hCG levels are detected, another blood sample at least 4 days later must be taken to assess the kinetics of the increase and transvaginal ultrasound must be performed to rule out pregnancy.
26) A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy including: a) 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 b) Visible retinal pathology as assessed by ophthalmic examination that is considered a risk factor for RVO or central serous retinopathy such as: 1) Evidence of new optic disc cupping; 2) Evidence of new visual field defects on automated perimetry; 3) Intraocular pressure >21 mmHg as measured by tonometry.
27) 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).
28) Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 150-days after stopping treatment with PDR001. Highly effective contraception methods include: a. Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. b. Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment. c. Male sterilization (at least 6 months prior to screening).
Criteria truncated, please contact Prinicipal Investigator's office for full criteria
Information and next steps
Melanoma and other malignant neoplasms of skin
Melanoma Medical Oncology
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