A Phase I, open-label, dose escalation study of oral LGK974 in patients with malignancies dependent on Wnt ligands
This research is being done to: Determine the highest dose of the drug LGK974 that can be safely given to people with certain types of cancer [melanoma, breast cancer (lobular or triple-negative) or pancreatic adenocarcinoma]. It will also study what effect the body has on LGK974 and what effect LGK974 has on cancer. This is the first time it will be studied in humans.
Patients eligible for inclusion in this study have to meet all of the following criteria: -Histologically confirmed diagnosis of locally advanced or metastatic melanoma (except uveal melanoma), breast cancer (lobular or triple-negative), or pancreatic adenocarcinoma that has progressed despite standard therapy or for which no effective standard therapy exists -Age 18 years or older -WHO Performance Status of 0-2 -Absolute neutrophil count (ANC) greater than 1,500/mm3 -Platelets greater than 75,000/mm3 -Hemoglobin greater than 9.0 gm/dL [SI units gm/L] -Prothrombin time (PT) or aPTT less than ULN -Calculated or measured creatinine clearance greater than 50 ml/min(e.g. using Cockcroft-Gault formula) -Bilirubin less than 1.5 x ULN, except for patients with known Gilbert syndrome who are excluded if total bilirubin greater than 3.0 x ULN or direct bilirubin greater than 1.5 x ULN -Aspartate transaminase (AST) and / or Alanine transaminase (ALT) less than 3.0 x ULN, except for patients with liver metastasis who are excluded if AST and/or ALT greater than 5.0 x ULN -No biological therapy with a prolonged half-life (e.g., monoclonal antibodies) within 4 Weeks -No cytotoxic agents associated with delayed hematologic recovery (e.g., nitrosourea or mitomycin-C) within 6 weeks -No other systemic anti-cancer agents within 3 weeks -No radiotherapy within 2 weeks -During the dose escalation part of the study patients must have evaluable disease. During the expansion part of the study patients must have measurable disease as defined by (at least one lesion ï¿½ 10 mm in at least one dimension when assessed by CT or MRI, or a cutaneous lesion with clearly defined margins that measures ï¿½ 10 mm in at least one dimension) -Site of disease that in the opinion of the investigator can be safely biopsied using a core needle -Willingness and ability sign written informed consent and to comply with all study procedures Exclusions -Impaired cardiac function including any one of the following: -Corrected QT interval (QTc) greater than 480 milliseconds on baseline ECG -Clinically significant, uncontrolled heart disease (e.g., unstable angina, congestive heart failure, uncontrolled hypertension, ventricular or atrial arrhythmias) -Heart attack within the prior 3 months -Ongoing anticoagulant therapy (eg, aspirin, low molecular weight heparin) that can not be temporarily discontinued to allow tumor biopsy - Impairment of GI function or GI disease that may significantly alter the absorption of oral LGK974 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection) - Presence of ï¿½ CTCAE Grade 2 toxicity (except alopecia) due to prior therapy -Patients with a primary central nervous system tumor or with uncontrolled, symptomatic brain metastases that have not been adequately treated. Patients with symptomatic brain metastases that have been adequately treated, such as with radiotherapy or resection, are not excluded if any associated symptoms are stable, and do not require ongoing glucocorticoid therapy. -Malignant disease, other than that being treated in this study(exceptions to this exclusion criterion include the following: malignancies that were treated curatively, and have not recurred within 3 years prior to study entry; completely resected basal cell and squamous cell skin cancers; and completely resected carcinoma in situ of any type) -Patients who are currently receiving treatment with medications that meet one of the following criteria and that cannot be discontinued at least one week prior to the start of treatment with LGK974: 1. Strong inhibitors or inducers of CYP3A4/5 2. CYP3A4/5 substrates with narrow therapeutic index 3. Known to prolong the QT interval and are also CYP3A4/5 substrates -Patients who have undergone any major surgery within 2 weeks prior to starting study drug or who have not adequately recovered from previous surgery -Active hepatitis B or C infection -Pregnant or nursing (lactating) women -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 30 days after study treatment. Highly effective contraception methods include: ï¿½ Total abstinence or ï¿½ Male or female sterilization or ï¿½ Combination of any two of the following (a+b or a+c, or b+c): a. Use of oral, injected or implanted hormonal methods of contraception b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) c. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository -Sexually active males must use a condom during intercourse while taking the drug and for 90 days after stopping treatment and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid -Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or that may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for the study
LGK974 will be administered once daily (QD) in 28 day cycles and there is no planned break in administration between cycles. When clinical safety and lab data become available, an alternative dosing schedule, such as twice daily (BID), one dose in the morning and the second dose approximately 8 hours later in the evening, or intermittent dosing, such as 3 weeks of dosing followed by a 1 week break, may be examined, but a total cycle length of 28 days will be maintained.
12/20/2013 04:02 AM