An Open-Label Pilot Study to Evaluate the Efficacy and Safety of a Combination Treatment of Sonidegib (LDE225) and Buparlisib (BKM120) For the Treatment of Advanced Basal Cell Carcinomas
An Open-Label Pilot Study to Evaluate the Efficacy and Safety of a Combination Treatment of Sonidegib (LDE225) and Buparlisib (BKM120) For the Treatment of Advanced Basal Cell Carcinomas
This pilot trial studies how well sonidegib and buparlisib work in treating patients with basal cell carcinoma that has spread to other places in the body. Sonidegib and buparlisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
PRIMARY OBJECTIVES:
Estimate the overall response rate (ORR) of sonidegib (erismodegib) in combination with buparlisib (hereby referred to as "LB therapy") for patients with locally advanced or metastatic basal cell carcinoma (BCC) in Smoothened inhibitor-naive patients (Cohort 1) and those whose disease is refractory or relapsed on Smoothened inhibitor monotherapy (Cohort 2).
NOTE: This study does not compare the treatment effect between these 2 dissimilar participant groups.
SECONDARY OBJECTIVES:
OUTLINE:
Patients receive sonidegib orally (PO) once daily (QD) and buparlisib PO QD on days 1 to 28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and then every 3 months.
INCLUSION CRITERIA:
EXCLUSION CRITERIA:
Prior treatment with a P13K inhibitor
Known hypersensitivity to buparlisib or to its excipients
Untreated brain metastases are excluded; however, patients with metastatic central nervous system (CNS) tumors may participate in this trial, if the patient is > 4 weeks from therapy completion (including radiation and/or surgery), is clinically stable at the time of study entry and is not receiving corticosteroid therapy
Acute or chronic liver, renal disease or pancreatitis
Baseline creatinine kinase (CK) > ULN
The following mood disorders as judged by the Investigator or a psychiatrist, or as a result of patient's mood assessment questionnaire:
Diarrhea ≥ CTCAE grade 2
Active cardiac disease including any of the following:
Patient has a history of cardiac dysfunction including any of the following:
Patient has poorly controlled diabetes mellitus [defined as hemoglobin A1C (HgA1c) > ULN], steroid-induced diabetes mellitus, or insulin dependent diabetes mellitus
Other concurrent severe and/or uncontrolled concomitant medical conditions (eg, active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol
Significant symptomatic deterioration of lung function; if clinically indicated, pulmonary function tests including measures of predicted lung volumes, diffusing capacity of the lung for carbon monoxide (DLco), oxygen (O2) saturation at rest on room air should be considered to exclude pneumonitis or pulmonary infiltrates
Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of buparlisib (eg, ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection); patients with unresolved diarrhea will be excluded as previously indicated
Patients who have been treated with any hematopoietic colony-stimulating growth factors (eg, filgrastim (granulocyte-colony stimulating factor, G-CSF), sargramostim (granulocyte-macrophage colony-stimulating factor, GM-CSF) ≤ 2 weeks prior to starting study drug; erythropoietin or darbepoetin therapy, if initiated at least 2 weeks prior to enrollment, may be continued
Patients who are currently receiving treatment with medication with a known risk to prolong the QT interval or inducing Torsades de Pointes and the treatment cannot either be discontinued or switched to a different medication prior to starting study drug
Patients receiving chronic treatment with steroids or another immunosuppressive agent
Patients who have taken herbal medications and certain fruits within 7 days prior to starting study drug; herbal medications include, but are not limited to St. John's Wort, Kava, ephedra (ma huang), dehydroepiandrosterone (DHEA), gingko biloba, yohimbe, saw palmetto, and ginseng; fruits include the cytochrome P450, family 3, subfamily A (CYP3A) inhibitors Seville oranges, grapefruit, pummelos, or exotic citrus fruits
Patients who are currently treated with drugs known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A, and the treatment cannot be discontinued or switched to a different medication prior to starting study drug; please note that co-treatment with weak inhibitors of CYP3A is allowed
Patients who have received chemotherapy or targeted anticancer therapy ≤ 4 weeks (6 weeks for nitrosourea, antibodies or mitomycin-C) prior to starting study drug must recover to a grade 1 before starting the trial
Patients who have received any continuous or intermittent small molecule therapeutics (excluding monoclonal antibodies) ≤ 5 effective half lives prior to starting study drug or who have not recovered from side effects of such therapy
Use of statin drugs or other medications known to associate with rhabdomyolysis; these drugs must be discontinued at enrollment
Patients who have received wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy
Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy
Patients who are currently taking therapeutic doses of warfarin sodium or any other coumadin-derivative anticoagulant; low molecular weight heparin is allowed
Women who are pregnant or breast feeding or adults of reproductive potential not employing an effective method of birth control; double barrier contraceptives must be used through the trial by both sexes; oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are therefore not considered effective for this study; women of child-bearing potential, defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (ie, who has had menses any time in the preceding 12 consecutive months), must have a negative serum pregnancy test ≤ 72 hours prior to initiating treatment
Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (eg, age appropriate, history of vasomotor symptoms) or 6 months of spontaneous amenorrhea with serum follicle stimulating hormone (FSH) levels > 40 mIU/mL (for US only: and estradiol < 20 pg/mL) or have had surgical bilateral oophorectomy (with or without hysterectomy) at least 6 weeks prior; in the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential
Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use highly effective contraception during the study and through 20 months after the final dose of study treatment; for males with partners with childbearing potential, highly effective contraception is required for 6 months; the highly effective contraception is defined as either:
True abstinence: when this is in line with the preferred and usual lifestyle of the subject; periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago; in case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate); for female subjects on the study, the vasectomized male partner should be the sole partner for that patient
Use of a combination of any two of the following (a+b):
Oral contraception, injected or implanted hormonal methods are not allowed
Fertile males, must use highly effective (double barrier) methods of contraception (eg, spermicidal gel plus condom) for the entire duration of the study, and continuing using contraception and refrain from fathering a child for 6 months following the study drug; a condom is required to be used also by vasectomized men as well as during intercourse with a male partner in order to prevent delivery of the study treatment via seminal fluid; female partner of male study subject should use highly effective contraception during dosing of any study agent and for 16 weeks after final dose of study therapy
Note: hormonal contraception methods (eg, oral, injected, implanted) are not allowed
Note: woman are considered post-menopausal and not child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (eg, age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL and estradiol < 20 pg/mL or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago; in the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential
Known diagnosis of human immunodeficiency virus (HIV) infection, hepatitis B or hepatitis C
History of another malignancy within 3 years, except cured basal cell carcinoma of the skin or excised carcinoma in situ of the cervix
Patient is unable or unwilling to abide by the study protocol or cooperate fully with the investigator