A Phase I Study of the PI3-Kinase Inhibitor BKM120 in Combination With Gemcitabine and Cisplatin in Patients With Advanced Solid Tumors
A Phase I Study of the PI3-Kinase Inhibitor BKM120 in Combination With Gemcitabine and Cisplatin in Patients With Advanced Solid Tumors
This phase I trial studies the side effects and the best doses of buparlisib, gemcitabine hydrochloride, and cisplatin in treating patients with solid tumors that have spread to other places in the body. Buparlisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as gemcitabine hydrochloride and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving buparlisib, gemcitabine hydrochloride, and cisplatin may be a better treatment for solid tumors.
PRIMARY OBJECTIVES:
I. To describe the dose-limiting toxicities, maximally tolerated dose, and identify the recommended Phase II dose (RP2D) of the combination of BKM120 (buparlisib), gemcitabine (gemcitabine hydrochloride), and cisplatin in patients with advanced solid tumors.
SECONDARY OBJECTIVES:
I. To describe safety and tolerability of the combination of BKM120, gemcitabine, and cisplatin in patients with advanced solid tumors.
II. To describe preliminary evidence of efficacy with this combination. III. To describe any pharmacokinetic (PK) effect of gemcitabine and cisplatin on the plasma concentrations of BKM120.
IV. To evaluate phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations as predictive biomarkers of efficacy for the combination.
V. To evaluate PIK3CA polymorphisms and polymorphisms in BKM120 transport and metabolism as predictors of toxicity and/or efficacy.
OUTLINE: This is a dose-escalation study.
Patients receive buparlisib orally (PO) once daily (QD) on days 1-21, gemcitabine hydrochloride intravenously (IV) over 30 minutes on days 1 and 8, and cisplatin IV over 2 hours on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 30 days.
Inclusion Criteria:
Exclusion Criteria:
Previous anti-cancer chemotherapy, immunotherapy or investigational agents < 4 weeks, or palliative radiation < 2 weeks prior to the first day of study treatment, or who have not recovered to grade 1 or better from related side effects of such therapy (except alopecia); patients who receive gamma knife radiosurgery for brain metastases are eligible if procedure was performed > 2 weeks before treatment is started, is clinically stable and has been on stable low dose corticosteroid treatment (e.g., dexamethasone 2 mg/day, prednisolone 12 mg/day for at least 14 days before start of study treatment are eligible); ongoing hormonal therapies (luteinizing hormone-releasing hormone [LHRH] antagonists, megestrol) are allowed
Previous treatment with a phosphatidylinositol 3-kinase (P1-3K) inhibitor
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), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng; fruits include the cytochrome P450, family 3, subfamily A (CYP3A) inhibitors Seville oranges, grapefruit, pummelos, or exotic citrus fruits
Patient has a known hypersensitivity to any of the excipients of BKM120
Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects
Patient is currently receiving increasing or chronic treatment (> 5 days) with corticosteroids or another immunosuppressive agent, as chronic administration of corticosteroids (> 5 days) can induce cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)
Patient is being treated at start of study treatment with any of the following drugs:
Patient is currently receiving warfarin or other Coumarin derived anti-coagulant, for treatment, prophylaxis or otherwise; therapy with heparin, low molecular weight heparin (LMWH), or fondaparinux is allowed
Patients who have other concurrent severe and/or uncontrolled medical conditions that would, in the investigator's judgment, contraindicate patient participation in the clinical study (eg. active or uncontrolled severe infection, chronic active hepatitis, immunocompromised, acute or chronic pancreatitis, uncontrolled high blood pressure, interstitial lung disease, etc.)
Patient has a known history of human immunodeficiency virus (HIV) infection (testing not mandatory) infection
Patient has any of the following cardiac abnormalities:
Symptomatic congestive heart failure
Myocardial infarction =< 6 months prior to enrollment
Unstable angina pectoris
Serious uncontrolled cardiac arrhythmia
Symptomatic pericarditis
Corrected QT interval using Fridericia's formula (QTcF) > 480 msec on the screening electrocardiogram (ECG) (using the QTcF formula)
Currently receiving treatment with medication that has a known risk to prolong the QT interval or inducing Torsades de Pointes, and the treatment cannot be discontinued or switched to a different medication prior to starting study drug
Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
Patient has a score >= 12 on the Patient Health Questionnaire (PHQ)-9 questionnaire
Patient selects a response of "1, 2 or 3" to question number 9 on the PHQ-9 questionnaire regarding potential for suicidal thoughts or ideation (independent of the total score of the PHQ-9)
Patient has a General Anxiety Disorder (GAD)-7 mood scale score >= 15
Patient has a medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (e.g. risk of doing harm to self or others), or patients with active severe personality disorders (defined according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV]) are not eligible; Note: for patients with psychotropic treatments ongoing at baseline, the dose and the schedule should not be modified within the previous 6 weeks prior to start of study drug
Patient has >= Common Terminology Criteria for Adverse Events (CTCAE) grade 3 anxiety
Patient has other prior or concurrent malignancy (except for the following: adequately treated basal cell or squamous cell skin cancer, or other adequately treated in situ cancer, early gastric or GI cancer resected completely by endoscopy procedures or any other cancer from which the patient has been disease free for >= 3 years)
Patient has a history of non-compliance to medical regimen or inability to grant consent
Patient is concurrently using other approved or investigational antineoplastic agent
Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test (> 5 mIU/mL); patients with elevated hCG at baseline that is judged to be related to the tumor are eligible if hCG levels do not show the expected doubling when repeated 5-7 days later, or pregnancy has been ruled out by vaginal ultrasound
Patient who does not apply highly effective contraception during the study and through the duration as defined below after the final dose of study treatment:
Sexually active males should use a condom during intercourse while taking drug and for 8 weeks after the final dose of study treatment and should not father a child in this period, but may be recommended to seek advice on conservation of sperm; a condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid
Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use highly effective contraception during the study and through at least 4 weeks after the final dose of study treatment
Highly effective contraception is defined as either:
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)
Female sterilization: have had surgical bilateral oophorectomy (with or without 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
Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate); (for female study subjects, the vasectomized male partner should be the sole partner for that patient)
Use a combination of the following:
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 (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago; for women with therapy-induced amenorrhea, oophorectomy or serial measurements of follicle-stimulating hormone (FSH) and/or estradiol are needed to ensure postmenopausal status; NOTE: ovarian radiation or treatment with a luteinizing hormone-releasing hormone (LH-RH) agonist (goserelin acetate or leuprolide acetate) is not permitted for induction of ovarian suppression