http://jco.ascopubs.org/content/30/3/282.full
Phase I, Dose-Escalation Study of BKM120, an Oral Pan-Class I PI3K Inhibitor, in Patients With Advanced Solid Tumors
INTRODUCTION
The intracellular phosphatidylinositol-3-kinase (PI3K) pathway regulates such cellular functions as cell proliferation, growth, survival, apoptosis, protein synthesis, and glucose metabolism.1–3 Of the three classes of PI3K (I to III), class IA is the most implicated in cancer.4 Class-IA PI3K heterodimers comprise a p85-regulatory and a p110-catalytic subunit with several isoforms.4 Mutation or amplification of PIK3CA, the gene encoding the p110α isoform, promotes oncogenic activation of the PI3K pathway and occurs frequently in human cancers.4–8 Inactivation of the phosphatase and tensin homolog (PTEN), a key negative regulator of PI3K, via mutations or loss of protein expression is associated with tumorigenesis and observed in many cancers.4,9–11 Moreover, PI3K pathway activation may be associated with resistance to chemotherapy and targeted agents in different cancers.12–15 Selective inhibition of the PI3K pathway in cancer represents a promising therapeutic approach and is the focus of significant efforts in research and clinical development of novel agents targeting this pathway. Preclinical studies of inhibitors of PI3K signaling have shown antiproliferative activity in cancer cells and inhibition of tumor growth in tumor xenograft models.4,16–18
BKM120 (Novartis Pharma AG, Basel, Switzerland) is an oral pyrimidine-derived pan-PI3K inhibitor with specific and potent activity against class I PI3Ks. BKM120 inhibits wild-type and mutant PI3Kα isoforms and PI3Kβ, -γ, and -δ isoforms at nanomolar concentrations.19 BKM120 has no inhibitory activity against the class III PI3K, or mammalian target of rapamycin (mTOR).19 In vitro experiments show a strong antiproliferative effect of BKM120 on human cancer cell lines with alterations in the PI3K pathway. This was confirmed in a screen of more than 400 cancer cell lines (Novartis, data on file), including MCF7-PIK3CA–mutated breast cancer cells.19 In vivo, BKM120 demonstrated significant antitumor activity in human tumor xenograft models with or without PIK3CA/PTEN mutations, with good correlation between BKM120 exposure and inhibition of PI3K signaling.20
The primary objective of this first-in-human, phase I, dose-escalation study was to determine the maximum-tolerated dose (MTD) of oral BKM120 on a once-daily continuous schedule in adult patients with advanced solid tumors. Secondary objectives included assessment of safety and tolerability of BKM120, preliminary antitumor activity, and characterization of the pharmacokinetic (PK) and pharmacodynamic profiles. Pharmacodynamic assessments to measure clinical PI3K inhibition included tumor metabolic response by [18F]fluorodeoxyglucose positron emission tomography ([18F]FDG-PET), fasting plasma C-peptide levels, fasting plasma glucose (FPG), and phosphorylated ribosomal protein S6 (Ser240/244; pS6) in skin biopsies.
Previous SectionNext SectionPATIENTS AND METHODS
Supplementary methods can be found in the Appendix (online only).
Previous SectionNext SectionPatient Population
Patients had histologically confirmed advanced tumors failing standard therapy; one or more lesion as defined by Response Evaluation Criteria In Solid Tumors (RECIST); age ≥ 18 years; life expectancy ≥ 12 weeks; World Health Organization performance status ≤ 2; adequate bone marrow, hepatic, and renal function; and FPG levels ≤ 140 mg/dL (7.8 mmol/L). A representative tissue specimen for analysis of tumor molecular status was required. Key exclusion criteria were corticosteroid treatment ≤ 2 weeks before starting BKM120; clinically manifest diabetes mellitus, including a history of gestational diabetes; and prior treatment with a PI3K inhibitor.
Approval was obtained from the ethics committees at the participating institutions and regulatory authorities. All patients gave informed consent. The study followed the Declaration of Helsinki and good clinical practice guidelines.
Previous SectionNext SectionStudy Design and BKM120 Dose Escalation
This was a phase I, multicenter, open-label, single-agent, dose-escalation study. Patients received oral, once-daily BKM120 capsule(s) starting at 12.5 mg on a 28-day continuous schedule until disease progression, unacceptable toxicity, or consent withdrawal. Assignment to treatment was based on Bayesian inference of a logistic regression model describing the dose-toxicity relationship and was guided by the escalation with overdose control principle.21 Dose-limiting toxicities (DLTs) were evaluated during the first treatment cycle (28 days). Main DLTs were defined as Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 ≥ grade 3 hematologic or nonhematologic toxicity. Exceptions were ≥ grade 2 pancreatitis, ≥ 1 grade level increase in neurotoxicity, ≥ grade 2 phototoxicity or skin rash necessitating treatment interruption for more than 21 consecutive days, non-CTCAE grade 2 hyperglycemia not resolved to grade 0 within 14 consecutive days of initiation of oral antidiabetes medications, ≥ non-CTCAE grade 3 hyperglycemia (Appendix Table A1, online only), grade 2 mood alteration not resolved to grade 1 within 14 days despite medical treatment (grade 2 anxiety was considered a DLT only if worsened from baseline), and ≥ grade 3 mood alteration (per protocol amendment).
The MTD was defined as the highest dose of BKM120 not causing DLT in more than 33% of patients in the first treatment cycle. Twenty-one or more evaluable patients had to be treated before MTD declaration, with six or more evaluable patients treated at the MTD for one cycle. Criteria for evaluation were ≥ 21 days BKM120 treatment in cycle 1, sufficient safety evaluation, or early discontinuation owing to DLT.
Previous SectionNext SectionSafety and Efficacy Assessments
Clinical and laboratory assessments were conducted at baseline and on a weekly basis during cycle 1; on days 8, 15, and 22 of cycle 2; and on days 1 and 15 of subsequent cycles. Safety assessments included electrocardiograph monitoring and monitoring of urine glucose, FPG, plasma glucose per 2-hour 75-g oral glucose tolerance test, and hemoglobin A1C levels. Adverse events were graded using the CTCAE version 3.0, unless otherwise specified (Appendix Table A1). Responses were assessed after two cycles, and every other cycle thereafter, using RECIST version 1.0.22
Previous SectionNext SectionPharmacokinetic Assessments
Plasma levels of BKM120 were determined from samples (collected predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours postdose on days 1, 8, and 28 of cycle 1) using a validated liquid chromatography–tandem mass spectrometry assay with a lower limit of quantification of 1 ng/mL (Novartis, data on file). Standard PK parameters were determined using a noncompartmental method (WinNonlin; Pharsight, Mountain View, CA).
Previous SectionNext SectionPharmacodynamic Assessments
Whole-body [18F]FDG-PET scans were performed at baseline and on day 28 of cycles 1 and 2. Response thresholds were maximum standardized uptake value changes ≥ 25%.23
pS6 was measured by semiquantitative immunohistochemistry in fresh-paired postprandial skin biopsies from pretreatment and 2 to 4 hours posttreatment on day 1 of cycle 2.
Blood samples for fasting glucose, insulin, and fasting C-peptide were collected at predose and 0.5, 1, 2, 4, and 24 hours postdose on days 1, 8, and 28 of cycle 1. C-peptide (cleavage product of proinsulin) was chosen over insulin as a more robust and stable pharmacodynamic marker based on its longer half-life (30 v 5 minutes).24
Previous SectionNext SectionRESULTS
Study Population
Thirty-five patients from three clinical sites were enrolled and treated in dose-escalation cohorts from November 2008 to October 2009 (Table 1). Patients with colorectal (15, 43%) or breast (nine, 26%) cancer constituted the majority. Thirty-three patients (94%) had received prior antineoplastic therapy; 18 patients (51%) had received more than three prior antineoplastic regimens.
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In this window In a new window Table 1.
Patient Baseline Characteristics and Tumor Molecular Status
Thirty-one tumor samples were found to be evaluable; 16 (46%) had PI3K pathway alterations (Table 1), including a PIK3CA mutation (n = 5) or null or low PTEN protein expression (n = 11). In four patients the mutation involved the H1047R amino acid substitution; in one patient the mutation involved the E545G amino acid substitution. Of 10 patients with tumor KRAS mutations, three had both a KRAS mutation and null or low PTEN protein expression.
Dose Escalation and MTD
Patients received oral, once-daily BKM120 starting at 12.5 mg (12.5, 25, 50, 80, 100, or 150 mg). Intrapatient dose escalation occurred in three patients. DLTs occurred in seven patients of 30 evaluable for DLT (Appendix Table A2): one patient (of six) at 80 mg (grade 2 mood alteration), four patients (of 16) at 100 mg (one each of grade 3 epigastralgia, grade 3 rash, grade 2 mood alteration, and grade 3 mood alteration), and two patients (of three) at 150 mg (both with grade 4 hyperglycemia). Mood alterations consisted of anxiety, euphoria, and depression and were reversible with dose hold and reduction. The 150-mg dose level was evaluated after a single DLT of epigastralgia was observed of five patients at 100 mg. After DLTs of hyperglycemia at the 150-mg dose level, additional patients were enrolled at 100 mg, and an 80-mg cohort was initiated to further explore the mood disorder and overall safety. The 100-mg dose level was defined as the MTD on the basis of the largest posterior probability of DLT rate in the target toxicity interval and with less than 25% risk of overdose. Six patients (17.1%) had dose reductions in cycle 1 and 12 (34.3%) overall in the study. In eight patients overall (22.9%), dose reductions were due to adverse events. Dosing was delayed in 12 patients (34.3%) in cycle 1 and in 20 patients (57.1%) overall.
Safety Findings
BKM120 was well tolerated. Grade 3/grade 4 adverse events (AEs), regardless of causality, were observed in 22 patients (63%) (Table 2). Of the grade 3/grade 4 AEs regardless of causality, rash (11%), hyperglycemia (9%), performance status decreased (9%), mood alteration (9%; including mood altered [6%] and affective disorder [3%]), and pruritus (6%) were observed in two or more patients (Table 2). The majority of treatment-related AEs were observed at dose levels ≥ 100 mg (Table 2).
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Adverse Events by Treatment Cohort and Grade
Rash was primarily a pruritic maculopapular rash concentrated on the torso (Appendix Fig A1). Terms used to describe mood alterations included mood altered, anxiety, depression, emotional disorder, crying episodes, hallucinations, irritability, and affective disorder. After interruption of BKM120, mood alterations resolved within the treatment cycle. Grade 3 mood alterations consisted of anhedonia followed by an increase in anxiety and irritability.
Five patients (14%) experienced serious AEs considered to be treatment related: hyperglycemia (80 mg, 150 mg [n = 2]), skin rash (150 mg), and diarrhea (100 mg). All four deaths on study resulted from disease progression.
Pharmacokinetic Analysis
BKM120 is rapidly absorbed after oral administration, with the median time to reach peak plasma concentrations (Tmax) between 0.5 and 4 hours post dose (Fig 1, Table 3). Tmax seemed to be independent of dose and did not change after multiple oral doses. After reaching the peak drug concentration (Cmax), BKM120 plasma concentrations decreased in a bi-exponential manner (Fig 1) with an apparent long terminal elimination half-life (T1/2). Because of the study sampling schedule and the long half-life, T1/2 and related PK parameters could not be accurately estimated by noncompartmental analysis.
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Summary of Pharmacokinetic Parameters by Cohort
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PowerPoint Slide for Teaching Fig 1.
Plasma pharmacokinetic profile of BKM120 in patients with advanced solid tumors. Each line represents the mean BKM120 plasma concentration for a single-dose cohort measured on day 8, cycle 1 (error bars reflect standard deviation of the mean [SD]). Time scale is hours after dose.
BKM120 exposure within a dosing interval (AUC0-24) and Cmax was similar between days 8 and 28 of daily oral dosing, indicating the absence of significant drug accumulation after day 8 (Table 3). BKM120 accumulated ∼three-fold in achieving steady-state, consistent with a half-life of ∼40 hours. Apparent total body clearance from plasma at steady-state (calculated as dose/AUC0-24) was low (∼5.0 L/h). Approximate dose-proportional increase in Cmax and AUC0-24 was observed across the entire dose range. Interpatient variability (CV%) in Cmax and AUC0-24 differed at each dose level but was moderate and generally approximately 40%.
At the MTD, steady-state levels of BKM120 were in the range predicted to be efficacious based on in vivo preclinical tumor models. Physiologically based models predicted a fraction of absorbed dose and hepatic clearance (CLhep) of BKM120 of approximately 0.95 and 2 to 8 L/h, respectively, with an absolute oral bioavailability of more than 90% (data not shown). These predictions are in close agreement with the oral clearance of 5 L/h found in this study. BKM120 is a low-clearance drug with a first-pass hepatic extraction limited to less than 10% (CLhep<5 L/h).
Antitumor Activity
Thirty-one of 35 patients were evaluable for response by investigator; baseline and postbaseline target lesion radiologic assessments were available for 24 patients by central review (Fig 2A). One patient with triple-negative breast cancer and a KRAS mutation achieved a partial response (PR) on a BKM120 dose of 100 mg/d. Sixteen patients (of 31; 52%) had stable disease (SD) for more than 6 weeks, including five with colorectal cancer and five with breast cancer. As of August 2010, seven patients had been on the study for ≥ 8 months, most at 100 mg/d (two patients each with breast cancer and colorectal cancer and one patient each with prostate cancer, angiosarcoma, and lung adenocarcinoma). Five of these patients had tumors with PI3K pathway dependence (PTEN low/no protein expression or PIK3CA gene mutation).
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PowerPoint Slide for Teaching Fig 2.
Radiologic response to BKM120 with corresponding status of tumor PIK3CA, phosphatase and tensin homolog (PTEN), and KRAS alterations. Gold indicates no alterations, and dark blue indicates a gene mutation or altered protein expression. Gray shading indicates status unknown. Primary tumor type of colorectal cancer (blue), breast cancer (tan), or other (red) is indicated. (A) Best percentage change from baseline in the sum of the longest diameter and response as per investigator for 24 patients with baseline and postbaseline target lesion assessments. Solid lines indicate Response Evaluation Criteria in Solid Tumors thresholds for response: 30% decrease for partial response (PR) and 20% increase for progressive disease (PD). (B) Best percentage change from baseline to cycle 1, day 28 in the sum of the maximum standardized uptake values (sSUVmax) and metabolic response (mResponse) as per investigator. Patient numbers correlate to those in panel A. The solid line indicates a 25% decrease threshold for mResponse. FDG-PET, [18F]fluorodeoxyglucose positron emission tomography; SD, stable disease; UNK, unknown; WT, wild type.
Pharmacodynamic Analysis
Nineteen patients were evaluable for [18F]FDG-PET assessments (Fig 2B). A more than 25% decrease in tumor [18F]FDG uptake was observed in 10 patients per central review, three of whom demonstrated tumor shrinkage on CT assessment. Nine patients had a metabolic PR; eight of these patients had received BKM120 doses of ≥ 100 mg.
BKM120 administration was associated with sustained dose-dependent increases in fasting C-peptide. Increases in fasting blood glucose were more evident at higher doses, including hyperglycemia as a DLT at 150 mg/d (Fig 3A).
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PowerPoint Slide for Teaching Fig 3.
Biomarker assessment in patients receiving oral BKM120. (A) Comparison of plasma fasting C-peptide and fasting glucose levels over time (0 to 300 days) by dose cohort (n corresponds to the number of patients). Each line represents a single patient. Normalized C-peptide values are listed as fold increase from upper limit of normal; glucose values are given in milligrams per deciliter. Ranges for hyperglycemia grade 1 (140 to 199 mg/dL [7.8 to 11.0 mmol/L]), grade 2 (200 to 249 mg/dL [11.1 to 13.8 mmol/L]), and grade 3 (250 to 399 mg/dL [13.9 to 22.2 mmol/L]) are indicated. Analysis time points are at baseline, on days 1, 8, 15, 22, and 28 of cycle 1; day 15 of cycle 2; and days 1 and 15 of subsequent cycles. Increases in C-peptide are evident at all doses tested, whereas increases in glucose become more evident at doses ≥ 80 mg. (B) Effect of BKM120 on pS6 (Ser240/244) levels in skin biopsies, by dose cohort. Data are represented as percentage change from baseline of the H-score of the whole epidermis for evaluable paired pre- and post-treatment (day 28) patient samples. Red solid line marks a 40% decrease in pS6 levels from baseline.
Assessments of baseline and post-treatment pS6 levels in skin were available for 23 patients (Fig 3B; Appendix Fig A2, online only). At BKM120 doses of 80 to 150 mg/d, 15 (80%) of 19 patients demonstrated a 40% to 85% decrease in pS6 levels compared with baseline (Fig 3B).
Expansion Part of the Study
The study has been expanded, and, as of August 20, 2010, five additional patients have been enrolled at 80 mg and 26 additional patients at 100 mg. Median age was 55 years (range, 30 to 77 years). Most common tumor types were colorectal (24 patients), breast (18 patients), lung (three patients), and endometrial (three patients) cancer. Median duration of treatment was 7.5 weeks (range, 0.1 to 69+ weeks), with 17 patients treated for more than 16 weeks. Most frequent AEs of all grades suspected to be related to BKM120 were decreased appetite (33%); rash, diarrhea, nausea (27%); fatigue, hyperglycemia (24%); anxiety (20%); depression (18%); and mucosal inflammation (17%). Most frequent grade 3/grade 4 AEs (> 5%) were transaminase increase (9.1%), asthenia (7.6%), and rash (6.1%). Two patients in the expansion have demonstrated PRs: one patient with estrogen receptor–positive/human epidermal growth factor receptor 2 negative metastatic breast cancer (PIK3CA mutation) and one patient (unconfirmed) with parotid cancer (PIK3CA mutation and null PTEN). Twenty-six of 45 patients evaluable by CT (58%) had SD as best response. A trend toward better activity was observed at the higher dose cohorts, also expressed as metabolic FDG-PET response. Eighteen patients had SD lasting for at least 16 weeks, including eight patients who had tumors with either PI3K mutations or low/absent PTEN expression. A more detailed analysis of the expansion cohort will be presented in a separate publication.
Previous SectionNext SectionDISCUSSION
The results from this dose-escalation study of the novel PI3K inhibitor BKM120 provide evidence of the feasibility of pan-Class I PI3K inhibition in patients with cancer. The MTD of oral BKM120 administered on a continuous daily schedule was defined as 100 mg/d on the basis of DLTs of mood alteration, hyperglycemia, epigastralgia, and rash.
At the MTD, steady-state levels of BKM120 were in the range predicted to be efficacious based on in vivo preclinical tumor models. Given the good absorption properties and apparent low intra- and inter-individual variability, BKM120 shows a favorable pharmacokinetic profile.
BKM120 was well tolerated, with a dose-dependent safety profile. Hyperglycemia, a class effect, is consistent with inhibition of PI3K signaling and has been observed with other PI3K/mTOR/Akt pathway inhibitors.25–27 p110-PI3K activity mediates insulin signaling; inhibition blocks the metabolic actions of insulin, including glucose transport and glycogen synthesis,2,3,28–30 resulting in increased blood glucose and compensatory release of insulin (and C-peptide) from pancreatic β-cells.3 Disturbance of glucose homeostasis as evidenced by hyperglycemia was more common at higher doses and may be attributed to BKM120 inhibition of p110.16 Hyperglycemia was managed initially with metformin and subcutaneous insulin, when necessary. Hyperglycemia was primarily controlled with metformin. Insulin was used in four patients, including three of whom developed hyperglycemia on starting steroids and one who was unable to tolerate oral medication. At the 150-mg dose level, discontinuation of BKM120 was required to control hyperglycemia.
Skin rash was a frequent AE potentially related to BKM120 administration in 37% of patients; this may be considered a class effect.25,27,31,32 Rash was primarily responsive to antihistamines and topical corticosteroids. Dose interruption was required in severe cases; most patients were able to resume the previous dose level.
Mood alterations seen may reflect effects of PI3K inhibition in the CNS, given that BKM120 can cross the blood–brain barrier (Novartis, data on file; also demonstrated by a 28% shrinkage of a brain metastasis in one patient). Dysfunction of the PI3K pathway in the CNS has been linked to anxiety and low serotonin levels in the amygdala33 and to schizophrenia.34 Mood alterations were responsive to BKM120 dose-reduction, dose-hold, and treatment with selective serotonin reuptake inhibitors and anxiolytics. Once mood alterations were identified as potentially drug-related, patients with grade 1 alterations were immediately treated with selective serotonin reuptake inhibitors, and no further mood alterations greater than grade 1 were seen. Future studies of BKM120 will exclude patients with major risk factors for these AEs.
Pharmacodynamic effects suggested dose-dependent inhibition of PI3K signaling. Increases in fasting C-peptide were detected at doses lower than those associated with hyperglycemia, suggesting that increased pancreatic insulin/C-peptide release can effectively compensate for decreased glucose transport and metabolism due to PI3K inhibition at BKM120 doses less than 100 mg. Although glucose has typically been used as a pharmacodynamic marker for PI3K pathway inhibition, C-peptide may be more appropriate. Additionally, significant decrease in pS6, a downstream PI3K target, was observed in a majority of skin biopsies at doses of BKM120 ≥ 80 mg. Decreased [18F]FDG uptake (> 25%) was observed in 53% of evaluable patients; however, the role of PI3K signaling in glucose uptake may skew the use of [18F]FDG uptake as a marker of tumoricidal effect,23 as seen with mTOR inhibitors.35 In studies of PI3K pathway inhibitors, [18F]FDG-PET may reflect pharmacodynamic effects of target inhibition as well as antitumor effects.16 Similar to the profile of tumor radiologic response, decreases in tumor [18F]FDG uptake were most significant at BKM120 doses ≥ 100 mg/d, suggesting that this effect may be due to a combination of antitumor activity and direct PI3K inhibition.
It is too early to conclude whether tumors with PI3K pathway alterations have a higher probability of response to BKM120. Five of seven patients treated for ≥ 8 months had tumors with PI3K pathway dependence. Further clinical studies are needed to evaluate the predictive value of oncogenic alterations in PI3K or PTEN, as well as other mutations such as AKT1/2 or PIK3R1, the regulatory subunit of PI3K, in patient populations selected for PI3K pathway alterations.
Preclinical data suggest KRAS mutations may predict resistance to PI3K inhibition36–38; however, the PR in a patient with breast cancer suggests that implications of breast cancer KRAS mutation may differ from colon cancer, in which it predicts resistance to inhibition of growth factor signaling.39 In our study, one of seven patients with KRAS mutant colon cancer had SD for more than 3.5 months; the rest had progressive disease.
In conclusion, this study's findings demonstrate the clinical safety and tolerability, favorable PK profile, consistent pharmacodynamic effects, and early antitumor activity of pan-Class I PI3K inhibition with BKM120 on a continuous daily schedule in patients with advanced solid tumors. Further characterization of BKM120 at the selected dose of 100 mg is ongoing in patients with PI3K pathway-activated tumors.
Previous SectionNext SectionAUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: Diana Birle, Novartis Institutes of Biomedical Research (C); David Demanse, Novartis Pharma (C); Stefan S. De Buck, Novartis Pharma (C); Qinhua C. Ru, Novartis Oncology (C); Malte Peters, Novartis Pharma (C); Michael Goldbrunner, Novartis Pharma (C) Consultant or Advisory Role: Jaap Verweij, Novartis (C); José Baselga, Novartis (C) Stock Ownership: Diana Birle, Novartis Pharma; Stefan S. De Buck, Novartis Pharma; Malte Peters, Novartis Pharma; Michael Goldbrunner, Novartis Pharma Honoraria: Jaap Verweij, Novartis Research Funding: None Expert Testimony: Jordi Rodon, Novartis (C) Other Remuneration: None
Previous SectionNext SectionAUTHOR CONTRIBUTIONS
Conception and design: Jordi Rodon, Jaap Verweij, Stefan S. De Buck, Malte Peters, Michael Goldbrunner, José Baselga
Provision of study materials or patients: Johanna C. Bendell, Jordi Rodon, Howard A. Burris, Maja de Jonge
Collection and assembly of data: Johanna C. Bendell, Jordi Rodon, Howard A. Burris, Maja de Jonge, Jaap Verweij, David Demanse, Qinhua C. Ru, José Baselga
Data analysis and interpretation: All authors
Manuscript writing: All authors
Final approval of manuscript: All authors
Previous SectionNext SectionAcknowledgment
We thank Jeffrey Infante, Suzanne Jones, Shireen Williams, and Sara Ramsey at Sarah Cannon Research Institute; Adelaida Piera, Gemma Parramon, Amanda Rodriquez, Miquel Bel, Javier Cortes, and Cristina Saura at Vall d'Hebron University Hospital; Ferry Eskens, Stefan Sleijfer, Diane van der Biessen, and Leni van Doorn at Erasmus University Medical Center; CBKM120×2101 clinical study team at Novartis; the patients; and their families. We also thank John Monahan and Lilli Petruzzelli for their most valuable analysis of the tumor molecular status.
We thank Dina Marenstein and Sara Mariani of Chameleon Communications International, who provided medical writing services with funding from Novartis Pharma.
Previous SectionNext SectionAppendix
Previous SectionNext SectionSupplementary Methods
Patient population.
Patients were required to have the following laboratory values: absolute neutrophil count ≥ 1.5 × 109/L, hemoglobin ≥ 9 g/dL, platelets ≥ 100 × 109/L, potassium within normal limits, total calcium (corrected for serum albumin) within normal limits, magnesium ≥ the lower limit of normal, AST/SGOT and ALT/SGPT ≤ 2.5× upper limit of normal (ULN) or ≤ 5.0× ULN if liver metastases are present, serum bilirubin ≤ 1.5× ULN, serum creatinine ≤ 1.5× ULN or 24-hour clearance ≥ 50 mL/min, serum amylase ≤ ULN, serum lipase ≤ ULN, serum triglycerides ≤ 500 mg/dL, and fasting plasma glucose ≤ 140 mg/dL (7.8 mmol/L).
Dose modifications/interruptions.
Treatment was delayed in patients experiencing ≥ Common Terminology Criteria of Adverse Events (CTCAE) grade 2 toxicities, until toxicities returned to ≤ CTCAE grade 1. Dose reduction meant treatment at the preceding BKM120 dose level. BKM120 treatment was discontinued if, after resumption at a lower dose, the same toxicity occurred with the same or worse severity (except for hyperglycemia). For each patient, once a dose level reduction occurred, the dose level could not be re-escalated during subsequent treatment cycles with BKM120, except for the second occurrence of grade 2 hyperglycemia.
Statistical methodology.
Cohorts of one to three patients were enrolled until a second patient experienced CTCAE v3.0 ≥ grade 2 toxicity or the first CTCAE ≥ grade 3 toxicity was observed; minimum size for subsequent cohorts was three or more patients. Intrapatient dose escalation was allowed for the first three dose cohorts. A two-parameter logistic model was used to describe the safety profile for single-agent BKM120. Preclinical data for BKM120 dose-limiting toxicity (DLT) rates were used to set up the model. The primary objective of this design was to find the dose maximizing the probability that the true DLT rate lies in the interval of 16% to 33%. On completion of 28 days dosing, dosing and safety observations for each cohort estimates of the two parameters were updated, and the dose-toxicity relationship for single-agent therapy was derived. Using data from all patients completing cycle 1 or experiencing DLT during cycle 1 at the completion of a new cohort, the Bayesian inference40 on the model parameters allowed quantification of the estimated risk of a dose being unacceptably toxic (ie, risk of the true rate of DLT for any dose being more than 33%). A limit on this risk was set to 25%, and any dose estimated to exceed this risk was excluded. This conservative escalation approach to find the MTD defined above allowed investigators to select the next dose from a predicted set of acceptable doses.
Safety and efficacy assessments.
A serious adverse event was defined as any untoward medical occurrence that resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, or was a congenital anomaly/birth defect.
Objective measurement of tumor mass was performed by computed tomography or magnetic resonance imaging, or by physical examination. Central review of radiologic assessments was performed by VirtualScopics (Rochester, NY).
Pharmacodynamic assessments.
Central review of [18F]fluorodeoxyglucose positron emission tomography was performed by VirtualScopics.
Semi-quantitative immunohistochemistry to measure pS6 was performed using Serine 240/244, M7300 antibody (Dako, Carpinteria, CA). H-scores were derived by evaluating the whole epidermis and were calculated as the sum of the percentages of stained cells × intensity, or (%1+) + (2 × %2+) + (3 × %3+).
Tumor molecular status.
PIK3CA and KRAS gene status and phosphatase and tensin homolog (PTEN) protein expression were determined in evaluable archival or fresh tumor samples. PIK3CA status (exons 9 and 20) was determined by SNaPshot genotyping assay.8 KRAS status was determined by direct genomic DNA sequencing. PTEN protein expression was determined by semi-quantitative immunohistochemistry (M3627 antibody, Dako); designations were “low or null” (H-score < 50) and “not low” (H-score ≥ 50).
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PowerPoint Slide for Teaching Fig A1.
(A) Example of grade 3 skin rash in a patient with adenoid cystic carcinoma of the lung (patient 19) in the first cycle of treatment with 100 mg/day BKM120. (B) Histologic assessment revealed perivascular inflammatory infiltrate with some eosinophils. Rash resolved with antihistamine treatment. Patient continues on study with stable disease > 12 months.
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PowerPoint Slide for Teaching Fig A2.
Representative immunohistochemical assessment of pS6 (Ser240/244) levels in skin biopsies (×20 magnification) at baseline and day 28 in selected patients treated with BKM120 at (A and B) 100 mg/day (breast cancer) or (C) 150 mg/day (angiosarcoma). Data are represented as percent change from baseline of the H-score of the whole epidermis. Patient numbers correspond to those in Figure 2.
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