Continuous Daily Schedule Research Articles

A first-in-human, open-label, phase I trial of daily oral zelenirstat, an NMT inhibitor, in patients with relapsed/refractory advanced cancer including gastrointestinal cancers.

129 Background: Myristoylation catalyzed by N-myristoyltransferases (NMT) 1 and 2 regulates membrane-bound signaling important in cancer, including Src and Src-family tyrosine kinases. Zelenirstat is a potent oral small molecule pan-NMT inhibitor. Transcriptomic analysis of zelenirstat treated cell lines identified an expression signature that predicts cancers most likely to be responsive to NMT inhibition; high sensitivity scores were seen in colorectal carcinomas and diffuse large B-cell lymphoma. The objectives of this phase I study were to determine the safety, tolerability, and maximum tolerated dose (MTD) of zelenirstat monotherapy in patients (pts) with refractory cancers. Methods: Pts with advanced solid malignancies or relapsed/refractory B-cell lymphomas were dose escalated with daily oral zelenirstat in 28-day cycles until progressive disease or dose-limiting toxicity (DLT). Results: Between September 2021 and July 2023, pts received 28-day cycles of zelenirstat ranging from 20 mg/d to 280 mg/d. In 21 evaluable patients, DLT was not observed up to and including the 210 mg/d cohort. Gastrointestinal DLTs were seen in the 280 mg/d cohort, establishing 210 mg/d to be the MTD. In doses up to and including 210 mg/d, gastrointestinal adverse events were the most common, reported in 29% of pts; these were primarily Gr 1 or 2 diarrhea, nausea or vomiting. Transient Gr 2 thrombocytopenia was seen in 3 pts. Zelenirstat did not induce neuropathy, alopecia, or prolong QT intervals. Plasma concentrations peaked between 1h and 4 h, terminal half-lives were 6.7 to 12 h, and steady state was achieved by day 8. Proton pump inhibitors lowered exposure and were prohibited in the higher dose cohorts. At 100 mg/d and higher, trough plasma concentrations exceeded the levels predicted to be therapeutic. Stable disease as best response was seen in 5 (30%) of 17 evaluable pts, including 1 patient with advanced refractory colon cancer who received 6 cycles of therapy at 140 mg daily dosing prior to PD. Another colon cancer patient with 5 prior lines of therapy continues 210 mg/d dosing after > 5 cycles of therapy, with non-RECIST criteria reductions of approximately 50% in CEA and tumor volumes. Conclusions: Zelenirstat was well-tolerated on a continuous daily oral schedule at doses as high as 210 mg/d, establishing the MTD to be 210 mg. The absence of severe toxicities, attainment of plasma concentrations highly active in preclinical models, and early evidence of clinical benefit in patients with refractory colon cancer warrant further trials. Updated data will be presented. Clinical trial information: NCT04836195 .

Zandelisib (ME-401) in Japanese patients with relapsed or refractory indolent non-Hodgkin’s lymphoma: an open-label, multicenter, dose-escalation phase 1 study

The selective phosphatidylinositol 3-kinase δ inhibitor zandelisib demonstrated favorable safety and efficacy [objective response rate (ORR) 79%] in patients with B-cell malignancies in a phase 1b study in the US and Switzerland. In this phase 1 dose-escalation study (NCT03985189), 9 Japanese patients with relapsed/refractory indolent non-Hodgkin’s lymphoma (R/R iNHL) received zandelisib on a continuous daily schedule (45 or 60 mg) until progressive disease/unacceptable toxicity. No dose-limiting toxicities were observed. The maximum tolerated dose was not reached. At a median follow-up of 17.5 months, Grade ≥ 3 treatment-emergent adverse events that occurred in 2 or more patients were neutrophil count decreased (55.6%; 5/9) and diarrhea (33.3%; 3/9). Immune-related toxicities, including hepatobiliary disorder, aspartate/alanine aminotransferase increased, diarrhea/colitis, organizing pneumonia, stomatitis, and rash, led to zandelisib discontinuation in 4 patients. The investigator-assessed ORR, based on modified Lugano criteria, was 100%, including 2 complete responses (22.2%; in follicular lymphoma patients receiving 60 mg/day). Median duration of response, progression-free survival, and time to response were 7.9, 11.1, and 1.9 months, respectively. Zandelisib demonstrated a manageable safety profile at 60 mg, the recommended phase 2 dose (RP2D) in Japanese patients. The RP2D resulted in favorable pharmacokinetics and anti-tumor efficacy in Japanese patients with R/R iNHL.Trial registration. NCT03985189 (ClinicalTrials.gov).

FIREFLY-1: A phase 2 study of the pan-RAF inhibitor DAY101 in pediatric patients with low-grade glioma.

TPS10056 Background: The mitogen-activated protein kinase (MAPK) signaling pathway is an essential pathway that regulates key cell functions such as growth, survival, and differentiation. Genomic alterations and dysregulation of the MAPK pathway including BRAF fusions, point mutations (e.g. BRAF V600) and in-frame deletions have been described in many different types of malignancies, including pediatric low-grade glioma (pLGG) and other pediatric cancers. The identification of the KIAA1549:BRAF fusion in 2008 led to deeper understanding of the genomic events driving growth of pLGG (Jones, Cancer Res 2008). Despite the low-grade histology and excellent long-term survival, pLGGs are often associated with tumor- and treatment-associated morbidity and significant late-effects that persist throughout the lifespan of the patient. DAY101 is an oral, highly selective, CNS-penetrant small-molecule, Type II pan-RAF kinase inhibitor that is being developed for patients with pLGG harboring an activating BRAF-alteration. DAY101 has demonstrated tumor inhibition in preclinical models and has achieved clinically meaningful and durable responses in 7/8 patients with RAF-altered LGG in a pediatric phase 1 trial, including 2 complete responses, 3 partial responses, 2 stable disease and 1 progressive disease with a median time to response of 10.5 weeks. Patients have been treated for up to two years with no discontinuations due to toxicity or disease progression (Wright, SNO 2020). Methods: FIREFLY-1 is an open-label, multi-center, international Phase 2 study with DAY101 in pediatric and young adult patients between the ages of 6 months and 25 years with LGG harboring a documented BRAF-alteration as determined by local laboratory testing. DAY101 is administered orally once a week on a continuous 28-day schedule. Patients who respond will be treated for a minimum of two years after which they may at any point, opt to enter a “drug holiday” discontinuation period. Dosing is based on body surface area. DAY101 is available in a pediatric-friendly oral liquid formulation and tablets. The primary endpoint is objective response rate based on Response Assessment for Neuro-Oncology (RANO) as determined by an independent review committee. Secondary endpoints include objective response rate based on Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group criteria, duration of response and safety. Exploratory endpoints include quality-of-life measurements as well as functional outcomes. Molecular abnormalities will be characterized through the analysis of archival tissue. Enrollment began in February 2021 and is ongoing. Clinical trial information: NCT03429804.

Long-term efficacy and safety of larotrectinib in patients with TRK fusion-positive lung cancer.

9109 Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions have been identified as oncogenic drivers in a diverse array of tumor types including lung cancer. Larotrectinib is a first-in-class, highly selective, central nervous system (CNS)-active tropomyosin receptor kinase (TRK) inhibitor approved for the treatment of adult and pediatric patients (pts) with TRK fusion cancer, with an objective response rate (ORR) of 78% across multiple non-CNS cancers (McDermott et al, ESMO 2020). Here, we report the updated data on pts with lung cancer treated with larotrectinib. Methods: Pts with lung cancer harboring a NTRK gene fusion enrolled in two clinical trials (NCT02576431 and NCT02122913) were identified for this analysis. Larotrectinib 100 mg PO BID was administered on a continuous 28-day schedule until disease progression, withdrawal, or unacceptable toxicity. Response was assessed by the investigator per RECIST v1.1. Results: As of July 20, 2020, a total of 20 pts with TRK fusion-positive lung cancer (19 with non-small cell lung cancer and 1 with small cell lung cancer) were enrolled. Median age was 48.5 years (range 25.0–76.0). The gene fusions involved NTRK1 (n = 16; 80%) or NTRK3 (n = 4; 20%). Pts were heavily pre-treated with a median of 3 systemic therapies (range 0–6). Among 15 evaluable pts, the confirmed ORR was 73% (95% CI 45–92): 1 complete response, 10 partial responses (PR), 3 stable disease (SD) and 1 progressive disease (PD). The median time to response was 1.8 months. Among 8 evaluable pts with baseline measurable and non-measurable CNS metastases, the ORR was 63% (95% CI 25–91): 5 PR, 2 SD, and 1 PD. In all evaluable pts, the 12-month rates for duration of response and progression-free survival were 81% and 65%, respectively. Median overall survival was 40.7 months (95% CI 17.2 to not estimable) at a median follow-up of 16.2 months. Duration of treatment ranged from 0.03+ to 51.55+ months. Adverse events (AEs) were predominantly Grade 1–2. Treatment-related AEs were reported in 16 pts, of which 2 experienced Grade 3 events (myalgia, hypersensitivity, weight increase). There were no treatment discontinuations due to AEs. Conclusions: These data confirm that larotrectinib is highly active with rapid and durable responses, extended survival benefit, and a favorable long-term safety profile in pts with advanced lung cancer harboring NTRK gene fusions, including in pts with CNS metastases. These results underscore the importance of screening for NTRK gene fusions in pts with lung cancer. Clinical trial information: NCT02576431 and NCT02122913.

MA11.09 Efficacy and Safety of Larotrectinib in Patients with Tropomyosin Receptor Kinase (TRK) Fusion Lung Cancer

Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers that occur in a wide range of tumor types. Larotrectinib, a highly selective Food and Drug Administration and European Medicines Agency approved TRK inhibitor, demonstrated an objective response rate (ORR) of 79% and a median duration of response (DoR) of 35 months across multiple cancers (Hong et al. Lancet Oncol 2020). Here we report updated data for patients with TRK fusion lung cancer assessed by independent review committee (IRC) and investigators (INV). Patients with lung cancer harboring an NTRK gene fusion enrolled in two clinical trials (NCT02122913 and NCT02576431) were included in this analysis. Larotrectinib 100 mg twice daily was administered on a continuous 28-day schedule. Response was assessed by IRC and by INV per RECIST v1.1. As of July 15, 2019, 14 patients with metastatic TRK fusion lung cancer were enrolled: 13 with non-small cell lung cancer (NSCLC) and 1 patient with small cell lung cancer (SCLC). Seven (6 NSCLC, 1 SCLC) patients had baseline central nervous system (CNS) metastases. The median age was 52 years (range 25–76). Eleven patients (79%) had fusions involving NTRK1 and three patients (21%) had fusions involving NTRK3. Patients were heavily pre-treated with a median of three prior therapies (range 1–5). Among 13 IRC-evaluable patients the ORR was 77% (95% confidence interval [CI] 46–95). ORR was 71% (95% CI 42–92) per INV. ORR in patients with CNS metastases was 71% (95% CI 29–96) and 57% (95% CI 18–90) per IRC and per INV, respectively (Table). The overall DoR per IRC ranged from 3.6 to 36.8+ months. The median progression-free survival (PFS) had not been reached (range 1.8 to 30.3+ months), with an estimated PFS rate at 12 months of 69%. Larotrectinib was well tolerated, with treatment-emergent adverse events being mainly Grade 1–2.Tabled 1All patients (N=14)Patients with brain metastases at baseline (n=7)INVIRC†INVIRCORR, % (95% CI)71 (42–92)77 (46–95)57 (18–90)71 (29–96)CR, n (%)1 (7)2 (15)00PR, n (%)9 (64)8 (62)4 (57)5 (71)SD, n (%)3 (21)3 (23)2 (29)2 (29)PD, n (%)1 (7)‡01 (14)‡0†IRC data missing for one patient. ‡Extracranial progression detected. CI, confidence interval; CR, complete response; INV, investigator assessment; IRC, independent review committee assessment; PD, progressive disease; PR, partial response; SD, stable disease. Open table in a new tab †IRC data missing for one patient. ‡Extracranial progression detected. CI, confidence interval; CR, complete response; INV, investigator assessment; IRC, independent review committee assessment; PD, progressive disease; PR, partial response; SD, stable disease. In this updated dataset, larotrectinib was shown to be highly active in patients with advanced lung cancer harboring NTRK gene fusions, including those with CNS metastases. The drug has a favorable safety profile. These results support inclusion of NTRK gene fusions in the routine molecular testing of patients with lung cancer.

Abstract PS11-06: Efficacy and safety of larotrectinib in patients with TRK fusion breast cancer

Abstract Introduction: Larotrectinib is a first-in-class, CNS-active, highly selective tropomyosin receptor kinase (TRK) inhibitor approved by the US Food and Drug Administration and European Medicines Agency for the treatment of adult and pediatric patients with tumor agnostic indication for TRK fusion-positive cancer. Larotrectinib produced an objective response rate (ORR) of 79% in 159 patients with TRK fusion-positive cancer across various tumor types (Hong DS et al. Lancet Oncol. 2020). Here we report the efficacy and safety of larotrectinib in the six patients from the NAVIGATE phase II study (NCT02576431) with TRK fusion-positive breast cancer. Methods: Data were obtained for patients with breast cancer harboring a neurotrophic tyrosine receptor kinase (NTRK) gene fusion and treated with larotrectinib in the NAVIGATE study. All patients received 100 mg twice daily on a continuous 28-day schedule. Responses were investigator-assessed per RECIST v1.1 (data cut-off: July 15, 2019). Results: A total of 6 patients with TRK fusion breast cancer were included: 3 with secretory carcinomas, 2 with triple-negative breast cancer (TNBC), and 1 with ER+/HER2− disease. The median age was 49 years (range 32-65). One of the patients with secretory breast cancer was male. All of the secretory cases and 1 TNBC patient harbored an ETV6-NTRK3 fusion, 1 TNBC patient had an LMNA-NTRK1 fusion, and the ER+/HER2− patient had a TPM3-NTRK1 fusion. Four patients had received ≥3 prior systemic therapies. The majority of patients had metastatic disease (n=5); 1 patient had locally advanced disease. The ORR was 83% (95% confidence interval [CI] 36-100) with 5 partial responses, while the ER+/HER2− patient had progressive disease. One of the TNBC patients had brain metastasis with complete resolution of CNS disease while on therapy. The median time to response was 1.7 months (range 0.9-1.9) and the duration of treatment ranged from 0.9 to 12+ months, with 4 patients (3 secretory and 1 TNBC) continuing on therapy at time of data cut. Median duration of response was not reached (95% CI 8.2-NE). Median progression-free survival was 9.1 months (95% CI 1.0-NE). Median overall survival was not reached at a median follow-up of 7.4 months. Four of the 6 patients had worst-grade adverse events (AEs) Grade 1-2; the most common Grade 1-2 AEs were dizziness and nausea. One patient had Grade 3 hepatocellular injury and Grade 4 hepatitis that were related to larotrectinib. There were no discontinuations due to AEs. Conclusion: Larotrectinib demonstrated an ORR in breast cancer patients similar to the ORR reported for larotrectinib across all tumor types, which supports the routine testing for NTRK gene fusions in patients with breast cancer regardless of histology. Citation Format: Ezra Y. Rosen, Antoine Italiano, Dejan Juric, John A. Reeves, Laura Dima, Nicoletta Brega, Alexander Drilon. Efficacy and safety of larotrectinib in patients with TRK fusion breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-06.

Abstract PR07: A pediatric phase 1 study of larotrectinib, a highly selective inhibitor of the tropomyosin receptor kinase (TRK) family: An updated analysis

Abstract Background: NTRK gene fusions occur in a broad range of pediatric and adult malignancies at low frequencies, but are present in the vast majority of infantile fibrosarcomas. Larotrectinib is the first selective small-molecule inhibitor of TRKA, B, and C in clinical development. Larotrectinib has demonstrated a high response rate and a favorable safety profile in children and adults with TRK-fusion positive cancers. Here we report an updated analysis from the pediatric phase 1 study of larotrectinib. Methods: This multicenter, rolling 6 phase 1 study enrolled pediatric patients with refractory solid or CNS tumors. Patients with locally advanced infantile fibrosarcoma who would require disfiguring surgery or limb amputation to achieve a complete surgical resection were also eligible. Measurable or evaluable disease by RECIST v1.1/RANO was required. Patients were dosed orally BID on a continuous 28-day schedule either by capsule or oral solution. Pharmacokinetic (PK)-directed intra-subject dose escalation was permitted, with exposures targeting the adult recommended phase 2 dose (RP2D) of 100 mg BID. The primary objective was to define the maximum tolerated dose (MTD) / RP2D; secondary objectives included pharmacokinetics (PK) and efficacy using RECIST v1.1/RANO. Results: As of July 17, 2017, 24 patients (17 with TRK fusions, 7 without TRK fusions) with a median age of 4.5 years (range 1 month-18 years) were enrolled. Patients had diverse TRK fusions (9 NTRK1, 1 NTRK2, and 7 NTRK3) in heterogeneous tumor diagnoses (8 infantile fibrosarcoma (IFS), 7 other sarcoma, and 2 papillary thyroid cancer). Patients were treated on 3 dose levels: 100 mg BID (DL1, n=4) and 150 mg BID (DL2, n=11) adult equivalent doses by SimCyp modeling, and 100 mg/m2/dose BID with a cap of 100 mg/dose (DL3, n=9). The RP2D was determined to be 100 mg/m2 (capped at 100 mg) BID based on PK, safety and efficacy. No MTD was defined. The most common AEs attributed to larotrectinib were increased AST, vomiting, and neutropenia. No grade 4/5 AEs were attributed to larotrectinib. Both capsule and solution formulations delivered similar dose-dependent PK. AUC0-24 at the RP2D was comparable to the adult RP2D across the pediatric age spectrum (<2, 2-11, and 12-18 years). No responses were seen in patients (n=7) without TRK fusions (all had PD as best response). Among patients with TRK fusions and measureable disease by RECIST (n=15), the investigator-assessed confirmed objective response rate was 93% (67% PR, 27% CR). 1 patient (7%) had SD with tumor shrinkage. All patients with TRK fusions (n=17) had a reduction in tumor burden regardless of histology or specific TRK fusion. With median follow-up of 6.5 (range 1.5+ to 12.5+) months, 14 patients with TRK fusions remain on treatment. Three patients have discontinued therapy, including two patients with responses that led to surgical resection; both had negative margins (R0 surgery) and one had a pathologic complete response. These patients remain on study and off larotrectinib without recurrence. Only one case of acquired resistance has been observed, which involved a TRKC G623R mutation. Conclusions: Larotrectinib demonstrated broad histology-independent efficacy in pediatric patients harboring TRK fusions and a favorable tolerability profile. A pediatric RP2D of 100 mg/m2/dose BID with a cap of 100 mg/dose has been defined. Blinded central review of responses and a minimum of 6 months of follow-up for all patients will be presented. Citation Format: Brian Turpin, Catherine M. Albert, Leo Mascarenhas, Noah Federman, Ramamoorthy Nagasubramanian, Mark Reynolds, Steven Smith, Scott Cruickshank, Michael C. Cox, Alberto S. Pappo, Douglas S. Hawkins, Steven G. DuBois, Theodore W. Laetsch. A pediatric phase 1 study of larotrectinib, a highly selective inhibitor of the tropomyosin receptor kinase (TRK) family: An updated analysis [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr PR07.

Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study

Gene fusions involving NTRK1, NTRK2, or NTRK3 (TRK fusions) are found in a broad range of paediatric and adult malignancies. Larotrectinib, a highly selective small-molecule inhibitor of the TRK kinases, had shown activity in preclinical models and in adults with tumours harbouring TRK fusions. This study aimed to assess the safety of larotrectinib in paediatric patients. This multicentre, open-label, phase 1/2 study was done at eight sites in the USA and enrolled infants, children, and adolescents aged 1 month to 21 years with locally advanced or metastatic solid tumours or CNS tumours that had relapsed, progressed, or were non-responsive to available therapies regardless of TRK fusion status; had a Karnofsky (≥16 years of age) or Lansky (<16 years of age) performance status score of 50 or more, adequate organ function, and full recovery from the acute toxic effects of all previous anticancer therapy. Following a protocol amendment on Sept 12, 2016, patients with locally advanced infantile fibrosarcoma who would require disfiguring surgery to achieve a complete surgical resection were also eligible. Patients were enrolled to three dose cohorts according to a rolling six design. Larotrectinib was administered orally (capsule or liquid formulation), twice daily, on a continuous 28-day schedule, in increasing doses adjusted for age and bodyweight. The primary endpoint of the phase 1 dose escalation component was the safety of larotrectinib, including dose-limiting toxicity. All patients who received at least one dose of larotrectinib were included in the safety analyses. Reported here are results of the phase 1 dose escalation cohort. Phase 1 follow-up and phase 2 are ongoing. This trial is registered with ClinicalTrials.gov, number NCT02637687. Between Dec 21, 2015, and April 13, 2017, 24 patients (n=17 with tumours harbouring TRK fusions, n=7 without a documented TRK fusion) with a median age of 4·5 years (IQR 1·3-13·3) were enrolled to three dose cohorts: cohorts 1 and 2 were assigned doses on the basis of both age and bodyweight predicted by use of SimCyp modelling to achieve an area under the curve equivalent to the adult doses of 100 mg twice daily (cohort 1) and 150 mg twice daily (cohort 2); and cohort 3 was assigned to receive a dose of 100 mg/m2 twice daily (maximum 100 mg per dose), regardless of age, equating to a maximum of 173% of the recommended adult phase 2 dose. Among enrolled patients harbouring TRK fusion-positive cancers, eight (47%) had infantile fibrosarcoma, seven (41%) had other soft tissue sarcomas, and two (12%) had papillary thyroid cancer. Adverse events were predominantly grade 1 or 2 (occurring in 21 [88%] of 24 patients); the most common larotrectinib-related adverse events of all grades were increased alanine and aspartate aminotransferase (ten [42%] of 24 each), leucopenia (five [21%] of 24), decreased neutrophil count (five [21%] of 24), and vomiting (five [21%] of 24). Grade 3 alanine aminotransferase elevation was the only dose-limiting toxicity and occurred in one patient without a TRK fusion and with progressive disease. No grade 4 or 5 treatment-related adverse events were observed. Two larotrectinib-related serious adverse events were observed: grade 3 nausea and grade 3 ejection fraction decrease during the 28-day follow-up after discontinuing larotrectinib and while on anthracyclines. The maximum tolerated dose was not reached, and 100 mg/m2 (maximum of 100 mg per dose) was established as the recommended phase 2 dose. 14 (93%) of 15 patients with TRK fusion-positive cancers achieved an objective response as per Response Evaluation Criteria In Solid Tumors version 1.1; the remaining patient had tumour regression that did not meet the criteria for objective response. None of the seven patients with TRK fusion-negative cancers had an objective response. The TRK inhibitor larotrectinib was well tolerated in paediatric patients and showed encouraging antitumour activity in all patients with TRK fusion-positive tumours. The recommended phase 2 dose was defined as 100mg/m2 (maximum 100 mg per dose) for infants, children, and adolescents, regardless of age. Loxo Oncology Inc.

Mathematical modeling identifies optimum lapatinib dosing schedules for the treatment of glioblastoma patients.

Human primary glioblastomas (GBM) often harbor mutations within the epidermal growth factor receptor (EGFR). Treatment of EGFR-mutant GBM cell lines with the EGFR/HER2 tyrosine kinase inhibitor lapatinib can effectively induce cell death in these models. However, EGFR inhibitors have shown little efficacy in the clinic, partly because of inappropriate dosing. Here, we developed a computational approach to model the in vitro cellular dynamics of the EGFR-mutant cell line SF268 in response to different lapatinib concentrations and dosing schedules. We then used this approach to identify an effective treatment strategy within the clinical toxicity limits of lapatinib, and developed a partial differential equation modeling approach to study the in vivo GBM treatment response by taking into account the heterogeneous and diffusive nature of the disease. Despite the inability of lapatinib to induce tumor regressions with a continuous daily schedule, our modeling approach consistently predicts that continuous dosing remains the best clinically feasible strategy for slowing down tumor growth and lowering overall tumor burden, compared to pulsatile schedules currently known to be tolerated, even when considering drug resistance, reduced lapatinib tumor concentrations due to the blood brain barrier, and the phenotypic switch from proliferative to migratory cell phenotypes that occurs in hypoxic microenvironments. Our mathematical modeling and statistical analysis platform provides a rational method for comparing treatment schedules in search for optimal dosing strategies for glioblastoma and other cancer types.

Abstract CT151: CNS activity of ensartinib in ALK-positive non-small cell lung cancer patients

Abstract Background: Ensartinib (X-396) is a novel, potent anaplastic lymphoma kinase (ALK) small molecule tyrosine kinase inhibitor (TKI) with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1 and SLK. In animal studies, brain concentration of ensartinib in mice given at the therapeutic dose was 4 times higher than the IC50 for growth inhibition of ALK positive cells in vitro. Ensartinib was significantly more effective than crizotinib at inhibiting the intracranial growth of the SH-SY5Y neuroblastoma model harboring the F1174L mutation. We subsequently evaluated the CNS activity of ensartinib in patients with ALK positive non-small cell lung cancer (NSCLC). Methods: In this multicenter phase I/II study, patients (pts) with advanced solid tumors were enrolled and given ensartinib orally on a continuous 28-day schedule (NCT01625234). Doses from 25 mg up to 250 mg once daily were evaluated and 225 mg was selected for further evaluation in the phase II expansion. We report on patients enrolled with CNS metastases (with or without systemic disease) who were ALK TKI naïve or had received prior crizotinib or a second generation ALK TKI. Patients with untreated asymptomatic CNS metastases were allowed to enroll. All pts were assessed for adverse events using CTCAE version 4.03, and response to therapy was assessed using RECIST 1.1. Patients with only CNS disease had to have at least one measurable target lesion ≥ 3 mm in diameter. Results: As of the December 13, 2016 data cutoff, 26 pts with ALK+ NSCLC and baseline CNS metastases have been treated at ≥ 200 mg. Of the 26 pts, 13 pts had baseline target lesions (8 of which also had non-target lesions) and 13 pts had baseline non-target lesions only. Median age is 52 (21-72) years and the majority of patients had ECOG performance status of 1 (69%). CNS responses have been observed in both ALK TKI naïve pts and pts that received prior crizotinib. In the 13 pts with baseline target CNS lesions, intracranial response was achieved in 9 pts (69%), including 1 CR, and 4 pts (31%) had SD, a 100% disease control rate. In the 13 pts with non-target baseline lesions only, 1 CR was achieved and 8 pts had SD. All 3 (100%) ALK TKI naïve pts with baseline target lesions achieved CR or PR, and 5/8 pts (62%) that received prior crizotinib only and had baseline target lesions responded. The median duration of intracranial response in the 10 pts who responded (9 with target lesions, 1 with non-target lesions only) is 5.8+ months, with the longest duration being 24 months. Conclusions: Our clinical findings support the preclinical results that the use of ensartinib at doses generally well-tolerated in the clinic may result in favorable therapeutic outcomes in pts with ALK+ NSCLC with baseline CNS metastases. The ongoing phase III eXalt3 study will assess CNS response rate and time to CNS progression in pts receiving first-line ensartinib vs crizotinib (NCT02767804 and NCT01625234). Citation Format: Leora Horn, Karen L. Reckamp, Sandip Patel, George Blumenschein, Joel W. Neal, Barbara Gitlitz, Saiama Waqar, Geoffrey Oxnard, Christina Brzezniak, Gary Dukart, Fenlai Tan, Kimberly Harrow, Chris Liang, James Gibbons, Heather A. Wakelee. CNS activity of ensartinib in ALK-positive non-small cell lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT151. doi:10.1158/1538-7445.AM2017-CT151

The efficacy of larotrectinib (LOXO-101), a selective tropomyosin receptor kinase (TRK) inhibitor, in adult and pediatric TRK fusion cancers.

LBA2501 Background: Larotrectinib is the first selective small-molecule pan-TRK inhibitor. TRK fusions appear oncogenic independent of tumor lineage, are widely distributed across cancers, and affect all ages. We present an integrated dataset from 3 studies intended to support regulatory approval. Methods: All NTRK fusion pts with RECIST measurable disease enrolled to the adult (NCT02122913, n=8) and pediatric (NCT02637687, n=12) phase I trials and adult/adolescent phase 2 trial (NCT02576431, n=35) were analyzed. TRK fusion status was determined by local testing prior to enrollment. Pts were dosed predominantly at 100mg BID on a continuous 28-day schedule. Primary objective was investigator-assessed overall response rate (ORR) per RECIST v1.1. Secondary endpoints included duration of response (DOR) and safety. Data were cut on 31-JAN-2017. Results: 55 TRK fusion pts (12 peds, 43 adult, range: 4 mo.-76 yrs) were enrolled (median priors=2). Fusions involved NTRK1 (n=25), NTRK2 (n=1), and NTRK3 (n=29), and 14 unique partners. 13 discrete tumor types were treated: salivary (12), sarcoma (10), infantile fibrosarcoma (7), lung (5), thyroid (5), colon (4), melanoma (4), cholangio (2), GIST (2), and other (4). For the 46 pts evaluated to date, the ORR was 78% (95% CI: 64%–89%) with responses in 12 unique tumor types. Responses are ongoing in 29/33 (88%) pts, excluding 3 peds pts whose DOR was censored at attempted curative resection. A median DOR has not been reached as the majority of responders remain on treatment without progression. The longest responder remains on treatment at 23 mos., 8 pts remain in response at &gt;12 mos., and 16 pts at &gt;6 mos. NTRK solvent front mutations were detected in all 4 pts to develop acquired resistance. The most common TEAEs were fatigue (30%), dizziness (28%), and nausea (28%). 5 (11%) pts required dose reductions. Conclusions: Larotrectinib has demonstrated consistent and durable antitumor activity in TRK fusion cancers, across a wide range of ages and tumor types, and was well-tolerated. Larotrectinib could be the first targeted therapy developed in a tissue type-agnostic manner, and the first developed simultaneously in adults and pediatrics. Clinical trial information: NCT02576431, NCT02122913, NCT02637687.

Phase 1/2 study of the selective TRK inhibitor larotrectinib in pediatric patients with cancer.

TPS10577 Background: Neurotrophin ligands and their receptors TRKA, TRKB, and TRKC (encoded by NTRK1, NTRK2, and NTRK3) are important for growth regulation, differentiation and survival of neurons. Translocations involving the NTRK1/2/3 kinase domain, mutations involving the TRK ligand-binding site, and amplifications of NTRK, have been described in diverse tumor types and may contribute to tumorigenesis. A broad range of pediatric malignancies have been found to harbor NTRK fusions, including infantile fibrosarcoma (IFS), spindle-cell sarcoma, congenital mesoblastic nephroma, pediatric papillary thyroid cancer, pediatric gliomas and Ph-like acute lymphoblastic leukemia. Larotrectinib is the first small-molecule selective inhibitor of TRKA, -B, and -C in clinical development and preliminary data from the adult phase 1 trial demonstrate prolonged responses in patients with TRK fusions and a favorable safety profile. Methods: We have initiated an open-label, multi-center, international Phase 1/2 study with larotrectinib in pediatric patients with solid tumors and primary CNS tumors (NCT02637687). Patients with advanced cancer between the ages of 1 year and 21 years are eligible, as well as patients as young as 1-month of age with a documented NTRK fusion. Patients with IFS who have not had definitive surgery are also eligible. Larotrectinib is administered orally twice daily on a continuous 28-day schedule. Dosing is based on body surface area. Larotrectinib is available in an oral liquid formulation and capsules. Following identification of the maximum tolerated dose of larotrectinib in the phase 1 portion, the phase 2 portion will commence. The phase 2 portion will enroll patients with NTRK-translocated tumors and measurable disease into three cohorts: 1) infantile fibrosarcoma; 2) extracranial solid tumors; and 3) primary CNS tumors. The primary endpoint for the phase 2 portion is objective response rate, with duration of response and progression free survival as secondary efficacy endpoints. Each phase 2 cohort will enroll in a single stage of up to 10 patients per cohort. Molecular abnormalities will be characterized through the analysis of archival tissue. Enrollment began in December 2015 and is ongoing. Clinical trial information: NCT02637687.

A pediatric phase I study of larotrectinib, a highly selective inhibitor of the tropomyosin receptor kinase (TRK) family.

10510 Background: Larotrectinib is the first selective small-molecule inhibitor of TRKA, B, and C in clinical development. Data from the adult phase I trial demonstrate prolonged responses in patients (pts) with TRK fusions and a favorable tolerability profile. Methods: This multicenter, rolling 6 phase I study enrolled pts with refractory solid or CNS tumors aged ≥ 1 month – 21 years. Pts were dosed orally BID on a continuous 28-day schedule either by capsule or solution. Pharmacokinetic (PK)-directed intra-subject dose escalation was permitted, with exposures targeting the adult recommended Phase II dose (RP2D) of 100 mg BID. The primary objective was to define the MTD / RP2D; secondary objectives included PK and efficacy using RECIST v1.1. Results: As of December 31, 2016, 17 pts (12 with TRK fusions, 5 without TRK fusions) with a median age of 5.2 years (0.4 – 18.3) were enrolled to 3 dose levels. Pts were enrolled with fusions of all 3 NTRK genes: NTRK1 (n=6), NTRK2 (n=1), and NTRK3 (n=5) in heterogeneous tumor diagnoses: infantile fibrosarcoma (IFS) (n=6), other sarcoma (n=4), and papillary thyroid cancer (n=2). Most common AEs regardless of attribution were vomiting, diarrhea, and fatigue. While 8 (47%) pts experienced grade 3-4 AEs, none were attributed to larotrectinib. No DLTs were observed and an MTD was not established. Both formulations delivered dose-dependent PK comparable to the adult RP2D at dose level 3. 12 pts (10 with TRK fusions, 2 without TRK fusions) remain on treatment with median follow-up of 2.8 months (0.7 – 8.4). Among TRK fusion pts, the vast majority have achieved confirmed RECIST responses regardless of tumor diagnoses. No responses were seen in pts without TRK fusions (n=4). 5 pts discontinued therapy, including 2 with TRK fusions: 1 pt with IFS had sufficient response to allow tumor resection, and 1 pt with IFS progressed with a documented acquired resistance mutation. Conclusions: Larotrectinib has demonstrated a favorable tolerability profile and histology-independent efficacy in pediatric pts harboring TRK fusions. Updated safety and efficacy data will be presented, including the RP2D, response rate, duration of response, and use of larotrectinib in the pre-surgical setting. Clinical trial information: NCT02637687.

Abstract P2-08-03: Targeting inflammatory pathways: A phase 2 trial of the JAK-inhibitor ruxolitinib in combination with exemestane for aromatase inhibitor-resistant, estrogen receptor-positive breast cancer

Abstract Background: In vitro mechanisms link IL-6 to poor outcome in breast cancer via inflammatory pathways, activated JAK/STAT tumor signaling and upregulation of aromatase, leading to an aggressive tumor phenotype. Epidemiological data from our group and others support these mechanisms in women with ER-positive (+) disease. We therefore hypothesized that the JAK inhibitor, ruxolitinib (RUX, INCB018424; Incyte), would enhance activity of exemestane (EXE) in women with ER+ breast cancer who relapsed after non-steroidal aromatase inhibitor therapy, particularly among carriers of a germ-line polymorphism in IL-6, conferring elevated levels of IL-6 in the tumor microenvironment. Methods: The “JAKEE trial” is a phase II trial to determine the safety and efficacy of RUX + EXE in postmenopausal women with relapsed, ER+ advanced breast cancer. Eligible patients were required to have progressed on a non-steroidal AI and either measureable or bone-only disease. CRP, a putative biomarker of tumor microenvironment inflammation, was measured at baseline and serially during treatment. Using a Simon 2-stage design, we treated 15 patients with RUX at 25 mg BID and EXE at 25mg daily on a continuous 28-day schedule. First stage results were previously presented (AACR, 2014). Accrual proceeded to second stage after no patient met the pre-defined stopping rule of grade (G) 3/4 toxicity requiring discontinuation from the study within the first treatment cycle. Due to the substantial rate of anemia requiring dose reductions, however, RUX dose was reduced to 15 mg BID in second stage. Results: A total of 25 patients were enrolled; 24/25 had progressed on AI in metastatic setting; 1 relapsed on adjuvant AI. RUX+EXE was well-tolerated overall, with only 2 G4 events (creatinine elevation, hepatic failure); both were due to disease progression. 16% had G3 fatigue, anemia or hypertension; 12% had G3 neutropenia or depression. Other lower grade toxicities in &amp;gt;20% included musculoskeletal pain, increased ALT, and headache. Overall, patients stayed on therapy for a median of 3 cycles (range 2 – 21). There were no CR or PR, but 6/25 (24%) had prolonged disease control (SD&amp;gt; 6 months). Median CRP at study entry was 6.4 (range 0.3-38.9), with 8/25 (32%) having CRP&amp;gt;10. Achieving SD&amp;gt;6 months was not associated with baseline CRP (CRP&amp;gt;10 in 32% with vs. 33% without SD&amp;gt;6 months, p(exact)=1.0). A novel pharmacodynamic assay to assess STAT3 phosphorylation in peripheral blood mononuclear cells after RUX exposure demonstrated differential effects in patients with response. Conclusions: Targeting JAK/STAT signaling in AI-resistant breast cancer with RUX+EXE was safe and well-tolerated. 24% of patients had prolonged SD, but baseline CRP level did not predict response. Correlative studies to determine whether host and/or tumor biomarkers predict response to therapy, including germline IL-6 genotype, immune profiles, p-STAT3 and estradiol levels, are currently underway. Citation Format: DeMichele AM, Clark AS, Holmes R, Volpe M, Medrano C, Troxel A, Fox K, Domchek S, Matro J, Bradbury A, Shih N, Feldman M, Hexner E, Bromberg J. Targeting inflammatory pathways: A phase 2 trial of the JAK-inhibitor ruxolitinib in combination with exemestane for aromatase inhibitor-resistant, estrogen receptor-positive breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-08-03.

Abstract OT1-04-07: VICTORIANE: A randomized phase 3 study assessing the addition of oral vinorelbine to aromatase inhibitors for the treatment of patients with metastatic breast cancer

Abstract Background : The addition of anti-proliferative agents such new inhibitors of CDK4/6 to hormonotherapy have significantly improved the efficacy in patients with metastatic breast cancer (MBC). Oral vinorelbine provided the opportunity to give new schedules of chemotherapy with favourable tolerability and prolonged exposure. The present trial was designed to evaluate the clinical effects of the addition of oral vinorelbine to aromatase inhibitors in first line treatment for MBC. Methods : In this phase III, randomized, prospective, open trial named VICTORIANE (NCT02730091), postmenopausal women with HR+/HER2– with MBC are randomized (1:1) between letrozole or anastrozole once a day (Arm A) versus oral vinorelbine 50 mg three times a every week with letrozole or anastrozole (Arm B). Continuous daily schedule (days 1-28 of each 28 days cycle) is planned until disease progression or discontinuation for other reasons. A minimisation algorithm was used stratifying treatment allocation according to the existence of visceral metastases, prior adjuvant hormonal treatment and centers. The study is conducted in compliance with the principles of good clinical practice and the declaration of Helsinki. Key inclusion criteria include, histologicaly proven HER2-negative and Estrogen Receptor-positive breast cancer, metastatic setting, no prior systemic anti-cancer therapy for MBC, recurrence after prior hormonal therapy in the adjuvant setting is allowed if disease free interval is greater than 24 months from the completion of treatment, normal liver, bone marrow and renal functions, Performans status greater than 2. Non inclusion criteria include symptomatic visceral disease, or disease burden precluding endocrine therapy, and prior therapy with vinorelbine. The primary endpoints is progression-free survival (PFS; local assessment, RECIST v1.1) and secondaries endpoints are overall survival, health-related quality of life, overall response rate and safety. Analysis of the primary endpoint will be performed with a stratified log-rank test (95% confidence interval). A 30 percent reduction in the risk of events (Hazard Ratio (HR) = 0.70) was assumed under H1 in the arm B. This reduction was estimated based on an absolute gain of 3.857 months in terms of median PFS, from 9 months (arm A) to 12.857 months (arm B). Global recruitment of the planned 340 pts is ongoing and should be completed in march 2018. Final results will be expected in 2019. Citation Format: Villanueva CB, Barthelemy P, Ferrero JM, Jacquin JP, Bonnetain F, Mansi L, Pivot X. VICTORIANE: A randomized phase 3 study assessing the addition of oral vinorelbine to aromatase inhibitors for the treatment of patients with metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-04-07.

Abstract CT088: Phase I/II trial of X-396, a novel anaplastic lymphoma kinase (ALK) inhibitor, in patients with ALK+ non-small cell lung cancer (NSCLC)

Abstract Background: X-396 is a novel, potent anaplastic lymphoma kinase (ALK) small molecule tyrosine kinase inhibitor (TKI) with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1 and SLK. It has demonstrated significant anti-tumor activity in both ALK TKI-naive and crizotinib-resistant models of ALK fusion-positive NSCLC. Methods: In this multicenter phase I/II study, patients (pts) with advanced solid tumors were enrolled in the phase I dose escalation portion of the study and given X-396 on a continuous 28-day schedule (NCT01625234). Doses from 25 up to 250 mg once daily were evaluated and 225mg was selected for further evaluation in the phase II expansion. Patients in this phase were required to have ALK+ NSCLC and measurable disease. Cohorts included pts who were 1) ALK TKI-naïve, 2) pts who progressed on prior crizotinib and had not received a 2nd generation ALK TKI, 3) pts who progressed on a 2nd generation ALK TKI (may also have received crizotinib), 4) pts with untreated or recurrent central nervous system (CNS) metastases, and 5) pts with leptomeningeal disease. All pts were assessed for adverse events (AEs) using CTCAE version 4.03, response to therapy was assessed using RECIST 1.1. Results: As of the December 09, 2015 data cutoff, 57 pts (31 men, 26 women) have been enrolled. Median age is 56 (20-79) years, the majority of patients had ECOG performance status 1 (67%). The most common drug-related AEs included rash (49%), nausea (28%), vomiting (25%), and fatigue (23%). Most AEs were Grade (G) 1-2. The G3 treatment-related AEs were rash (7 pts), fatigue (1 pt), decreased appetite (1 pt), dehydration (1 pt), pruritus (1 pt), and face edema (1 pt). In particular, no G3 treatment-related gastrointestinal toxicity or liver enzyme elevation has been reported. To date, 27 ALK+ NSCLC pts treated at doses ? 200 mg are evaluable for response; partial response (PR) was achieved in 19 pts (70%) and stable disease (SD) in 2 pts (7%). In the crizotinib-naïve pts (n = 8), responses were observed in 7 pts (88%). In the 12 pts with prior crizotinib but no other ALK TKI, 10 pts (83%) achieved PR and 1 (8%) SD. CNS responses have been observed in both crizotinib naïve and crizotinib resistant pts. The median duration of treatment in the 27 evaluable ALK+ pts is 16+ weeks, with the longest being 128+ weeks. Conclusion: X-396 is well-tolerated and induces responses in both crizotinib-naïve and crizotinib-resistant ALK+ NSCLC pts, as well as patients with CNS lesions. Enrollment is ongoing in the expansion cohorts. Citation Format: Christine M. Lovly, Jeffrey R. Infante, George R. Blumenschein, Karen Reckamp, Heather Wakelee, Corey A. Carter, Saiama N. Waqar, Joel Neal, Jon P. Gockerman, Gary Dukart, Kimberly Harrow, Chris Liang, James J. Gibbons, Leora Horn. Phase I/II trial of X-396, a novel anaplastic lymphoma kinase (ALK) inhibitor, in patients with ALK+ non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT088.

Updated results of a phase 1 study of EGF816, a third-generation, mutant-selective EGFR tyrosine kinase inhibitor (TKI), in advanced non-small cell lung cancer (NSCLC) harboring T790M.

9044Background: Up to 60% of patients (pts) with NSCLC harboring an activating EGFR mutation (mut) and treated with a first-generation EGFR TKI develop a secondary gatekeeper T790M mut. EGF816 is an irreversible EGFR TKI that is highly potent against activating mut (L858R, ex19del) and T790M mut, while sparing wild-type EGFR. Methods: Pts with NSCLC with locally or centrally confirmed T790M status were enrolled in this multicenter, dose-escalation study to determine the safety, tolerability, and antitumor activity of EGF816 (NCT02108964). EGF816 was administered in capsule or tablet form on a continuous 28-day schedule. Dose escalation began at 75 mg QD and was guided by adaptive Bayesian logistic regression models to determine the maximum tolerated dose. Results: As of 30 Sept 2015, 132 pts had been treated (104 capsule; 28 tablet) across 7 dose levels (75, 150, 225, 300, and 350 mg QD for capsules; 100, 150, 200, and 225 mg QD for tablets), with median age 61.5 (range 32-82) years, 36% male, and 64% Asi...

Abstract OT1-03-12: MANTA: A randomized phase II study of fulvestrant in combination with the dual mTOR inhibitor AZD2014 or everolimus or fulvestrant alone in estrogen receptor-positive advanced or metastatic breast cancer

Abstract Background: Resistance to endocrine therapy remains a major clinical challenge in ER+ breast cancer. Aberrant PI3K/AKT/mTOR pathway activation frequently occurs in ER+ breast cancer and is associated with resistance to endocrine therapy. Randomised clinical trials have demonstrated a substantial benefit of adding everolimus to endocrine treatment. However, there is increasing evidence that inhibition of only mTORC1 with rapalogues such as everolimus sets off a negative feedback mechanism that leads to increased AKT signalling and is linked with treatment resistance. AZD2014 is a dual inhibitor of both mTORC1 (rapamycin-sensitive) and mTORC2 (rapamycin insensitive); compared to rapalogues, AZD2014 has a broader range of growth inhibitory activity in preclinical models based on a more profound mTORC1 inhibition and the additional inhibition of mTORC2. AZD2014 is especially effective in ER+ breast cancer models, showing superior activity to everolimus both in hormone-sensitive and resistant models. Trial objectives: The main aims of this trial are (i) to determine whether dual inhibition of mTORC1 and mTORC2 with AZD2014 will increase the activity of endocrine therapy with fulvestrant in ER+ breast cancer, (ii) whether inhibition of mTORC1 and mTORC2 using AZD2014 will have superior anti-tumour activity compared to inhibition of mTORC1 alone with everolimus, and (iii) to compare the safety and efficacy of two schedules of AZD2014. Methods: MANTA is an international investigator led, sponsored, open-label, randomised phase II trial. Patients are randomised in a 2:3:3:2 ratio to receive either fulvestrant (500mg) alone, fulvestrant and AZD2014 at a continuous daily schedule (50mg BD), fulvestrant and AZD2014 at an intermittent schedule (2 days on, 5 days off; 125mg BD) or fulvestrant and everolimus (10mg OD). Patients are stratified by disease measurability and response to prior endocrine therapy. Treatment is given until disease progression (RECIST 1.1), intolerable toxicity or elective withdrawal. Eligibility criteria: This study enrols post-menopausal women with ER+, HER2-negative, advanced or metastatic, hormone refractory breast cancer. Patients must have at least one measurable lesion and no life-threatening visceral disease. Patients with significant pulmonary dysfunction, cardiovascular disease or uncontrolled diabetes are excluded. Patients must not have had previous treatment with fulvestrant, PI3K/Akt or mTOR inhibitors or no more than one line of chemotherapy for metastatic breast cancer. Endpoints: The primary endpoint is progression-free survival . Secondary endpoints include objective response rate, change in tumour size, clinical benefit rate, overall survival, duration of response, patient reported outcomes and pharmacokinetic parameters of AZD2014 and fulvestrant. Archival tumour tissue must be available to evaluate biomarkers associated with therapeutic response and resistance. Target accrual: Approximately 316 patients will be enrolled at ∼90 sites in the UK, Germany, Spain, Portugal, France, Hungary, Romania, Georgia, and South Korea. Recruitment opened in 2014 and 121 patients have been recruited to date. NCT02216786. Citation Format: Schmid P, Ferreira M, Dubey S, Zaiss M, Harper-Wynne C, Makris A, Brown V, Kristeleit H, Patel G, Perelló A, Jones A, Mithal N, Ruiz I, Kümmel S, Brunt AM, Guerra JA, Gonzalez Cao M, Saura C, Mousa K, Sarker S-J, Coetzee C, Swann R, Cortes J. MANTA: A randomized phase II study of fulvestrant in combination with the dual mTOR inhibitor AZD2014 or everolimus or fulvestrant alone in estrogen receptor-positive advanced or metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-12.

Abstract C188: A phase 1 study of RXDX-105, an oral RET, BRAF and EGFR tyrosine kinase inhibitor, in patients with advanced or metastatic cancers

Abstract Background: RXDX-105 is a potent RET, BRAF and EGFR tyrosine kinase inhibitor (TKI) that exhibits high target affinity at low nanomolar concentrations. The RET proto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor (GDNF) family of extracellular signaling molecules. RET gain of function alterations are associated with the development of various types of human cancer, including non-small cell lung cancer (NSCLC). BRAF plays a key role in regulating the MEK/ERK signaling pathway, which affects cell division and differentiation. Acquired BRAF mutations can result in constitutive activation of this pathway, thereby fueling cancer growth. RXDX-105 is being developed as an oral therapy for patients with solid tumors that harbor RET or BRAF mutations or gene rearrangements. Methods: Adult pts with advanced solid tumors were enrolled in a Ph 1 single agent dose escalation study with a standard 3 + 3 design to determine the recommended Ph 2 dose. Oral RXDX-105 was given as a fixed dose on a continuous daily schedule. Tumor response was assessed at baseline and every 8 wks (RECIST v1.1). Treatment-emergent adverse events (AEs) were recorded according to NCI CTC v4.03. Pharmacokinetic (PK) assessment was also a study objective. Results: To date, 35 pts (17 M and 18 F) received RXDX-105 across 7 dose levels (20 to 275 mg QD). Median age was 60.5 years (range 27-81). The most frequent tumors (pts) were metastatic CRC (13), ovarian cancer (3), NSCLC (3), cholangiocarcinoma (3), and pancreatic cancer (3). Median number of cycles was 2 (range 1 to 23). 34 pts experienced AEs; 6 pts experienced treatment-related G3 AEs, including anemia, hypophosphatemia, fatigue, diarrhea, abdominal pain, rash and muscle weakness. 22 SAEs were reported from 9 pts, with none considered treatment-related. No treatment-related deaths occurred. The most common AEs were: fatigue (17 pts), vomiting (13 pts), abdominal pain (12 pts), nausea (11 pts), decreased appetite (10 pts), and rash (10 pts). At the time of this report, 3 pts have had DLTs; 1 pt at 200 mg with G2 hand and foot syndrome, 1 pt at 275 mg with G3 fatigue, and 1 pt at 275 mg with G3 asymptomatic hypophosphatemia. The protocol was amended to exclude hypophosphatemia as a DLT since it has been observed with approved TKIs and can be managed by supplementation. The PK data to date have demonstrated that RXDX-105 is absorbed with a median Tmax between 2 and 6 hrs at steady state. RXDX-105 plasma concentrations declined slowly after reaching Cmax with an average terminal half-life of 28 to 42 hrs across dose levels. There was a loss of dose proportionality at doses above 150 mg, possibly due to pH-dependent drug dissolution in the stomach. The impact of the fed state on exposure is being explored. 11 pts have been on treatment for ≥ 12 weeks. No objective responses have been observed; however, 1 pt with BRAF V600E-positive papillary thyroid cancer, previously treated with RAI, EBRT and multiple surgical resections, has been on study with stable disease for almost 2 years (23 cycles). Additionally, 2 heavily pre-treated pts with squamous NSCLC achieved clinical benefit with SD for &amp;gt; 6 months; 1 patient continues. Conclusions: To date, treatment with RXDX-105 demonstrates an acceptable safety profile. Improvements in bioavailability are being investigated. Dose escalation continues. Citation Format: Ding Wang, Manish Patel, Marwan Fakih, A. Craig Lockhart, Anthony J. Olszanski, Rupal Patel, Peter D. Brown, Jennifer W. Oliver, Pratik S. Multani. A phase 1 study of RXDX-105, an oral RET, BRAF and EGFR tyrosine kinase inhibitor, in patients with advanced or metastatic cancers. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C188.

Abstract CT303: A phase I pharmacokinetic and pharmacodynamic evaluation of the combination of everolimus and buparlisib for concurrent mTOR and PI3K pathway blockade in patients with advanced solid tumors

Abstract Background: Preclinical work showed improved anticancer efficacy with the combination of an mTOR and a PI3K inhibitor over either agent alone. We conducted a phase I study to determine the recommended phase II dose (RP2D) of the combination of everolimus (E), an mTOR inhibitor and buparlisib or BKM120 (B), a pan-PI3K inhibitor. Methods: Patients with advanced solid malignancies who have exhausted standard treatment options were enrolled. Main eligibility criteria include ECOG performance status 0-2, adequate end organ function and absence of glucose intolerance, uncontrolled hepatitis, anxiety or depression. Dose escalation was performed using a Bayesian Escalation with Overdose Control (EWOC) design to evaluate different doses of E (5mg or 10mg) and B (20, 40, 60 and 80 mg,) once daily continuously. Eligible patients were enrolled in cohorts of 3 patients. Pharmacokinetic (PK) assessment was conducted in cycle 1 on day 8 using peripheral blood samples collected at time 0, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours and prior to dosing on cycle 1 D day 15. Pharmacodynamic (PD) impact on mTOR/PI3K pathway modulation was evaluated in skin punch biopsies collected at baseline and at end of cycle 1. Results: We enrolled 35 patients: Median age 63yrs (range:40-79), 21 females (58%); 2 Latinos (6%), 7 Blacks (20%) and 26 Caucasians (74%); with cancers of the lung (8), colorectal (7), sarcomas (3), salivary gland (3), breast (3), thyroid (3), thymic (2), bladder (2), ovarian (2), head and neck (1) and PNET (1). The safety of 6 different dose combinations of E and B (5/20; 10/20; 5/40; 5/60; 10/60; 5/80) was assessed. The most frequent toxicities were: hyperglycemia, diarrhea, nausea, fatigue and AST elevation. The dose limiting toxicities observed in 6 patients were: fatigue (3), hyperglycemia (1), mucositis (1), acute renal failure (1) and urinary tract infection (1). The 5/60 combination was defined as the RP2D. The median number of cycles completed was 2 (range: 0-20). Of the 25 patients evaluable for efficacy, 8 (32%) had disease progression while 17 (68%) achieved stable disease (SD). Median duration of SD was 18 weeks (range: 2-83) and 7 patients had SD lasting ≥6 months. Steady-state PK data for both agents in 24 evaluable patients showed no evidence of drug-drug interaction, with dose-normalized maximum concentrations (Cmax) and area-under-the-curve (AUC0-∞) values for E and B in combination being comparable to single agent data. Preliminary signal of efficacy for the combination was observed in patients with thymic, breast and lung cancer. PD analysis is ongoing and will be presented at the meeting. Conclusion: The safety profile of the combination of everolimus plus buparlisib is well tolerated and the RP2D is 5mg/day and 60mg/day respectively on a continuous daily schedule. The efficacy data are encouraging and warrant further evaluation in phase II studies. Citation Format: Taofeek Kunle Owonikoko, R.Donald Harvey, Colleen Lewis, Zhengjia Chen, John S. Kauh, Meredith Renfroe, Rijalda Deovic, Gabriel L. Sica, Bradley C. Carthon, Wayne Bernard Harris, Bassel F. El-Rayes, Suresh S. Ramalingam, Fadlo R. Khuri. A phase I pharmacokinetic and pharmacodynamic evaluation of the combination of everolimus and buparlisib for concurrent mTOR and PI3K pathway blockade in patients with advanced solid tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT303. doi:10.1158/1538-7445.AM2015-CT303