Expansion part of phase I study of E7090 in patients with cholangiocarcinoma harboring FGFR2 gene fusion and with gastric cancer harboring FGFR2 gene amplification or FGFR2 protein high expression.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 538-538
Author(s):  
Chigusa Morizane ◽  
Makoto Ueno ◽  
Tatsuya Ioka ◽  
Masahiro Tajika ◽  
Masafumi Ikeda ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase I ◽  
Gene Amplification ◽  
Phase I Study ◽  
Gene Fusion ◽  
Kinase Inhibitor ◽  
High Expression ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
Fgfr2 Gene

538 Background: E7090 is a selective tyrosine kinase inhibitor against FGFR1-3. This first-in-human phase I study has been conducted in Japan and consists of 2 parts. Based on the toxic, pharmacokinetic, and pharmacodynamic profiles in Part 1, dose escalation study, the recommended dose was determined to be 140 mg QD for Part 2, an expansion study part restricted to patients with tumors harboring FGFR gene alterations. Here we provide the interim analysis results of Part 2. Methods: In Part 2, patients with cholangiocarcinoma harboring FGFR2 gene fusion (CCA cohort) and gastric cancer harboring FGFR2 gene amplification or FGFR2 protein high expression (GC cohort) were enrolled. Patients received oral dosing of E7090 until disease progression or unacceptable toxicity. Safety was assessed using CTCAE version 4.03. Tumor response was evaluated by site investigators using RECIST 1.1. Results: As of 31 March 2019, 16 patients including 6 patients in CCA cohort and 10 patients in GC cohort received E7090 in Part2. Median age was 63 years, 25% were female, ECOG PS of 0 and 1 were 50% respectively. 5 patients (83%) in CCA cohort and 1 patient (10%) in GC cohort achieved partial response as the best overall response. The disease control rates were 100% in CCA cohort and 30% in GC cohort, respectively. Median progression-free survivals were 8.3 months in CCA cohort and 2.8 months in GC cohort at the cut-off date. 2 patients with CCA remain on treatment. The most common treatment-related TEAEs occurring in 30% or more of patients in Part 2 were hyperphosphatemia (100%), palmar–plantar erythrodysesthesia syndrome (56%), paronychia (50%), dysgeusia (38%), stomatitis (31%), diarrhea (31%), increased AST (31%) and blood creatinine increased (31%). Grade≥3 treatment-related TEAEs were reported in 2 out of 16 patients (13%); they were increased AST, lipase increased and retinopathy. Conclusions: This study indicated that E7090 has a manageable safety profile in Part 2 and the promising clinical activity in CCA patients with FGFR2 gene fusion.

A phase I study of nilotinib alone and in combination with imatinib (IM) in patients (pts) with imatinib-resistant gastrointestinal stromal tumors (GIST) - Study update

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10023-10023 ◽  
Author(s):  
M. Von Mehren ◽  
P. Reichardt ◽  
P. G. Casali ◽  
J. Blay ◽  
M. Debiec-Rychter ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Skin Toxicity ◽  
Clinical Activity ◽  
Imatinib Resistant ◽  
Exon 9 ◽  
Exon 11

10023 Background: Nilotinib is a novel tyrosine kinase inhibitor (TKI) targeting KIT, PDGFR, and Bcr-Abl and inhibiting the proliferation of both IM-sensitive and -resistant cells in vitro. We report the results of a phase I study in GIST pts resistant to IM and other TKIs. Methods: Pts with progressive disease received nilotinib alone (400 mg p.o. bid) or escalating doses of nilotinib (200 mg qd, 400 mg qd, or 400 mg bid) in combination with IM (400 mg p.o. bid), or nilotinib 400 mg bid plus IM 400 mg qd. Pharmacokinetic (PK) analyses were performed. Tumor assessments (RECIST) were done every 8 weeks. Baseline samples of 18 GISTs were analyzed for KIT and PDGFR mutations. Results: 53 pts received nilotinib, alone (n=18) or in combination with IM (n=35), for a median of 134 days (range 8 to 430 days). Thirty-nine pts (74%) had failed second-line therapies including sunitinib, AMG-706, dasatinib or RAD001. Most frequent adverse events were grade 1 (17% of pts) or 2 (51% of pts) including: skin toxicity, fatigue, myalgia, headache, abdominal pain, nausea, vomiting, diarrhea, constipation, hyperbilirubinemia and edema. Six pts experienced dose limiting hyperbilirubinemia or skin rash. One pt on nilotinib alone achieved partial response (PR) for > 6 months and 36 pts (68%)-13 on nilotinib alone-, had SD ranging from 6 weeks to > 6 months. Median progression-free survival was 134 days overall and 178 days for pts on nilotinib alone. Genotyping revealed mutations in KIT exon 9 (n=4) or 11 (n=11), and KIT WT (n=3). The single PR occurred in KIT exon 11 mutant GIST following previous adjuvant imatinib and intolerance to imatinib 800 mg. KIT was WT in 2 out of 8 pts with SD > 6 months. Conclusions: Nilotinib, alone and in combination with IM has promising clinical activity in pts with GIST resistant to prior TKIs. Tolerability is acceptable for both nilotinib 400 mg bid, alone and in combination with IM 400 mg qd, which are the recommended doses for future studies. No significant financial relationships to disclose.

Phase I study of nilotinib in patients (pts) from Japan with imatinib-resistant Ph+ chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 17511-17511 ◽  
Author(s):  
A. Tojyo ◽  
Y. Miyazaki ◽  
N. Usui ◽  
Y. Kobyashi ◽  
S. Okamoto ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Systemic Exposure ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Serum Samples ◽  
Open Label ◽  
Dose Escalation Study ◽  
Imatinib Resistant

17511 Background: Nilotinib is a highly selective Bcr-Abl tyrosine kinase inhibitor designed to be more potent than imatinib. Results from a phase I study in Japanese pts with imatinib-resistant/intolerant Ph+CML/ALL are reported. Methods: Japanese pts with imatinib-resistant/intolerant Ph+CML (5 CP; 2 AP; 2 BC) or ALL (2) were enrolled in an open-label, dose-escalation study evaluating safety, efficacy and pharmacokinetics (PK) of oral nilotinib. A standard three-pt-per-cohort design was used; initial cohorts included 200mg QD, 400mg QD, and 400mg BID. Serum samples were collected on days 1 and 15 of cycle 1 in all 11 pts. Results: Peak serum concentration was achieved at 4 hrs in most pts. Systemic exposure increased with dose. Serum level reached steady-state within 1 week and was stable over time. The accumulation ratio (AUC day15/day1) was 2 to 3. Nilotinib 400mg BID maintained serum levels >/= 30 times higher than the IC50 required to inhibit Bcr-Abl phosphorylation. No pt experienced dose-limiting toxicity. 7/11 pts had Grade 3/4 AEs, only 1 pt had an AE (thrombocytopenia) suspected as being related to nilotinib treatment. No pt had EKG abnormalities. 57% of all pts and 75% of CML CP pts achieved MCyR. 3 pts in the 200mg QD cohort discontinued due to disease progression, all other pts completed the study. PK results are summarized in Table 1 . Conclusions: Nilotinib PK profile in Japanese pts is comparable to that reported for pts outside Japan. Based on these data, the recommended starting dose of nilotinib in Japanese pts with imatinib-resistant/intolerant Ph+ CML/ALL is 400mg BID. [Table: see text] No significant financial relationships to disclose.

Phase I study of irinotecan/5-fluorouracil/leucovorin (FOLFIRI) with sunitinib for advanced gastroesophageal cancers (EGC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15569-e15569
Author(s):  
Sarbajit Mukherjee ◽  
Christos Fountzilas ◽  
Patrick McKay Boland ◽  
Kristopher Attwood ◽  
Wei Tan ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Clinical Activity ◽  
Free Survival

e15569 Background: Sunitinib (S) is a multi-targeted tyrosine kinase inhibitor with activity against VEGFR, PDGRF, KIT, FLT-3, and RET. S is synergistic with chemotherapy in preclinical models. We hypothesized that S+FOLFIRI combination will have increased efficacy in advanced EGC. Methods: This was a phase I study for patients with advanced chemo naïve EGC. Dose escalation used a standard 3+3 design. The primary objective was to determine the tolerability and safety of S+FOLFIRI. Secondary objectives were overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). Results: Twenty-three patients participated in the study (Male 78%, Female 22%). Median age was 60 (Range: 37-77) years. Median follow up time was 67.5 (95% CI: 58.9, 76) months. The most frequently reported adverse events were neutropenia (78%; G3/4: 43%), nausea (74%; G3/4:13%), diarrhea (65%; G3/4: 4%), vomiting (61%, G3/4: 9%) lymphopenia (52%; G3/4: 13%) and fatigue (52%; G3/4:17%).Two dose limiting toxicities (DLTs) were noted each at dose level (DL) 1 and 1A, one at DL 1B and 3 at DL 2 (Table 1). Maximum tolerated dose was determined at DL 1B. At the time of data reporting 21 patients had died. Two patients came off the study per investigator request. All patients were evaluated for efficacy. The median OS and PFS were 12.4 (95% CI: 8.9, 16.5) months and 6.2 (95% CI: 3.4, 13.5) months, respectively. Conclusions: S+FOLFIRI was reasonably tolerated, with a manageable safety profile and signs of clinical activity in patients with advanced EGC. This study was supported by a research grant from Pfizer, Inc. Clinical trial information: NCT00524186. [Table: see text]

Phase I Study of Forodesine (BCX1777), An Oral PNP Inhibitor In Patients with Relapsed or Refractory T/NK Malignancies.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1796-1796 ◽  
Author(s):  
Kunihiro Tsukasaki ◽  
Michinori Ogura ◽  
Hirokazu Nagai ◽  
Jun Taguchi ◽  
Tatsuya Suzuki ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Phase I Study ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
Maximum Tolerated Dose ◽  
T Cell Lymphoma ◽  
Clinical Activity ◽  
Open Label ◽  
Dose Escalation Study

Abstract Abstract 1796 Background: Forodesine is a rationally designed potent inhibitor of purine nucleoside phosphorylase (PNP) that leads to elevation of plasma deoxyguanosine (dGuo) and intracellular accumulation of dGTP levels and then apoptosis mainly in T cells. Oral forodesine has shown clinical activity in patients with cutaneous T-cell lymphoma (CTCL) (M. Duvic et al, ASH 2007). The objective of this phase I study was to evaluate the safety, PK profile, and efficacy of oral forodesine in patients with recurrent or refractory T/NK malignancies in Japan. Methods: An open-label dose-escalation study of forodesine, 100 to 300 mg/body qd for 4 weeks, was conducted to evaluate safety profile (dose-limiting toxicities, DLT), tolerability and PK profile as primary endpoints. Forodesine was administered until disease progression or unacceptable toxicity is observed. Relapsed or refractory T/NK malignancies with PS 0 to 1 and without major organ dysfunction were eligible. Results: Overall, 13 Japanese patients, 8 males and 5 females, with a median age of 69 (range 30–77) years were enrolled in the study: 5 patients in the 100mg cohort, 3 in the 200mg cohort and 5 in the 300mg cohort. Patients’ histopathologic subtypes were as follows: peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) (6 patients), anaplastic large cell lymphoma (ALCL) (3), primary cutaneous ALCL (C-ALCL) (2) and mycosis fungoides (MF) (2). Median stage and prior treatment regimen were IIIA (range IA-IVA) and 2 (range 1, 8), respectively. No DLT was observed and a maximum tolerated dose was never defined. The most common toxicities of grade 2 or less were constipation (39 %), rash (31%), lymphopenia (31 %), neutropenia (23 %), nausea (23 %), peripheral edema (23 %), LDH elevation (23 %) and leukopenia (23 %). The toxicities of grade 3 or greater were lymphopenia (62 %), anemia (15 %), leukopenia (8 %), thrombocytopenia (8 %) and viral infection (8 %). Median baseline, nadir, and last visit lymphocytes counts (1,000/μL) were 0.69 (95% CI: 0.56, 1.18), 0.35 (95% CI: 0.14, 0.60) and 0.60 (95% CI: 0.24, 0.95), respectively. Plasma levels for forodesine showed less than dose-proportional increase in exposure as mean AUC at Day 1 was 1,948 (ng·h/mL) in the 100mg cohort, 4,608 (ng·h/mL) in the 200mg cohort, and 4,596 (ng·h/mL) in the 300mg cohort. The levels for dGuo displayed a similar trend, with mean AUC at Day 1 4,023 (ng·h/mL) in the 100mg cohort, 5,705 (ng·h/mL) in the 200mg cohort, and 6,074 (ng·h/mL) in the 300mg cohort. One patient with ALCL reached complete response (CR) in the 100mg cohort and 2 patients with MF reached partial response in the 200mg cohort. In addition, 4 patients with stable disease (SD) were observed: 1 patient with PTCL-NOS in the 100mg cohort, 1 with C-ALCL in the 200mg cohort and 2 with C-ALCL and PTCL-NOS in the 300mg cohort. As of Aug, 2010, 2 patients with ALCL (CR patient in the 100mg cohort) and PTCL-NOS (SD patient in the 300mg cohort) have continued the treatment for more than 510 days and 290 days, respectively. Conclusion: Oral forodesine was well tolerated at all the dose levels tested with similar PK findings to those in the CTCL study in USA, demonstrating potential efficacy against relapsed or refractory T/NK lymphomas including PTCL for the first time. Based on these promising data, we are planning a phase I /II study of forodesine in patients with relapsed or refractory PTCL. Disclosures: No relevant conflicts of interest to declare.

Phase I Study of the Cyclin-Dependent Kinase Inhibitor Flavopiridol in Combination With Paclitaxel in Patients With Advanced Solid Tumors

2002 ◽  
Vol 20 (8) ◽  
pp. 2157-2170 ◽  
Author(s):  
Gary K. Schwartz ◽  
Eileen O’Reilly ◽  
David Ilson ◽  
Leonard Saltz ◽  
Sunil Sharma ◽  
...  
Keyword(s):  
Phase I ◽  
Pulmonary Toxicity ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Fixed Dose ◽  
Clinical Activity ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Induction Of Apoptosis ◽  
Dose Limiting Toxicity

PURPOSE: Preclinical studies indicate that the cyclin-dependent kinase inhibitor flavopiridol potentiates the induction of apoptosis by paclitaxel, provided paclitaxel is followed by flavopiridol. We therefore designed a phase I clinical trial of sequential paclitaxel and flavopiridol. PATIENTS AND METHODS: Paclitaxel was administered at a fixed dose, as either a 24- or 3-hour infusion on day 1, followed by a 24-hour infusion of flavopiridol on day 2. Doses of flavopiridol were escalated in successive cohorts according to a modified Fibonacci design. Flavopiridol pharmacokinetics were obtained on all patients. RESULTS: Dose-limiting neutropenia developed with 24-hour paclitaxel doses of 135 and 100 mg/m2 and flavopiridol doses of 10 and 20 mg/m2, respectively. With 3-hour paclitaxel at 100 mg/m2, flavopiridol could be escalated to 70 mg/m2 without dose-limiting toxicity. With 3-hour paclitaxel next escalated to 135 mg/m2, dose-limiting neutropenia and pulmonary toxicity occurred when flavopiridol was escalated to 94 mg/m2. This did not correlate with any change in flavopiridol or paclitaxel pharmacokinetics. At a 3-hour paclitaxel dose of 175 mg/m2, dose-limiting pulmonary toxicity occurred in only one patient at flavopiridol doses under 94 mg/m2. Clinical activity was observed in patients with esophagus, lung, and prostate cancer, including patients who had progressed on paclitaxel. CONCLUSION: The recommended phase II doses will be a 3-hour infusion of paclitaxel at 175 mg/m2 on day 1 followed by a 24-hour infusion of flavopiridol at 70 mg/m2 on day 2. Flavopiridol dose escalations to 80 mg/m2 are possible. At these doses, toxicities are manageable and clinical activity is promising.

A phase I study of MK-2206 in combination with lapatinib in patients (pts) with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2607-2607
Author(s):  
Kari Braun Wisinski ◽  
Amye Tevaarwerk ◽  
Maria Bell ◽  
Mark E. Burkard ◽  
Jens C. Eickhoff ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Biologically Active ◽  
Clinical Activity ◽  
Her2 Positive ◽  
Combination Methods

2607 Background: The AKT protein kinase is a key mediator of signaling in the human epidermal growth factor receptor-2 (HER2) pathway. HER2 inhibition can result in feedback regulation of signaling, leading to high AKT activity. Preclinical studies demonstrate activity of combined HER2 and AKT inhibition. Lapatinib is an oral tyrosine kinase inhibitor of HER2. MK-2206 is an oral selective inhibitor of AKT with a maximum tolerated dose (MTD) of 60mg qod. Both agents cause rash and diarrhea. This study was designed to determine the MTD, dose limiting toxicities (DLTs), adverse events (AEs), clinical activity and pharmacokinetic (PK) parameters of the combination. Methods: This phase I study evaluated the safety of MK-2206 (30-60 mg qod) and lapatinib (1000-1500 mg qd) continuously. Cycles were 28 days, except cycle 1 (35 days), due to a 1 week MK-2206 lead-in to evaluate for PK interactions. Because of the continuous nature of therapy, protocol-specified intolerable grade 2 AEs were considered DLTs during cycle 1. Results: 23 pts (median age 59 [range 22-72];15 female:8 male) were enrolled. The most common malignancies were colorectal (8 pts), lung (4 pts), and breast (3 pts). 4 pts were unevaluable per protocol; 19 evaluable pts were on study a median of 8 weeks (range 3-35). 3 pts experienced DLTs. At dose level one, 1 pt had grade (gr) 3 hyponatremia and fatigue. At dose level four, 1 pt had gr 4 hyponatremia, gr 3 rash and hypocalcemia and 1 pt had intolerable gr 2 mucositis with delivery of <75% of drug. The most common AEs at least possibly related to therapy included diarrhea (gr 3-4 in 3 pts; gr 1-2 in 16 pts), nausea (gr 3 in 2 pts; gr 1-2 in 14 pts) and rash (gr 3 in 2 pts; gr 1-2 in 12 pts). The MTD was 45mg po qod of MK-2206 with 1500 mg po qd of lapatinib, exceeding biologically active doses for each agent. One pt with adrenal cortical carcinoma was on study for 6 months with stable disease (SD) and 1 pt with colorectal cancer was on study for 5 months with significant tumor marker decline and SD. PK analyses are ongoing. Conclusions: MK-2206 in combination with lapatinib is well-tolerated at biologically active single agent doses. Anti-tumor activity will be evaluated further in a dose expansion cohort in pts with advanced HER2-positive breast cancer. Clinical trial information: NCT01245205.

Phase I study of the safety and pharmacokinetics of epitinib, an oral EGFR tyrosine kinase inhibitor, in patients with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e19042-e19042
Author(s):  
Qing Zhou ◽  
Yi Long Wu ◽  
Xiyong Yu ◽  
Jinji Yang ◽  
Limin Wen ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Dose Range ◽  
Human Study ◽  
Human Tumor ◽  
Egfr Mutations ◽  
Clinical Activity ◽  
Systemic Treatments

e19042 Background: Epitinib is an oral small molecule compound selectively inhibits epidermal growth factor receptor (EGFR). It has demonstrated potent inhibitory effects on multiple human tumor xenografts with a large safety window and broad tissue distribution including high drug contribution in brain. This first-in-human study is being conducted to assess the safety and tolerability, pharmacokinetics (PK), and preliminary anti-tumor activity of Epitinib. Methods: This phase I study uses a 3+3 design for dose-escalation of Epitinib given once daily (QD) in 28-day treatment cycles in patients with solid tumors who failed or have no access to standard therapies. Safety and tumor response are assessed according to NCI CTCAE 4.0 and RECIST 1.1, respectively. Results: By Dec 31, 2012, 19 pts aged 40-66 yr old (ECOG PS 1) with NSCLC (n=16) or breast cancer (n=3) were enrolled in 5 dose cohorts of 20-160 mg. Six NSCLC pts had EGFR mutations (3 with T790M). All pts had ≥2 lines of prior systemic treatments (7 pts with gefitinib or elotinib). Most AEs were mild (Gr1). Treatment-related AEs included skin rash (36.8%), abnormal liver function tests (42.1%), diarrhea (10.5%), vomiting (5.3%), paronychia (5.3%), decreased neutrophil count (5.3%) and increased creatinine (5.3%). Three SAEs were reported as possibly unrelated to the study drug. No DLT was observed and MTD has not been reached yet. PK analysis showed that the mean elimination half-life of Epitinib was approximately 40 hours and Tmax was around 2 h. Both Cmaxand AUC exhibited good dose proportionality over the studied dose range with low inter-patient variability following single and multiple doses. Among 15 evaluable pts, 1 EGFR mutation+ NSCLC pt achieved confirmed partial response (66.7% tumor reduction) for more than 6 months and the treatment is ongoing; 8 pts had stable disease, including 1 with T790M for 6 months and 1 with brain metastasis for 12 months who is still on treatment. Conclusions: Epitinib was well tolerated at doses up to 160mg QD to date with manageable adverse events and excellent pharmacokinetic properties. Encouraging clinical activity was observed, including durable SD in NSCLC patients with T790M or brain mets.

Bosutinib in combination with pemetrexed in patients with selected metastatic solid tumors: A phase I study (NCT03023319).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3022-3022
Author(s):  
Nagla Fawzy Abdel Karim ◽  
Mahran Shoukier ◽  
Ihab Eldessouki ◽  
Ahmed Khaled ◽  
John Morris
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Stable Disease ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Weekly Schedule ◽  
Dose Escalation Study ◽  
Grade 3

3022 Background: Activation of the Src kinase pathway has been observed in about 50% of cancers of the colon, liver, lung, breast and pancreas. Ceppi, et al, explored that Src inhibitors might be synergistic in combination with pemetrexed. Bosutinib is an approved oral ATP-competitive Bcr-Abl tyrosine-kinase inhibitor with an inhibitory effect on Src kinases. Methods: In this phase 1, dose-escalation study, we enrolled 10 patients with advanced metastatic solid tumors who progressed on standard of care chemotherapy, 9 of whom were evaluable, to receive bosutinib and pemetrexed. Bosutinib was administered once daily in a 3 + 3 dose-escalation study design where the first cohort started at an oral dose of 200 mg daily with I.V. pemetrexed 500 mg/m2 on a three weekly schedule. The primary objective was to determine the dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) of bosutinib with pemetrexed, and the type and frequency of adverse events. Secondary objective(s) were to estimate tumor response rate (RR), progression-free survival (PFS), and overall survival (OS). Results: All patients had progressed on prior chemotherapy and included 9 patients with adenocarcinoma of the lung, and 1 patient with metastatic adenocarcinoma of the appendix. Two patients (22%) had prior pemetrexed exposure. Median age was 62 years (range, 58-44). The median number of bosutinib and pemetrexed cycles received was 2 (range, 1-4). Nine patients were evaluable. The MTD of bosutinib was 300 mg daily in this combination as 2 out of the 3 patients who received 400 mg experienced elevated liver transaminases (>CTCAE Grade 3) and one patient experienced grade 3 fatigue. Two patients (22%) had a partial response, and 6 patients (67%) had stable disease, including 2 patients with prior pemetrexed exposure, and 1 patient had disease progression. The two responders and the subject with the longest stable disease duration demonstrated Src overexpression on immunohistochemical staining of their tumor. Two patients died of sepsis; both had stable disease. Median PFS was 4.1 months (range, 1.2-11.6), and the median OS was 11.9 months (range, 4-36.7). Adverse events included pneumonia/sepsis, diarrhea, fatigue, rash, weakness, transaminitis, hypertension, and thrombocytopenia. Conclusions: The MTD of oral bosutinib was 300 mg daily in combination with pemetrexed 500 mg/m2 every 3 weeks. Despite the limitations of this phase I study there appears potential efficacy of this combination in pretreated patients. We are currently enrolling patients in the expansion cohort. Clinical trial information: NCT03023319.

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