Efficacy and safety of lorlatinib in patients (pts) with ALK+ non-small cell lung cancer (NSCLC) with one or more prior ALK tyrosine kinase inhibitor (TKI): A phase I/II study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9006-9006 ◽  
Author(s):  
Alice Tsang Shaw ◽  
Sai-Hong Ignatius Ou ◽  
Enriqueta Felip ◽  
Todd Michael Bauer ◽  
Benjamin Besse ◽  
...  
Keyword(s):  
Advanced Nsclc ◽  
Kinase Inhibitor ◽  
Primary Objective ◽  
Clinical Activity ◽  
Efficacy And Safety ◽  
Resistance Mutations ◽  
Small Cell Lung ◽  
Cns Metastases ◽  
Grade 3 ◽  
Clinical Trial Information

9006 Background: Lorlatinib is a selective, potent, brain-penetrant, next generation ALK/ROS1 TKI active against most known resistance mutations. In Ph I of this Ph I/II study, lorlatinib showed robust clinical activity in ALK+ or ROS1+ advanced NSCLC pts, most of whom had CNS metastases (mets) and were heavily pre-treated. In Ph II of this study, efficacy was explored based on prior ALK TKI tx as well as safety across all patients treated at the recommended Ph II dose. Methods: In this ongoing Ph II study (NCT01970865), pts with ALK+ or ROS1+ NSCLC, ± asymptomatic untreated or treated CNS mets, were enrolled into 6 expansion cohorts (EXP) based on prior tx (EXP 1-5, ALK+) and rearrangement status (EXP 6, ROS1+). Pts received lorlatinib 100mg QD. Primary objective was ORR and intracranial ORR (IC-ORR) by independent central review (ICR). Results: Efficacy (ALK+ pts with prior tx): At data cut-off (15 Aug 2016), 82 ALK+ pts were enrolled in cohorts EXP 2-5, received C1 no later than 31 Mar 2016 and were evaluated for ORR (ITT population); 52 were evaluated for IC-ORR and 35 were evaluated for IC-ORR response based on target lesions only (≥5mm; no prior radiotherapy or progression post prior radiotherapy). Confirmed response rates by ICR are reported in the table below. Safety (all pts): 116 ALK/ROS1+ pts were evaluated for safety at data cut-off. Most common tx-related AEs (TRAEs) and grade 3/4 TRAEs were hypercholesterolemia (90%, 17%) and hypertriglyceridemia (72%, 17%). Dose interruptions and reductions due to TRAEs were reported in 29% and 20% of pts, respectively. 14% of pts had tx-related SAEs. 5 pts (4%) discontinued tx due to TRAEs and there were no tx-related deaths. 74/116 pts (64%) remain on tx. Conclusions: Lorlatinib showed compelling clinical activity, with substantial IC activity, in ALK+ pts who received ≥1 prior ALK TKI, many of whom were heavily pre-treated. Clinical trial information: NCT01970865. [Table: see text]

Clinical activity of avapritinib in ≥ fourth-line (4L+) and PDGFRA Exon 18 gastrointestinal stromal tumors (GIST).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 826-826 ◽  
Author(s):  
Michael C. Heinrich ◽  
Robin L. Jones ◽  
Margaret von Mehren ◽  
Sebastian Bauer ◽  
Yoon-Koo Kang ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Phase 1 ◽  
Clinical Activity ◽  
Resistance Mutations ◽  
Secondary Resistance ◽  
Resistant Disease ◽  
Treatment Paradigm ◽  
Grade 3 ◽  
Selective Kinase Inhibitor ◽  
Advanced Gist

826 Background: Targeting oncogenic KIT and PDGFRA mutations revolutionized treatment of patients (pts) with advanced GIST; however, nearly all pts succumb to resistant disease. Avapritinib is a potent and selective kinase inhibitor with broad activity against oncogenic KIT/PDGFRA mutants, including PDGFRA D842V and other primary or secondary resistance mutations. Results from the phase 1 NAVIGATOR (NCT02508532) study of avapritinib in pts with advanced GIST are presented. Methods: Adult pts with unresectable PDGFRA D842V or other mutant GIST who progressed on imatinib and ≥1 other tyrosine kinase inhibitor (TKI) were treated with oral, daily, continuous avapritinib. Adverse events (AE) and response by mRECIST 1.1 per central radiology were assessed. Overall population safety (30-600 mg starting doses) and efficacy in the response-evaluable 4L+ and PDGFRA Exon 18 (Ex 18) populations treated at the MTD (400 mg)/RP2D (300 mg) were analyzed. Results: As of 16 Nov 2018, 237 pts [172 KIT, 62 PDGFRA Ex 18 [56 D842V, 6 non-D842V), 2 PDGFRA N659K, 1 missing] were enrolled including 111 in the 4L+ population (primarily KIT, median 4 prior TKI) and 43 in the Ex 18 population (median 1 prior TKI). The 4L+ ORR was 22% [1 CR, 23 PR (1 pending)], and 52 SD with mDOR of 10.2 months (95% CI: 7.2–NE). The Ex 18 ORR was 86% [3 CR, 34 PR (1 pending)] and 5 SD; mDOR was not reached (95% CI: 11.3–NE). Most AEs were grade 1–2, most commonly nausea (63%), fatigue (58%), anemia (49%), periorbital edema (42%), diarrhea (40%), vomiting (40%), decreased appetite (38%), increased lacrimation (33%), peripheral edema (33%) and memory impairment (most common cognitive AE, 29%). 10% of pts discontinued due to a related AE. Grade 3–4 related AE ≥ 2% were anemia, fatigue, hypophosphatemia, hyperbilirubinemia, neutropenia, and diarrhea. Conclusions: Avapritinib has important clinical activity in pts with advanced GIST who have no effective therapies. The ORR and DOR of avapritinib in 4L+ exceeds that of approved 2nd and 3rd line therapies and shows impressive activity in D842V and other Ex 18 mutant PDGFRA GIST. Results suggest avapritinib has the potential to change the treatment paradigm of pts with advanced GIST. Clinical trial information: NCT02508532.

Immune checkpoint inhibition (ICI) in combination with SBRT in patients with advanced pancreatic adenocarcinoma (aPDAC).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 192-192 ◽  
Author(s):  
Gagandeep Brar ◽  
Changqing Xie ◽  
Charalampos S. Floudas ◽  
M. Pia Morelli ◽  
Suzanne Fioravanti ◽  
...  
Keyword(s):  
Partial Response ◽  
Locally Advanced ◽  
Primary Objective ◽  
Clinical Activity ◽  
Correlative Analysis ◽  
Progression Of Disease ◽  
New Treatment ◽  
Grade 3 ◽  
Unacceptable Toxicity ◽  
Clinical Trial Information

192 Background: Chemotherapy in aPDAC has resulted in only modest improvements in outcome. The effectiveness of ICI monotherapy is also limited in PDAC, suggesting an immunogenic inert tumor microenvironment. SBRT is safe and effective in locally advanced PDAC and exhibits enhanced antitumor immunity. We hypothesize that ICI plus SBRT will improves immunomodulatory effects of ICI in patients with aPDAC resulting in a greater clinical benefit. Methods: Eligible patients with aPDAC were enrolled to four different treatment cohorts. Cohort 1: Durvalumab (Durva) 1500 mg every 4 weeks + SBRT 1 fraction x 8Gy on day 1. Cohort 2: SBRT 5 fractions x 5Gy followed by Durva. Cohort 3: Durva + Tremelimumab (Treme) 75 mg every 4 weeks + SBRT 1 fraction x 8Gy on day 1. Cohort 4: SBRT 5 fractions x 5Gy followed by Durva + Treme. This was continued until unacceptable toxicity or progression of disease. A biopsy was performed at baseline and pre-cycle 2 of treatment for exploratory correlative analysis. The primary objective was to evaluate the safety and feasibility of combining ICI and SBRT to enhance the efficacy of ICI. Results: 51 patients with aPDAC were enrolled and 31 patients were evaluable for the efficacy. The most commonly TRAEs were lymphopenia. Grade 3-4 AEs were lymphopenia and anemia. No dose limiting toxicities were seen. Out of total 31 evaluable patients, 1 patient achieved a confirmed partial response seen in Cohort 1 and 2 patients in Cohort 4, and 7 stable disease across the 4 treatment arms. Median PFS and OS was 1.7 months (95% CI 0.7-2.8 months) and 3.4 months (95% CI 0.9-11.4 months) in cohort 1; 2.6 months (95% CI 2.1-4.7 months) and 9.1 months (95% CI 3.4-18.7 months)in cohort 2; 1.6 months (95% CI 0.5-4.0 months) and 3.0 months (95% CI 0.7-6.6 months) in cohort 3; and 3.2 months (95% CI 1.5-16.5months) and 6.4 months (95% CI 1.5-17.6 months) in cohort 4. Conclusions: The combination of ICI and SBRT is safe and well tolerated in patients with aPDAC. The overall response rate of 9.6% including 2 patients who achieved a durable partial response lasting over 12 months, suggests meaningful clinical activity. This signifies that ICI and SBRT is a potential new treatment for aPDAC. Clinical trial information: NCT02311361.

scholarly journals Report of a Multicenter Phase II Trial Testing a Combination of Biweekly Bevacizumab and Daily Erlotinib in Patients With Unresectable Biliary Cancer: A Phase II Consortium Study

2010 ◽  
Vol 28 (21) ◽  
pp. 3491-3497 ◽  
Author(s):  
Sam J. Lubner ◽  
Michelle R. Mahoney ◽  
Jill L. Kolesar ◽  
Noelle K. LoConte ◽  
George P. Kim ◽  
...  
Keyword(s):  
Growth Factor ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Evaluation Criteria ◽  
Growth Factor Receptor ◽  
Primary Objective ◽  
Clinical Activity ◽  
Biliary Cancer ◽  
Vegf Inhibitor ◽  
Grade 3

Purpose Biliary cancers overexpress epidermal growth factor receptor (EGFR), and angiogenesis has been correlated with poor outcome. Erlotinib, an EGFR tyrosine kinase inhibitor, and bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor have each been shown to have activity in biliary cancer. The primary objective of this study was to evaluate the response rate by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary end points included overall survival (OS), time to progression (TTP), VEGF levels, and molecular studies of EGFR and k-ras. Patients and Methods Eligible patients had advanced cholangiocarcinoma or gallbladder cancer. Patients were treated with bevacizumab 5 mg/kg intravenously on days 1 and 15 and erlotinib 150 mg by mouth daily on days 1 through 28. Responses were evaluated by RECIST. VEGF levels were collected, and samples were analyzed for EGFR mutation by polymerase chain reaction. Results Fifty-three eligible patients were enrolled at eight sites. Of 49 evaluable patients, six (12%; 95% CI, 6% to 27%) had a confirmed partial response. Stable disease was documented in another 25 patients (51%). Rash was the most common grade 3 toxicity. Four patients had grade 4 toxicities. Median OS was 9.9 months, and TTP was 4.4 months. Low repeats (< 16) in EGFR intron 1 polymorphism and G>G k-ras Q38 genotype (wild type) were associated with improved outcomes. Conclusion Combination chemotherapy with bevacizumab and erlotinib showed clinical activity with infrequent grade 3 and 4 adverse effects in patients with advanced biliary cancers. On the basis of preliminary molecular analysis, presence of a k-ras mutation may alter erlotinib efficacy. The combination of bevacizumab and erlotinib may be a therapeutic alternative in patients with advanced biliary cancer.

Phase II study of amrubicin plus erlotinib in previously treated, advanced non-small cell lung cancer with wild-type EGFR (TORG1320).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20677-e20677
Author(s):  
Shinobu Hosokawa ◽  
Akihiro Bessho ◽  
Sakiko Otani ◽  
Jiichiro Sasaki ◽  
Satoshi Igawa ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Combination Therapy ◽  
Advanced Nsclc ◽  
Response Rate ◽  
Small Cell ◽  
Wild Type ◽  
Small Cell Lung ◽  
Previously Treated ◽  
Grade 3 ◽  
Clinical Trial Information

e20677 Background: Amrubicin (AMR) is a totally synthetic 9-aminoanthracycline and clinically active against non-small cell lung cancer (NSCLC). We found that the combination of AMR and erlotinib (ERL) had significant synergistic effect on NSCLC cell line with wild-type EGFR in vitro. We conducted a phase I study of AMR and ERL combination therapy in previously treated patients with advanced NSCLC, and have already reported the safety and the effectiveness. Furthermore we observed a high response rate of 33% in EGFR wild-type NSCLC. Methods: We conducted a multi-center, single-arm phase II trial to evaluate the efficacy of AMR and ERL combination therapy in patients with previously treated, advanced NSCLC, PS 0-1, and aged < 75 years, EGFR wild type. Patients were treated at 3weeks intervals with AMR(35mg/m2, intravenous injection on days 1-3) plus ERL(100mg/day, once daily on days 1-21). The primary endpoint is progression free survival (PFS). Secondary endpoints are response rate (RR), disease control rate (DCR), time to treatment failure (TTF), overall survival (OS), and toxicity. The concentration of trough ERL was measured after first cycle of treatment as additional investigation. Results: From June 2013 to July 2016, 25 patients were enrolled in this trial. The PFS according to the central test was 3.6 months (95%CI 2.1 - 5.1). The RR and the DCR were 24.0% and 64.0%, respectively. We observed grade 3 or 4 hematological toxicities such as leukopenia (68%), neutropenia (72%), anemia (8%) and febrile neutropenia (12%). The grade 3 or 4 non-hematological toxicities were anorexia (12%), oral mucositis (12%) and rash (8%). We had no treatment related death in this study. Conclusions: The PFS of AMR and ERL combination therapy in this study was superior to that of AMR monotherapy in historical setting. This combination therapy might be an option for previously treated NSCLC patients without a driver oncogene mutation. Clinical trial information: UMIN 000010582. Clinical trial information: UMIN 000010582.

Efficacy and safety of atezolizumab (atezo) and bevacizumab (bev) in a phase Ib study of microsatellite instability (MSI)-high metastatic colorectal cancer (mCRC).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 673-673 ◽  
Author(s):  
Howard S. Hochster ◽  
Johanna C. Bendell ◽  
James M. Cleary ◽  
Paul Foster ◽  
Wei Zhang ◽  
...  
Keyword(s):  
Immune Responses ◽  
Primary Objective ◽  
Clinical Activity ◽  
Efficacy And Safety ◽  
T Cell Infiltration ◽  
Heavily Pretreated ◽  
Anti Tumor Activity ◽  
Immunologic Approach ◽  
Clinical Trial Information

673 Background: Blockade of the PD-L1/PD-1 axis is a proven immunologic approach for treatment of many cancers; however, not all pts respond to monotherapy. Bev, an anti–VEGF-A antibody, has demonstrated clinical efficacy in mCRC and enhanced T-cell infiltration in tumors in preclinical studies. Thus, we postulated that combining atezo (anti-PD-L1) with bev would augment anti-tumor immune responses, resulting in improved and more durable clinical benefit. We report results from the first study of an anti-PD-L1 agent + VEGF-A blockade in MSI-high mCRC. Methods: A Ph Ib study (NCT01633970) investigated atezo + various chemotherapeutic/biologic regimens (eg, bev) in pts with advanced solid tumors, including mCRC. Pts received atezo 1200 mg q3w plus bev 15 mg/kg q3w (data cutoff, May 20, 2016). The primary objective was to evaluate the safety of atezo + bev. Secondary objectives included anti-tumor activity per RECIST v1.1. MSI status was tested locally. Results: Ten MSI-high mCRC pts were enrolled. Three pts had received 1 prior chemotherapy and 7 pts had received ≥ 2. Median age was 52.5 y. The minimum (range) of safety follow-up was 2.6 (2.6-20.3) mo. Median (range) treatment duration with atezo + bev was 10.1 (2-20) and 9.0 (2-19) mo, respectively. Efficacy results are shown below; the confirmed ORR per RECIST v1.1 was 30% (95% CI, 6.7%-65.3%). Median OS had not been reached with a median follow-up of 11.1 mo. Treatment-related all-grade AEs occurred in 80% of pts; 40% of pts had a related G3/4 AE. The most common related AE was proteinuria (40%; n = 3 G2 and n = 1 G3). No G5 events occurred. One AE led to discontinuation of atezo and 3 AEs led to discontinuation of bev. Biomarker data will be presented. Conclusions: Initial clinical activity was observed in heavily pretreated pts with MSI-high mCRC receiving atezo + bev; the disease control rate was 90%. This combination was well tolerated without unexpected toxicities. Further follow-up is ongoing. Clinical trial information: NCT01633970. [Table: see text]

Clinical activity of avapritinib in ≥ fourth-line (4L+) and PDGFRA Exon 18 gastrointestinal stromal tumors (GIST).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 11022-11022 ◽  
Author(s):  
Michael C. Heinrich ◽  
Robin Lewis Jones ◽  
Margaret von Mehren ◽  
Sebastian Bauer ◽  
Yoon-Koo Kang ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Phase 1 ◽  
Clinical Activity ◽  
Resistance Mutations ◽  
Secondary Resistance ◽  
Resistant Disease ◽  
Duration Of Response ◽  
Treatment Paradigm ◽  
Grade 3 ◽  
Advanced Gist

11022 Background: Targeting oncogenic KIT and PDGFRA mutations revolutionized treatment of patients (pts) with advanced GIST; however, nearly all pts succumb to resistant disease. Avapritinib is a potent and selective kinase inhibitor with broad activity against oncogenic KIT/PDGFRA mutants, including PDGFRA D842V and other primary or secondary resistance mutations. Updated results from the phase 1 NAVIGATOR (NCT02508532) study of avapritinib in pts with advanced GIST are presented. Methods: Adult pts with unresectable PDGFRA D842V or other mutant GIST who progressed on imatinib and ≥ 1 other tyrosine kinase inhibitor (TKI) were treated with oral, daily, continuous avapritinib. Adverse events (AE) and response by mRECIST 1.1 per central radiology were assessed. Safety from the overall population (30-600 mg doses) and efficacy in the response evaluable 4L+ and PDGFRA Exon 18 (Ex 18) populations treated at the MTD (400 mg)/RP2D (300 mg) were analyzed. Results: As of 16 Nov 2018, 237 pts [172 KIT, 62 PDGFRA Ex 18 (56 D842V, 6 non-D842V), 2 PDGFRA N659K, 1 missing] were enrolled including 111 in the 4L+ population (primarily KIT, median 4 prior TKI) and 43 in the Ex 18 population (median 1 prior TKI). The 4L+ ORR was 22% [1 CR, 23 PR (1 pending)], and 52 SD with median duration of response (mDOR) of 10.2 months (95% CI: 7.2-NE). The Ex 18 ORR was 86% [3 CR, 34 PR (1 pending)] and 5 SD; mDOR was not reached (95% CI: 11.3-NE). Most AE were grade 1-2, most commonly nausea (63%), fatigue (58%), anemia (49%), periorbital edema (42%), diarrhea (40%), vomiting (40%), decreased appetite (38%), increased lacrimation (33%), peripheral edema (33%) and memory impairment (most common cognitive AE, 29%). 10% of pts discontinued due to a related AE. Grade 3-4 related AE ≥ 2% were anemia, fatigue, hypophosphatemia, hyperbilirubinemia, neutropenia, and diarrhea. Conclusions: Avapritinib has important clinical activity in pts with advanced GIST who have no effective therapies. The ORR and DOR of avapritinib in 4L+ exceeds that of approved 2nd and 3rd line therapies and shows unprecedented activity in D842V and other Ex 18 mutant PDGFRA GIST. Results suggest avapritinib has the potential to change the treatment paradigm of pts with advanced GIST. Clinical trial information: NCT02508532.

scholarly journals Nivolumab Monotherapy for First-Line Treatment of Advanced Non–Small-Cell Lung Cancer

2016 ◽  
Vol 34 (25) ◽  
pp. 2980-2987 ◽  
Author(s):  
Scott Gettinger ◽  
Naiyer A. Rizvi ◽  
Laura Q. Chow ◽  
Hossein Borghaei ◽  
Julie Brahmer ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Advanced Nsclc ◽  
Objective Response ◽  
Primary Objective ◽  
Small Cell ◽  
Small Cell Lung ◽  
First Line ◽  
Grade 3

Purpose Nivolumab, a programmed death-1 (PD-1) immune checkpoint inhibitor antibody, has demonstrated improved survival over docetaxel in previously treated advanced non–small-cell lung cancer (NSCLC). First-line monotherapy with nivolumab for advanced NSCLC was evaluated in the phase I, multicohort, Checkmate 012 trial. Methods Fifty-two patients received nivolumab 3 mg/kg intravenously every 2 weeks until progression or unacceptable toxicity; postprogression treatment was permitted per protocol. The primary objective was to assess safety; secondary objectives included objective response rate (ORR) and 24-week progression-free survival (PFS) rate; overall survival (OS) was an exploratory end point. Results Any-grade treatment-related adverse events (AEs) occurred in 71% of patients, most commonly: fatigue (29%), rash (19%), nausea (14%), diarrhea (12%), pruritus (12%), and arthralgia (10%). Ten patients (19%) reported grade 3 to 4 treatment-related AEs; grade 3 rash was the only grade 3 to 4 event occurring in more than one patient (n = 2; 4%). Six patients (12%) discontinued because of a treatment-related AE. The confirmed ORR was 23% (12 of 52), including four ongoing complete responses. Nine of 12 responses (75%) occurred by first tumor assessment (week 11); eight (67%) were ongoing (range, 5.3+ to 25.8+ months) at the time of data lock. ORR was 28% (nine of 32) in patients with any degree of tumor PD–ligand 1 expression and 14% (two of 14) in patients with no PD–ligand 1 expression. Median PFS was 3.6 months, and the 24-week PFS rate was 41% (95% CI, 27 to 54). Median OS was 19.4 months, and the 1-year and 18-month OS rates were 73% (95% CI, 59 to 83) and 57% (95% CI, 42 to 70), respectively. Conclusion First-line nivolumab monotherapy demonstrated a tolerable safety profile and durable responses in first-line advanced NSCLC.

Gefitinib Therapy for Advanced Non–Small-Cell Lung Cancer

2003 ◽  
Vol 37 (11) ◽  
pp. 1644-1653 ◽  
Author(s):  
Chin Y Liu ◽  
Susan Seen
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Advanced Nsclc ◽  
Kinase Inhibitor ◽  
Treatment Options ◽  
Optimal Dose ◽  
Small Cell ◽  
Clinical Activity ◽  
Small Cell Lung

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, and toxicity of gefitinib in non–small-cell lung cancer (NSCLC). DATA SOURCES: Primary literature search through MEDLINE and CANCERLIT, and abstract presentations (1966–May 2003). STUDY SELECTION AND DATA EXTRACTION: All published trials and abstracts citing gefitinib were evaluated, and all information deemed relevant was included in this article. DATA SYNTHESIS: NSCLC is known to overexpress epidermal growth factor receptor (EGFR). Gefitinib is a selective EGFR tyrosine kinase inhibitor. Based on the Phase I/II trial results, the optimal dose is 250 mg/d orally. It is well tolerated, with minimal and reversible toxicity. Skin rash and diarrhea are the most common adverse effects. Recent trials have shown that gefitinib provided a 10% tumor response rate and improved disease-related symptoms in patients with refractory, advanced NSCLC. CONCLUSIONS: Gefitinib, with a unique mechanism of action and favorable toxicity profile, has demonstrated clinical activity in NSCLC patients with chemotherapy-refractory disease. It provides a valuable addition to the treatment options as monotherapy in patients with advanced NSCLC after failure of both platinum-based and docetaxel chemotherapies. Further research is required to evaluate the use of gefitinib in different clinical settings.

A phase I study of enzastaurin (Enz) combined with pemetrexed (Pem) in advanced non-small cell lung cancer (NSCLC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2572-2572
Author(s):  
T. Takahashi ◽  
N. Yamamoto ◽  
H. Murakami ◽  
Y. Ohe ◽  
H. Kunitoh ◽  
...  
Keyword(s):  
Steady State ◽  
Advanced Nsclc ◽  
Kinase Inhibitor ◽  
Total Daily Dose ◽  
Clinical Activity ◽  
Synergistic Activity ◽  
Loading Dose ◽  
Platinum Based Chemotherapy ◽  
Daily Dose ◽  
Grade 3

2572 Background: Enz is an oral serine-threonine kinase inhibitor that is designed to suppress tumor growth through PKC and PI-3 kinase/AKT. Pre-clinical data shows Enz's synergistic activity with Pem in many cancer cell lines including NSCLC. This phase 1 study is to evaluate the safety, pharmacokinetics (PK), and clinical activity of two schedules of Enz combined with Pem in patients (pts) with previously treated advanced NSCLC. Methods: An oral daily dose of 500 mg Enz was given once daily (QD) in cohort 1 or twice daily (BID) in cohort 2 in combination with 500 mg/m2 Pem on day 1 in repeated 21-day cycles. Cycle 1 started with a 7-day Enz lead-in treatment that preceded Pem administration: a loading dose of 1125 mg on day 1 followed by 500 mg total daily dose on days 2–7. Blood samples for PK evaluation were collected on day 2 of cycle 1 (following loading dose) and day 1 of cycle 2 (steady- state). Samples were analyzed for Enz, Pem, and its active metabolites. Results: 12 pts (8 males, 4 females; ECOG PS 0–1) with median age of 62 (49 - 74) were enrolled into this study and completed safety evaluation for cycle 1: 8 pts with adenocarcinoma, 3 pts with squamous cell carcinoma, and one with other. All pts had received prior platinum-based chemotherapy. Total analyte concentrations (sum of Enz and its metabolites) reached steady-state by day 8 of dosing. Total analyte mean steady-state average concentrations (%CV) following QD and BID dosing were 2850 nmol/L (53.5%) and 3420 nmol/L (39.5%), respectively. Exposures following loading dose were within the range of concentrations seen at steady-state. Enz dosing regimen (QD or BID) did not alter Pem PK. One dose-limiting toxicity (Grade 3 QTc prolongation) occurred 1 day after the Enz loading dose in cohort 1. Grade 3/4 toxicities occurring in 6 pts included leukocytopenia, neutropenia (3 pts each), increased ALT, and increased AST (2 pts each). To date, 1 pt achieved PR and 6 pts achieved SD. 5 pts received more than 10 cycles of treatment without disease progression; 4 of these pts are still on therapy. Conclusions: Both schedules of Enz in combination with Pem are well tolerated and clinically active in pts with advanced NSCLC. [Table: see text]

Phase II study of docetaxel and cisplatin in advanced non-small-cell lung cancer.

1998 ◽  
Vol 16 (5) ◽  
pp. 1948-1953 ◽  
Author(s):  
J Zalcberg ◽  
M Millward ◽  
J Bishop ◽  
M McKeage ◽  
A Zimet ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Phase Ii ◽  
Advanced Nsclc ◽  
Response Rate ◽  
Phase Ii Study ◽  
Performance Status ◽  
Objective Response ◽  
Small Cell ◽  
Small Cell Lung ◽  
Grade 3

PURPOSE Docetaxel (Taxotere, Rhone-Poulenc Rorer, Antony, France) and cisplatin are two of the most active single agents used in the treatment of non-small-cell lung cancer (NSCLC). A recently reported phase I study of the combination of docetaxel and cisplatin recommended a dose of 75 mg/m2 of both drugs every 3 weeks for subsequent phase II study. PATIENTS AND METHODS Eligible patients were aged 18 to 75 years with a World Health Organization (WHO) performance status < or = 2 and life expectancy > or = 12 weeks, with metastatic and/or locally advanced NSCLC proven histologically or cytologically. Patients were not permitted to have received prior chemotherapy, extensive radiotherapy, or any radiotherapy to the target lesion and must have had measurable disease. Concurrent treatment with colony-stimulating factors (CSFs) or prophylactic antibiotics was not permitted. Docetaxel (75 mg/m2) in 250 mL 5% dextrose was given intravenously (i.v.) over 1 hour immediately before cisplatin (75 mg/m2) in 500 mL normal saline given i.v. over 1 hour in 3-week cycles. Premedication included ondansetron, dexamethasone, promethazine, and standard hyperhydration with magnesium supplementation. RESULTS A total of 47 patients, two thirds of whom had metastatic disease, were entered onto this phase II study. The majority of patients were male (72%) and of good (WHO 0 to 1) performance status (85%). All 47 patients were assessable for toxicity and 36 were for response. Three patients were ineligible and eight (17%) discontinued treatment because of significant toxicity. In assessable patients, the overall objective response rate was 38.9% (95% confidence limits [CL], 23.1% to 56.5%), 36.1% had stable disease, and 25% progressive disease. On an intention-to-treat analysis, the objective response rate was 29.8%. Median survival was 9.6 months and estimated 1-year survival was 33%. Significant (grade 3/4) toxicities included nausea (26%), hypotension (15%), diarrhea (13%), and dyspnea mainly related to chest infection (13%). One patient experienced National Cancer Institute (NCI) grade 3 neurosensory toxicity after eight cycles. Grade 3/4 neutropenia was common and occurred in 87% of patients, but thrombocytopenia > or = grade 3 was rare (one patient). Significant (grade 3/4) abnormalities of magnesium levels were common (24%). Febrile neutropenia occurred in 13% of patients and neutropenic infection in 11%, contributing to two treatment-related deaths. No neutropenic enterocolitis or severe fluid retention was reported. CONCLUSION Compared with other active regimens used in this setting, the combination of docetaxel and cisplatin in advanced NSCLC is an active regimen with a similar toxicity profile to other combination regimens.

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