Lenvatinib combined with dacarbazine versus dacarbazine alone as first-line treatment in patients with stage IV melanoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9027-9027 ◽  
Author(s):  
Michele Maio ◽  
Jessica Cecile Hassel ◽  
Michele Del Vecchio ◽  
Alessandro Testori ◽  
Paolo Antonio Ascierto ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Single Agent ◽  
Stage Iv ◽  
Fold Increase ◽  
Circulating Tumor Dna ◽  
Therapeutic Effects ◽  
Common Grade ◽  
Grade 3 ◽  
Ecog Ps ◽  
To Receive

9027 Background: Lenvatinib (E7080; LEN) is an oral, receptor tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT and PDGFRβ . In a phase I study qd dosing of >/= 20mg LEN demonstrated PRs and prolonged SD in patients (pts) with advanced melanoma. Dacarbazine (DTIC) upregulates the proangiogenic factor VEGF and has been shown to confer resistance in melanoma cell lines (Lev, JCO 2004; 22:2092-2100). Treatment of melanoma pts with LEN + DTIC may potentiate the therapeutic effects of DTIC. Methods: This was a phase II study in pts with metastatic melanoma randomized 1:1 to receive LEN (20 mg QD) + DTIC (1000 mg/m2 Q 21 d) or DTIC (1000 mg/m2Q 21 d). Pts were stratified by LDH level and stage IV subclass. Eligible pts were ECOG PS 0/1 and had no prior systemic therapies. BRAF status was determined from circulating tumor DNA. The primary endpoint was PFS by independent assessment. Results: In a modified ITT analysis,a total of 78 of 81 pts were evaluable for efficacy; 59% were male, 59% were Stage IV M1c, 22% had elevated LDH, 29% had prior adjuvant therapy and 49% BRAF wild-type (wt). Most common AEs in the LEN + DTIC arm were hypertension (48%), nausea (38%), constipation (33%), and diarrhea (31%). Most common Grade 3/4 AEs in LEN + DTIC were hypertension (26%) and neutropenia (10%). There were no deaths due to an AE. Median PFS increased in LEN + DTIC compared to DTIC alone (see Table). An improvement in median PFS was observed in BRAFwt pts on the combination. Conclusions: A 2.7-fold increase in the median PFS was observed in pts administered LEN + DTIC compared to single agent DTIC. A 2.5 fold increase in the median PFS was observed in the combination arm in pts with BRAFwt melanoma. The AE profile observed with the LEN + DTIC was consistent with observed LEN monotherapy studies. These data suggest further evaluation of LEN + DTIC in BRAFwt melanoma is warranted. Clinical trial information: NCT01133977. [Table: see text]

Everolimus in combination with paclitaxel and carboplatin in patients with advanced melanoma: A phase II trial of the Sarah Cannon Research Institute (SCRI).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8556-8556
Author(s):  
Ralph J. Hauke ◽  
Jeffrey R. Infante ◽  
Kent C. Shih ◽  
Mark S. Rubin ◽  
Edward Arrowsmith ◽  
...  
Keyword(s):  
Single Agent ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Advanced Melanoma ◽  
Entire Group ◽  
Combination Regimen ◽  
Eligibility Criteria ◽  
Common Grade ◽  
Grade 3 ◽  
Ecog Ps

8556 Background: The PI3k/AKT pathway is activated in most metastatic melanomas; mTOR is a critical component of this pathway. Everolimus, an mTOR inhibitor, has demonstrated single-agent activity in patients with advanced melanoma. We evaluated the efficacy and toxicity of everolimus in combination with paclitaxel/carboplatin in patients with advanced melanoma. Methods: Eligible patients had stage IV or unresectable stage III melanoma, unselected for braf status, previously untreated with chemotherapy or targeted agents. Previous immunotherapy was allowed. Additional eligibility criteria: ECOG PS 0 or 1; measurable disease; no active brain metastases; adequate bone marrow, kidney, and liver function; informed consent. All patients received paclitaxel 175mg/m2, 1-3 hour IV infusion, and carboplatin AUC 6.0 IV on day 1 of each 21-day cycle. Everolimus 5mg PO was given daily. Patients were evaluated for response every 6 weeks; treatment continued until progression or undue toxicity. Median progression-free survival (PFS) for paclitaxel/carboplatin treatment is 4 months; we looked for a median PFS of 6 months with this novel combination. Results: Seventy patients were treated between 2/2010 and 2/2011; median age 63, 90% had stage IV melanoma. 91% of patients received at least 2 cycles of therapy; median cycles received: 4 (range: 1-25+). Twelve patients (17%) had partial responses; an additional 42 patients (60%) had stable disease at first reevaluation. After a median 13 months of followup, the median PFS for the entire group was 4 months (95% CI: 2.8 – 5.0 months); 96% had progressed during the first 12 months. Median survival was 10 months (95% CI: 7.3 – 10.9 months). Toxicity was as previously described with these agents; neutropenia was the most common grade 3/4 toxicity (27%). Only 3 patients stopped treatment due to toxicity. Conclusions: The addition of everolimus to paclitaxel/carboplatin was feasible and well-tolerated; however, efficacy results were similar to those reported with paclitaxel/carboplatin alone. Further development of this combination regimen for treatment of metastatic melanoma is not recommended.

Phase I/II study of ABI-007 as first line chemotherapy in advanced non-small cell lung cancer (NSCLC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7105-7105 ◽  
Author(s):  
N. A. Rizvi ◽  
C. Azzoli ◽  
V. Miller ◽  
K. Ng ◽  
J. Fiore ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Dose Level ◽  
Response Rate ◽  
Single Agent ◽  
Stage Iv ◽  
Sensory Neuropathy ◽  
Phase 2 ◽  
Grade 3 ◽  
Ecog Ps

7105 Background: ABI-007 is a 130-nm albumin-bound form of paclitaxel. This study was designed to determine (1) the MTD and DLTs of ABI-007 in patients with stage IV chemotherapy-naive NSCLC and (2) the efficacy and safety of ABI-007 at the MTD. Methods: Eligibility requirement included ECOG PS 0–1, adequate organ function and sensory neuropathy ≤ grade 1. No prior chemotherapy for metastatic disease was allowed. Prior EGFR TKI therapy was allowed. ABI-007 was administered on days 1, 8, and 15 every 28 days (IV over 30 min. without premedication). In the phase I portion, 3 dose levels were studied (100, 125 and 150 mg/m2) and in the phase 2 portion, 40 patients were treated at the MTD. Results: 50 patients received ABI-007; the median age was 70 yo and 76% of patients were ≥ 65 yo. No DLTs were observed at the 100 and 125 mg/m2 dose level. However at the 150 mg/m2 dose level 2/6 patients had a DLT (febrile neutropenia and sensory neuropathy, respectively) during cycle 1 such that the MTD was exceeded. The 125 mg/m2 dose level was identified as the MTD and expanded to 40 patients in the phase 2 portion of this study. Toxicity and efficacy data is presented for the phase 2 portion. Ten patients (25%) had received prior neoadjuvant or adjuvant chemotherapy and 5 (13%) had received prior gefitinib or erlotinib. Sensory neuropathy was the most frequent toxicity with grade 2 and 3 toxicity occurring in 8% and 15% of patients. Grade 2 and 3 fatigue was observed in 8% and 13% of patients. Grade 3 and 4 neutropenia occurred in 10% and 3% of patients with no febrile neutropenia observed. Response was assessed by RECIST. One CR and 14 PRs were observed for an overall response rate of 15/40 (38%). The median survival was 10.3 months. Conclusions: The MTD for ABI-007 administered over 30 min. on days 1, 8, and 15 every 28 days was 125 mg/m2. No hypersensitivity reactions were observed and no premedication was given. In the phase 2 portion, a 38% response rate and 10.3 month survival was observed. Non-hematologic toxicities were primarily sensory neuropathy and fatigue. Myelosuppression was minimal and no febrile neutropenia was observed. Further development of ABI-007 in NSCLC is warranted based on the encouraging single agent activity observed in this study. [Table: see text]

A phase II trial of thalidomide (T), irinotecan (I) and gemcitabine (G) in chemonaive patients with advanced non-small cell lung cancer (NSCLC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17068-17068
Author(s):  
A. R. Jazieh ◽  
R. Komrokji ◽  
S. Patil ◽  
D. Flora ◽  
M. Knapp ◽  
...  
Keyword(s):  
Phase Ii ◽  
Advanced Nsclc ◽  
Survival Rates ◽  
Stage Iv ◽  
Thromboembolic Events ◽  
Early Withdrawal ◽  
Common Grade ◽  
Grade 3 ◽  
Ecog Ps ◽  
Lost To Follow Up

17068 Background: Chemotherapy with platinum based doublets provides only a modest benefit in advanced NSCLC with a median overall survival (OS) of 8 months and 1-year survival rate of 33% (Schiller JH et al, N Engl J Med 2002). We performed a phase II study to determine the efficacy of thalidomide, an immunomodulatory agent with antiangiogenic activity, in combination with chemotherapy in patients with advanced NSCLC. Methods: Chemonaive patients with stage IIIB/IV NSCLC with ECOG PS≤ 2 and adequate organ function were treated with G (1000 mg/m2) and I (100 mg/m2) IV on days 1 and 8 of a 21 day cycle. Patients also received T (200 mg orally with escalation as tolerated to a maximum of 400 mg daily). Therapeutic anticoagulation with coumadin was given to the last 11 patients. Results: Twenty four patients were enrolled: median age 57 years (41–76); M:F=17:7; ECOG PS 0/1/2=13/7/3; stage IV: IIIB= 21:3 and CNS involvement: 6. Two pts died before treatment, 1 was ineligible and 1 was lost to follow up. The remaining 20 pts received a median of 4 treatment cycles (range 1–6). The regimen was generally well tolerated and the most common grade 3–4 toxicities encountered were: diarrhea (4); pneumonia (3) and thromboembolic events (3). There were no thromboembolic events after anticoagulation was initiated. Two patients (10%) experienced partial response, 14 (70%) experienced stable disease, 1 had progressive disease. Three patients (15%) were not evaluable for response due to early withdrawal. The median OS was 10.8 months (range 0.6–37+) and 1-year and 2-year survival rates were 37% and 16%, respectively. The median time to progression was 3.6 months (range 0.2–11+). Conclusions: The combination of thalidomide and chemotherapy is reasonably well tolerated and active in advanced NSCLC as evidenced by good OS and 1- and 2-year survival rates. The addition of thalidomide to a non-platinum based regimen appears to compare favorably to the results of the traditional platinum based doublets. [Table: see text]

Single-agent pemetrexed in patients with advanced and metastatic hepatoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14064-14064
Author(s):  
A. Cohn ◽  
J. W. Myers ◽  
S. Mamus ◽  
C. Deur ◽  
S. Nicol ◽  
...  
Keyword(s):  
Liver Failure ◽  
Histological Grade ◽  
Hepatoma Cell ◽  
Single Agent ◽  
Stage Iv ◽  
The United States ◽  
Toxicity Profile ◽  
Hepatoma Cell Lines ◽  
Grade 3 ◽  
Ecog Ps

14064 Background: The incidence of hepatoma is rising in the United States, primarily due to the increase in the prevalence of hepatitis C. Surgical treatments are rarely an option for patients with advanced hepatoma, and while chemotherapy, particularly with doxorubicin-based regimens, has marginally prolonged survival, response rates have been poor with the burden of high toxicity. Pemetrexed, a folate antimetabolite, has demonstrated activity in hepatoma cell lines with a manageable toxicity profile, making it a potentially useful agent in hepatocellular carcinoma. Methods: A multicenter, Phase II study was conducted to assess the response rate and evaluate the toxicity profile of single-agent pemetrexed (ALIMTA) in first-line patients with advanced or metastatic hepatoma. Pemetrexed 600 mg/m2 IV was administered on Day 1 of each 21-day cycle until disease progression (PD). Patients were premedicated with dexamethasone 4 mg PO BID and received daily folic acid 350–1000 μg PO and Vitamin B12 1000 μg IM every 9 weeks. Results: This nonrandomized study employed Simon’s 2-stage design. There were 21 eligible patients enrolled in the first stage, and all 21 patients were enrolled within 4 months of trial opening. Median age was 72 years (range, 44–88), and most patients were white (62%) and male (81%). Ten percent (10%) had an ECOG PS of 2, 48% Stage IV disease, 52% prior surgery, and 33% tumors of unknown histological grade. The plan was to stop accrual if ≤2 responders were observed among the 21 patients. Of the 21 patients, 3 had SD, 2 had early toxicities (renal/liver failure, sepsis), 15 progressed, and 1 was noncompliant. The trial was closed due to lack of response. The most common Grade 3 hematological toxicities were neutropenia 6/21 (28.6%) and thrombocytopenia 3/21 (14.3%). One patient experienced both Grade 3 nausea and vomiting. There were no Grade 4 toxicities. There were 10 on-study deaths: 9 PD and 1 liver failure. None of the deaths were drug-related. The median actual survival was 2.5 months (range, <1–8). Conclusions: While pemetrexed was well tolerated in this patient population, it was not active. Most adverse events were related to disease state, not study treatment. Supported by Eli Lilly and Company, Indianapolis, IN [Table: see text]

A pharmacodynamic study of JI-101, an orally active inhibitor of VEGF-2, PDGF-β, and EphB4 receptors, in patients with refractory/recurrent ovarian cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13548-e13548
Author(s):  
Theresa Louise Werner ◽  
Aaron Lynn Luebke ◽  
Mark Wade ◽  
Nuggehally R Srinivas ◽  
Dhiraj J. Abhyankar ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Mechanism Of Action ◽  
Stable Disease ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Single Agent ◽  
Recurrent Ovarian Cancer ◽  
Active Inhibitor ◽  
Common Grade ◽  
Grade 3

e13548 Background: JI-101 is an oral multi-kinase inhibitor, which targets VEGFR-2, PDGF-β, and EphB4. By targeting multiple angiogenesis signaling pathways, JI-101 has the potential advantage of inhibiting all vital stages of tumor angiogenesis, reducing tumor resistance, and enhancing anti-tumor efficacy. None of the currently approved angiogenesis inhibitors have any appreciable inhibition of EphB4, and therefore, this represents a novel mechanism of action. JI-101 has preclinical activity in various tumor models and has been well tolerated in phase 1 trials. Methods: Eleven women with refractory/recurrent ovarian cancer were enrolled with a median age of 54 yrs (range 52-76). All patients had adequate organ function and ECOG performance status ≤ 2. Each patient received single agent JI-101 at 200mg BID for 28 day treatment cycles. Toxicity and response were evaluated at two month intervals. Results: Eight of 11 patients were evaluable for response (3 were unevaluable due to inability to complete two cycles). A median of 3 cycles (range 2-6) was given. No grade 4 adverse events (AEs) were seen. The most common grade 2/3 hematological AEs were grade 2 anemia (1) and lymphopenia (1). The most common grade 2/3 non-hematological AEs were grade 3 hypertension (7), grade 3 bowel obstruction (2), grade 3 transaminitis (2), and abdominal pain (2). Six patients had stable disease (SD) at two months and two had progressive disease. Best response was SD at four months. Two-month progression free survival was 71% (90% CI 52-99%). Conclusions: JI-101 is well tolerated in refractory/recurrent ovarian cancer patients with the majority of patients with stable disease at two months. The most common toxicity was hypertension, which was easily controlled with anti-hypertensives. The novel mechanism of action of JI-101 is promising in ovarian cancer treatment and further prospective studies of this agent could be pursued in a less refractory patient population.

scholarly journals The BCL2 Targeted Deoxyribonucleic Acid Inhibitor (DNAi) PNT2258 Is Active in Patients with Relapsed or Refractory Non-Hodgkin’s Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1716-1716 ◽  
Author(s):  
Wael A. Harb ◽  
Nehal Lakhani ◽  
Ana Logsdon ◽  
Mary Steigelman ◽  
Heidi Smith-Green ◽  
...  
Keyword(s):  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
Low Grade ◽  
Acid Inhibitor ◽  
Medical Issues ◽  
Best Response ◽  
Common Grade ◽  
Grade 3 ◽  
Ecog Ps ◽  
Richter’S Syndrome

Abstract Background: PNT2258 is a 24-base, single-stranded liposome-encapsulated DNA oligonucleotide that hybridizes to regions of the BCL2 gene, modulating its function. As previously reported, PNT2258 demonstrates antitumor activity in patients with advanced-stage NHL. The updated clinical data that are provided in this abstract (as of 07/25/14) now include anti-tumor activity in patients with DLBCL and Richter’s syndrome. Methods: All patients had CT-measureable, FDG-PET positive disease with progression prior to study entry, and had previously received rituximab and combination cytotoxic chemotherapy. Refractory tumor status or concomitant medical issues precluded the use of additional cytotoxic therapy in all patients included in the study. PNT2258 induction cycles were administered as a 3-hour IV infusion at 120 mg/m2 days 1-5 of each 21-day cycle for up to 8 cycles. Response evaluation occurred at the end of cycles 2, 6 and 8. Following induction, patients could receive maintenance dosing at 100 mg/m2days 1-2 of each 28-day cycle until PD. Results: Thirteen patients (median age 65; 8 males, 5 females; ECOG PS 0/1/2: 3/9/1) received all scheduled doses of PNT2258. Regardless of attribution, there were no cycle 1, grade 3/4 AEs. The most common grade 1/2 AEs in cycle 1 included chills, low-grade fever, transient nausea, and tumor or back pain (n=5 for each). There was no evidence of tumor lysis syndrome, febrile neutropenia or significant GI toxicity. Of 4 patients with DLBCL, including 1 with Richter’s syndrome and 1 with Burkitt-like histology, PFS was 9.2 months, range 5.5-12.3 months as of 7/25/14. Best response data (CR/PR/SD/PD) for the DLBCL group was 2/1/1/0. Additionally, in 5 FL patients, best response was 1/1/3/0. Five patients, including 3 DLBCL and 2 FL remain on study as of 7/25/14 receiving maintenance treatment with PNT2258. Conclusions: PNT2258 is well tolerated and can be administered over prolonged periods of time. Durable single agent activity was previously reported in patients with FL, and has now been observed in patients with aggressive DLBCL. Studies in DLBCL and Richter’s syndrome are being implemented and updated information will be provided at the time of the meeting. Clinical trial information: NCT01733238. Disclosures Gaylor: ProNAi Therapeutics: Employment. Rodrigueza:ProNAi Therapeutics: Employment. Woolliscroft:ProNAi Therapeutics: Employment. Sooch:ProNAi Therapeutics: Employment. Messmann:ProNAi Therapeutics: Employment.

Single agent, canfosfamide (C, TLK286) vs pegylated liposomal doxorubicin (D) or topotecan (T) in 3rd-line treatment of platinum (P) refractory or resistant ovarian cancer (OC): Phase 3 study results

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. LBA5528-LBA5528 ◽  
Author(s):  
I. Vergote ◽  
N. Finkler ◽  
J. del Campo ◽  
A. Lohr ◽  
J. Hunter ◽  
...  
Keyword(s):  
Single Agent ◽  
Pegylated Liposomal Doxorubicin ◽  
Progression Free Survival ◽  
Glutathione S Transferase ◽  
Bulky Disease ◽  
Risk Of Death ◽  
Study Results ◽  
Common Grade ◽  
Grade 3 ◽  
Ecog Ps

LBA5528 Background: Canfosfamide (C) is a novel glutathione analog prodrug activated by glutathione S-transferase P1–1. P resistant OC has a poor prognosis and non-P agents are used for palliation. C reported objective responses in multicenter Phase 2 OC trials. Methods: Pts with P resistant OC who progressed after D or T, measurable disease (RECIST), adequate liver/renal/bone marrow function were eligible. Randomization was stratified by prior D or T treatment, ECOG PS (0 or 1 vs 2) and presence or absence of bulky disease (= 5cm). Patients received C at 1000 mg/m2 IV q3wks, or to D at 50 mg/m2 IV q4wks or T at 1.5 mg/m2 IV daily × 5 q3wks until progression. The trial had a 90% power to detect a 29% reduction in the relative risk of death. Results: 461 pts (C=232 and D or T=229) received 1052 cycles [median 3; range (r) 1–33], 699 (median 4; r 1–32), and 469 (median 5; r 1–21) for C, D and T respectively. Most common Grade 3–4 AEs for C were: nausea (31.6%), vomiting (8.7%), fatigue (6.1%), and anemia (5.6%), for D/T were: nausea (55.3%), anemia (15.2%), fatigue (6.9%), neutropenia (23.5%), thrombocytopenia (12.4%), febrile neutropenia (6%), stomatitis (6%), and PPE syndrome (6%). ORR for C was 4.3% including a CR, vs 10.9% ORR for D/T. Median survival (MS) was 8.5 mos for C, 13.6 mos for D/T (p=0.0001). Median progression-free survival was 2.3 mos for C and 4.4 mos for D/T, (p=0.0001). D/T MS was 14.2/10.8 mos, respectively. Conclusions: Canfosfamide did not meet the primary endpoint. C demonstrated single agent activity in P refractory or resistant OC and was well tolerated. C in combination with standard agents in less heavily treated OC trials are in progress. No significant financial relationships to disclose.

Capecitabine and cisplatyl as neoadjuvant treatment of locally advanced nasopharyngeal carcinoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e17036-e17036
Author(s):  
E. Kerboua
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Single Agent ◽  
Locally Advanced ◽  
Neoadjuvant Treatment ◽  
Stage Iv ◽  
Complete Response ◽  
Tolerability Profile ◽  
Common Grade ◽  
Hand Foot Syndrome ◽  
Grade 3

e17036 Background: The main objective of this study is to evaluate the activity and safety of capecitabine (X) and cisplatyl (C) in patients (pts) with locally advanced nasopharyngeal carcinoma(NPC). Capecitabine was reported to have single-agent activity in advanced/metastatic NPC. Combination of X and C should provide a convenient and active regimen. Methods: Pts with undifferentiated NPC type were enrolled from July 2007 to September 2008. They received X 1,000 mg/m2orally bid on days 1–14 + C 75/m2 IV day 1 q 3W, Three cycles were administered in a neoadjuvant setting before radiotherapy. The primary endpoint was overall response rate (ORR). Results: Forty-one (41) pts have been enrolled 28 male/13 female with locally advanced NPC: 15 pts (36,6% ) were stage III (UICC 1997) 26 pts (63,3%) stage IV (n = 6 IVA and n = 20 IVB). All pts were evaluated for safety and 36 pts for response. ORR was 86% with 63,8% (n = 23) complete response (CR), 22,2% (n = 8) partial response (PR), 2 progression disease (PD) and 2 stable disease (SD). The most common grade 3/4 adverse events were diarrhea 4,8% (n = 2), neutropenia 7,3% (n = 3), thrombocytopenia 7,3% (n = 3), vomiting 9,7% (n = 4) . Two pts died from sepsis that was probably treatment-related. A hand-foot syndrome was observed in 25% of pts (grade 1/2). Conclusions: Preliminary results show that X plus C provide an active regimen with an acceptable tolerability profile as neoadjuvant chemotherapy for locally advanced NPC. This regimen requires a shorter hospital stay and is more convenient for pts compared with the gold standard 5-FU plus cisplatyl. No significant financial relationships to disclose.

Nivolumab (nivo) + nab-paclitaxel (nab-P) + carboplatin (C) in patients (pts) with non-small cell lung cancer (NSCLC): Interim results from a multicenter phase I study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9095-9095 ◽  
Author(s):  
David Michael Waterhouse ◽  
Jonathan Wade Goldman ◽  
Ben George ◽  
Peter J. O'Dwyer ◽  
Moncy Ye ◽  
...  
Keyword(s):  
Phase I ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Metastatic Breast ◽  
Primary Endpoints ◽  
Common Grade ◽  
Secondary Endpoints ◽  
Grade 3 ◽  
Ecog Ps ◽  
Clinical Trial Information

9095 Background: Despite success of single-agent immune checkpoint inhibitors, an unmet therapeutic need remains in pts with NSCLC. Chemotherapy and immunotherapy may have synergistic antitumor activity, but safety and efficacy need to be established. Here, we present interim results for pts with NSCLC (Arm C) from the phase I safety trial of nivo + nab-P in pancreatic cancer (± gemcitabine), NSCLC (+ C), and metastatic breast cancer. Methods: Part 1 evaluated potential dose-limiting toxicities (DLTs) before Part 2 expansion. Chemotherapy-naive pts with histologically/cytologically confirmed stage IIIB/IV NSCLC received 4 cycles of nab-P 100 mg/m2d 1, 8, 15 + C AUC 6 d 1 + nivo 5 mg/kg d 15 of each 21-d cycle; in cycles 5+, nivo was continued as maintenance monotherapy. Primary endpoints: number of pts with DLTs (Part 1) and percentage of pts with grade 3/4 treatment-emergent adverse events (TEAEs) or treatment discontinuation due to TEAEs (Parts 1 and 2). DLT-evaluable pts included those who received ≥ 2 complete nivo cycles and remained on study for 14 d after the last nivo dose in cycle 2, received ≥ 1 nivo dose and discontinued due to DLT before completing 2 nivo cycles, or experienced equivocal DLT after ≥ 1 nivo dose. Secondary endpoints included safety, PFS, OS, DCR, ORR, and DOR. Results: All pts (n = 22) received nab-P/C; results for nivo-treated pts (n = 20) are presented. Of the nivo-treated pts, the median age was 66 y (55% ≥ 65 y), 75% were female, 80% were white, and 70% had ECOG PS 1. More pts had adenocarcinoma (50%) than squamous cell carcinoma (35%; 10% other, 5% data pending). No DLTs reported (5 DLT-evaluable pts). Most common grade 3/4 TEAEs were neutropenia (45%) and anemia (35%). No grade 3/4 immune-related colitis or pneumonitis reported. Best ORR (RECIST v1.1) was 50% (1 CR [unconfirmed, 5%] and 9 PRs [45%]; 6 pts had SD [30%]; 4 pts had PD [20%]). Best ORR by histology: squamous, 71%; nonsquamous, 54%. Median PFS was 10.5 months (squamous, 10.5 months; nonsquamous, not evaluable). Conclusions: Results demonstrated safety of the nivo + nab-P/C combination in NSCLC with no unexpected safety signals. Preliminary efficacy results are promising. (NCT02309177) Clinical trial information: NCT02309177.

scholarly journals Long-term safety of single-agent ibrutinib in patients with chronic lymphocytic leukemia in 3 pivotal studies

2019 ◽  
Vol 3 (12) ◽  
pp. 1799-1807 ◽  
Author(s):  
Steven E. Coutre ◽  
John C. Byrd ◽  
Peter Hillmen ◽  
Jacqueline C. Barrientos ◽  
Paul M. Barr ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Integrated Analysis ◽  
Common Grade ◽  
Long Term Follow Up ◽  
Grade 3 ◽  
Dose Modifications

Abstract Ibrutinib, a first-in-class once-daily oral Bruton tyrosine kinase inhibitor indicated for chronic lymphocytic leukemia (CLL), is continued until progressive disease or unacceptable toxicity. We conducted an integrated safety analysis of single-agent ibrutinib from randomized phase 3 studies PCYC-1112 (RESONATE, n = 195) and PCYC-1115/1116 (RESONATE-2, n = 135), and examined longer-term safety separately in the phase 1b/2 PCYC-1102/1103 study (n = 94, 420 mg/d). In the integrated analysis (ibrutinib treatment up to 43 months), the most common adverse events (AEs) were primarily grade 1/2; diarrhea (n = 173, 52% any-grade; n = 15, 5% grade 3) and fatigue (n = 119, 36% any-grade; n = 10, 3% grade 3). The most common grade 3/4 AEs were neutropenia (n = 60, 18%) and pneumonia (n = 38, 12%). Over time, prevalence of AEs of interest (diarrhea, fatigue, grade ≥3 infection, bleeding, and neutropenia) trended down; prevalence of hypertension increased, but incidence decreased after year 1. AEs led to dose reductions in 42 (13%) patients and permanent discontinuations in 37 (11%); dose modifications due to AEs were most common during year 1 and decreased in frequency thereafter. The most common AEs (preferred term) contributing to discontinuation included pneumonia (n = 4), anemia (n = 3), and atrial fibrillation (n = 3). With long-term follow-up on PCYC-1102/1103 (ibrutinib treatment up to 67 months), grade 3/4 AEs were generally similar to those in the integrated analysis. Overall, AEs were primarily grade 1/2 and manageable during prolonged ibrutinib treatment in patients with CLL. These trials were registered at www.clinicaltrials.gov as #NCT01578707, #NCT01722487, #NCT01724346, #NCT01105247, and #NCT01109069.

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