Phase II Study of Dasatinib In Patients with Relapsed Chronic Lymphocytic Leukemia.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4488-4488 ◽  
Author(s):  
Ali M Al-Ameri ◽  
Xavier Badoux ◽  
Alessandra Ferrajoli ◽  
William G. Wierda ◽  
Luis Fayad ◽  
...  
Keyword(s):  
Phase Ii ◽  
Kinase Inhibitor ◽  
Phase Ii Study ◽  
Performance Status ◽  
Objective Response ◽  
Lymphocytic Leukemia ◽  
Hematological Toxicity ◽  
Abl Kinase ◽  
Grade 3

Abstract Abstract 4488 Src-family kinases (SFK) are described to be over expressed in CLL resulting in increased BCR signaling. Aberrant activation of the SFK, Lyn, leads to defective apoptosis of CLL cells in-vitro. C-Abl kinase is also overexpressed in CLL cells compared to normal B-lymphocytes. Since dasatinib is a dual Src and c-abl kinase inhibitor with in-vitro pro-apoptotic properties in CLL cells, we investigated the activity of dasatinib in patients (pts) with CLL. We designed a phase II study of dasatinib in pts with relapsed CLL/SLL and T-PLL. Pts were eligible if they were previously treated and had indication for therapy according to NCI-working group criteria. All pts had adequate performance status, renal and liver function prior to therapy. Treatment consisted of dasatinib 50mg given orally twice daily. In case of suboptimal response the dose of dasatinib could be increased up to a maximum dose of 70mg twice daily. Dose reductions to 20mg twice daily were permitted for toxicity. Pts were assessed for treatment response according to 1996 NCI-WG criteria. Seventeen pts have been enrolled in this study. The median age was 67 years (42-83 years), 9 (52%) had Rai stage III-IV, median beta-2 microglobulin levels was 5.9 (3.0 – 11.8) mg/L. The median number of prior treatments was 4 (1 – 8). An objective response (PR) was observed in 1 patient, 13 pts had no objective response and 3 pts were not evaluable for response due to early discontinuation of therapy (0-3 days). Fourteen pts remained on therapy for a median of 2 (0-19) months with 4 pts discontinuing due to disease progression and 9 pts discontinuing due to adverse events and lack of response. Hematological toxicities consisted of grade 3–4 neutropenia in 76% of the pts, grade 3–4 thrombocytopenia in 44% of pts and grade 1–2 anemia in 80%. Non-hematological toxicity consisted of grade 3–4 fatigue in 1 patient and grade 3 pleural effusions in another patient. Grade 1 and 2, toxicities included flushing 38%, headache 38%, fatigue 46% anorexia and nausea 46%, and diarrhea 23%. Several pts showed evidence of biological activity. Treatment with dasatinib lacks efficacy in pts with heavily pretreated CLL. Responses occurred in only 6% of pts and dasatinib administration was associated with a high incidence of neutropenia. Disclosures: O'Brien: Bristol-Myers Squibb: Research Funding.

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.

A phase II study of sunitinib in recurrent or metastatic endometrial carcinoma: A trial of the PMH Phase II Consortium

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5576-5576
Author(s):  
S. Welch ◽  
H. J. Mackay ◽  
H. Hirte ◽  
G. F. Fleming ◽  
R. Morgan ◽  
...  
Keyword(s):  
Phase Ii ◽  
Kinase Inhibitor ◽  
Phase Ii Study ◽  
Objective Response ◽  
Progression Free Survival ◽  
Open Label ◽  
Second Stage ◽  
Best Response ◽  
Grade 3 ◽  
Ecog Ps

5576 Background: Endometrial cancer (EC) is the most common gynecologic malignancy. Vascular endothelial growth factor (VEGF) overexpression in EC correlates with poor outcome, thus targeting VEGF is a rational therapeutic approach. We have conducted a two-stage open-label phase II study in advanced EC with sunitinib, an oral tyrosine kinase inhibitor of multiple VEGF receptors. Methods: Eligible pts have recurrent or metastatic EC and have received up to 1 prior chemotherapy (CT) regimen for metastatic disease. Sunitinib is given at 50 mg daily (OD) for 4 consecutive weeks (wks) followed by 2 wks off. Dose could be reduced to 37.5 mg OD and then 25 mg OD in the setting of toxicity. Imaging is repeated every 12 wks. Primary objectives are objective response rate (ORR by RECIST) and rate of 6-month progression-free survival (PFS). If 1 or more responses occur in the first 15 evaluable pts, the study would continue to a second stage (total = 30 pts). Secondary objectives are time to progression (TTP), overall survival (OS), and safety. Results: We report the results of the first stage of this study. Sixteen pts have been treated (median age: 63; range 41–74) with 37 cycles of sunitinib (median 2; range: 1–7). Baseline ECOG PS was 0 (7 pts), 1 (8 pts), or 2 (1 pt). Histology was endometrioid (7 pts), serous (5 pts), clear cell (1 pt), or mixed/other (3 pts). Most pts had high-grade histology (G3: 8; G2: 4; G1: 2; GX: 2). Nine pts had prior adjuvant CT, 8 pts had 1 prior CT for advanced EC, 4 pts had prior hormones and 7 pts had prior radiotherapy. Partial response was achieved by 2 pts (ORR = 12.5%), and 2 other pts had a best response of stable disease; 3 of these pts remained progression-free > 6 months. Median TTP = 2.5 months (95% CI: 2.47-NR), and median OS = 6.2 months (95% CI: 5.1-NR). Grade 3/4 adverse events (AE) in >10% of pts were fatigue (7 pts, 44%) and hypertension (5 pts, 31%). Dose reduction was required for 11 of 16 pts (69%). Two pts were inevaluable after receiving <2 cycles due to AE (grade 4 hyponatremia; grade 3 fatigue) and 1 other pt has yet to complete 2 cycles. Conclusions: Sunitinib shows preliminary activity in EC. This trial will proceed to a second stage of accrual to further explore the efficacy and safety of sunitinib in advanced EC. [Table: see text]

Phase II Study of Capecitabine and Oxaliplatin in First- and Second-Line Treatment of Advanced or Metastatic Colorectal Cancer

2002 ◽  
Vol 20 (7) ◽  
pp. 1759-1766 ◽  
Author(s):  
Markus M. Borner ◽  
Daniel Dietrich ◽  
Roger Stupp ◽  
Rudolf Morant ◽  
Hanspeter Honegger ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Phase Ii ◽  
Advanced Colorectal Cancer ◽  
Phase Ii Study ◽  
Performance Status ◽  
Objective Response ◽  
World Health ◽  
Pretreated Patients ◽  
Grade 3 ◽  
Dose Reductions

PURPOSE: To determine the efficacy and tolerability of combining oxaliplatin with capecitabine in the treatment of advanced nonpretreated and pretreated colorectal cancer. PATIENTS AND METHODS: Forty-three nonpretreated patients and 26 patients who had experienced one fluoropyrimidine-containing regimen for advanced colorectal cancer were treated with oxaliplatin 130 mg/m2 on day 1 and capecitabine 1,250 mg/m2 bid on days 1 to 14 every 3 weeks. Patients with good performance status (World Health Organization grade 0 to 1) were accrued onto two nonrandomized parallel arms of a phase II study. RESULTS: The objective response rate was 49% (95% confidence interval [CI], 33% to 65%) for nonpretreated and 15% (95% CI, 4% to 35%) for pretreated patients. The main toxicity of this combination was diarrhea, which occurred at grade 3 or 4 in 35% of the nonpretreated and 50% of the pretreated patients. Grade 3 or 4 sensory neuropathy, including laryngopharyngeal dysesthesia, occurred in 16% of patients on both cohorts. Capecitabine dose reductions were necessary in 26% of the nonpretreated and 45% of the pretreated patients in the second treatment cycle. The median overall survival was 17.1 months and 11.5 months, respectively. CONCLUSION: Combining capecitabine and oxaliplatin yields promising activity in advanced colorectal cancer. The main toxicity is diarrhea, which is manageable with appropriate dose reductions. On the basis of our toxicity experience, we recommend use of capecitabine in combination with oxaliplatin 130 mg/m2 at an initial dose of 1,250 mg/m2 bid in nonpretreated patients and at a dose of 1,000 mg/m2 bid in pretreated patients.

A Phase II Study of Dasatinib in Relapsed and Refractory Chronic Lymphocytic Leukemia (CLL/SLL).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3126-3126 ◽  
Author(s):  
Philip C. Amrein ◽  
Eyal C. Attar ◽  
Tak Takvorian ◽  
Ephraim P. Hochberg ◽  
Karen Ballen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Performance Status ◽  
Lymphocytic Leukemia ◽  
Electrolyte Imbalance ◽  
Fish Analysis ◽  
Bone Marrow Biopsies ◽  
Lyn Kinase ◽  
Grade 3

Preclinical studies have shown that proliferation and survival of CLL cells are associated with overexpression of the Lyn kinase protein, and in vitro inhibition of Lyn kinase leads to apoptosis of the CLL cells (Contri, J Clin Invest 2005). Because dasatinib inhibits Lyn kinase in CML cells at doses easily achievable in patients, we undertook this phase II study of dasatinib in patients with previously treated CLL/SLL. Patients were required to be over 18 years of age, have a diagnosis of CLL/SLL by flow cytometry/immunostains, and have failed at least 1 course of treatment with a fludarabine-containing regimen or at least 2 courses of non-fludarabine containing regimens. The starting dose of dasatinib was 140 mg daily by mouth. This dose could be reduced to 100 mg or 80 mg daily for toxicity. At baseline all patients had bone marrow biopsies and CT scans, and these were repeated at 2 months. Sequential blood and bone marrow samples were tested for Lyn kinase activity. The design of the study provided for 2 phases such that if 3 responses were seen among the first 15 patients, the trial would expand to enroll another 20 patients. Among the first 9 patients enrolled there were 4 male and 5 female subjects with a median age of 59 years (40–78 years). ECOG performance status was 0 in 4 subjects, 1 in 3, and 2 in 2 subjects. All patients had previously received fludarabine: 1 subject had 1 prior treatment, 3 had 2 prior treatments, 3 had 3 prior treatments, and 2 had 4 prior treatments. By cytogenetic/FISH analysis there were 2 patients with del(17p) and another 4 patients with del(11q). All patients required treatment by NCI Working Group criteria. The major toxicity encountered was myelosuppression: grade 3 + 4 neutropenia in 7 subjects, grade 3 + 4 thrombocytopenia in 5 subjects. Gastrointestinal toxicity was minor with only 1 subject experiencing grade 3 diarrhea. One subject developed a grade 2 pleural effusion. There was 1 patient with an electrolyte imbalance consisting of a transient serum K=6.8, and in 1 patient there was a transiently prolonged QTc of 516 ms. There were no fatal events, and all toxicities were reversible. The median duration of treatment on study was 9 weeks with a range of 4 to 23 weeks. The clinical response data of the first 15 patients will be presented along with the correlative studies of Lyn kinase inhibition by dasatinib.

A phase II multicenter trial of the multitargeted kinase inhibitor sulfatinib in advanced medullary thyroid cancer (MTC) and radioiodine (RAI)-refractory differentiated thyroid cancer (DTC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 6037-6037 ◽  
Author(s):  
Jiaying Chen ◽  
Qinghai Ji ◽  
Junning Cao ◽  
Dongmei Ji ◽  
Chunmei Bai ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Growth Factor ◽  
Disease Progression ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Phase Ii Study ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Stage I ◽  
Grade 3

6037 Background: Sulfatinib is an oral tyrosine kinase inhibitor targeting Vascular Endothelial Growth Factor Receptor (VEGFR), Fibroblast Growth Factor Receptor 1 (FGFR 1), and Colony Stimulating Factor 1 Receptor (CSF1R). In a proof of concept (PoC) phase II study, sulfatinib showed promising efficacy in patients (pts) with neuroendocrine tumors (NETs). Methods: This is an open label, two cohorts phase II study using Simon's two-stage design. In stage I, 15 pts will be enrolled in each cohort (advanced MTC or iodine-refractory DTC), and 10 more pts will be enrolled in a cohort in stage II if at least 2 PR observed in that cohort in stage I. Pts are required to have progressive disease in the past 12 months, but could not have received > 1 prior anti-angiogenesis therapy. Pts are treated with oral sulfatinib 300 mg once daily until disease progression, death, or intolerable toxicity. Primary endpoint is Objective Response Rate (ORR) by investigator per RECIST 1.1. Results: As of Dec 31 2016,the studyenrolled 18 pts (MTC: 6, DTC: 12), amongst whom 17 pts were efficacy evaluable. There were a total of 4 confirmed PRs, 1 in the MTC cohort and 3 in the DTC cohort, respectively. The others best response was stable disease (SD). 11 pts (61.1%) had dose interruption due to adverse events (AEs) and 5 pts (27.8%) had dose reduction. Two pts discontinued therapy (1 patient due to disease progression, another due to subject's decision). The most commonly reported AEs were proteinuria 72.2% (Grade 3-4: 22.2%), hypertriglyceridemia 50.0% (Grade 3-4: 0%), hypertension 44.4% (Grade 3-4: 16.7%), blood bilirubin increased 44.4% (Grade 3-4: 5.6%), and diarrhea 33.3% (Grade 3-4: 0%). No Grade 5 AE was reported by the time of data cut-off. Conclusions: Sulfatinib appears to be well tolerated in the pts with advanced MTC and RAI refractory DTC. Safety profile seems to be consistent to previous report, with mostly manageable AEs. Efficacy is encouraging in both indications. Further investigation is warranted. Clinical trial information: NCT02614495.

COSMOS: MOR208 plus idelalisib or venetoclax in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) previously treated with a Bruton's tyrosine kinase inhibitor (BTKi)—A two-cohort phase II study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS7567-TPS7567
Author(s):  
Clemens-Martin Wendtner ◽  
John C. Byrd ◽  
Robin Foà ◽  
Richard Greil ◽  
Peter Hillmen ◽  
...  
Keyword(s):  
Phase Ii ◽  
Kinase Inhibitor ◽  
Residual Disease ◽  
Phase Ii Study ◽  
Performance Status ◽  
Single Agent ◽  
Data Monitoring Committee ◽  
Lymphocytic Leukemia ◽  
Survival Duration ◽  
Dismal Prognosis

TPS7567 Background: Patients (pts) with R/R CLL who discontinue treatment with the BTKi ibrutinib due to progression have a particularly dismal prognosis. A phase I study showed that the Fc-enhanced, humanized, CD19 antibody MOR208 was well tolerated with encouraging single-agent activity in pts with R/R CLL/SLL. In preclinical models, MOR208 showed synergy with idelalisib (an inhibitor of PI3K delta) and venetoclax (an inhibitor of BCL-2), both approved for the treatment of CLL. Methods: This two-cohort, phase II study will investigate MOR208 combined with idelalisib (cohort A) or venetoclax (cohort B) in pts with R/R CLL or R/R SLL and includes a safety run-in phase for each cohort, to be evaluated by an Independent Data Monitoring Committee. Key inclusion criteria: aged ≥18 years, R/R CLL/SLL while receiving a BTKi therapy or intolerance of such therapy, BTKi administered as a single-agent or in combination for at least 1 month as the most recent prior anticancer therapy, ECOG performance status of 0–2, and adequate organ function. Key exclusion criteria: transformed CLL/SLL or Richter’s syndrome, BTKi treatment within 5 days prior to study drug dosing, prior treatment with a CD19-targeted therapy, a PI3K inhibitor (cohort A) or a BCL-2 inhibitor (cohort B). Pts will be treated for a maximum of 24 (28-day) cycles or until disease progression. Treatment will be MOR208 12 mg/kg IV (weekly for the first 3 months, every second week for the next 3 months, and monthly thereafter) in combination with oral idelalisib 150 mg twice-daily or venetoclax administered on a weekly ramp-up dosing schedule to the recommended daily dose of 400 mg. Primary endpoint: overall response rate based on independent review; secondary and exploratory endpoints include: progression-free and overall survival, duration of response, safety, pharmacokinetics, MOR208 immunogenicity, quality of life and minimal residual disease negativity. 120 pts per cohort are planned. Clinical trial information: 2015-002915-14.

Ofatumumab Added To Dexamethasone In Patients With Relapsed Or Refractory Chronic Lymphocytic Leukemia. Results From a Phase II Study Of The Czech Leukemia Study Group For Life

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2877-2877 ◽  
Author(s):  
Michael Doubek ◽  
Yvona Brychtova ◽  
Anna Panovska ◽  
Jakub Trizuljak ◽  
Ludmila Sebejova ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Disease Progression ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Lymphocytic Leukemia ◽  
High Dose ◽  
In Vitro Testing ◽  
Grade 3

Abstract The treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) remains a challenging clinical issue despite remarkable improvements in prognostication and therapy. One emerging treatment option for relapsed/refractory CLL is the use of high-dose corticosteroids. High-dose methylprednisolone or dexamethasone combined with rituximab are active in relapsed/refractory CLL, but serious infections are frequent and progression-free survival (PFS) is short. The purpose of this clinical trial was to determine the efficacy and toxicity of ofatumumab-dexamethason (O-dex) combination in relapsed or refractory CLL population. The trial was an open-label, multi-center, non-randomized, phase II study. The O-dex regimen consisted of intravenous ofatumumab (Cycle 1: 300mg on day 1, 2000mg on days 8, 15, 22; Cycles 2-6: 1000mg on days 1, 8, 15, 22) and oral dexamethasone (40mg on days 1-4 and 15-18; Cycles 1-6). Premedication consisted of glucocorticoid, paracetamol, and antihistamine before each ofatumumab infusion. All patients received allopurinol, omeprazol, co-trimoxazole, and fluconazole for prophylaxis of tumor lysis syndrome and infections. The O-dex regimen was given for a minimum of 3 cycles, until best response, or a maximum of 6 cycles. Between July 2010 and December 2012, 32 patients (pts.) were recruited at 3 centers. Basic patient characteristics at the start of O-dex therapy were as follows: median age 66 years (range, 50-77); 24 males, 8 females; median CIRS score 7 (0-15); median previous treatment lines 3 (1-10); 30 (94%) pts. were pretreated with fludarabine and 12 (38%) with alemtuzumab; Rai III/IV stage was present in 20 (63%) pts.; 6 (19%) pts. had bulky lymphadenopathy; IgVH genes were unmutated in 30 (94%) pts.; del 11q was present in 6 (19%) and p53 defects (del 17p and/or TP53 mutation) in 8 (25%) pts. The median number of O-dex cycles administered was 6 (1-6). Twenty two (69%) pts. completed at least 3 cycles of therapy. The remaining 9 patients were prematurely discontinued due to CTCAE grade 3/4 infections (7 pts.), disease progression (1 pt.), or uncontrollable diabetes mellitus (1 pt.). Overall responses/complete remissions (ORR/CR) were achieved in 22/5 pts. (69/16%). One patient achieved minimal residual disease negativity (measured by 4-color flow cytometry) at the end of therapy. Median PFS was 10 months. In patients with p53 defects, ORR/CR were achieved in 5/2 pts. (63/25%). The Median PFS was 10.5 months for this subgroup. Median overall survival (OS) has not yet been reached. During therapy, CTCAE grade 3/4 toxicity consisted of bacterial infections (25%), ofatumumab infusion-related side-effects (9%), neutropenia (9%), hyperglycemia (6%), and anemia (3%). No reactivation of herpetic viral infection was observed during the course of therapy. Nine patients died during the follow-up as a result of disease progression (6 pts.), infections (2 pts.), or complications after allogeneic stem cell transplantation (1 relapsed pt.). The median CD20 antigen density in CLL cells was 4766 (881-18515) MESF (molecules of equivalent soluble fluorochrome) units at baseline. At the end of therapy, CD20 density had significantly decreased (median 821 MESF; 443-2637); nevertheless, it was high once more at relapse (median 6619 MESF; 628-21359). In vitro testing of malignant pts. cells sensitivity to dexamethasone and ofatumumab did not show synergistic or additive effect of these compounds in majority of patients. Also, in vitro testing did not clearly predict the outcome of O-dex therapy. Conclusions The O-dex regimen shows relatively high ORR and CR, with promising findings for PFS and OS (including pts. harboring p53 defects), as compared to published data on rituximab plus dexamethasone regimen or ofatumumab in monotherapy. The infectious toxicity in 1/4 of pts. represents the most frequent side effect for this regimen. The study was registered at www.clinicaltrials.gov (NCT01310101). Disclosures: Doubek: GlaxoSmithKline: Research Funding. Mayer:Roche: Consultancy, Research Funding; Glaxo: Consultancy, Research Funding.

A phase II study of mammalian target of rapamycin (mTOR) inhibitor RAD001 plus imatinib mesylate (IM) in patients with previously treated advanced renal carcinoma (RCC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15600-15600 ◽  
Author(s):  
J. S. Chan ◽  
J. Vuky ◽  
L. A. Besaw ◽  
T. M. Beer ◽  
C. W. Ryan
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Phase Ii Study ◽  
Performance Status ◽  
Growth Factor Receptor ◽  
High Dose ◽  
Grade 3 ◽  
Asco 2006 ◽  
Free Rate

15600 Background: The serine-threonine kinase mTOR is a valid target for RCC therapy with temsirolimus treatment resulting in improved overall survival in poor-risk patients (Hudes G et al., ASCO 2006). RAD001 is an oral inhibitor of mTOR which has demonstrated activity in RCC at 10mg/day (Amato R et al., ASCO 2006). IM is a tyrosine kinase inhibitor (TKI) of platelet-derived growth factor receptor (PDGFR), a target that may promote angiogenesis and growth of RCC. Combined mTOR and PDGFR inhibition with RAD001 and IM may achieve vertical blockade through the PI3K/AKT pathway. Methods: Eligibility: metastatic clear cell RCC, performance status (PS) 0–2, adequate organ function, and prior treatment with = 1 systemic therapy. Doses were based on a phase I study of the combination in GIST (Van Oosterom AT et al., ASCO 2005): RAD001 2.5 mg p.o. daily and IM 600 mg p.o. daily. Patients were reimaged every 6 weeks. This is a 2-stage phase II study to determine the 3-month progression-free rate. Results: 14 pts have been enrolled. Median age 66 years (51–79). 6 pts PS 0 and 8 pts PS 1. Median number of prior therapies 1.5 (1–4). 12 of 14 patients had prior TKI therapy. Prior therapies included sorafenib (11 pts), interferon (7), sunitinib (3), bevacizumab (2), erlotinib (1), panitumumab (1), high-dose IL-2 (1). Of 10 pts evaluable for the primary endpoint, 3 are progression-free = 3 months. Best response for 9 pts evaluable by RECIST: PR/CR 0, SD 7, PD 2. Most common adverse events in 11 evaluable patients include nausea (8), edema (7), increased creatinine (7), fatigue (7), transaminase elevation (6), thrombocytopenia (5), leukopenia (5), cough (5), diarrhea (5). Grade 3 adverse events include fatigue (3), LE edema, rash, pleural effusion, increased creatinine, abdominal pain, and thrombocytopenia (1 each). There were no grade 4 toxicities. Unique suspected RAD001 toxicities include grade 3 pneumonitis (1) and angioedema (1). Conclusions: The combination of RAD001 and IM has moderate toxicity. This is one of the first studies in RCC patients predominantly pretreated with a TKI. 3 month progression-free rate appears to be a clinically relevant endpoint in this population. [Table: see text]

Sunitinib as second-line treatment for advanced gastric cancer: preliminary results from a phase II study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4603-4603 ◽  
Author(s):  
Y. Bang ◽  
Y. Kang ◽  
W. Kang ◽  
N. Boku ◽  
H. Chung ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Phase Ii Study ◽  
Single Agent ◽  
Objective Response ◽  
Mucosal Inflammation ◽  
Open Label ◽  
Preliminary Results ◽  
Grade 3

4603 Background: Sunitinib malate (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, and FLT3, approved internationally for the treatment of advanced RCC and imatinib-resistant or -intolerant GIST. We investigated the safety and activity of SU monotherapy in pts with previously-treated gastric cancer. Preliminary results from this open-label, multicenter, phase II study are reported. Methods: Eligibility criteria included measurable stage IV disease; 1 prior chemotherapy regimen; and ECOG PS =1. Pts took SU 50 mg/day for 4 wks followed by 2 wks off treatment in 6-wk cycles. A Simon 2-stage design was used with a target accrual of 38 pts in the first stage, expanding to 63 pts if =2 partial responses (PRs) were observed. The primary endpoint was RECIST-defined objective response rate. Secondary endpoints included duration of response and safety. Pharmacokinetic (PK) Ctrough parameters were also monitored. Results: As of Sept 15 2006, 38 evaluable pts (median age 56 years [range 29–78]; 2–3 metastatic sites [63%]; prior treatment with 5-FU ± platinum [P] [24%], capecitabine ± P [13%], TS-1 ± P [26%], other [37%]) have received a median of 2 SU cycles (range 1–3). Of 21 pts evaluable for efficacy, 1 PR has been confirmed and 8 pts had stable disease (SD), 4 with SD for =2 cycles. The most commonly reported AEs were typically grade 1/2 in severity and included stomatitis, skin discoloration, fatigue, anorexia, diarrhea, hand-foot syndrome (HFS), nausea and vomiting. Grade 3/4 toxicities included HFS (10.5%), fatigue (7.9%), anorexia (7.9%) and mucosal inflammation (5.3%). Grade 3/4 hematologic toxicities included neutropenia (29%), thrombocytopenia (29%) and anemia (11%). 7 pts experienced serious SU- related AEs requiring dose modifications in 3 pts and treatment discontinuation in 1 pt. Preliminary PK investigations indicate that concentrations seen in gastric pts are similar to those seen in other pts treated with SU. Conclusions: These initial findings show that SU is generally well tolerated and may have single-agent antitumor activity in pre-treated gastric cancer pts. Further trials with SU in combination with standard chemotherapy regimens are planned. No significant financial relationships to disclose.

NCT04552223: A phase II study of nivolumab plus BMS-986016 (relatlimab) in patients with metastatic uveal melanoma (UM) (CA224-094).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS9590-TPS9590
Author(s):  
Jose Lutzky ◽  
Lynn G. Feun ◽  
Norma Magallanes ◽  
Deukwoo Kwon ◽  
J. William Harbour
Keyword(s):  
T Cells ◽  
Mhc Class Ii ◽  
Uveal Melanoma ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Performance Status ◽  
Objective Response ◽  
Type I ◽  
Tumor Escape ◽  
Potential Candidate

TPS9590 Background: Uveal melanoma (UM) is a rare disease but 50% of patients will eventually develop metastatic disease, for which not effective therapy is available. Liver-directed therapies, immunotherapy, targeted therapy and chemotherapy have limited activity [1]. Lymphocyte activation gene 3(LAG-3) is an immune checkpoint receptor associated with decreased T-cell effector function and tumor escape. Preclinical models have shown that dual inhibition of LAG-3 and PD-1 blockade generates synergistic anti-tumor activity [2]. Recent preclinical data indicates that uveal melanoma CD8+ T cells express the checkpoint receptor LAG3 to a greater extent than PD1 or CTLA4 [3,4]. Therefore, LAG3 is a potential candidate for checkpoint inhibitor immunotherapy in UM. Relatlimab is a human LAG-3-specific antibody isolated from immunized transgenic mice which binds to a defined epitope on LAG-3 with high affinity and specificity and potently blocks the interaction of LAG-3 with its ligand, MHC Class II. Methods: This is an open-label, single arm, single site investigator-initiated phase II study, NCT04552223. Based on Simon two-stage minimax design, 13 patients will be enrolled in Stage 1. If at least one response is noted, the study will proceed to Stage 2 and enroll an additional 14 patients. The null hypothesis will be rejected if 4 or more responses are observed among 27 patients. This design achieves 5% type I error and 80% power when the true ORR is 20%. The trial opened to accrual in December 2020. As of February 15, 2021 four patients had been enrolled the first stage of accrual. Main eligibility criteria include patients with biopsy proven metastatic uveal melanoma, previously untreated with PD-1, CTLA-4 and/or LAG-3 blocking antibodies and in good performance status. Enrolled patients are treated in the outpatient setting. Nivolumab 480 mg is mixed in the same bag with relatlimab 160 mg and administered intravenously over 60 minutes every 4 weeks until disease progression or intolerable toxicity for up to 24 months. The primary endpoint is best objective response rate (ORR). Secondary endpoints include disease control rate (DCR), progression-free survival (PFS), overall survival (OS), median duration of response (mDOR), and adverse events (AEs). Correlative studies will evaluate pre- and post-treatment characteristics of T cells in the tumor microenvironment and blood. Clinical trial information: NCT04552223.

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