TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies: A phase I/II dose finding and biomarker study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3563-3563 ◽  
Author(s):  
E. Angevin ◽  
J. A. Lopez ◽  
A. Pande ◽  
C. Moldovan ◽  
M. Shi ◽  
...  
Keyword(s):  
Phase I ◽  
Kinase Inhibitor ◽  
Sinus Bradycardia ◽  
Safety Data ◽  
Maximum Tolerated Dose ◽  
Preliminary Evidence ◽  
Primary Objective ◽  
Dose Finding ◽  
Minor Response ◽  
Suprarenal Mass

3563 Background: TKI258 is a potent receptor tyrosine kinase inhibitor (TKI) that selectively targets VEGFR, PDGFR, FGFR, CSF1R, c-KIT, RET, TrKA, and FLT3. Compared to other TKI agents, TKI258 additionally targets FGFR. FGF has been reported as an important escape mechanism of anti-VEGFR therapies. Methods: The primary objective of this phase I was to determine the maximum tolerated dose (MTD) of TKI258, administered orally on a 5 days on / 2 days off schedule in repeated 28 day cycles, in mRCC pts refractory to standard therapies. A two-parameter Bayesian logistic regression model and safety data for at least 21 pts will be used to determine MTD. Results: A phase I study is ongoing. As of December 2008, 11 pts (9 m, 2 f), median age: 55 (29–66 yrs) have been enrolled. Four pts have been treated at 500 mg/day (start dose): 2 are ongoing at cycle (C) 7; 1 pt discontinued due to PD and 1 due to sinus bradycardia. Five pts received 600 mg/day: 2 DLTs (G4 hypertension and G3 fatigue - pts discontinued) leading to dose reduction of all patients to 500mg/day; 2 pts in C5 and C4, 1 pt discontinued for PD. Two pts just entered the extension cohort at 500 mg. Other toxicities ≥G2 included fatigue, nausea, vomiting, diarrhea, neutropenia, folliculitis and dizziness. PK data showed CMax range (180–487 ng/mL, n = 8), and AUC range (2200–8251 ng/mL*h). Preliminary biomarker data indicated pts had high baseline VEGF (506 ± 203 pg/ml, n=6) and bFGF (220 ± 185 pg/ml, n = 6) levels, which may reflect failure of previous anti-VEGF agents. Induction of plasma FGF23 levels, a pharmacodynamic biomarker of FGFR1 inhibition, was observed in pts from the first 500 mg/day dosing cohort. Preliminary evidence of efficacy is observed with one minor response (-17% at C4), 4 stable disease and 1 dramatic shrinkage/necrosis of some target lesions (lymph node & suprarenal mass). Conclusions: TKI258 500mg/day seems a feasible schedule in heavily pre-treated mRCC patients with some indications of clinical benefit. These preliminary findings will be confirmed in the extension cohort. [Table: see text]

Phase I Study of IMGN901 in Patients with Relapsed and Relapsed/Refractory CD56-Positive Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3689-3689 ◽  
Author(s):  
Asher Alban Chanan-Khan ◽  
Mecide Gharibo ◽  
Sundar Jagannath ◽  
Nikhil C. Munshi ◽  
Kenneth C Anderson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Preliminary Evidence ◽  
Clinical Activity ◽  
Weekly Schedule ◽  
Minor Response

Abstract Background: IMGN901 (huN901-DM1) is a novel conjugate of the cytotoxic maytansinoid, DM1, with the humanized CD56-binding monoclonal antibody, N901. Once bound to CD56 on a cancer cell, the conjugate is internalized and releases DM1. About 70% of multiple myeloma (MM) cases have surface expression of CD56. Preclinical investigations demonstrated significant in vitro and in vivo anti-myeloma activity of IMGN901. Objectives: To determine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of increasing doses of IMGN901 given for MM on a weekly schedule. Methods: Patients with relapsed or relapsed/refractory MM who have failed at least one prior therapy and have CD56-expressing MM received a single IV infusion of IMGN901 on 2 consecutive weeks every 3 weeks. Patients are enrolled in cohorts of 3 at each dose level, with DLT triggering cohort expansion. Results: Eighteen patients have received IMGN901 to date in this study - 3 patients each at 40, 60, 75, 90, 112, and 140 mg/m2/week. One patient experienced a DLT (grade 3 fatigue) on 140 mg/m2/week, and this cohort is being expanded to enroll up to 6 patients. No patients have experienced serious hypersensitivity reactions or evidence of presence of humoral responses against the huN901 antibody component (HAHA) or against the DM1 component (HADA). Preliminary PK results indicate an approximately linear relationship between dosing and observed maximal serum concentration. A confirmed minor response (MR) was documented in 3 heavily pretreated patients (1 patient each at 60, 90, and 112 mg/m2/week) using the European Bone Marrow Transplant criteria. Durable stable disease was reported at doses of 60, 90, 112, and 140 mg/m2/week. Of the 18 patients treated in the study, eight patients remained on treatment with IMGN901 for at least 15 weeks, five of these 8 patients remained on treatment for at least 24 weeks, and two of these 5 patients remained on treatment for at least 42 weeks. This phase I study provides preliminary evidence of safety as well as clinical activity of IMGN901 in patients with CD56-positive MM who have failed established MM treatments. Updated results of this ongoing study will be presented.

Phase I evaluation of AZD2171, a highly potent and selective inhibitor of VEGFR signaling, in combination with selected chemotherapy regimens in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3034-3034 ◽  
Author(s):  
P. M. Lorusso ◽  
E. Heath ◽  
M. Valdivieso ◽  
M. Pilat ◽  
A. Wozniak ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Growth Factor Receptor ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Selective Inhibitor ◽  
Minor Response ◽  
Heavily Pretreated ◽  
Grade 3

3034 Background: AZD2171 is an oral, potent, selective inhibitor of vascular endothelial growth factor receptor (VEGFR). Trials have demonstrated that inhibition of the VEGF pathway, in combination with certain chemotherapy, provides benefit to patients with a broad range of solid tumors. Methods: This Phase I trial was conducted in heavily pretreated solid tumor patients. In a single protocol, escalating doses of AZD2171 were evaluated (20, 30 and 45 mg) in combination with four separate chemotherapy regimens: mFOLFOX6 (oxaliplatin 85 mg/m2; 5-FU 400 mg/m2; leucovorin 400 mg/m2 q2 weeks; Arm 1); irinotecan 300 mg/m2 q3 week (Arm 2); docetaxel 75 mg/m2 (Arm 3) and pemetrexed 500 mg/m2 (Arm 4). The primary objective was to evaluate safety and tolerability of the combinations and secondary objective to evaluate pharmacokinetic (PK) interaction and clinical efficacy. Maximum tolerated dose (MTD) toxicity was defined through two cycles. Results: 46 patients have been enrolled: 28/35 evaluable for efficacy/toxicity. The MTD has been reached in two arms: Arm 2 - 20 mg AZD2171 and Arm 4 - 30 mg AZD2171. Arm 3 enrollment continues at 45 mg AZD2171. Two dose-limiting toxicities (DLTs) were observed in eight patients at 30 mg AZD2171 in Arm 1. Enrollment of an additional cohort of less heavily pre-treated patients is ongoing to determine the tolerability of 30 mg AZD2171 with FOLFOX. DLTs have included grade 3 fatigue in Arms 1, 2 & 4; grade 3 diarrhea in Arm 1; grade 3 hand-foot syndrome & grade 4 neutropenic fever in Arm 2; and grade 3 hypertension in Arm 4. AZD2171 did not appear to have a major effect on the PK profile of any chemotherapy regimen tested. Steady-state values are comparable with AZD2171 monotherapy. There have been 13 responses (minor response, n=5; partial response, n=6; complete response, n=2; stable disease ≥ 4 cycles, n=6) in heavily pretreated patients, some having demonstrated resistance to identical chemotherapies. Duration of response has been impressive (4-22+ cycles). Conclusions: AZD2171 combinations have been well tolerated with expected toxicities and encouraging responses. [Table: see text]

A phase I dose-escalation and pharmacokinetic (PK) study of sunitinib (SU) plus docetaxel (D) in patients (pts) with advanced solid tumors (STs)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3543-3543 ◽  
Author(s):  
F. Robert ◽  
A. Sandler ◽  
J. H. Schiller ◽  
J. Ilagan ◽  
W. VerMeulen ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Kinase Inhibitor ◽  
Pulmonary Hemorrhage ◽  
Pulseless Electrical Activity ◽  
Primary Objective ◽  
Dose Finding ◽  
Grade 5 ◽  
Finding Study ◽  
Multitargeted Tyrosine Kinase Inhibitor

3543 Background: SU is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET and FLT3, approved multinationally for the treatment of advanced RCC and imatinib-resistant or -intolerant GIST. In mouse xenograft models of breast cancer, SU enhanced the antitumor activity of D. This study was designed to assess the safety/maximum tolerated doses (MTDs), PK profile and preliminary efficacy of SU+D in pts with advanced STs. Methods: This is a phase I, dose-finding study in pts with advanced STs. The primary objective is to determine the MTD and safety of SU and D administered in combination. Successive cohorts of pts with advanced STs were to receive oral SU at 25, 37.5 or 50 mg daily for 4 wks of a 6-wk cycle (4/2 schedule) or for 2 wks of a 3-wk cycle (2/1 schedule) in combination with IV D at 60 or 75 mg/m2 every 21 days (q21d). The MTD was defined as the highest dose at which 0 of 3 or 1 of 6 pts encountered dose-limiting toxicities (DLTs) during cycle 1. Antitumor activity was assessed by CT or MRI scan. Results: 37 pts (most common primary tumor types: mRCC [n=10], NSCLC [n=13]) have been enrolled as of Nov. 2006: 10 pts on the 4/2 schedule and 27 pts on the 2/1 schedule (see table ). The most commonly observed DLT was neutropenia (with or without fever; maximum grade 4), which occurred in 5 pts and was manageable/reversible. There was 1 grade 5 event on the 2/1 schedule (C1D3), of pulseless electrical activity and pulmonary hemorrhage. The MTDs on the 4/2 schedule were SU 25 mg and D 60 mg/m2. The MTDs on the 2/1 schedule were SU 37.5 mg and D 75 mg/m2; PK analysis at this dose level is ongoing. Stable disease has been observed in 5 of 9 evaluable pts (56%) on the 4/2 schedule and 20 of 25 evaluable pts (80%) on the 2/1 schedule at the MTD. Conclusions: The combination of oral SU 37.5 mg/day on the 2/1 schedule with D 75 mg/m2 IV q21d has a manageable safety profile in pts with advanced STs. PK and preliminary efficacy analyses are ongoing to support these dosing combinations for further study. [Table: see text] No significant financial relationships to disclose.

A first-in-human, phase I safety and pharmacokinetic study of genz-644282, a non-camptothecin topoisomerase I inhibitor, in patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2534-2534
Author(s):  
Hyo S. Han ◽  
Antoinette R. Tan ◽  
Glen J. Weiss ◽  
Daniel Sullivan ◽  
Jonathan R. Strosberg ◽  
...  
Keyword(s):  
Phase I ◽  
Dna Cleavage ◽  
Topoisomerase I ◽  
Safety Data ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Ring Structure ◽  
Small Cell ◽  
Small Cell Lung ◽  
Minor Response

2534 Background: The approved topoisomerase I (TopI) inhibitors (irinotecan and topotecan) are camptothecin derivatives. The lactone ring structure of camptothecins negatively impacts their clinical potential.Genz-644282 is a novel non-camptothecin that induces TopI-DNA cleavage complexes at similar as well as unique genomic positions; that are more persistent. This study was designed using a pharmacokinetic-pharmacodynamic (PK-PD) model to predict the maximum tolerated dose (MTD). Methods: A PK-PD relationship of Genz-644282 to inhibit tumor growth was derived (Simeoni, Can Res 2004). Using an accelerated titration design, cohorts of 1, 3 or 6 patients received 3 weekly doses of Genz-644282 on a 28 day schedule starting with 0.5 mg/m2. After MTD on the 28 day schedule was exceeded, 21 day schedule was initiated. Results: 49 patients (N=44 data available: 26M :18F) were dosed. Tumor types were colorectal (15), breast (5), small cell lung (SCLC 3), non-small cell lung (4), others (17). As predicted from the PK-PD model 8 cohorts were evaluated on the 28 day schedule before defining the MTD. The MTD was 8 mg/m2 and 9 mg/m2 for the 28 day and 21 day schedules, respectively. Dose limiting toxicities that determined the MTD were: gr 4 thrombocytopenia (n=2); gr 2 thrombocytopenia (n=1) and gr 4 neutropenia (n=1) both of which resulted in ≥72h delays in initiating cycle 2. Treatment emergent adverse events (>10%) were nausea (45%), fatigue (39%), anorexia (32%), anemia (27%), vomiting (23%), thrombocytopenia (18%), diarrhea (16%), dehydration (16%), hyperglycemia (16%), cough (16%), dyspnea (14%), depression (11%) and hyponatremia (11%). Efficacy data suggest 2 responders with SCLC (1 minor response;1 complete response), and 2 patients (breast, gastric) with stable disease (≥ 6 months). PK data show a Genz-644282 half-life of approximately 50 h, a linear dose-exposure relationship, and no accumulation in between doses. Conclusions: Genz-644282 is a non-camptothecin TopI inhibitor in phase I development with ongoing expansion phase. The emerging pk, efficacy and safety data are suggestive of a distinct clinical profile of Genz-644282 from the camptothecins.

Phase I evaluation of tipifarnib in combination with low-dose Ara-C (LDAC) in high-risk myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML): Interim results

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14014-14014
Author(s):  
J. E. Cortes ◽  
E. J. Feldman ◽  
D. Douer ◽  
A. Raza ◽  
S. Fruchtman
Keyword(s):  
Phase I ◽  
Dose Level ◽  
The Elderly ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Dose Finding ◽  
Clinical Activity ◽  
Open Label ◽  
Entire Cohort ◽  
Investigational Agent

14014 Background: Tipifarnib (T) is a farnesyltransferase inhibitor with clinical activity in MDS and AML. LDAC has utility in the elderly with MDS/AML; hence its use in combination with the investigational agent T to improve outcomes is warranted. Methods: The primary objective of this ongoing phase I, dose finding, multicenter, open-label study was to determine the maximum tolerated dose (MTD) based on dose limiting toxicities (DLT) of T+LDAC observed during the first 28 day cycle. MDS (IPSS Int 1, 2 or High) and untreated AML pts (age =75y or =65y with preceding MDS) or relapsed/refractory AML (age >18y) were included. Planned sample size was up to 57 pts with a traditional 3+3 dose escalation and a minimum of 3 pts enrolled per cohort. T (Dose Level 0) was administered initially at 200mg PO BID x 21 days in combination with LDAC 10mg SC BID x 10 days; both repeated every 28 days. Efficacy will be assessed by bone marrow and peripheral blood count studies. Results: 15 pts have been enrolled to date: 2 MDS (Int 1 n=1, High n=1) and 13 AML (7/13 pts with no previous therapy); all 15 pts were evaluable. Mean baseline characteristics for the entire cohort were: age 76.2y, 67% men, Hb 9.4 ± 0.9 g/dL, WBC 8.7 ± 11.3 x 103/μL, platelets 96.8 ± 96.6 x 103/μL. The observed DLT for T+LDAC was generalized rash seen at Dose Level 3. The MTD was therefore determined to be T 300mg and LDAC 15mg. The most common grade 3/4 adverse events were neutropenia, thrombocytopenia, anemia, and rash. Conclusions: These interim findings show the combination of T at 300mg PO BID x 21 days and LDAC at 15mg SC BID x 10 days to be the MTD in this study. Assessment for efficacy is ongoing. [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]

Dasatinib phase I/II study of patients with chronic myeloid leukemia (CML) resistant or intolerant to imatinib: Results of the CA180031 study in Japan

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 17515-17515 ◽  
Author(s):  
H. Sakamaki ◽  
K. Ishizawa ◽  
M. Taniwaki ◽  
S. Fujisawa ◽  
Y. Morishima ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Safety Data ◽  
Chronic Phase ◽  
Japanese Patients ◽  
Maximum Tolerated Dose ◽  
Imatinib Resistant ◽  
Grade 3 ◽  
Dose Levels

17515 Background: Dasatinib is a potent, orally active, multi-targeted kinase inhibitor of BCR-ABL and SRC family kinases. Studies outside Japan have shown dasatinib to be highly effective in overcoming resistance and intolerance to imatinib, inducing durable cytogenetic (CyR) and hematologic responses (HR) in this population. The maximum tolerated dose was not reached in the Phase-I trial outside Japan and a 70-mg BID dose was determined to provide the optimal benefit-risk profile. Methods: This Phase-I/-II study was designed to assess the safety and efficacy of dasatinib in Japanese patients with imatinib-resistant or -intolerant CML or Ph+ALL. In the 4-week Phase-I portion in patients with chronic-phase (CP) CML, three dose levels were evaluated: 50 mg, 70 mg, and 90 mg BID. The Phase-II portion is currently evaluating the CyR of dasatinib in patients with CP-CML at 24 weeks, and the HR rate in accelerated- (AP) or blast-phase (BP) CML and Ph+ ALL at 12 weeks. Results: As of December 2006, 17 eligible patients have been treated in Phase I. Six patients (4F, 2M; median age 43 y [range 27–56]) were treated with 50 mg BID and 1 dose-limiting toxicity (DLT) was observed (Grade 4 thrombocytopenia). Two patients experienced transient Grade 3 ALT elevations but as treatment was uninterrupted, these were not considered DLTs. Six patients (6M; median age 42 y [range 27–55]) were treated with 70 mg BID and again 1 DLT was observed (Grade 4 thrombocytopenia). No DLT has been observed among 4 patients (3M, 1F; median age 41 y [range 27–64]) at the 90-mg BID dose. Major CyRs have been achieved in all three cohorts in the Phase-I segment of the trial. Thirty six patients were enrolled and treated in the Phase-II part of the trial (12 CP-CML, 7 AP- CML, 4 BP-CML, and 13 Ph+ALL). Efficacy and safety data as well as the baseline BCR-ABL mutation data are currently being assessed and will be presented. Conclusions: Dasatinib can be safely administered at doses of up to 90 mg BID to Japanese patients with imatinib-resistant or -intolerant CP-CML. No significant financial relationships to disclose.

Phase I/II dose-finding study of crizotinib (CRIZ) in combination with erlotinib (E) in patients (pts) with advanced non-small cell lung cancer (NSCLC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2610-2610 ◽  
Author(s):  
Sai-Hong Ignatius Ou ◽  
Ramaswamy Govindan ◽  
Keith D. Eaton ◽  
Gregory Alan Otterson ◽  
Martin Gutierrez ◽  
...  
Keyword(s):  
Phase I ◽  
Advanced Nsclc ◽  
Kinase Inhibitor ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Dry Eyes ◽  
Egfr Inhibition ◽  
Development Of Resistance ◽  
Finding Study ◽  
Dose Finding Study

2610 Background: c Met expression is common in NSCLC tumors and has been implicated in the development of resistance to EGFR inhibitors. CRIZ is an ALK and MET/HGF receptor tyrosine kinase inhibitor (TKI). In pre-clinical studies, combining CRIZ with an EGFR inhibitor enhanced anti-tumor activity in NSCLC cell lines that were either sensitive or resistant to EGFR inhibition. The phase I portion of a phase I/II study (A8081002; NCT00965731) investigated the combination of E (EGFR TKI) and CRIZ in pts with advanced NSCLC. Methods: Pts had advanced NSCLC, 1 or 2 prior chemotherapy regimens, and no previous MET-directed therapy. Endpoints included maximum tolerated dose (MTD) determination, safety, and pharmacokinetics (PK). Pts received CRIZ 150 or 200 mg BID combined with E 100 mg QD (150/100 and 200/100, respectively). Results: Twenty-five pts have been treated to date. Median duration of combination therapy in 150/100 (n=18) was 6.6 weeks (0.1–25.3); for 200/100 (n=7) was 6.9 weeks (3.0–64.7). Five pts had dose-limiting toxicities (grade [G] 2 and unable to receive at least 80% of the planned dose or ≥G3), all of which resolved: 3 pts at 150/100, G2 vomiting, G2 esophagitis and dysphagia, G3 diarrhea and dehydration; and at 200/100, G3 dry eye (1 pt) and G3 esophagitis (1 pt). Most pts (92%) experienced treatment-related adverse events (TRAEs), mainly of G1 or 2 severity. Common TRAEs were diarrhea (72%), rash (56%) and fatigue (44%). Six pts discontinued therapy due to TRAEs (150/100: G3 diarrhea, G3 dehydration, and G2 rash in 1 pt, G2 asthenia, G2 vomiting, G2 esophagitis, n=1 each; 200/100: G3 dry eyes, G1 esophagitis, n=1 each). One partial response (200/100; duration 61 weeks) and 9 stable diseases (n=7 150/100, n=2 200/100; duration 7–54 weeks) were observed overall. Co-administration of both doses of CRIZ with E increased E AUC by 1.8 fold, while CRIZ PK parameters appeared to be unaffected. Plasma exposure to E 100 mg QD with CRIZ was comparable to that of 150 mg QD from historical data. Conclusions: E plus CRIZ at the MTD was well tolerated, with no unexpected AEs, and showed signs of activity in a pre-treated population. E 100 mg QD plus CRIZ 150 mg BID was defined as MTD.

scholarly journals Prospective Phase I Multi-Center Trial Incorporating Lenalidomide (LEN) into Dose-Adjusted EPOCH Plus Rituximab (DA-EPOCH-R) in Patients with Double Hit (DHL) or Double Expressing (DEL) Lymphomas: Final Results

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4191-4191 ◽  
Author(s):  
Chadi Nabhan ◽  
Theodore Karrison ◽  
Justin Kline ◽  
Kenneth Cohen ◽  
Michael R. Bishop ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Maximum Tolerated Dose ◽  
Sales Force ◽  
Primary Objective ◽  
Dose Finding ◽  
Hematologic Toxicity ◽  
Serious Adverse Events ◽  
Ecog Ps

Abstract Background: There are no prospective studies that define best therapy for DHL (presence of c-MYC and BCL-2 translocations) or DEL (co-expression of c-MYC ³40% and BCL-2 ³50% by IHC). Retrospective data for both entities show suboptimal outcomes with R-CHOP and perhaps improved outcomes with intensified regimens such as DA-EPOCH-R. We conducted a phase I prospective multicenter study adding escalating doses of LEN to DA-EPOCH-R in pts with DHL or DEL. Herein, we report the final results of the dose-finding portion of this ongoing clinical trial. Patients and Methods: Eligible pts had DHL or DEL as defined above. They were allowed to receive radiotherapy for neurologic compromise or one cycle of R-CHOP prior to enrollment at the investigator's discretion. Pts had measurable disease, ECOG PS 0-2, and adequate liver, kidney, and marrow function and no known HIV or CNS involvement. Either aspirin or warfarin prophylaxis was required. Primary objective was to determine the maximum-tolerated dose (MTD) of LEN when added to DA-EPOCH-R. We utilized a standard (3+3 design) where LEN was started at 10mg (days 1-14, Q21-days) with each cycle of DA-EPOCH-R, and escalated to a maximum of 25 mg unless a MTD was reached at an earlier dose. Dose-limiting toxicities (DLTs) were assessed during cycle 1; DA-EPOCH-R administration and dose modifications were conducted as per usual protocol. Cycles were repeated every 3-weeks for a maximum of 6 cycles and were followed by an end of therapy PET scan. CNS prophylaxis was strongly encouraged with 12.5 mg IT-methotrexate for 4 doses during induction. Patients attaining PET negativity after induction were continued on maintenance LEN 10 mg (days 1-14 Q21 days) for 12 cycles. During the LEN dose escalation portion of the study, a hematologic toxicity did not count as a DLT to allow DA-EPOCH-R dose adjustments. Results: 15 pts (6: DHL and 9: DEL; 13 DLBCL and 2 BCL-U) were enrolled; median age was 62 years (range: 26-83). There were 5 males and 10 females (11 whites, 3 African Americans, and 1 Asian pts). Two pts had ECOG PS 2 while all others were 0-1. All pts (100%) had stage III/IV disease, 13 pts (86%) had high-risk IPI score, and median LDH was 673 (range: 193-1,835). All ptsare assessable for toxicity. Serious adverse events (SAEs) per dose levels are summarized in the Table. DA-EPOCH-R dose escalation was feasible in 10 pts (67%), one pt (6.7%) maintained the same dose throughout, and another (6.7%) required dose de-escalation. Two DLTs were observed (grade 4 sepsis and hypotension for both) at dose-level 20 mg of LEN leading to 15 mg being the MTD and RP2D. Most common grade 1 and/or 2 non-hematologic toxicities were fatigue (70%), constipation (47%), alopecia (53%), nausea (47%), peripheral sensory neuropathy (40%), diarrhea (33%), and hypokalemia (33%). The only grade 3 and/or 4 non-hematologic toxicity occurring in ³2 pts (13%) was hypokalemia. All others occurred in 1 pt (6%) and were: constipation, fever, hyperglycemia, hypertension, mucositis, and hypoalbumenemia. One pt (6%) developed treatment-related myelodysplasia, (T-MDS), 18 months after treatment initiation. Twelve patients are evaluable for response at time of analysis, (1 patient lost to follow-up, and 2 with ongoing therapy). Best responses at completion of induction based on PET were 6 complete responses (CR: 50%), 3 partial responses (PR: 25%) and 1 pt with progressive disease (8%). All CR pts received LEN maintenance but only 1 completed 12 cycles to date (1 came off due to cytopenias found later to have T-MDS, 1 due to AE, 1 due to finding of unrelated colon cancer, 2 on active maintenance). With median follow up 10.7 months (range: 1.3-18.6 months), 14 pts remain alive and one pt has died for an OS of 93%. Conclusions: LEN can safely be added to DA-EPOCH-R in DHL and DEL patients at a dose of 15 mg (days 1-14 Q21 days). Chemotherapy dose escalation was not compromised and preliminary safety/efficacy data appear promising. A phase II study in this pt population with LEN+DA-EPOCH-R is underway. Disclosures Nabhan: Celgene, Genentech, Seattle Genetics, Astellas: Research Funding; Celgene, Genentech, Abbvie, Infinity, Cardinal Health: Consultancy. Karmali:Celgene: Speakers Bureau. Fishkin:Biogen: Other: Owns Stocks. Smith:Genentech: Consultancy, Other: on a DSMB for two trials ; Juno: Consultancy; TGTX: Consultancy; AbbVie: Consultancy; Gilead: Consultancy; Amgen: Other: Educational lecture to sales force; Portola: Consultancy; Celgene: Consultancy; Pharmacyclics: Consultancy.

A phase I dose escalation study of sunitinib in combination with gemcitabine + cisplatin for advanced non-small cell lung cancer (NSCLC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18057-18057 ◽  
Author(s):  
M. Reck ◽  
N. Frickhofen ◽  
U. Gatzemeier ◽  
H. Fuhr ◽  
S. Lanzalone ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Dose Escalation Study ◽  
Finding Study ◽  
Grade 3 ◽  
Multitargeted Tyrosine Kinase Inhibitor

18057 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. SU has also shown single- agent activity in NSCLC. In this study we assess the safety, tolerability, and pharmacokinetics (PK) of SU in combination with gemcitabine (G) and cisplatin (C). Methods: This is a phase I, dose-finding study in pts with untreated, stage IIIB/IV NSCLC not amenable to curative treatment. Planned dose levels include: oral SU (37.5 or 50 mg/day for 2 wks followed by 1 wk off treatment [2/1 schedule]) plus G (1000 or 1250 mg/m2 iv on days 1 and 8 of a 21-day cycle) and C (80 mg/m2 iv on day 1 of each cycle). SU doses are escalated in serial pt cohorts to determine the maximum tolerated dose (MTD) for both schedules. SU continuous dosing (CD) schedule will also be tested. PK and antitumor efficacy are also assessed. Results: As of Oct 2006, 13 pts were treated on the 2/1 schedule: 6 pts with SU 37.5 mg + G 1000 mg/m2 + C 80 mg/m2, and 7 pts with SU 50 mg + G 1000 mg/m2 + C 80 mg/m2. No dose-limiting toxicities (DLTs) were observed with SU 37.5 mg, while 2 pts experienced neutropenia and infection as DLTs with SU 50 mg. Grade 3/4 hematological AEs included neutropenia (n=3 at dose level 1 and n=5 at dose level 2), thrombocytopenia (n=1 and 5) and anemia (n=2 and 0). 3 pts achieved a partial tumor response at the SU 50 mg/day dose level. There were no apparent drug-drug interactions between SU in combination with G and C based on their systemic exposures in this study. Conclusions: The combination of SU (37.5 mg) on schedule 2/1 with G (1000 mg/m2) and C (80 mg/m2) in advanced NSCLC appears safe and tolerable in this pt population. Testing with G escalated to 1250 mg/m2 or with SU administered on a CD schedule is ongoing. No significant financial relationships to disclose.

Sign in / Sign up

Export Citation Format

Share Document