Final results of a pharmacokinetic (PK) and pharmacodynamic (PD) phase I trial of ARQ 197 incorporating dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) studies investigating the antiangiogenic activity of selective c-Met inhibition

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3523-3523 ◽  
Author(s):  
T. A. Yap ◽  
S. Frentzas ◽  
N. Tunariu ◽  
J. Barriuso ◽  
D. Harris ◽  
...  
Keyword(s):  
Competitive Inhibitor ◽  
Maximum Tolerated Dose ◽  
Dce Mri ◽  
Arq 197 ◽  
Disease Stabilization ◽  
Hand Foot Syndrome ◽  
Magnetic Resonance Imaging Mri ◽  
Recommended Phase Ii Dose ◽  
Expansion Cohort ◽  
Immunohistochemical Studies

3523 Background: ARQ 197 (ARQ) is a selective non-ATP competitive inhibitor of c-Met, a receptor tyrosine kinase implicated in tumor cell proliferation, invasion and angiogenesis. Preclinical data and declines in circulating endothelial cell (CEC) levels in patients (pts) receiving ARQ suggest antiangiogenic potential of c-Met inhibition. Methods: ARQ was administered orally twice daily (bid) to pts with advanced solid tumors. Pre and post-therapy tumor biopsies were mandated for c-Met and FAK immunohistochemical studies during dose escalation (n = 16). CEC enumeration was evaluated. 12 pts are being investigated in the maximum tolerated dose (MTD) expansion cohort with DCE and Diffusion Weighted (DW) MRI. Results: 29 pts (14 F/15 M; mean 54.4 yrs) received ARQ at doses of 100 (n = 3), 200 (n = 6), 300 (n = 16), and 400 (n = 4) mg bid. 3 pts experienced dose limiting toxicities of CTCAEv3 grade (G)3 fatigue (200 mg bid); G3 hand-foot syndrome, G3 mucositis and G3 febrile neutropenia (400 mg bid). This established the ARQ MTD/recommended phase II dose (RP2D) at 300 mg bid. Other toxicities were G1–2, such as fatigue (n = 5); diarrhea, nausea and vomiting (n = 3). Mean AUC0–12h and Cmax increased linearly through the MTD. Statistically significant post-ARQ inhibition of high baseline phosphorylated c-Met and FAK expression in tumor tissue was seen in all dose cohorts confirming target inhibition. Disease stabilization (SD) was seen in 11 pts for up to 23 weeks with tumor regressions up to 12.4%. 13 of 20 pts had post-ARQ CEC declines of up to 100%. In the DCE-MRI cohort to date, preliminary analyses of ktrans histograms from pelvic lesions were consistent with antiangiogenic effects, with a ktrans median reduction of 20.1% on day 7 of ARQ (intrapatient baseline variability: 2.8%). This effect was still present (ktrans median decline: 8.3%) on day 56 of ARQ. Conclusions: ARQ is well tolerated with MTD/RP2D of 300mg bid, linear PK and evidence of phosphorylated c-Met and FAK inhibition. CEC and preliminary DCE-MRI data support the antiangiogenic effects of c-Met inhibition with ARQ. Correlation with other DCE parameters and DW changes will be presented. [Table: see text]

Phase I trial of temsirolimus (TEM) plus sorafenib (SOR) in advanced hepatocellular carcinoma (HCC) with pharmacokinetic (PK) and biomarker correlates.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4102-4102 ◽  
Author(s):  
Robin Katie Kelley ◽  
Halla Sayed Nimeiri ◽  
Pamela N. Munster ◽  
Mary Frances Mulcahy ◽  
Maxwell Thomas Vergo ◽  
...  
Keyword(s):  
Phase 1 ◽  
Mammalian Target Of Rapamycin ◽  
Maximum Tolerated Dose ◽  
Advanced Hepatocellular Carcinoma ◽  
Best Response ◽  
Hand Foot Syndrome ◽  
Prior Systemic Therapy ◽  
Expansion Cohort ◽  
Cancer Network ◽  
Dose Limiting Toxicity

4102 Background: Mammalian target of rapamycin inhibitors added to SOR augment antitumor effect in HCC models. We developed a phase 1 trial to determine maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of TEM plus SOR in HCC patients (pts). The study was approved and funded by the National Comprehensive Cancer Network (NCCN) from general research support from Pfizer, Inc., and conducted at 2 NCCN centers. Methods: Eligibility: ≥1 measurable site. No prior systemic therapy (Tx). ECOG ≤2, Child Pugh ≤7, bilirubin ≤2 mg/dL, platelets (PLT) ≥75,000/mcL. Design: 3+3 escalation. Dose-limiting toxicity (DLT) window 28 days. MTD expansion cohort of 9 pts for PK and biomarkers. Endpoints: 1°: MTD, RP2D. 2°: Safety, toxicity, PK for TEM. Exploratory: Tumor necrosis, alpha fetoprotein (AFP)-L3, des-γ-carboxyprothrombin, and circulating tumor cells (CTC) by slide-based assay. Results: 21 pts enrolled. Median age: 60 (47-77). Male/Female: 15/6. Etiology: HCV 9 (43%), HBV 4 (19%), HBV+HCV 2 (10%), ETOH 2 (10%), unknown 4 (19%). Toxicity: DL1: 1 DLT Grade (Gr) 3 PLT. All pts required reductions for adverse events (AE); de-escalated to DL-1 for intolerability. DL-1: 1 DLT Gr3 hand-foot syndrome (HFS). Most common related ≥Gr 3 AE: HypoPO4 (52%); PLT (24%); transaminitis (19%); diarrhea, fatigue, HFS (10% each). Possibly related serious AE (SAE): Gr4 tumor rupture, Gr4 urosepsis, Gr3 dental infection with Gr2 ANC, Gr2 pneumonia (1 pt, 5% each). Best response: Confirmed partial response (PR) 2/21 (10%), stable disease (SD) 11/21 (52%), progression 1/21 (5%), 7/21 (33%) not evaluable. Time on study: Range <1 to 19+ months; median 3+ months for pts who completed ≥1 cycle (16/21). 16/21 (76%) had baseline elevated AFP ≥20; 8/16 (50%) had >50% decline. CTC were detected in 5/5 of tested samples. Decreased tumor enhancement on Tx was seen. Conclusions: DL-1 is MTD and RP2D, lower than a prior trial in pts without HCC; tolerability may be impacted by cirrhosis. Encouraging durable radiographic and AFP responses occurred. [Table: see text]

Phase I Trial of Intrathecal Liposomal Cytarabine in Children With Neoplastic Meningitis

2004 ◽  
Vol 22 (19) ◽  
pp. 3916-3921 ◽  
Author(s):  
L. Bomgaars ◽  
J.R. Geyer ◽  
J. Franklin ◽  
G. Dahl ◽  
J. Park ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Phase I Trial ◽  
Maintenance Phase ◽  
Maximum Tolerated Dose ◽  
Neoplastic Meningitis ◽  
Liposomal Cytarabine ◽  
Disease Stabilization ◽  
Recommended Phase Ii Dose

Purpose We performed a phase I trial of intrathecal (IT) liposomal cytarabine (DepoCyt; Enzon Pharmaceuticals, Piscataway, NJ and SkyePharma Inc, San Diego, CA) to determine the maximum-tolerated dose, the dose-limiting toxicities, and the plasma and CSF pharmacokinetics of IT lipsomal cytarabine in children ≥ 3 years of age with advanced meningeal malignancies. Patients and Methods Eighteen assessable patients received IT liposomal cytarabine through either an indwelling ventricular access device or via lumbar puncture. Liposomal cytarabine was given once every 2 weeks during induction, once every 4 weeks during consolidation, and once every 8 weeks during the maintenance phase of treatment. The initial dose was 25 mg, with subsequent escalations to 35 and 50 mg. CSF pharmacokinetic samples were obtained in a subset of patients. Results Arachnoiditis, characterized by fever, headache, nausea, vomiting, and back pain was noted in the first two patients at the 25 mg dose level. Therefore, subsequent patients were treated with dexamethasone, beginning the day of liposomal cytarabine administration and continuing for 5 days. Headache (grade 3) was dose limiting in two of eight patients enrolled at the 50 mg dose level. Eight of the 14 patients assessable for response demonstrated evidence of benefit manifest as prolonged disease stabilization or response. Conclusion The maximum-tolerated dose and recommended phase II dose of liposomal cytarabine in patients between the ages of 3 and 21 years is 35 mg, administered with dexamethasone (0.15 mg/kg/dose, twice a day for 5 days). A phase II trial of IT liposomal cytarabine in children with CNS leukemia in second or higher relapse is in development.

A phase I, pharmacokinetic (PK) and pharmacodynamic (PD) study of the combination of an oral antimicrotubular agent, DJ-927 (D), and capecitabine (C) in patients (Pts) with advanced cancers

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2016-2016
Author(s):  
M. Beeram ◽  
W. M. Saif ◽  
J. Sarantopoulos ◽  
G. Schwartz ◽  
A. Patnaik ◽  
...  
Keyword(s):  
Phase I ◽  
Maximum Tolerated Dose ◽  
Preliminary Evidence ◽  
Prior Therapy ◽  
Elimination Half ◽  
Disease Stabilization ◽  
Hand Foot Syndrome ◽  
Age Range ◽  
Microtubule Stabilizer ◽  
Dose Limiting Toxicity

2016 Background: DJ-927, an oral microtubule stabilizer, has impressive cytotoxic activity in taxane-resistant tumors and an acceptable toxicity profile. C and Taxane combinations are active in solid tumors such as breast cancer. Non-overlapping mechanism of action and toxicity profiles and the convenience of an orally administered therapy have prompted a phase I evaluation of the combination. D was given orally once on day 1 and C for 14-days (D1–14), every three weeks. Methods: Eligible pts had evaluable cancer, minimal prior therapy and PS 0 - 2 ECOG. D was started at 18 mg/m2 on day 1 along with 1,250 mg/m2 of C orally B.I.D for 14 days, of a 21-day cycle. Incremental doses of both drugs were explored until the maximum tolerated dose (MTD) was reached. PK samples were collected during cycles 1 and 2, for assays of C and for D when given concurrently with C during cycle 1 and D given alone during cycle 2. Results: Twenty-seven pts [18 Male/ 9 Female; median age (range)- 58 yrs (33–70); PS 0 (n=8) ; PS 1 (n=19)] received 81 cycles [median (range)- 3 (1–8)] in 5 cohorts, with D and C 18/ 1250 mg/m2 (n = 3), 27/ 1250 mg/m2 (n = 7), 27/ 1900 mg/m2 (n = 7), 35/ 1900 mg/m2 (n = 3),and 27/ 2500 mg/m2 (n = 7). Dose-limiting toxicity (DLT) was grade 4 neutropenia in 2 of 3 pts at 35/ 1900 mg/m2 dose. Other common drug-related toxicities were leukopenia, nausea & vomiting (12 pts each, 44.4%), neutropenia, diarrhea and hand-foot syndrome (11 pts each, 40.7%), and fatigue (7 pts, 25.9%). A pt with hepatocellular carcinoma had an unconfirmed partial response at cycle 2 and 10 pts experienced disease stabilization lasting ≥ 12 weeks. The median elimination half-life (t½) of D was 182 hrs for cycle 1 (with C) and 204 hrs for cycle 2 (without C). Median tmax values for D with and without C occurred at 2 hours. Median clearance values (CL/F) for D in plasma were similar with and without C at 18.4 L/h/m2 and 19.8 L/h/m2, respectively. Conclusions: The combination of D and C is feasible and safe at the MTD of 27 mg/m2 and 2500 mg/m2, respectively. Co-administering C with D did not alter the PK of either drug. Preliminary evidence of antitumor activity suggests that further studies of this combination are warranted. [Table: see text]

Final results of a dose escalation (DE), pharmacokinetic (PK), and pharmacodynamic (PD) study of two schedules of OSI-930 in patients (pts) with advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3564-3564
Author(s):  
S. George ◽  
R. Lal ◽  
D. R. Camidge ◽  
H. Arkenau ◽  
J. Chick ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Tumor Regression ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Dce Mri ◽  
Glycolytic Activity ◽  
Heavily Pretreated ◽  
Xenograft Models ◽  
Expansion Cohort

3564 Background: OSI-930 is an oral TKI with potent activity against Kit, VEGFR2, and PDGFR. Preclinical studies demonstrate tumor regression with long-term remissions across multiple xenograft models. Methods: Sequential cohorts of pts with advanced solid tumors received continuous daily OSI-930 to determine the maximum tolerated dose (MTD) and to evaluate safety, PK/PD and efficacy of OSI-930 with both QD and BID dosing. An expansion cohort was enrolled for detailed PD analysis including sVEGFR2 plasma levels, PET imaging in GIST pts or DCE-MRI in selected pts. Results: A total of 58 pts were treated (20M/38F; median 60 years (range 19–83)). OSI-930 was dosed up to 1600 mg QD without reaching MTD. 46 pts received BID dosing [mg(# pts treated)]; 400(7), 500 (31) and 600(8). DLT's were seen in 3/8 pts at 600 mg BID; G3 rash (2 pts) and G4 GGT; and 3/31 at 500 mg BID; G3 myalgia, G3 fatigue and G3 lipase. G3 hypertension was noted in 3/46 pts but not dose-limiting. Common G1/2 toxicities were fatigue (37%), diarrhea (27%), nausea (31%), and rash (24%). Objective (CA125) responses were seen in platinum-resistant ovarian cancer (2 PR/8) while in heavily pretreated GIST (median 4 prior therapies including imatinib/sunitinib), 8/18 pts achieved SD ≥12 w. Median therapy duration in the BID arm was 9 w and 18/46 pts with SD ≥12 w. PK indicated that Css were achieved after ∼7d with BID dosing. PET scans showed reduction in glycolytic activity in 4/9 pts and DCE-MRI response was seen in 4/6 pts. A trend in decreased sVEGFR levels was seen at higher doses. Conclusions: At the MTD level of 500 mg BID OSI-930 is an active, well-tolerated compound with clinically relevant antitumor activity and exposure levels consistent with antitumor activity in preclinical models. PD data indicate mechanistic proof of concept for OSI-930. OSI-930/erlotinib combination phase I study is currently enrolling. [Table: see text]

ABT-888 (veliparib) in combination with weekly carboplatin and paclitaxel in advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS1138-TPS1138
Author(s):  
Jorge Arturo Rios-Perez ◽  
Jan H. Beumer ◽  
Leonard Joseph Appleman ◽  
Hussein Abdul-Hassan Tawbi ◽  
Edward Chu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Solid Tumors ◽  
Maximum Tolerated Dose ◽  
Cytotoxic Agents ◽  
Parp Inhibition ◽  
Advanced Solid Tumors ◽  
Breast Cancer Patients ◽  
Expression Of Genes ◽  
Recommended Phase Ii Dose ◽  
Expansion Cohort

TPS1138 Background: The combination of paclitaxel and carboplatin is widely used for the treatment of patients with advanced solid tumors of diverse histologies. In breast cancer patients, a weekly regimen of paclitaxel has shown greater efficacy with comparable safety, when compared to every-three-weeks dosing (ECOG 1199). ABT-888 (veliparib) is an oral inhibitor of poly-ADP-ribose polymerase (PARP). Inhibition of PARP has been shown in preclinical studies to potentiate the effect of cytotoxic agents which induce DNA damage, such as platinum agents. The preclinical synergy of carboplatin with veliparib and the efficacy of the combination of paclitaxel with carboplatin supports exploration of this triplet regimen. Methods: This 3+3 phase I trial will seek to determine the maximum tolerated dose (MTD) of the combination of carboplatin (AUC 2), paclitaxel (80 mg/m2), and veliparib in patients with advanced solid tumors. Veliparib will be escalated beginning at 50 mg PO BID to a maximum of 200mg PO BID. Treatment will be given on a weekly basis over a 21-day cycle. There will be an expansion cohort of 6-12 patients with triple negative breast cancer at the maximum tolerated dose. This group of patients will undergo mandatory pre- and post-cycle 1 tumor biopsies. Secondary aims of the study include safety and toxicity of the combination, its pharmacokinetic and pharmacodynamic effects, documentation of any anti-tumor response, and assessment of the characteristics of the tumor specimens obtained in the expansion cohort that may contribute to efficacy. The latter will include whole genome microarray analysis to evaluate expression of genes involved in DNA repair pathways. Currently, the recommended phase II dose has not been determined and enrollment is ongoing on the last planned dose level (veliparib 200 mg BID).

A phase I study of the safety and pharmacokinetics of DSTP3086S, an anti-STEAP1 antibody-drug conjugate (ADC), in patients (pts) with metastatic castration-resistant prostate cancer (CRPC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5020-5020 ◽  
Author(s):  
Daniel Costin Danila ◽  
Russell Zelig Szmulewitz ◽  
Celestia S. Higano ◽  
Houston Gilbert ◽  
Robert S. Kahn ◽  
...  
Keyword(s):  
Study Drug ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Antibody Drug Conjugate ◽  
Grade 3 ◽  
Prostate Cancers ◽  
Recommended Phase Ii Dose ◽  
Expansion Cohort ◽  
Ecog Ps

5020 Background: Six-transmembrane epithelial antigen of the prostate-1 (STEAP1) protein is a cell-surface antigen overexpressed in human epithelial prostate cancers. The ADC DSTP3086S contains the humanized IgG1 anti-STEAP1 monoclonal antibody linked to the potent anti-mitotic agent MMAE. Methods: This study evaluated safety, pharmacokinetics, and pharmacodynamic activity of intravenous DSTP3086S (0.3-2.8 mg/kg) given every 3 weeks (q3w) to pts with CRPC. A traditional 3+3 design was used to determine maximum-tolerated dose, followed by cohort expansion at the recommended Phase II dose (RP2D). Clinical activity was evaluated per PCWG criteria. Dose escalation results are presented. Results: Twenty-eight pts were enrolled with a median age of 67 (43-76), all ECOG PS 0-1, and with a median of 7 prior systemic regimens (including a median of 4 hormonal and 3 non-hormonal regimens). Pts received a median of 3 doses (range 1-10) of DSTP3086S. Reversible Grade 3 transaminitis DLTs occurred in one pt each in the 2.25 mg/kg and 2.8 mg/kg cohorts. Serious AEs (SAE) related to study drug (3 total) included one DVT (Grade 3) in the 1.5 mg/kg cohort, as well as one GI hemorrhage (Grade 3) and one sepsis event (Grade 5) in the 2.25 mg/kg cohort. The most common related AEs across all doses were fatigue (36%), nausea (32%), constipation (25%), decreased appetite and diarrhea (each 21%), and musculoskeletal pain and vomiting (each 18%). Exposure for total antibody, free MMAE, and conjugated MMAE was dose proportional. Approximately 60% of the tumor samples assessed showed high STEAP1 expression. CTC reductions were most robust at 2.8 mg/kg; 4/4 patients with unfavorable CTCs at baseline (median of 99, range: 21-205) exhibited CTC conversions from unfavorable to favorable (<5) after a single dose of DSTP3086S. CTC conversions were also observed at lower doses. PSA decreases of ≥ 50% were observed in 1 pt at 2.25 mg/kg, and 2 pts at 2.8 mg/kg who also had PCWG2 radiologic responses. Conclusions: DSTP3086S at the RP2D of 2.8 mg/kg q3w has a tolerable safety profile and shows evidence of anti-tumor activity. Enrollment in the expansion cohort is ongoing.

A phase I study of the combination of sorafenib (Sor) and bortezomib (Bor) in patients (pts) with metastatic melanoma (MM).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9076-9076 ◽  
Author(s):  
Ryan J. Sullivan ◽  
Nageatte Ibrahim ◽  
Donald P. Lawrence ◽  
Julie Aldridge ◽  
F. Stephen Hodi ◽  
...  
Keyword(s):  
Dose Level ◽  
Tumor Response ◽  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Free Survival ◽  
Hand Foot Syndrome ◽  
Expansion Cohort ◽  
Dose Levels ◽  
Clinical Trial Information

9076 Background: Sor is a small molecule tyrosine kinase inhibitor that has many targets and previously was developed for the treatment of MM. Bor is a proteasome inhibitor widely used to treat multiple myeloma and other malignancies. In preclinical studies, the combination of Sor and Bor has been shown to modulate expression of BCL-family members and augment cytotoxicity in MM cell lines. Methods: Pts with MM were enrolled in cohorts of 3 during dose escalation to determine the maximum tolerated dose (MTD) of Sor twice daily (BID) in combination with Bor given days 1, 8, 15 of a 28 day cycle. The MTD was defined as the highest dose level at which less than 33% of pts exhibited a dose limiting toxicity (DLT). Efficacy, as measured by 6-month progression free survival (PFS) and response rate (RR) per RECIST, was documented. Results: Eleven pts were enrolled in 3 dose levels. DLTs (fatigue and rash respectively) were seen in 2 of 3 patients enrolled at the highest dose level (Sor 400 mg and Bor 1.3 mg/m2). The next lowest dose level (Sor 400 BID and Bor 1.0) enrolled 5 pts and none had DLTs. Thus, this dose level was defined as the MTD. Toxicities seen in >20% of pts included hypertension, pruritus, hand-foot syndrome, mucositis, nausea, vomiting, rash, constipation, abdominal pain, anorexia and fatigue. Of 9 response evaluable pts, none had radiographic evidence of tumor response. Two of 11 (18%) pts remained progression free for greater than 6 months. Conclusions: The combination of Sor and Bor is safe, but minimally active in pts with MM. In the absence of tumor response at or above the MTD, the study was closed with only 5 pts treated at the provisional MTD and enrollment to a planned dose expansion cohort will not occur. Clinical trial information: NCT01078961.

Phase I Clinical Trial of Intrathecal Topotecan in Patients With Neoplastic Meningitis

2003 ◽  
Vol 21 (1) ◽  
pp. 143-147 ◽  
Author(s):  
Susan M. Blaney ◽  
Richard Heideman ◽  
Stacey Berg ◽  
Peter Adamson ◽  
Andy Gillespie ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Optimal Dose ◽  
Maximum Tolerated Dose ◽  
Neoplastic Meningitis ◽  
Toxic Effects ◽  
Fixed Dose ◽  
Pharmacokinetic Studies ◽  
Disease Stabilization ◽  
Recommended Phase Ii Dose

Purpose: A phase I trial of intrathecal (IT) topotecan was performed to determine the optimal dose, the dose-limiting toxic effects, and the incidence and severity of other toxic effects in patients 3 years and older with neoplastic meningitis. Patients and Methods: Twenty-three assessable patients received IT topotecan administered by means of either lumbar puncture or an indwelling ventricular access device (Ommaya reservoir). Intrapatient dose escalation from 0.025 mg to 0.2 mg was performed in the first cohort of patients. Subsequent cohorts of patients were treated at fixed dose levels of 0.2 mg, 0.4 mg, or 0.7 mg. Serial samples of CSF for pharmacokinetic studies were obtained in a subset of patients with Ommaya reservoirs. Results: Arachnoiditis, characterized by fever, nausea, vomiting, headache, and back pain, was the dose-limiting toxic effect in two of four patients enrolled at the 0.7 mg dose level. The maximum-tolerated dose (MTD) was 0.4 mg. Six of the 23 assessable patients had evidence of benefit manifested as prolonged disease stabilization or response. Conclusion: The MTD and recommended phase II dose of IT topotecan in patients who are 3 years or older is 0.4 mg. A phase II trial of IT topotecan in children with neoplastic meningitis is in progress.

scholarly journals Phase IB Study of Sorafenib and Evofosfamide in Patients with Advanced Hepatocellular and Renal Cell Carcinomas (NCCTG N1135, Alliance)

2021 ◽  
Author(s):  
Nguyen Tran ◽  
Nathan Foster ◽  
Amit Mahipal ◽  
Thomas Byrne ◽  
Joleen Hubbard ◽  
...  
Keyword(s):  
Renal Cell ◽  
Maximum Tolerated Dose ◽  
First Line ◽  
Renal Cell Carcinomas ◽  
Phase Ib ◽  
Hand Foot Syndrome ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Dose Levels ◽  
Anti Tumor Activity

Abstract Background: Sorafenib (Sor) remains a first-line option for hepatocellular carcinoma (HCC) or refractory renal cell carcinomas (RCC). PLC/PRF/5 HCC model showed upregulation of hypoxia with enhanced efficacy when Sor is combined with hypoxia-activated prodrug evofosfamide (Evo). Methods: This phase IB 3 + 3 design investigated 3 Evo dose levels (240, 340, 480 mg/m2 on days 8, 15, 22), combined with Sor 200 mg orally twice daily (po bid) on days 1-28 of a 28-day cycle. Primary objectives included determining maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of Sor + Evo. Results: Eighteen patients were enrolled (median age 62.5 years; 17 male /1 female; 12 HCC/6 RCC) across three dose levels (DL0: Sor 200 mg bid/Evo 240 mg/m2 [n=6], DL1:Sor 200 mg bid/Evo 480 mg/m2 [n=5], DL1a: Sor 200 mg bid/Evo 340 mg/m2 [n=7]). Two dose-limiting toxicities (DLTs) were reported with Evo 480 mg/m2 (grade 3 mucositis, grade 4 hepatic failure). Grade 3 rash DLT was observed in one patient at Evo 240 mg/m2. No DLTs were observed at Evo 340 mg/m2. MTD and RP2D were established as Sor 200 mg/Evo 340 mg/m2 and Sor 200/Evo 240 mg/m2, respectively. The most common treatment-related adverse events included fatigue, hand-foot syndrome, hypertension, and nausea/vomiting. Two partial responses were observed, one each at DL0 and DL1a.; disease control rate was 55%.Conclusions: RP2D was established as sorafenib 200 mg bid + Evo 240 mg/m2. While preliminary anti-tumor activity was observed, future development must account for advances in immunotherapy in HCC/RCC. NCT01497444Date of registration December 20, 2011

Phase I study of vandetanib (V) and bevacizumab (B) combination therapy evaluating the VEGF and EGF signal transduction pathways in adults with solid tumors and NHL

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3522-3522
Author(s):  
M. Gutierrez ◽  
A. J. Murgo ◽  
D. Allen ◽  
I. Turkbey ◽  
E. R. Gardner ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Circulating Endothelial Cells ◽  
Qtc Interval ◽  
Tumor Vascularity ◽  
Dce Mri ◽  
Disease Stabilization ◽  
Hand Foot Syndrome ◽  
Elevated Creatinine

3522 Background: (V), a small molecule tyrosine kinase inhibitor, has strong inhibitory activity against VEGFR-2 and the EGF RTK. (B), a humanized anti-VEGF monoclonal antibody, blocks the binding of human VEGF to its receptors. We proposed that dual blockade of the VEGF pathway provides an added therapeutic effect compared with either agent alone. Methods: A standard 3–6 pt/cohort design, dose-escalation Phase I study was performed. (V) was self-administered PO, days 1–21 of each 21-day cycle. (B) was administered by IV infusion Q 3 wks. Objectives: Determine the toxicity profile and the MTD of the combination of (V+B); evaluate (V) pharmacokinetics, changes in tumor vascularity by dynamic contrast enhanced MRI (DCE-MRI) and effects of (V+B) treatment on circulating endothelial progenitors and mature circulating endothelial cells. Eligibility: ECOG ≤ 2, adequate organ function. The MTD is the dose level at which no more than 1 of 6 patients experience DLT during the first 2 cycles of treatment, and the dose below at which at least 2 (of ≤6) patients have DLT due to drug treatment. Results: 9 pts have been accrued to date. Diagnosis: pancreatic-1, NSCLC-1, colorectal-3, peritoneal mesothelioma-1, melanoma-1, NHL-1, jejunal adenocarcinoma (JAC)-1. 1 DLT (gr 3 Allergic reaction) was observed at DL 2. HTN was the most common toxicity at DL 2. Other gr 2–3 toxicities seen beyond 2 cycles included: diarrhea, elevated creatinine, leucopenia, anemia, thrombocytopenia, hemorrhage, prolonged QTc interval, proteinuria, rash (hand-foot syndrome / acneiform). Partial Response (PR) was achieved in 2 pts (pancreatic 14 mos + and JAC 6 mos); disease stabilization in 5 pts (4 mos +). DCE-MRI results showed a reduction in the parameters of permeability, (ktrans and kep), associated with one PR. Conclusions: We decided not to escalate beyond DL 2 due to the gr 2–3 toxicities observed with chronic therapy. We recommend (V): 200mg daily and (B): 5mg/kg IV q3 weeks as the Phase II dose. [Table: see text] No significant financial relationships to disclose.

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