Inhibition of the Heat Shock Protein 90 (Hsp90) chaperone with the novel agent IPI-504 to overcome resistance to tyrosine kinase inhibitors (TKIs) in metastatic GIST: Updated results of a phase I trial

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10024-10024 ◽  
Author(s):  
G. D. Demetri ◽  
S. George ◽  
J. A. Morgan ◽  
A. Wagner ◽  
M. T. Quigley ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Drug Exposure ◽  
Kinase Inhibitors ◽  
Heat Shock Protein 90 ◽  
Resistance Mutations ◽  
Active Metabolites ◽  
Hsp90 Chaperone ◽  
Dose Levels ◽  
Fdg Avidity

10024 Background: Prior work from our team demonstrates that inhibition of the Hsp90 chaperone protein results in preferential destruction of the mutated KIT kinase in human GIST cell lines regardless of TKI-resistance mutations. To translate this into clinical application, we are conducting a phase I trial of IPI-504, a novel Hsp90 inhibitor, for patients (pts) with metastatic TKI-resistant GIST. Methods: Pts with metastatic TKI-resistant GIST were eligible to enter and receive IPI-504, IV in 250 cc of normal saline over 30 mins, on days 1, 4, 8 and 11 of a 21 day cycle. Serial monitoring with 18FDG-PET/CT imaging at baseline, day 11, and day 21, as well as PK profiling of IPI- 504 and its major active metabolites (17-AAG and 17-AG), were performed on all pts. Results: 21 pts with progressive GIST after both prior imatinib and sunitinib have been entered at 5 dose levels (90 mg/m2 IPI-504 [n=6], 150 [3], 225 [3], 300 [3], 400 [6]); 18 are now evaluable. The maximal tolerated dose has not been reached, and enrollment is ongoing. AEs possibly related to IPI-504 include Grade 1–2 elevation of alkaline phosphatase, fatigue, and headache; one DLT was observed in the 1st and 5th dose levels. PET demonstrated decreases in tumor FDG avidity in 1/6 pts, 1/3, 3/3, 1/3, and 2/3 at the respective dose levels in this schedule (3 patients were inevaluable by PET). Reactivation of tumor FDG uptake by PET was seen during the planned 10-day breaks in IPI-504 administration with reinduction of decreased tumor FDG avidity upon re-treatment with IPI-504. Although no RECIST-defined “anatomic responses” were noted, stable disease has allowed 7 pts to continue on study treatment for ≥ 4 cycles. Conclusions: Targeting Hsp90 is a novel therapeutic strategy in TKI-resistant GIST. IPI-504 has been well-tolerated overall, and the activity seen with decreased FDG avidity of GIST lesions, as well as the induction of SD in pts with documented prior progression, is promising with this non-TKI agent. Reactivation of PET signal in lesions during breaks in IPI-504 dosing is similar to flares with TKI discontinuation. To address this, a new schedule of continuous BIW dosing of IPI-504 has been added to optimize drug exposure. No significant financial relationships to disclose.

A phase I/II trial of pazopanib alternating with bevacizumab in treatment-naïve metastatic clear cell renal cell carcinoma (CCRCC) patients: Phase I results.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 561-561
Author(s):  
Saby George ◽  
Laurie Herbst ◽  
Marcus Sikorski ◽  
Ann Marie Diraddo ◽  
Gissou Azabdaftari ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Kinase Inhibitors ◽  
Single Agent ◽  
Objective Response ◽  
Progression Free Survival ◽  
Cell Renal Cell Carcinoma ◽  
Study Results ◽  
Treatment Naïve ◽  
Dose Levels

561 Background: Pazopanib as single agent and bevacizumab plus interferon were approved for use in metastatic RCC (MRCC) based on their ability to modulate the vasculature and prolong progression free survival. VEGF levels rose unopposed while using VEGF tyrosine kinase inhibitors (TKI) without break. We hypothesized that adding a break as well as bevacizumab which removes VEGF could prolong PFS in MRCC pts. Methods: This phase I trial was conducted in VEGF treatment naïve MRCC pts. This trial utilized a unique regimen of alternating Pazopanib (day 1-28) with bevacizumab (on days 36 and 50) in a 10-week cycle. The study employed a classic 3+3 design for dose escalation (dose levels in table 1). Safety utilized CTCAE version 4.0 and response evaluation was done using RECIST 1.1 criteria. The primary endpoint of this phase I trial was to find the recommended phase 2 dose (RP2D) of this novel regimen. Key secondary endpoints included objective response rate (ORR), safety/ toxicity and pharmacokinetics. Phase I safety committee acknowledged the completion and approved reporting of Phase I portion of this study. Results: This phase I study was conducted at two academic centers. Twenty-five pts were enrolled in the phase I portion. Median age was 64 years and 68% were male patients. The Commonest adverse events (AE) included fatigue (64%), diarrhea (52%), hypertension (48%), nausea (36%), dysgeusia (36%), vomiting (24%) and proteinuria (28%). The commonest grade 3/4 AE of more than 5% frequency included hypertension (20%) and proteinuria (12%). The dose levels 1 and 4 were expanded due to one DLT each and RP2D was established at dose level 4. The ORR was 25% among evaluable pts who completed at least one cycle of therapy (n=20). The median PFS of the ITT cohort (n=25) was 20.9 months. Conclusions: These data demonstrate that this novel regimen could be safely tested in a phase II trial. The safety and efficacy data suggest that this novel regimen could be optimal for MRCC patients with favorable/intermediate risk. Clinical trial information: NCT01684397. [Table: see text]

Phase I trial of concurrent intraperitoneal and continuous intravenous infusion of fluorouracil in patients with refractory cancer.

1988 ◽  
Vol 6 (1) ◽  
pp. 158-162 ◽  
Author(s):  
B Reichman ◽  
M Markman ◽  
T Hakes ◽  
N Kemeny ◽  
D Kelsen ◽  
...  
Keyword(s):  
Phase I ◽  
Intravenous Infusion ◽  
Phase I Study ◽  
Clinical Utility ◽  
Phase I Trial ◽  
Drug Exposure ◽  
Continuous Intravenous Infusion ◽  
Future Studies ◽  
Systemic Drug Exposure ◽  
Systemic Drug

In an effort to maximize both local-regional and systemic drug exposure to tumor in the peritoneal cavity, a phase I study was conducted that examined the simultaneous daily intraperitoneal (IP) and continuous intravenous infusion (CVI) of fluorouracil (5-FU) to 32 patients with refractory cancer. IP 5-FU administered at 1,000 mg/d with concurrent 5-FU by CVI at 1,000 mg/m2/d for four consecutive days was well tolerated. One patient with a primary gastrointestinal (GI) malignancy with minimal volume disease experienced a surgically defined complete remission. In theory, this regimen may demonstrate clinical utility as an adjuvant treatment of certain GI malignancies. Future studies are planned in this clinical setting.

Phase I trial of intramuscularly administered tumor necrosis factor in patients with advanced cancer.

1989 ◽  
Vol 7 (3) ◽  
pp. 298-303 ◽  
Author(s):  
A A Jakubowski ◽  
E S Casper ◽  
J L Gabrilove ◽  
M A Templeton ◽  
S A Sherwin ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Phase I ◽  
Tumor Necrosis ◽  
Phase I Trial ◽  
Human Tumor ◽  
Serum Concentrations ◽  
Clinically Significant ◽  
Enzyme Elevation ◽  
Dose Levels ◽  
Necrosis Factor

A phase I trial of intramuscularly administered recombinant human tumor necrosis factor (rTNF) was conducted in 19 adult patients with advanced solid tumors. The agent was administered daily for up to five consecutive days every other week for two to four courses. Doses of rTNF ranged from 5 to 200 micrograms/m2/d. Dose-limiting toxicities were encountered at doses greater than 100 micrograms/m2/d. Toxicities included tenderness, erythema and induration at the site of injection, fatigue, fever, chills, headache, anorexia, nausea, vomiting, and diarrhea. Moderate to marked reductions in WBC and platelet counts were observed regularly at the highest dose levels, but none were clinically significant. Hepatic enzyme elevation was seen frequently, and two patients developed hyperbilirubinemia. Only one of seven patients treated with doses greater than 100 micrograms/m2/d completed the planned course of therapy. Even at the highest dose levels, serum concentrations of rTNF could only rarely be detected in the serum. No therapeutic responses were observed. The maximal tolerated dose (MTD) of rTNF in this trial was 150 micrograms/m2/d, administered for two courses.

scholarly journals PV-0550: Combined high dose radiation and tyrosine kinase inhibitors in renal cell carcinoma: a phase I trial

2017 ◽  
Vol 123 ◽  
pp. S293-S294
Author(s):  
K. De Wolf ◽  
S. Rottey ◽  
K. Vermaelen ◽  
K. Decaestecker ◽  
N. Sundahl ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Tyrosine Kinase ◽  
Phase I ◽  
Cell Carcinoma ◽  
Tyrosine Kinase Inhibitors ◽  
Renal Cell ◽  
Phase I Trial ◽  
Kinase Inhibitors ◽  
High Dose ◽  
Dose Radiation

A Phase I Trial of Sirolimus (Rapamycin) in Pediatric Patients with Relapsed/Refractory Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2834-2834 ◽  
Author(s):  
Susan R. Rheingold ◽  
Nancy Sacks ◽  
Yueh J. Chang ◽  
Valerie I. Brown ◽  
David T. Teachey ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Stable Disease ◽  
Phase I Trial ◽  
Pediatric Patients ◽  
Loading Dose ◽  
Mtor Inhibition ◽  
Level 1 ◽  
Dose Levels

Abstract Background: Downstream inhibition of the mammalian Target of Rapamycin (mTOR) pathway by sirolimus affects a variety of cellular functions including cap-dependent protein translation and cell cycle progression from the G1-to-S phase. Inhibition of mTOR also leads to dysregulation of the upstream signaling pathway that couples growth factor-receptor binding to mTOR activation through the PI-3 kinase/Akt pathway and may render PTEN-induced resistant lymphoblasts sensitive to agents that target the mTOR pathway. This hypothesis is supported by preclinical data which shows that sirolimus inhibits growth of ALL lines in vitro and has activity in a murine model of leukemia including ALL xenografts. Based upon these preclinical data we have piloted a Phase I trial of sirolimus in pediatric patients with relapsed acute leukemia. Methods: Pediatric patients with ≥ 2nd relapse of acute leukemia were enrolled in a Phase I dose escalation trial of oral daily sirolimus. We used a starting dose that is known to be well tolerated in pediatric renal transplant recipients and results in levels that inhibit ALL growth in vitro. At dose level 1, a loading dose of 9 mg/m2 was given on day 0, and 3 mg/m2 was given daily on days 1 to 21 or 28. Dose level 2 has a loading dose of 12 mg/m2 and daily dose of 4mg/m2. Sirolimus trough levels were obtained on days 3, 7, and end of cycle. Bone marrow aspirates (BM) were performed prior to therapy, and on day 7 (if no peripheral blasts) and day 21 or 28. Peripheral blood (PB) mononuclear cells and PB and/or BM lymphoblasts were obtained on days 0, 3, 7, 14, and 21/28 to evaluate the effect of sirolimus on intracellular targets, including ribosomal protein S6 (a pharmocodynamic marker of mTOR inhibition), 4e-BP1 and STAT5. Results: To date, 5 males and 3 females, ages 1–21, have been enrolled on study at the first 2 dose levels. Six patients had ALL, 1 infant had MLL(r) ALL, and 1 had AML. They had received 2–4 prior therapies. Three patients with ALL had stable disease at the end of the first cycle. One had a decrease in BM lymphoblasts from 39% to 12% by day 28 and a drop in absolute blast count (ABC) in the PB from 1134 to 290 but remained thrombocytopenic. The patient with MLL(r) infant ALL had a decrease in PB ABC from 62,415 to 0 by day 14 but had no change in BM lymphoblast % on day 21. Two of the 3 patients with stable disease progressed during their second cycle of therapy. The remaining 5 patients had progressive disease or were removed from study prior to the end of cycle 1 and were non-evaluable. At dose level 1 average trough level on day 7 was 10.9 (range 1–20.7) and at the end of the first cycle for non-progressors was 8.5 (range 5.8–12.2). There have been no DLTs attributable to sirolimus in any cycle to date. Preliminary immunoblots show hypophosphorylation of S6 in patients’ PB and BM after initiating sirolimus therapy. Conclusions: Sirolimus was well tolerated in pediatric patients due to its ease of administration and lack of toxicity. At the first and second dose levels there have been 2 patients and 1 patient with stable disease, respectively. Preliminary biologic data shows evidence of inhibition of mTOR, manifested by a decrease in phosphorylated S6, suggesting that S6 may be used as a biomarker for response to mTOR inhibition. Although sirolimus at these doses had a modest impact on the leukemia burden, it may be more effective when used in concert with other cytotoxic agents that inhibit cell growth and survival. Combined therapy is being investigated.

Phase I Trial of High-Dose Clofarabine and Busulfan as a Myeloablative Regimen Prior to Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Relapsed or Refractory Acute Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 198-198 ◽  
Author(s):  
Sherif Farag ◽  
Lisa L Wood ◽  
Jennifer E. Schwartz ◽  
Shivani Srivastava ◽  
Robert P. Nelson ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Acute Leukemia ◽  
Phase I ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Phase I Trial ◽  
High Dose ◽  
Dose Levels

Abstract Abstract 198 Fludarabine in combination high-dose busulfan (Bu) is an effective myeloablative preparative regimen for allogeneic stem cell transplantation. At doses used, however, fludarabine has only modest anti-leukemic activity. Clofarabine (Clo) is a second-generation purine nucleoside antimetabolite with significant single agent activity in patients with AML and ALL. The novel combination of Clo with Bu may provide improved disease activity safely. Therefore, we conducted a phase I trial to determine the maximum tolerated dose (MTD) of Clo in combination with Bu in patients with high-risk acute leukemia. Patients received i.v. Bu (Busulfex) 0.8 mg/kg q 6 hrs on days −6 to −3 and Clo at 30–60 mg/m2/day on days −6 to −2 in successive cohorts. Stem cells were infused day 0. GvHD prophylaxis included sirolimus plus tacrolimus starting day −2 to day 100, tapering to day 180. Patients were eligible if they were 18–60 years, had primary refractory or relapsed and refractory AML or ALL, or were in CR2 or higher, had Karnofsky performance status ≥70%, and adequate organ function. Donors were HLA-matched related (5/6 or 6/6 antigen-matched) or unrelated (10/10 allele-matched). Toxicity was scored using the Common Terminology Criteria for Adverse events, version 3.0. Dose limiting toxicity (DLT) was defined as any grade 3–4 non-hematologic toxicity that did not resolve to grade 2 or less by day 30. A total of 15 patients were treated at 4 Clo dose levels, 30 (n=3), 40 (n=3), 50 (n=3), and 60 mg/m2 (n=6). Seven males and 8 females of median age 48 (30–58) years, with AML (n=13) or ALL (n=2) were treated. At transplant, leukemia was relapsed and refractory (n=8), primary refractory (n=6), or in CR2 (n=1). Median number of lines of treatment failed before transplant was 2 (1–3). Median marrow blasts at transplant was 12% (3%–83%). Hematopoietic cell transplants were from related (n=9) and unrelated (n=6) donors. All patients engrafted. Median time to neutrophils >0.5×109/l was 16 (12–20) days, and to platelets >20×109/l was 15 (10–42) days. One patient treated at the 30 mg/m2 dose level failed to achieve platelets > 20×109/l. No DLT was observed. Transient Grades 3–4 non-hematological toxicities were evenly distributed across all 4 dose levels, and included vomiting (n=3), mucositis (n=9), hand-foot syndrome (n=1), and elevation of AST/ALT (n=10). Grades 3–4 elevation of AST/ALT occurred in 2 of 3 patients treated at 30 mg/m2, 3 of 3 at 40 mg/m2, 2 of 3 at 50 mg/m2, and 3 of 6 patients at 60 mg/m2 dose levels. AST/ALT peaked at day −1 or 0 and returned to baseline in all patients by day 10, with no long-term sequelae. There was no correlation between Clo dose and peak AST/ALT. One patient developed acute renal failure at the 60 mg/m2 dose on day +12 in association with elevated tacrolimus levels, although the creatinine subsequently normalized. Two patients, both at the 30 mg/m2 dose, developed mild veno-occlusive disease of the liver which was self-limiting. One treatment-related death due to sepsis was observed at day +104 in a patient treated at the 30 mg/m2 dose. Thirteen of 15 patients were in CR by day 30; 2 patients, treated at 40 mg/m2 and 50 mg/m2, respectively, failed to achieve CR. Day 100 mortality was 0. With a median follow-up of 313 days, the 1-year relapse-free survival was 51% ± 15%, and the 1-year overall survival was 61% ± 14%. Clo at doses as high as 60 mg/m2/day × 5 days in combination with Bu 3.2 mg/kg/day × 4 days is well tolerated and demonstrates promising efficacy in a very-high risk acute leukemia population. The MTD has not been reached. We recommend Phase II testing of Clo 60 mg/m2/day × 5 days in combination with high-dose Bu as a myeloablative regimen for allogeneic stem cell transplantation in patients with acute leukemia. Disclosures: No relevant conflicts of interest to declare.

Final Results of a Phase I Study of the Fc Engineered CD19 Antibody XmAb®5574 (MOR00208) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2894-2894 ◽  
Author(s):  
Jennifer A. Woyach ◽  
Farrukh Awan ◽  
Ian W. Flinn ◽  
Rolondo Enoch ◽  
Paul A. Foster ◽  
...  
Keyword(s):  
High Risk ◽  
Febrile Neutropenia ◽  
Adverse Events ◽  
Phase I ◽  
B Cell ◽  
Dose Level ◽  
Phase I Trial ◽  
Hematologic Toxicity ◽  
B Cell Malignancies ◽  
Dose Levels

Abstract Abstract 2894 Antibody (Ab) therapies such as the CD20 monoclonal abs rituximab and ofatumumab are commonly used in CLL alone and in combination with chemotherapy, however, CD20 density is low on CLL cells, suggesting this may not be the ideal target. CD19, which is ubiquitously expressed on CLL cells and those of other B cell malignancies is a reasonable candidate for ab targeting. XmAb5574 is a novel humanized IgG1 CD19 monoclonal ab with an engineered Fc region to enhance Fc gamma receptor binding affinity. In vitro, this ab demonstrates direct cytotoxicity and antibody dependent cellular phagocytosis similar to rituximab, however, shows enhanced natural killer antibody dependent cellular cytotoxicity compared to other therapeutic abs used in CLL (Awan, FT Blood 2009). We have performed a first in human trial of this ab as a single agent in relapsed or refractory (R/R) CLL, and present the results in this report. This study is a multi-institutional phase I trial of XmAb5574 in patients (pts) with R/R CLL. Eligible pts were those with CLL who had at least 1 prior therapy and required treatment by International Working Group on CLL (IWCLL) 2008 Guidelines (Hallek, M Blood 2008), had Eastern Cooperative Oncology Group Performance Status <3, had platelets ≥50,000/mm3, and had adequate organ function. Primary endpoints were to determine maximal tolerated dose (MTD), describe toxicity, and characterize pharmacokinetics (PK). A secondary endpoint was to explore efficacy. An accelerated titration design was used in which 1 pt was accrued to the first two dose levels provided there were no dose limiting toxicities (DLT) or ≥ grade 2 adverse events (AE), and then a standard 3×3 design was employed from dose level 3 forward. Dose levels included 0.3, 1, 3, 6, 9, and 12 mg/kg with an expansion to a total of 16 pts at the MTD. XmAb5574 was administered as an intravenous infusion on days 1, 4, 8, 15, and 22 of cycle (C) 1, and on days 1, 8, 15, and 22 of C2. Toxicity was assessed using the National Cancer Institute's Common Criteria for Adverse Events v4.0 for non-hematologic toxicity, and IWCLL 2008 guidelines for hematologic toxicity. Disease response assessment by physical exam was performed on C1D28, C2D28, and 4, 8, and 12 weeks after the end of C2. Radiographic assessment was performed C2D28. 27 pts were enrolled to this phase I trial. The median age of all pts was 66 years (range 40–84). The pts were generally high risk: 14 (52%) had high-risk disease by Rai stage, 8 (30%) had del(11q22.3) and 10 (37%) had del(17p13.1) by FISH, and 24 (89%) had IgVH unmutated disease. The median number of prior therapies was 4 (range 1–14). Toxicity with this agent was modest. Dose escalation continued without dose limiting toxicity (DLT) until the highest dose level, in which one patient experienced grade 4 neutropenia associated with febrile neutropenia which required dose discontinuation. 100% of patients experienced any AE, with the majority of AE being grade 1–2. The most common AEs were infusion reactions in 18 patients (67%), all of which were grade 1 or 2. Treatment-related Grade 3 or 4 AEs occurred in 5 pts (19%), and included neutropenia (n=3), thrombocytopenia (n=2), increased aspartate aminotransferase (AST) (n=1), febrile neutropenia (n=1), and tumor lysis syndrome (n=1). All were on the 12 mg/kg dose level except one pt receiving 1mg/kg who experienced neutropenia. Overall response rate by IWCLL 2008 criteria is 11%, all of which have been partial responses (PR). Using IWCLL 1996 response criteria which does not include CT scan assessment of disease resulted in a PR in 13 pts (42%). Only 2 pts had PD at the 8 week evaluation point. Responses occurred at the 6, 9, and 12 mg/kg dose levels. All objective responses were in pts categorized as CLL as opposed to SLL, and no patients with lymph nodes >5cm responded. PK was best modeled by a two-compartment model. Half-life was 14 days, with clearance 5mL/day/kg that was not dose-dependent. Across the dose range, area under the curve increased in a dose-proportional manner, while maximum concentration increased in a less than proportional manner. A steady-state was reached at or before infusion 9. XmAb5574 shows acceptable toxicity and signs of preliminary efficacy in patients with high-risk, heavily pretreated CLL. These results justify movement into phase II study in CLL as well as other B cell malignancies. Modest toxicity, in particular infectious toxicity, will potentially allow combinations with other active agents in CLL. Disclosures: Enoch: Xencor, Inc.: Employment. Foster:Xencor, Inc: Consultancy.

PLX4032, a highly selective V600EBRAF kinase inhibitor: Clinical correlation of activity with pharmacokinetic and pharmacodynamic parameters in a phase I trial

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 9021-9021
Author(s):  
I. Puzanov ◽  
K. L. Nathanson ◽  
P. B. Chapman ◽  
X. Xu ◽  
J. A. Sosman ◽  
...  
Keyword(s):  
Phase I ◽  
Disease Progression ◽  
Fdg Pet ◽  
Phase I Trial ◽  
Drug Exposure ◽  
Kinase Inhibitor ◽  
Clinical Activity ◽  
Histological Changes ◽  
Multiple Tumor ◽  
Fdg Uptake

9021 Background: PLX4032 is an oral, highly selective inhibitor of oncogenic V600EBRAF kinase currently in phase I trial. V600EBRAF mutation activates Raf/MEK/ERK pathway in multiple tumor types. We evaluated the relationship between PK, PD (pERK, Ki67, FDG-PET), tumor histology and clinical activity following PLX4032 administration in a phase I trial. Methods: In the phase I trial, 6 melanoma pts with V600EBRAF were treated with PLX4032 daily at several dose levels and tumor biopsies (baseline vs. day 15) were assessed histologically and by semi-quantitative IHC analysis (modified H-score) for pERK and Ki67. The first 4 pts received a crystalline formulation of PLX4032; the last 2 pts received a formulation with increased bioavailability. Plasma PK parameters were collected at frequent time points on Days 1, 8 and 15. FDG-PET was performed on Days 1 and 15 on last 2 pts. Results: In the first 4 pts, no histological changes were observed with treatment and all developed disease progression. All had decreased percentage of Ki67 positive nuclei (pre-Rx, range 20–60%, median 45%; post-Rx, range 5–25%, median 12.5%) and 3 of the 4 had decreased pERK levels (pre-Rx, range 50–100, median 60; post-Rx, range 10–40, median 11). Mean PLX4032 AUC0–24h ∼ 126 μM*h was in the range for preclinical tumor stasis but below the threshold for shrinkage. In the last 2 pts, striking tumor necrosis and tumor melanosis was observed in the post-Rx samples. One pt remains on study with a confirmed PR, the other showed a clinical response before disease progression occurred in cycle 2. The percentage of Ki67 positive nuclei declined substantially (pre-Rx, 30% and 50% to post-Rx, 5% and 3%), as did the levels of pERK in the pt with PR (pre-Rx: 70 to post-Rx: 2). Mean PLX4032 AUC0–24h was well above the preclinical threshold in the range of 500 - 1000 μM*h. Both pts had decreased FDG uptake on D15. Conclusions: Clinical activity of PLX4032 treatment correlates with drug exposure levels as measured by AUC0–24h and was associated with histological changes in V600EBRAF positive melanomas on Day 15. Reduction of pERK, along with evidence of reduced proliferation and FDG uptake was observed. Further analysis of PD markers with additional pts at the MTD is planned. [Table: see text]

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