30-minute IV Infusion Research Articles

Cabozantinib (Cabometyx)


 CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class.
 The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec.
 This review assesses:
 
 Cabozantinib (Cabometyx): 40 mg once daily, oral tablet
 Nivolumab (Opdivo): 240 mg every 2 weeks, 30-minute IV infusion, or 480 mg every 4 weeks, 30-minute IV infusion.
 
 
 Indication: Cabozantinib, in combination with nivolumab, is indicated for the first-line treatment of adult patients with advanced (not amenable to curative surgery or radiation therapy) or metastatic renal cell carcinoma.

Phase 3 Study of Palonosetron IV Infusion Vs. IV Bolus for Chemotherapy-Induced Nausea and Vomiting Prophylaxis After Highly Emetogenic Chemotherapy

ContextPalonosetron (PALO) is one of the two active components of NEPA, the fixed-combination antiemetic comprising netupitant (oral)/fosnetupitant (IV) and PALO. To increase the convenience of NEPA administration, especially for patients with swallowing difficulties, an IV NEPA formulation has been developed, where PALO is administered as a 30-minute infusion instead of the approved 30-second bolus. ObjectivesTo determine the efficacy and safety of the PALO component used in IV NEPA. MethodsNoninferiority, double-blind, and randomized Phase 3 trial in chemotherapy-naive adult patients with cancer requiring highly emetogenic chemotherapy. Patients were randomized to receive a single dose of PALO 0.25 mg administered IV either as a 30-minute infusion or as a 30-second bolus before highly emetogenic chemotherapy. The primary objective was to demonstrate noninferiority of the 30-minute infusion vs. 30-second bolus in terms of complete response (CR; no emesis and no rescue medication) in the acute phase. Secondary efficacy endpoints were CR in the delayed and overall phases and no emesis and no rescue medication in all phases. Safety was a secondary endpoint. ResultsOverall, 440 patients received study treatment. In the infusion group, 186 (82.7%) patients reported CR in the acute phase vs. 186 (86.5%) patients in the bolus group, demonstrating the noninferiority of PALO infusion vs. bolus (P < 0.001). Secondary endpoints showed similar results between the two treatment groups. ConclusionPALO 0.25-mg 30-minute IV infusion was noninferior to 30-second IV bolus in terms of CR rate in the acute phase. These results support the use of PALO 0.25 mg as a component of IV NEPA.

Phase 1b Evaluation of the Safety and Efficacy of a 30-Minute IV Infusion of Carfilzomib In Patients with Relapsed and/or Refractory Multiple Myeloma

AbstractAbstract 3024 Background:Carfilzomib (CFZ) is a novel, highly selective, epoxyketone proteasome inhibitor. In two separate Phase 2 trials in patients (pts) with relapsed and/or refractory (R/R) multiple myeloma (MM), single-agent CFZ administered as an IV bolus over 1–10 minutes has demonstrated durable activity at 20/27 mg/m2 and is well-tolerated with no clinically significant cumulative toxicity. In rats, significantly improved tolerability of CFZ was obtained following administration as a 30 min infusion as compared to a rapid IV bolus. Notably, a dose of 48 mg/m2 via IV bolus resulted in 50% lethality, compared to minimal toxicity without lethality at the same dose via a 30 min infusion. The reduced toxicity with 30-min infusion may reflect the role of Cmax (45 μM for bolus vs. 1.5 μM for infusion), since proteasome inhibition in blood and tissue was equivalent in both groups. Here we report on the results of administration of CFZ as a 30-minute IV infusion in a Phase 1b study in pts with R/R MM. The goals of this study are to determine the maximum recommended dose for infusion, safety, efficacy, pharmacokinetics (PK), and pharmacodynamic (PD) parameters. Methods:This Phase 1b trial is enrolling pts with R/R MM after ≥2 prior treatment failures. CFZ is given as a 30-minute IV infusion on days (D) 1, 2, 8, 9, 15, and 16 of a 28-day cycle (C) until progression. Dosing in all cohorts is initiated at 20 mg/m2 for the first two doses, with subsequent escalation to 36, 45, 56, or 70 mg/m2. Dose escalation follows standard 3+3 rules. Dexamethasone (4 mg for doses up to 45 mg/m2) is given prior to each infusion, with 8 mg given at higher doses. Responses by IMWG Uniform Response Criteria are measured at every C. Plasma samples for PK analysis and peripheral blood samples for PD analysis were obtained from pts at C1D1 (20 mg/m2) and C2D1 (all dose cohorts). Results:To date, 16 pts with R/R MM have been enrolled in the Phase 1b infusion study (4 at 36 mg/m2; 3 at 45 mg/m2; 7 at 56 mg/m2 and 2 at 70 mg/m2). Pts have remained on study for a median of 4 cycles (range 1–13+). Dose Limiting Toxicity (DLT) was observed in both pts treated at 70 mg/m2: reversible Grade (G) 3 renal failure in one pt within 24-hours following his first dose at 70 mg/m2 (C1D8); reversible G3 fatigue with fevers 4 days following four doses of 70 mg/m2 (C1 D20). Both pts were successfully rechallenged and continue on treatment. Seven patients have started dosing at 56 mg/m2; to date, one DLT (reversible G3 hypoxia with fevers) was observed. Thirteen pts are evaluable for efficacy (2 pts withdrew prior to 1st response assessment; 1 pt is too early to assess). Responses, time on study and prior regimens are detailed in the following table.Preliminary PK analysis demonstrates that the Cmax with 30-minute infusion is lower than obtained with a 5–10 minute IV bolus of the same dose. Inhibition of proteasome activity in red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs) was >80% at 20 mg/m2 and >90% at 36 mg/m2 and above. Common adverse events (AEs) with CFZ delivered as a 30-minute infusion have included fatigue, fevers, myalgias, diarrhea, nausea, thrombocytopenia, and reversible elevations in serum creatinine. There have been no episodes of worsening of baseline peripheral neuropathy or hepatotoxicity. Conclusions:In pts with R/R MM, single-agent CFZ as 30-minute IV infusion is both active and well-tolerated at doses ≥36 mg/m2; the dose level of 56 mg/m2 is being expanded as the recommended phase 2 dose on this schedule. Responses were seen in 8 out of 13 evaluable MM pts, including three VGPRs in pts who had received 5–7 prior regimens. Similar to animal studies, improved safety outcomes in MM patients can be achieved with near complete proteasome inhibition when CFZ is administered as a 30-minute infusion. An additional schedule of CFZ using weekly dosing (30-minute infusion for 5 weeks out of every 6) will be investigated in this trial.Best ResponseDose (mg/m2)Prior RegimensPrior Bortezomib RegimensTime on Study (months)VGPR56733.7+56534.8+56625.1+PR361112.4+36734.845603.056300.9+70 −> 56411.6+SD36105.145424.870 −>36/45632.6+ Disclosures:Papadopoulos:Onyx Pharmaceuticals: Consultancy, Research Funding. Siegel:Millenium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Singhal:Celgene: Speakers Bureau; Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding. Gordon:Onyx Pharmaceuticals: Research Funding. Kauffman:Onyx Pharmaceuticals: Employment. Woo:Onyx Pharmaceuticals: Employment. Lee:Onyx Pharmaceuticals: Employment. Bui:Onyx Pharmaceuticals: Employment. Hannah:Onyx Pharmaceuticals: Consultancy.

A phase I study of sunitinib malate (S) and gemcitabine (G) in solid tumors.

3046 Background: Continuous daily dosing (CDD) of S with G is a novel regimen that may have broad clinical activity. Methods: Eligible patients had no curative therapy options, adequate organ function, and no prior antiangiogenic treatments. A 3+3 dose escalation design was followed with expansion of the recommended phase II dose (RP2D) to 10 patients. G was administered as a standard 30-minute IV infusion. G was initiated at 800 mg/m2 days 1, 8, 15 of each 28-day cycle, with escalating once-daily oral doses of S. Treatment-related grade (gr) 4 toxicity, gr 3 cardiac or venous thrombosis, unresolved noncardiac gr 3 event, or uncontrolled hypertension in cycle 1 was defined as DLT. Results: 31 patients were treated (most common tumor type: pancreatic adenocarcinoma, n=9). DLTs are shown in the TableTable. Dose level 1 was expanded to 10 patients after the occurrence of 2 DLTs at dose level 2 and was found to be tolerable. Four patients at dose level 1 did not receive the three planned doses of G due to toxicity. The study was amended to evaluate day 1 and day 8 G every 21 days with continuous daily S. Excessive DLT occurred at dose levels -1a and -1. Of the 8 patients enrolled to dose level -2, all received the full dose of G and S for cycle 1. Four patients had a confirmed PR: 2 with pancreatic adenocarcinoma (dose level 1), 1 with pancreatic neuroendocrine cancer (dose level -2) and 1 with thymic carcinoma (dose level -2). 9 patients had stable disease (median 20 weeks, range 14-49 weeks). Conclusions: The MTD of weekly G + daily S is 800 mg/m2 G on days 1, 8, and 15 every 28 days with 25 mg daily S. The RP2D is 675 mg/m2 G on days 1 and 8 every 21 days with 25 mg daily S. This clinically active and well-tolerated regimen warrants further investigation. Supported by NIH/Cancer Therapy Evaluation Program U01 CA62502. Dose level S mg daily G mg/m2; days of G;days/cycle N # subjects with DLT/type of DLT 1 25 800; 1,8,15; 28 10 1/gr 4 ANC 2 37.5 800; 1,8,15; 28 5 2/gr 4 ANC and gr 4 platelet −1a 37.5 800; 1,8; 21 3 2/gr 4 platelet −1 25 800; 1,8; 21 5 2/gr 4 platelet and gr 3 cardiac LV systolic dysfunction −2 25 675; 1,8; 21 8 1/gr 3 hemorrhage Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, ImClone Systems, Merck, Pfizer, sanofi-aventis, Wyeth

The Ghrelin Agonist TZP-101 for Management of Postoperative Ileus After Partial Colectomy: A Randomized, Dose-Ranging, Placebo-Controlled Clinical Trial

Ghrelin agonist TZP-101 is a potent prokinetic. This phase 2b study evaluated TZP-101 safety and efficacy in postoperative ileus management. Adults undergoing open partial colectomy were adaptively randomized to receive 20, 40, 80, 160, 320, 480 or 600 microg/kg TZP-101 (n = 168) or the placebo (n = 68) by 30-minute IV infusion within 1 hour of surgical closure and then daily for up to 7 days. The primary efficacy end point was the time to first bowel movement. Secondary end points included the percentage of patients with return of gastrointestinal function within 72 hours, and the time to readiness for discharge. TZP-101 accelerated the time to first bowel movement in all groups, with Cox proportional hazard ratios of 1.57 (P = .056) for the low-efficacious dose (80 microg/kg) and 1.67 (P = .03) for the most efficacious dose (480 microg/kg). Using Kaplan-Meier analysis, the median time to first bowel movement was reduced in all TZP-101 groups by 10 to 22 hours vs. the placebo. A greater number of patients who received TZP-101 achieved recovery (P <or= .001) by 72 hours postsurgery compared with the placebo. The median time to readiness for hospital discharge was significantly accelerated by 20.4 hours at the 480 microg/kg TZP-101 dose compared with the placebo (hazard ratio = 1.69; P = .03). The most common treatment-emergent adverse events were nausea and vomiting, which were reduced in the TZP-101 group compared with the placebo group. In patients undergoing major abdominal surgery, the first-in-class ghrelin agonist TZP-101 was well-tolerated and accelerated recovery of the upper and lower gastrointestinal tract, with a large proportion of subjects recovering within 72 hours compared with the placebo.

Pharmacokinetics (PK) of Adenosine A 1 Receptor Antagonist BG9928 in Healthy Subjects, Elderly Subjects, and Subjects with Severe Renal Insufficiency (SRI)

Introduction: BG9928, a potent adenosine A1 receptor antagonist that has been shown to increase sodium excretion and reduce body weight while preserving renal function, is currently being developed as an IV and oral agent to treat heart failure patients with concomitant renal insufficiency. Objectives: To evaluate the PK of BG9928 in healthy subjects with normal renal function, elderly subjects, and subjects with SRI. Methods: This was an open-label, parallel-group study. Healthy subjects (age 18-75y) with normal renal function, elderly subjects (age ≥81y) with normal renal function (per age), and subjects with SRI (age 18-75y; GFR ≤30 mL/min/1.73m2) received a single 30-minute IV infusion of BG9928 1 mg/kg.

Pharmacokinetics (PK) of the angiogenesis inhibitor ABT-510 in healthy subjects

3080 Background: ABT-510 is a subcutaneously (SC) administered nonapeptide thrombospondin analogue in phase 2 clinical development for treatment of advanced malignancies. In mouse, rat, dog and monkey, t1/2 ranged from 0.2 h (mouse) to 1.3 h (monkey); metabolism was dominated by a single peptide bond cleavage yielding two inactive peptides (including M-1) which were rapidly excreted in bile and urine. Methods: To assess the safety, tolerability and PK of ABT-510, a first-time-in-man, single-escalating-dose, double-blind study was conducted in 43 healthy male subjects (mean±SD 34±12 yrs, 76±8 kg), randomly assigned to receive ABT-510 by SC bolus (10, 50, 75, 100 or 130 mg), SC infusion of 100 mg over 24 h, or 30-minute IV infusion (10, 50 or 100 mg); one subject per group received placebo. Samples for ABT-510 and M-1 assay were collected predose and over 24 h (blood) or 48 h (urine); concentrations were determined using a validated LC/MS/MS method. Results: PK results for SC bolus groups are shown below: ABT-510 PK were dose-proportional both for IV and SC regimens. Following IV dosing, CL, Vd and t1/2 were 35±8 L/h, 44±9 L and 0.9±0.1 h. SC doses were completely bioavailable relative to IV. The SC infusion produced a mean steady-state concentration of 150 ng/mL. M-1 plasma exposure averaged 50% greater than parent drug. About 78% of the dose was recovered as M-1 in urine. ABT-510 was generally well-tolerated, most AEs were mild in severity and resolved quickly. Conclusions: ABT-510 PK were linear in the range studied, interindividual variability was low. SC doses were rapidly absorbed and completely bioavailable relative to IV. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories Abbott Laboratories

Pharmacokinetics (PK) of the angiogenesis inhibitor ABT-510 in healthy subjects

3080 Background: ABT-510 is a subcutaneously (SC) administered nonapeptide thrombospondin analogue in phase 2 clinical development for treatment of advanced malignancies. In mouse, rat, dog and monkey, t1/2 ranged from 0.2 h (mouse) to 1.3 h (monkey); metabolism was dominated by a single peptide bond cleavage yielding two inactive peptides (including M-1) which were rapidly excreted in bile and urine. Methods: To assess the safety, tolerability and PK of ABT-510, a first-time-in-man, single-escalating-dose, double-blind study was conducted in 43 healthy male subjects (mean±SD 34±12 yrs, 76±8 kg), randomly assigned to receive ABT-510 by SC bolus (10, 50, 75, 100 or 130 mg), SC infusion of 100 mg over 24 h, or 30-minute IV infusion (10, 50 or 100 mg); one subject per group received placebo. Samples for ABT-510 and M-1 assay were collected predose and over 24 h (blood) or 48 h (urine); concentrations were determined using a validated LC/MS/MS method. Results: PK results for SC bolus groups are shown below: ABT-510 PK were dose-proportional both for IV and SC regimens. Following IV dosing, CL, Vd and t1/2 were 35±8 L/h, 44±9 L and 0.9±0.1 h. SC doses were completely bioavailable relative to IV. The SC infusion produced a mean steady-state concentration of 150 ng/mL. M-1 plasma exposure averaged 50% greater than parent drug. About 78% of the dose was recovered as M-1 in urine. ABT-510 was generally well-tolerated, most AEs were mild in severity and resolved quickly. Conclusions: ABT-510 PK were linear in the range studied, interindividual variability was low. SC doses were rapidly absorbed and completely bioavailable relative to IV. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories Abbott Laboratories

A phase I trial of a novel mTOR inhibitor AP23573 administered weekly (wkly) in patients (pts) with refractory or advanced malignancies: A pharmacokinetic (PK) and pharmacodynamic (PD) analysis

3150 Background:AP23573 is a non-prodrug rapamycin analog that potently inhibits mTOR, a downstream effector of the PI3K/Akt and nutrient pathways. AP23573 demonstrated powerful antiproliferative activity in vitroand antitumor activity in mouse xenograft studies. Methods: This trial is utilizing an accelerated dose escalation scheme to determine safety and tolerability, establish a maximum tolerated dose, and characterize the PK and PD of AP23573. AP23573 is administered as 30-minute IV infusion wkly on 4-week cycles, and tumor responses are evaluated every 2 cycles. Potential PD markers are being assessed using western blot analysis of peripheral blood mononuclear cells. Results: As of 12/01/03: 9 pts (4M/5F), median age 55 yrs (range 27–79 yrs), have received doses ranging from 6.25 to 25 mg in 3 dose level cohorts (total cycles, 15; median cycles, 2/pt). No dose limiting toxicities or AP23573-related serious adverse events have been observed. Common reversible side effects for first cycle have been grade 1 chills, diarrhea, fatigue, rash, anorexia, mucositis, and one pt had grade 2 anemia. PK analyses (doses 6.25 and 12.5 mg) suggest a mean AP23573 half-life of 46–52 hours, with AP23573 concentration levels generally remaining above in vitro antiproliferation IC50 levels until the next wkly dose. PD analyses (doses 12.5 and 25 mg) show inhibition of mTOR activity until the next wkly dose as measured by decrease in phosphorylated 4EBP1 levels. One of 5 evaluable pts has stable medullary thyroid cancer for > 2 months. Conclusions: AP23573 can be administered safely using this schedule. There is evidence of a substantial PD effect at dose levels associated with minimal toxicity, and early evidence of antitumor activity. Given the promising PD findings, further dose escalation and new pt enrollment will include evaluation of maximum effective dose of AP23573 based on PK/PD relationship. If substantial interindividual PK variability is observed, the trial also is prospectively designed to evaluate the relevance of genetic variants in candidate drug metabolism genes. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ARIAD Pharmaceuticals, Inc. ARIAD Pharmaceuticals, Inc. ARIAD Pharmaceuticals, Inc.

Phase I, pharmacokinetic (PK), and pharmacodynamic (PD) study of AP23573, an mTOR Inhibitor, administered IV daily X 5 every other week in patients (pts) with refractory or advanced malignancies

3076 Background: AP23573, a non-prodrug rapamycin analog, potently inhibits mTOR, a downstream effector of the PI3K/Akt and nutrient signaling pathways. AP23573 demonstrated potent inhibition of proliferation in vitroin several human tumor cell lines and elicited antitumor activity in vivo in multiple xenograft animal models. Methods: This dose escalation trial utilizes an accelerated titration scheme to determine safety, tolerability and maximum tolerated dose of AP23573 administered without premedication as 30-minute IV infusion daily x 5 days every 2 weeks for 4-week cycles. It also is designed to characterize the PK profile, evaluate potential PD markers using western blot analysis of peripheral blood mononuclear cells (PBMCs) and immunohistochemical analysis of skin biopsies, and ascertain preliminary data on antitumor activity. Results: As of 01 Dec 03: 11 pts (6M/5F), median age 57 yrs (range 23–65 yrs), were treated with AP23573 doses ranging from 3 to 28 mg in 5 dose level cohorts (total cycles, 32; median cycles, 2/pt). No dose-limiting toxicity or AP23573-related serious adverse events have been observed. Side effects for first cycle included grade (gr) 2 anemia (2 pts); gr 3 transient transaminase elevation (1 pt with hepatocellular cancer); gr 2 mucositis (2 pts); gr 1 skin rash (2 pts). PK analyses (doses 3 to 12.5 mg) suggest a mean AP23573 half-life of 44–54 hours. PD analyses (doses 3 and 6.25 mg) indicate rapid (within 1 hr) and prolonged (up to 10 days between doses) inhibition of mTOR activity as demonstrated by >80% decrease in phosphorylated 4EBP1 levels in PBMCs. Of 8 evaluable pts, one partial response has been observed in a pt with metastatic renal cell cancer; (6.25 mg) and 1 pt with metastatic sarcoma (3 mg) has had stable disease > 6 months. Conclusions:AP23573 can be administered safely using this schedule, and has exhibited antitumor activity as well as evidence of a substantial PD effect. Patient dosing and enrollment are ongoing. Further dose escalation as well as exploration of the relationship between PD (PBMC and skin) and PK are planned. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ARIAD Pharmaceuticals, Inc. ARIAD Pharmaceuticals, Inc. ARIAD Pharmaceuticals, Inc. ARIAD Pharmaceuticals, Inc. ARIAD Pharmaceuticals, Inc.

A phase I trial of a novel mTOR inhibitor AP23573 administered weekly (wkly) in patients (pts) with refractory or advanced malignancies: A pharmacokinetic (PK) and pharmacodynamic (PD) analysis

3150 Background:AP23573 is a non-prodrug rapamycin analog that potently inhibits mTOR, a downstream effector of the PI3K/Akt and nutrient pathways. AP23573 demonstrated powerful antiproliferative activity in vitroand antitumor activity in mouse xenograft studies. Methods: This trial is utilizing an accelerated dose escalation scheme to determine safety and tolerability, establish a maximum tolerated dose, and characterize the PK and PD of AP23573. AP23573 is administered as 30-minute IV infusion wkly on 4-week cycles, and tumor responses are evaluated every 2 cycles. Potential PD markers are being assessed using western blot analysis of peripheral blood mononuclear cells. Results: As of 12/01/03: 9 pts (4M/5F), median age 55 yrs (range 27–79 yrs), have received doses ranging from 6.25 to 25 mg in 3 dose level cohorts (total cycles, 15; median cycles, 2/pt). No dose limiting toxicities or AP23573-related serious adverse events have been observed. Common reversible side effects for first cycle have been gra...

Phase I, pharmacokinetic (PK), and pharmacodynamic (PD) study of AP23573, an mTOR Inhibitor, administered IV daily X 5 every other week in patients (pts) with refractory or advanced malignancies

3076 Background: AP23573, a non-prodrug rapamycin analog, potently inhibits mTOR, a downstream effector of the PI3K/Akt and nutrient signaling pathways. AP23573 demonstrated potent inhibition of proliferation in vitroin several human tumor cell lines and elicited antitumor activity in vivo in multiple xenograft animal models. Methods: This dose escalation trial utilizes an accelerated titration scheme to determine safety, tolerability and maximum tolerated dose of AP23573 administered without premedication as 30-minute IV infusion daily x 5 days every 2 weeks for 4-week cycles. It also is designed to characterize the PK profile, evaluate potential PD markers using western blot analysis of peripheral blood mononuclear cells (PBMCs) and immunohistochemical analysis of skin biopsies, and ascertain preliminary data on antitumor activity. Results: As of 01 Dec 03: 11 pts (6M/5F), median age 57 yrs (range 23–65 yrs), were treated with AP23573 doses ranging from 3 to 28 mg in 5 dose level cohorts (total cycles, 32; median cycles, 2/pt). No dose-limiting toxicity or AP23573-related serious adverse events have been observed. Side effects for first cycle included grade (gr) 2 anemia (2 pts); gr 3 transient transaminase elevation (1 pt with hepatocellular cancer); gr 2 mucositis (2 pts); gr 1 skin rash (2 pts). PK analyses (doses 3 to 12.5 mg) suggest a mean AP23573 half-life of 44–54 hours. PD analyses (doses 3 and 6.25 mg) indicate rapid (within 1 hr) and prolonged (up to 10 days between doses) inhibition of mTOR activity as demonstrated by >80% decrease in phosphorylated 4EBP1 levels in PBMCs. Of 8 evaluable pts, one partial response has been observed in a pt with metastatic renal cell cancer; (6.25 mg) and 1 pt with metastatic sarcoma (3 mg) has had stable disease > 6 months. Conclusions:AP23573 can be administered safely using this schedule, and has exhibited antitumor activity as well as evidence of a substantial PD effect. Patient dosing and enrollment are ongoing. Further dose escalation as well as exploration of the relationship between PD (PBMC and skin) and PK are planned. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ARIAD Pharmaceuticals, Inc. ARIAD Pharmaceuticals, Inc. ARIAD Pharmaceuticals, Inc. ARIAD Pharmaceuticals, Inc. ARIAD Pharmaceuticals, Inc.