David Mendelson

Background 17-(Allylamino)-17-demethoxygeldanamycin (17-AAG) is a benzoquinone ansamycin that binds to and inhibits the Hsp90 family of molecular chaperones leading to the proteasomal degradation of client proteins critical in malignant cell proliferation and survival. We have undertaken a Phase 1 trial of CNF1010, an oil-in-water nanoemulsion of 17-AAG. Methods Patients with advanced solid tumors and adequate organ functions received CNF1010 by 1-h intravenous (IV) infusion, twice a week, 3 out of 4 weeks. Doses were escalated sequentially in single-patient (6 and 12 mg/m²/day) and three-to-six-patient (≥25 mg/m²/day) cohorts according to a modified Fibonacci’s schema. Plasma pharmacokinetic (PK) profiles and biomarkers, including Hsp70 in PBMCs, HER-2 extracellular domain, and IGFBP2 in plasma, were performed. Results Thirty-five patients were treated at doses ranging from 6 to 225 mg/m². A total of 10 DLTs in nine patients (2 events of fatigue, 83 and 175 mg/m²; shock, abdominal pain, ALT increased, increased transaminases, and pain in extremity at 175 mg/m²; extremity pain, atrial fibrillation, and metabolic encephalopathy at 225 mg/m²) were noted. The PK profile of 17-AAG after the first dose appeared to be linear up to 175 mg/m², with a dose-proportional increase in C _max and AUC_0–inf. Hsp70 induction in PBMCs and inhibition of serum HER-2 neu extracellular domain indicated biological effects of CNF1010 at doses >83 mg/m². Conclusion The maximum tolerated dose was not formally established. Hsp70 induction in PBMCs and inhibition of serum HER-2 neu extracellular domain indicated biological effects. The CNF1010 clinical program is no longer being pursued due to the toxicity profile of the drug and the development of second-generation Hsp90 molecules.

Summary: Background This trial evaluated the safety, tolerability and maximum tolerated dose (MTD) of afatinib, a novel ErbB Family Blocker. Methods In this open-label, dose-escalation Phase I study, afatinib was administered continuously, orally, once-daily for 28 days to patients with advanced or metastatic solid tumors. Dose escalation was performed in a 3 + 3 design, with a starting dose of 10 mg/day (d); doses were doubled for each successive cohort until the MTD was defined. The MTD cohort was expanded to a total of 19 patients. Incidence and severity of adverse events (AEs), antitumor activity and pharmacokinetics were assessed. Results Thirty patients received at least one dose of afatinib. Twenty-nine patients were evaluable for response. Dose-limiting toxicities (DLTs) consisting of Grade 3 diarrhea were observed in two out of three patients treated at 60 mg/d. The MTD was determined at 40 mg/d. The most frequent treatment-related AEs were diarrhea and mucosal inflammation reported in 76.7 % and 43.3 % of patients respectively. Five patients had stable disease with a median progression-free survival of 111 days. No objective responses occurred. Pharmacokinetic data showed no deviation from dose-proportionality and steady-state was reached on Day 8 at the latest. Conclusions Afatinib was well tolerated with manageable side effects when administered once-daily, continuously at a dose of 40 mg.

Afatinib is an oral, ErbB family blocker, which covalently binds and irreversibly blocks all kinase-competent ErbB family members. This phase II, open-label, single-arm study explored afatinib activity in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients progressing after trastuzumab treatment. Patients had stage IIIB/IV HER2-positive metastatic breast cancer, with progression following trastuzumab or trastuzumab intolerance and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2. Patients received 50 mg afatinib once-daily until disease progression. Primary endpoint was objective response rate (Response Evaluation Criteria in Solid Tumors 1.0), with tumor assessments every 8 weeks. Forty-one patients were treated. Patients had received a median of three prior chemotherapy lines (range, 0–15) and 68.3% had received trastuzumab for >1 year. Four patients (10% of 41 treated; 11% of evaluable patients) had partial response. Fifteen patients (37% of 41) had stable disease as best response and 19 (46% of 41) achieved clinical benefit. Median progression-free survival was 15.1 weeks (95% confidence interval [CI]: 8.1–16.7); median overall survival was 61.0 weeks (95% CI: 56.7–not evaluable). Most frequent common terminology criteria for adverse events grade 3 treatment-related adverse events were diarrhea (24.4%) and rash (9.8%). Afatinib monotherapy was associated with promising clinical activity in extensively pretreated HER2-positive breast cancer patients who had progressed following trastuzumab treatment.

3055 Background: CVX-241 is a fusion protein comprised of a recombinant humanized IgG1 scaffold designed to specifically and selectively fuse, via a chemical linker, to two engineered angiopoietin-2 (Ang2) binding and two vascular growth factor (VEGF) binding peptides. In preclinical studies, CVX-241 is antiangiogenic and decreases tumor proliferation. Methods: In stage 1, pts with solid tumors received escalating doses of CVX-241 in cohorts of 3-6 pts at the following doses: 0.3, 1, 3, 6, 12, 15 or 18 mg/kg. An additional 18 pts are planned to be treated at the maximum tolerated dose (MTD) in stage 2. CVX-241 was given once weekly in 4 week cycles as a 90 min IV infusion, decreased to 30 min as tolerated. DLTs were defined as ≥ Gr 3 AEs unrelated to tumor progression in cycle 1. Serum PK was assessed by ELISA. DCE-MRI were conducted pre-dose, Day 4, and Day 28, in pts at 3 mg/kg and higher. Results: Data is available on 17 pts enrolled in stage 1 at doses 0.3 to 12 mg/kg. Among the 17 pts (10F/7M), the median age was 62 years (42-77), ECOG performance status 0-1. Drug exposure in pts ranged from 15-113 days (median 49 days). No DLTs were observed. The most common AEs were fatigue (29%), decreased appetite (23%), back pain (18%), and dyspnea (18%). There were no pts with proteinuria or hemorrhage. Gr 2 hypertension was observed in 1 pt (6%) at 12 mg/kg. Gr 3 toxicities included cholecystitis, clostridium difficile, colitis and diarrhea which occurred in 1 pt and which were considered unrelated to CVX-241. Total serum Ang2 (bound plus free) increased by approximately up to 90 fold and total plasma VEGF (bound plus free) increased by 2-3 fold with escalating doses (up to 3 mg/kg). Low titer anti-drug antibodies have been observed in some patients without clear effects on PK or safety. The best overall response available to-date in 13 pts is SD in 7 pts. Conclusions: CVX-241 is a novel dual inhibitor which to-date is well-tolerated in pts with advanced malignancies. Updated safety, efficacy and PK/PD data will be reported at the meeting.

The purpose of this study was to investigate the effect of gimeracil (CDHP), a reversible dihydropyrimidine dehydrogenase (DPD) inhibitor, on the pharmacokinetics of 5-fluorouracil (5-FU) and other related metabolites by comparing the pharmacokinetic (PK) profile of S-1 (tegafur [FT] + CDHP + oteracil potassium [Oxo]) to that of FT alone. Patients with advanced solid tumors received single oral doses of S-1 (50 mg) and FT (800 mg) on days 1 and 8 in a randomized crossover fashion. Plasma samples were collected on days 1, 2, 3, 8, 9 and 10. Single-dose PK parameters were determined for FT, 5-FU and α-fluoro-β-alanine (FBAL). Following the single-dose crossover period, patients entered an extension phase and received treatment with S-1 b.i.d. for 14 days followed by a 7-day rest, repeated every 3 weeks. A total of 12 patients were enrolled; median age was 59 years and mean body surface area was 1.94 m(2). Following S-1 administration, 5-FU exposure was significantly greater (approximately 3-fold) compared to FT alone (p ≤ 0.0007 for AUC0-inf, AUC0-last, and C(max) of 5-FU) despite the 16-fold higher dose of FT administered alone compared to S-1, while plasma concentrations of FT and FBAL were significantly lower with S-1 (p < 0.0001 for all comparisons). Following both single- and multiple-dose administration of S-1, the average maximum DPD inhibition was observed at 4 h post-dose. The extent of inhibition was similar following single and multiple dosing. Following single- and multiple-dose administration of S-1, plasma concentrations of uracil returned to baseline levels within approximately 48 h of dosing, indicating reversibility of DPD inhibition by CDHP. Despite the differences in the FT dose administered, exposure to 5-FU was significantly greater following S-1 administration compared to FT administration. Conversely, exposure to FT and FBAL were significantly less following S-1 administration compared to FT administration. Thus, the DPD inhibitory action of CDHP contributes to a decrease in 5-FU catabolism and to significantly higher blood levels of 5-FU compared to FT alone.

8147 Background: CFZ is a novel, highly selective peptide epoxyketone proteasome inhibitor. This Ph Ib/II study assesses the maximum recommended dose, safety, efficacy, pharmacokinetics, and pharmacodynamics of IV bolus and infusion CFZ in pts with relapsed malignancies. Methods: The Ph I bolus trial enrolled pts with solid tumors failing ≥2 prior treatments. CFZ was given on days (d) 1, 2, 8, 9, 15, and 16 every 28d for ≤12 cycles (C). C1 d1, d2 dosing in all cohorts was 20 mg/m² with subsequent escalation to 20, 27, or 36 mg/m² on d8. At 20/36 mg/m², 1 pt had dose-limiting toxicity of grade (G) 3 fatigue. This was selected as the Ph II dose. Using a Simon 2-stage design, Ph II enrolled 14 pts into each of 5 cohorts (NSCLC, SCLC, RCC, ovarian, and other). Responses were measured every 2 C. The Ph I infusion trial delivered CFZ over a 30-min period. A separate treatment arm was added for multiple myeloma (MM). Planned doses range from 36–88 mg/m². Ph II will be repeated once the MTD is established. Results: To date 79 pts (12 SCLC, 17 NSCLC, 16 ovarian, 10 renal, and 24 other) have been enrolled (14 in Ph I, 65 in Ph II). Pts received a median of 1.5 C of bolus CFZ (range 1-12). 20 pts have been enrolled to the Ph I infusion study (14 solid tumor, 6 MM). Efficacy data are detailed below (Table). Common adverse events (AEs) with bolus CFZ included fatigue, headache, diarrhea, nausea, and constipation. Peripheral neuropathy >G1, severe hematologic toxicities, and hepatotoxicity were not observed. Early data show that CFZ is also well-tolerated and efficacious when administered as a 30-min infusion. Updated data for the Ph II bolus and Ph I infusion studies will be presented. Conclusions: Single-agent IV CFZ is active and well-tolerated as a bolus or an infusion with a manageable side effect profile in relapsed malignancies. PRs have been achieved in renal, SCLC, and MM as well as SD >16 wks in a variety of other tumor types.

3038 Background: TRC093 is a humanized IgG1 monoclonal antibody to cryptic collagen epitopes that are exposed during angiogenesis and tumor growth. These epitopes are recognized by integrin receptors on endothelial and cancer cells during angiogenesis and tumor progression. Intravenous TRC093 localizes to the subendothelial basement membranes in tumor tissues (but not normal tissues) and inhibits angiogenesis and tumor growth as monotherapy and in combination with bevacizumab. Methods: This phase I study evaluated the safety and PK of i.v. TRC093 monotherapy for advanced refractory cancer. Patients were required to have an ECOG PS ≤ 2 and adequate organ function. TRC093 was administered by 90 min i.v. infusion on days 1 and 15 of each 28-day cycle. Results: A total of 19 patients were treated including 3 each at 0.5, 1.5, and 5 mg/kg, 9 at 12 mg/kg, and 1 at 24 mg/kg. The median number of prior cancer regimens was 4 (range: 1 to 10). Dose-limiting toxicity was not observed. The 12 mg/kg dose level was considered the maximum feasible dose due to limited drug supply. The most common possibly related adverse event was grade 1/2 fatigue. Possibly related grade 3/4 adverse events were not observed. One patient experienced grade 1 infusion reaction with the initial dose that did not recur with diphenhydramine premedication. TRC093 demonstrated linear dose-dependent PK typical of a humanized antibody. Target TRC093 serum concentrations based on preclinical efficacy studies were achieved throughout the 2-week dosing interval at 12 mg/kg (mean C_max=467 ug/mL, T_1/2=10.9 days). Human antihuman antibody (HAHA) formation was not observed. Evidence of clinical activity included one ovarian cancer patient with a mixed response, five patients with stable disease lasting up to 10 months, and an overall decline in mean circulating VEGF levels with treatment. Conclusions: TRC093 was well-tolerated at clinically relevant doses with early evidence of activity. Phase Ib/II trials are planned to evaluate TRC093 in combination with bevacizumab in patients with glioblastoma.

2524 Background: CVX-060 is a recombinant humanized monoclonal antibody fused to two angiopoietin-2 (Ang2) binding peptides. In preclinical studies, CVX-060 is antiangiogenic and decreases tumor proliferation. Methods: In stage 1, pts with solid tumors received escalating doses of CVX-060 in cohorts of 3-6 pts at the following doses: 0.3, 1, 3, 6, 12, or 15 mg/kg. An additional 13 pts were treated at the 15 mg/kg dose in stage 2. CVX-060 was given once weekly in 4 week cycles as a 90 min IV infusion, decreased to 30 min as tolerated. DLTs were defined as ≥ Gr 3 AEs unrelated to tumor progression in cycle 1. Serum PK was assessed by ELISA. DCE-MRI were conducted pre- dose, Day 4, and Day 28, in pts at 3 mg/kg and higher. Results: Complete data are available on 30 of 34 pts who were enrolled in the study. Among the 30 pts (19F/11M), the median age was 65 years (21-90), ECOG performance status 0-1. Drug exposure in pts ranged from 6-407 days (median 49 days). One pt in the 0.3 mg/kg cohort experienced a DLT (Gr 3 back pain). The most common AE was fatigue (23%).The MTD was not defined. There were 5 (17%) pts with proteinuria (one with Gr 3 and the rest Gr 1-2) and 2 (7%) pts with Gr 1 hemorrhage (vaginal spotting). C_max and AUC increased linearly with dose, with mean ß t_1/2 of 5.5 days. Total serum Ang2 (bound plus free) increased with escalating doses, plateauing at 15 mg/kg. Patients with the highest baseline Ang2 levels had the highest increases in total Ang2 after treatment. There were significant mean decreases in K^trans by DCE-MRI at Day 4 (p=0.034) and Day 28 (p=0.0025) in 11 pts with data available at all 3 time points. 10/11 patients had decreases in K^transwith mean decreases of 12.9% (0.94%- 44%) at Day 4 and 25.6% (8-61%) at Day 28. Of the 34 patients enrolled, 24 (71%) remained on study ≥8 weeks and 4 patients continue on treatment (maximum of 17+ months in a patient with refractory cervical cancer). Based on the PK/PD analysis, 15 mg/kg is the recommended phase II dose. Conclusions: CVX-060 is a well-tolerated novel therapy targeting angiogenesis. PK results support once-weekly dosing. There is preliminary evidence of biological activity based on DCE-MRI and prolonged stable disease. A combination trial with sunitinib is underway.

3524 Background: CVX-045 is a recombinant humanized monoclonal antibody fused to two TSP-1 mimetic, nonamer peptides. CVX-045 inhibits endothelial cell migration in vitro, and is anti-angiogenic in vivo. A TSP-1 mimetic CovX Body has potential as an anti-angiogenic intervention via a previously unexploited mode of action. Methods: Pts with advanced solid tumors and no known bleeding risk received CVX-045 administered in 3 pt cohorts (0.3, 1, 3, 6, 12 and 18 mg/kg) by once weekly IV infusions (4 wk cycles) over 90 min lowered to 30 min upon individual tolerability. DLTs were grade ≥ 3 AEs in cycle 1 not directly related to tumor progression. MTD was highest dose at which 0/3 or 1/6 patients experience DLT. Serum PK assessed by highly specific ELISA. DCE-MRI pre-dose, on Day 2–4 and Day 28, in pts dosed at 3 mg/kg and higher. Results: 18 pts (M/F 6/12) were treated, median age 58.5 years (range 33–82), median prior regimens 7 (range 2–19), ECOG performance status 0–1, and median weeks on study at cut off 9 (range 3–22). No cycle 1 DLTs were observed. No obvious dose dependencies related to safety. Common adverse events (Grade 1–2) included gastrointestinal (abdominal pain, nausea, anorexia, flatulence, diarrhea and constipation), anemia, headache, fatigue and general muscle weakness. One case of suspected infusion reaction (Grade 1) in a patient receiving the highest dose (18 mg/kg) administered over 60 minutes. 6 serious AEs (Grade ≥ 3), only one of which, a case of radiation pneumonitis complicated by infectious pneumonia, was thought to be possibly drug related. C_max and AUC increased linearly with dose, mean β T_1/2 98.5 hrs. DCE-MRI showed effects on flow (21 - 42% decr. in K_trans) but not permeability (AUCBN(90)) in 2/3 pts in 12 mg/kg group and 1 pt in 6 mg/kg group. RECIST: unconfirmed PR in 1 pt with liver mets and SD currently 8 to 16 weeks in 5/12 pts. 12 mg/kg appears to be the appropriate dose for further study. Conclusions: CVX-045 is a well tolerated new therapy targeting angiogenesis by a novel pathway. PK results are consistent with once weekly dosing. There is preliminary evidence by DCE-MRI and RECIST to suggest biologic activity.

2528 Background: Most cancer cells are dependent on the G2 checkpoint to survive with DNA damage. The stable peptide CBP501 shows selective G2 checkpoint abrogation, with activity in various tumor models, alone and combined with DNA damaging agents. CBP501 was evaluated in 2 phase I studies, single agent and with CDDP, determining maximum tolerated dose (MTD), dose limiting toxicity (DLT), safety and PK. Methods: CBP501 was given over 1 hr, via central catheter, with prophylactic anti-allergics due to histamine release syndrome in animals. PK was examined in cycle (cy) 1. MTD is the level below that where 2 of 3–6 pts have DLT during cy 1–2. Study A: CBP501 day 1/8/15, q4w, initial dose 0.9 mg/m². Study B: q3w, initial CBP501/CDDP doses 3.6/50 mg/m². Results: Studies were run in 4 US centers from Jun-05 to Dec-07. A) 30 pts treated, M/F: 16/14, median age 61 (25–82), PS 0/1/2: 9/20/1, median 4 prior lines, colon (5 pts), pancreas/biliary (6), ovarian (6), melanoma (2), renal (2), NSCLC (2), other (7). Median cy/pt: 2 (1–8). All pts discontinued due to PD. 1 DLT occurred (transient asymptomatic G3 troponin elevation) at 22.5 mg/m² (top DL given). No other G3–4 adverse events (AEs) occurred; 13 pts (43%) had G1–2 allergy. MTD was not reached. 2 pts (pancreas, ovarian) had SD for 7 cy. B) 27 pts treated, M/F: 14/13, median age 61 (31–81), PS 0/1: 8/19, median 4 prior lines, mesothelioma (5), prostate (4), NSCLC (4), pancreas/biliary (3), esophageal (3), other (8). Two DLTs (G3 allergic reaction) occurred at CBP501/CDDP 36.4/75 mg/m². No other G3–4 AEs occurred. MTD was defined as 25 mg/m² CBP501, 75 mg/m² CDDP. Allergic reaction was the most common AE, observed in 12 (44%) pts. PR (unconfirmed) endometrial (7+ cy, CA125 50% drop); SD, 2 mesothelioma (11+, 5), adenoid cystic (8), neuroendocrine (4+), ovarian (3+, CA125 50% drop), NSCLC (3+). PK: CBP501 Cmax and AUC showed dose-proportionality, and no difference between day 1 and 15 for both studies. Conclusions: CBP501 was well tolerated, as single agent and with CDDP. The main toxicity was dose-limiting allergic reaction. Promising signs of efficacy are seen in pts already exposed to platinum. Phase I-II studies of CBP501/pemetrexed/CDDP are planned.