Single Agent Dose Escalation Research Articles

A Phase I Single-Agent Study of Twice-Weekly Consecutive-Day Dosing of the Proteasome Inhibitor Carfilzomib in Patients with Relapsed or Refractory Multiple Myeloma or Lymphoma

Carfilzomib is a next-generation, selective, proteasome inhibitor with clinical activity in relapsed and/or refractory multiple myeloma. The objectives of this phase I study were to establish the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of escalating doses of carfilzomib in patients with relapsed or refractory hematologic malignancies. Carfilzomib (doses ranging from 1.2-27 mg/m(2)) was administered i.v. on 2 consecutive days for 3 weeks of a 4-week cycle. Single-agent dose escalation (n = 37) was followed by a dose-expansion phase (n = 11) that comprised 2 cohorts (carfilzomib or carfilzomib + dexamethasone). During dose expansion, carfilzomib was administered starting with 20 mg/m(2) during the first week (days 1, 2) and then escalated to 27 mg/m(2) thereafter. A maximum tolerated dose (MTD) was not reached during dose escalation. Dosing in the expansion cohort was well tolerated. Adverse events were manageable and primarily of grade I or II. The main hematologic adverse events of ≥ grade III were anemia and thrombocytopenia. Notably, there were no observations of grade III or more peripheral neuropathy. Carfilzomib was cleared rapidly with an elimination half-life of less than 30 minutes but still induced dose-dependent inhibition of the 20S chymotrypsin-like proteasome activity. At doses of 15 to 27 mg/m(2), there was evidence of activity among patients with multiple myeloma and with non-Hodgkin lymphoma. Escalated dosing of carfilzomib on a schedule of 2 consecutive days for 3 weeks of a 4-week cycle was tolerable and showed promising activity. This dose regimen has been selected for ongoing and future clinical studies, including PX-171-003A1 and the pivotal trial ASPIRE.

Abstract A177: Phase 1, dose-escalation, safety, pharmacokinetic and pharmacodynamic study of single agent PF-03758309, an oral PAK inhibitor, in patients with advanced solid tumors.

Abstract Background: P21 activated kinase (PAK), a family of serine-threonine kinases, is a downstream effector of the Rho family and functions as a signaling node for various oncogenic pathways. The capability to transform cell cultures and the consistent anti tumor response associated with PAK inhibition in preclinical studies has raised the interest of PAK as a potential target for oncology. PAK consists in 6 isoforms divided into 2 subgroups. PAK isoforms 1 and 4 have been more frequently related to cancer biology. PF309 is a potent ATP-competitive inh of PAK1, 4, 5 and 6. Methods: Adult pts with advanced solid tumors were enrolled in a Ph 1 single agent dose escalation study with a standard 3 + 3 design. Oral PF309 was given on a continuous daily dosing. Tumor response was assessed at baseline and every 8 wks thereafter. AEs were recorded according NCI CTC v3.0. PK assessment was a study objective and PD endpoints (downstream substrates of the PAK pathway, eg: GEFH1, p-PAK4, p-cofilin) were to be explored in pre and post-treatment tumor biopsies as well as in surrogate tissue (hair follicles). Results: 33 pts (17 M and 16 F) were treated with PF309 among 8 dose levels (1 mg QD to 60 mg BID). Median age was 62.0 years (range 24–80) and median ECOG PS was 1. The most frequent tumors were CRC (16 pts), NSCLC (4 pts), breast cancer (2 pts), osteosarcoma (2 pts) and pancreatic cancer (2 pts). Median number of cycles was 3 (range 1 to 10). All subjects experienced treatment emergent AEs; 9 subjects experienced G3–4 AEs, and 2 SAEs were reported from 2 subjects: abdominal pain and hemoptysis (both at 60 mg BID). One patient died while on study due to PD. At the time of this report 2 patients experienced DLTs at 60 mg BID: G3 diarrhea (1 pt), and G2 nausea, vomiting and diarrhea, and G1 abdominal cramping leading to the administration of less than 80% of the planned dose during C1 (1pt). As a result 60 mg BID is the maximum administered dose (MAD). Treatment-related AEs were mainly from the GI tract: G3 diarrhea (1 pt), G1–2 diarrhea (10 pts), G1–2 vomiting (8 pts), G1–2 nausea (8 pts each), abdominal pain (5 pts) and fatigue (3 pts). G1–2 QTcF prolongation was observed in 11 pts (G1 in 6 pts, G2 in 5 pts), 6 of whom had an abnormal pre-treatment QTcF. No QTcF increase > 60 ms above baseline was observed in any patient. G3 lab abnormalities were rarely reported and included hyponatremia, thrombocytopenia, neutropenia and increased bilirubin (1 pt each). The PK data demonstrated that after attainment of Cmax within 5 hours after dosing, PF309 plasma concentrations declined in a multi-exponential manner with an average terminal half-life of 12.4 to 17.8 hs across doses. There was a lack of dose proportionality in the dose range of 10 to 60 mg, likely due to the high inter-patient variability. The inter-patient variability of AUCtau and Cmax at steady-state ranged from 21 to 177% and 45 to 184%, respectively, across doses. So far no tumor responses have been observed. A total of 10 pts have been on study treatment for ≥ 12 weeks. One heavily pretreated pt with CRC and progressive increase of the CEA serum level experienced a decrease in the CEA value from 1343.3 to 625.2 ng/ml, and remained on study for 4 months. Conclusions: GI toxicity is the most relevant toxicity associated with PF309 and 60 mg BID is the MAD. MTD confirmation is ongoing. Clinical development of PF309 is on hold due to PK findings. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A177.

Pharmacodynamic biomarkers of anti-NRP1 activity in phase I, dose-escalating clinical trials as a single agent and combined with bevacizumab.

e13551 Background: Neuropilin-1 (NRP1) is a receptor for multiple ligands including VEGF and semaphorins with broad expression on stromal cells, as well as a subset of tumor cells. In preclinical xenograft models, combining anti-NRP1 and anti-VEGF shows substantial antitumor activity. Anti-NRP1 is a fully human monoclonal antibody against NRP1 and is currently in phase I clinical trials. We explored the utility of circulating pharmacodynamic biomarkers from patient plasma in monitoring anti-NRP1 activity. Methods: Preclinically, in a dose ranging study in Cynomolgus monkeys, a panel of ninety distinct secreted plasma proteins, including VEGF, IL-8, sFlt1, sKDR, PlGF and bFGF, were evaluated as potential biomarkers of systemic inhibition of NRP1 signaling using ELISA based methods. PlGF was the only marker that demonstrated a desirable dynamic range to prompt serial evaluation as a potential biomarker of drug activity in the clinic. Results: A two-fold elevation in PlGF over baseline was observed as early as 24h in all patients from the dose of 5 mg/kg onwards in the single agent dose escalation trial. However, sustained elevation for 10 days or greater was observed at doses starting at 10 mg/kg. Increasing the dose of anti-NRP1 did not affect the magnitude of PlGF elevation but did increase the duration of elevation. The change in PlGF expression did not correlate strongly with PK parameters including AUC and Cmin. A dose dependent increase in sNRP1 was also observed in all patients, likely due to altered clearance associated with sNRP1:anti-NRP1 binding in circulation. Conclusions: Together, these data have allowed the translation of preclinical biology to humans and suggest PlGF as a biomarker of systemic pathway inhibition using anti-NRP1 in humans. PlGF levels are currently being evaluated in patients enrolled onto a phase Ib study of anti-NRP1 plus bevacizumab to determine if the combination of these two anti-angiogenesis agents will further potentiate the magnitude of PlGF elevation compared to either agent alone. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech

OGX-427, a 2'methoxyethyl antisense oligonucleotide (ASO), against HSP27: Results of a first-in-human trial

3506 Background: Heat shock protein 27 (Hsp27) is a chaperone protein expressed in many cancers and implicated as a therapeutic “hyper-node” affecting multiple pathways in cancer progression. Overexpression of Hsp27 confers a resistant phenotype. OGX-427 is a second generation ASO that inhibits Hsp27 expression which in preclinical models inhibited cell growth, induced apoptosis, and enhanced chemotherapy efficacy. The purpose of this phase 1 study was to determine the recommended phase 2 dose of OGX-427 alone and in combination with docetaxel. Methods: Eligible patients (pts) had to have metastatic breast, ovarian, prostate, NSCLC, or bladder cancer. OGX-427 was administered IV weekly on a 21-day cycle after 3 loading doses (LD) within 9 days. OGX-427 was escalated over 5 planned dose levels (DL) (200, 400, 600, 800, 1,000 mg), with 6 pts/DL. Plasma PK and serial ECGs were performed in cycle 1. Circulating tumor cells (CTC), Hsp27+ CTC and serum Hsp27 levels were evaluated serially. Results: 34 pts have been accrued and single agent dose escalation is complete. Median age was 62 (range: 33–86) yrs; 16 pts had prostate, 10 breast, 5 ovary and 3 lung ca. Median cycles administered were 2 (0–8) with 2 pts remaining on treatment. Most common related AEs: chills (53%), pruritis (29%), flushing (21%), elevated creatinine (18%), fatigue (15%), arthralgia (15%). More than 80% of pts had grade (Gr) 1/2 infusion reactions during the LDs or C1. One pt on 1,000 mg DL was hospitalized with Gr 3 infusion reaction. Gr 3 elevations of PTT (with normal INR) were seen in >50% of pts on 800 and 1,000 mg DL. At 600 mg DL, one pt had a Gr 3 epistaxis and one pt had a DLT with a Gr 3 cerebral bleed into a metastasis. No significant QTcF changes were observed. Three pts with prostate ca had PSA declines of 43%, 58%, 62% and 3 pts with ovarian cancer had CA-125 declines of 27%, 28%, and 41%. Five pts have had stable disease for >3 months. Preliminary mean PK data for 200–600 mg DLs: T1/2 = 2.8–3.1 hrs, peak concentration = 21,756 - 102,591 ng/mL and AUCinf ranged from 63,552 - 328,153 ng.h/mL, increasing with dose. Declines in CTC and Hsp27+ CTC have been observed at all DL. Conclusions: OGX-427 was well tolerated. Toxicity consisted mainly of infusion reactions and transient PTT changes. Changes in tumor markers suggest single-agent activity. [Table: see text]

Genistein combined polysaccharide (GCP) is highly active in both human and canine lymphoma models

14126 Background: The soy isoflavones genistein and daidzein have demonstrated anticancer activity in vitro in multiple tumor types including leukemia/lymphoma, with evidence for a role in chemoprevention. GCP (Amino Up Chemical Co.) is a fermentation product of soy extract and the mycelium of Basidiomycetes, a process which converts soy isoflavones to their aglycone form, greatly increasing intestinal absorption. In humans, GCP has negligible toxicity at potentially active concentrations. We hypothesized that GCP would have significant anticancer activity in hematologic malignancies. Methods: Three human lymphoma cell lines (Jurkat, Raji, and Ramos), a leukemia line (HL60), and four canine lymphoid cell lines (GL-1, CLGL-90, CL1, and CLL-1390) were treated with GCP at doses ranging from 25 to 200 μg/ml. Growth effects were assessed by trypan blue exclusion 5–7 days following a single treatment. Flow cytometry and Westerns were used to measure changes in cell cycling, protein expression and apoptosis. We are conducting a single-agent dose escalation clinical trial in chemo-naïve canines with lymphoma. Results: GCP had striking cytotoxic effects in both canine and human lymphoma cell lines. In all human lines, the 50% inhibitory concentrations (IC50s) were less than 25μg/ml. At 100μg/ml, a concentration achievable in patient plasma, virtually no viable cells remained. Three of four canine lines were sensitive with IC50s in the range of 15–50μg/ml. Substantial G2 cell cycle accumulation was observed, apparent within two hours and maintained for at least 48h. GCP treatment induced apoptosis, as shown by an increase in sub-G1 DNA content and cleavage of PARP and caspase 3. At higher doses, elevated Bcl-2 levels were observed, suggesting a potential mechanism of resistance. These results provided the rationale for a clinical trial in canine patients at UC Davis. One patient with aggressive diffuse large B-cell lymphoma treated at 93 mg/kg/day (dose level 2) had a confirmed partial response. Conclusions: GCP has potent anticancer activity in vitro against lymphoid cell lines, with almost complete cell kill at doses achievable in patient plasma with minimal toxicity. A phase I clinical trial in canine lymphoma will determine whether testing in human lymphoma patients is warranted. No significant financial relationships to disclose.