Carla Kurkjian

A phase I dose escalation study of oral c-MET inhibitor tivantinib (ARQ 197) in combination with gemcitabine in patients with solid tumors

BACKGROUND Tivantinib (ARQ 197) is an orally available, non-adenosine triphosphate competitive, selective c-MET inhibitor. The primary objective of this study was to evaluate the safety, tolerability and to establish the recommended phase II dose (RP2D) of tivantinib and gemcitabine combination. PATIENTS AND METHODS Patients with advanced or metastatic solid tumors were treated with escalating doses of tivantinib (120-360 mg capsules) in combination with gemcitabine (1000 mg/m(2) weekly for 3 of 4 weeks). Different schedules of administration were tested and modified based on emerging preclinical data. Tivantinib was given continuously, twice a day (b.i.d.) for 2, 3 or 4 weeks of a 28-day cycle or on a 5-day on, 2-day off schedule (the day before and day of gemcitabine administration). RESULTS Twenty-nine patients were treated with gemcitabine and escalating doses of tivantinib: 120 mg b.i.d. (n = 4), 240 mg b.i.d. (n = 6) and 360 mg b.i.d. (n = 19). No dose-limiting toxicities were observed in escalation. The RP2D was 360 mg b.i.d. daily, and 45 additional patients were enrolled in the expansion cohort. Grade ≥3 treatment-related toxicities were observed in 54 of 74 (73%) patients with the most common being neutropenia (43%), anemia (30%), thrombocytopenia (28%) and fatigue (15%). There was one treatment-related death due to neutropenia. Administration of gemcitabine did not affect tivantinib concentration. Fifty-six patients were assessable for response. Eleven (20%) patients achieved a partial response and 26 (46%) had stable disease (SD), including 15 (27%) who achieved SD for over 4 months. Ten of 37 patients with clinical benefit had prior exposure to gemcitabine. CONCLUSION The combination of tivantinib at its monotherapy dose and standard dose gemcitabine was safe and tolerable. Early signs of antitumor activity may warrant further development of this combination in nonsmall-cell lung cancer, ovarian, pancreatic and cholangiocarcinoma. CLINICALTRIALSGOV IDENTIFIER NCT00874042.BACKGROUND Tivantinib (ARQ 197) is an orally available, non-adenosine triphosphate competitive, selective c-MET inhibitor. The primary objective of this study was to evaluate the safety, tolerability and to establish the recommended phase II dose (RP2D) of tivantinib and gemcitabine combination. PATIENTS AND METHODS Patients with advanced or metastatic solid tumors were treated with escalating doses of tivantinib (120-360mg capsules) in combination with gemcitabine (1000mg/m2 weekly for 3 of 4 weeks). Different schedules of administration were tested and modified based on emerging preclinical data. Tivantinib was given continuously, twice a day (b.i.d.) for 2, 3 or 4 weeks of a 28-day cycle or on a 5-day on, 2-day off schedule (the day before and day of gemcitabine administration). RESULTS Twenty-nine patients were treated with gemcitabine and escalating doses of tivantinib: 120mg b.i.d. (n = 4), 240mg b.i.d. (n = 6) and 360mg b.i.d. (n = 19). No dose-limiting toxicities were observed in escalation. The RP2D was 360mg b.i.d. daily, and 45 additional patients were enrolled in the expansion cohort. Grade ≥3 treatment-related toxicities were observed in 54 of 74 (73%) patients with the most common being neutropenia (43%), anemia (30%), thrombocytopenia (28%) and fatigue (15%). There was one treatment-related death due to neutropenia. Administration of gemcitabine did not affect tivantinib concentration. Fifty-six patients were assessable for response. Eleven (20%) patients achieved a partial response and 26 (46%) had stable disease (SD), including 15 (27%) who achieved SD for over 4 months. Ten of 37 patients with clinical benefit had prior exposure to gemcitabine. CONCLUSION The combination of tivantinib at its monotherapy dose and standard dose gemcitabine was safe and tolerable. Early signs of antitumor activity may warrant further development of this combination in nonsmall-cell lung cancer, ovarian, pancreatic and cholangiocarcinoma. CLINICALTRIALS. GOV IDENTIFIER NCT00874042.

Mitosis-Targeting Natural Products for Cancer Prevention and Therapy

Mitosis is a complex process resulting in division of a cell into two daughter cells, and its failure often results in the death of the daughter cells (via apoptotic, necrotic, or proliferative/senescent death). Many chemicals that inhibit the mitotic process (anti-mitotic drugs) have proven effective for killing cancer cells in vitro and in clinical settings. Among the most studied anti-mitotic drugs are plant-origin natural products including taxanes (e.g. paclitaxel, docetaxel) and vinca alkaloids (e.g. vincristine, vinblastine), whose validated target is the spindle microtubules. With the success of these agents, efforts have been made to develop other spindle poisons as well as to improve efficacy of existing spindle poisons with structural modifications. Novel drugs and natural products that inhibit other proteins involved in mitosis (nonmicrotubule targets) have been sought in hopes of expanding available cancer-directed therapies. Recently, significant advances have been made in the understanding of mitotic mechanisms in tumor cells as well as in normal epithelial cells. These advances help us to identify and develop potential natural agents for the prevention and treatment of cancer. This review will focus on natural products that target mitotic process and/or proteins involved in mitotic progression.

Advances in the Treatment of Metastatic Colorectal Cancer

The treatment of metastatic colorectal cancer has undergone major advances yielding significant improvements in survival over the past decade. These advances have evolved due to the benefits of combination chemotherapy and the incorporation of biologic therapy. However, as we struggle to provide optimum care while sparing patients ineffective therapy and undue cost, the importance of tailored therapy to maximize benefit will become increasingly important. This article reviews the major advances in the treatment of patients with metastatic colorectal cancer and the burgeoning developments in individualized therapy.

Antitumor Activity of an Enzyme Prodrug Therapy Targeted to the Breast Tumor Vasculature

The L-methioninase-annexin V/selenomethionine enzyme prodrug system, designed to target the tumor vasculature and release the methylselenol anticancer drug in the tumor, was tested in mice with implanted MBA-MB-231 breast tumors. This therapy was able to cause a reduction in the size of the tumors during the treatment period. It was shown that L-methioninase-annexin V was uniformly bound at the blood vessel surface in the tumor and also that there was a substantial cutoff of blood flowing through the treated tumor, consistent with the therapys design. This new approach for enzyme prodrug therapy of breast cancer appears promising.

Targeted enzyme prodrug therapy for metastatic prostate cancer - a comparative study of L-methioninase, purine nucleoside phosphorylase, and cytosine deaminase.

BackgroundEnzyme prodrug therapy shows promise for the treatment of solid tumors, but current approaches lack effective/safe delivery strategies. To address this, we previously developed three enzyme-containing fusion proteins targeted via annexin V to phosphatidylserine exposed on the tumor vasculature and tumor cells, using the enzymes L-methioninase, purine nucleoside phosphorylase, or cytosine deaminase. In enzyme prodrug therapy, the fusion protein is allowed to bind to the tumor before a nontoxic drug precursor, a prodrug, is introduced. Upon interaction of the prodrug with the bound enzyme, an anticancer compound is formed, but only in the direct vicinity of the tumor, thereby mitigating the risk of side effects while creating high intratumoral drug concentrations. The applicability of these enzyme prodrug systems to treating prostate cancer has remained unexplored. Additionally, target availability may increase with the addition of low dose docetaxel treatment to the enzyme prodrug treatment, but this effect has not been previously investigated. To this end, we examined the binding strength and the cytotoxic efficacy (with and without docetaxel treatment) of these enzyme prodrug systems on the human prostate cancer cell line PC-3.ResultsAll three fusion proteins exhibited strong binding; dissociation constants were 0.572 nM for L-methioninase-annexin V (MT-AV), 0.406 nM for purine nucleoside phosphorylase-annexin V (PNP-AV), and 0.061 nM for cytosine deaminase-annexin V (CD-AV). MT-AV produced up to 99% cell death (p < 0.001) with limited cytotoxicity of the prodrug alone. PNP-AV with docetaxel created up to 78% cell death (p < 0.001) with no cytotoxicity of the prodrug alone. CD-AV with docetaxel displayed up to 60% cell death (p < 0.001) with no cytotoxicity of the prodrug alone. Docetaxel treatment created significant increases in cytotoxicity for PNP-AV and CD-AV.ConclusionsStrong binding of fusion proteins to the prostate cancer cells and effective cell killing suggest that the enzyme prodrug systems with MT-AV and PNP-AV may be effective treatment options. Additionally, low-dose docetaxel treatment was found to increase the cytotoxic effect of the annexin V-targeted therapeutics for the PNP-AV and CD-AV systems.

Phase 1, open-label, dose escalation, safety, and pharmacokinetics study of ME-344 as a single agent in patients with refractory solid tumors.

The current phase 1, open‐label, dose escalation study was conducted to establish the safety, tolerability, pharmacokinetic profile, and preliminary antitumor activity of the novel mitochondrial inhibitor ME‐344 in patients with refractory solid tumors.

Abstract PD1-3: Ph1b study of the PI3K inhibitor GDC-0032 in combination with fulvestrant in patients with hormone receptor-positive advanced breast cancer

Background: GDC-0032 is a next-generation PI3K inhibitor with increased anti-tumor activity against PIK3CA mutant cancers. GDC-0032 is an orally bioavailable, potent, and selective inhibitor of Class I PI3K alpha, delta, and gamma isoforms, with 30-fold less inhibition of the PI3K beta isoform relative to the PI3K alpha isoform. Preclinical data show that GDC-0032 has enhanced activity against PI3K alpha isoform (PIK3CA) mutant breast cancer cell lines. Preclinical data also show enhanced antitumor activity when GDC-0032 is combined with fulvestrant. Material and Methods: A Phase 1b dose escalation study was conducted with evaluation of GDC-0032 doses ranging from 6-9 mg QD in combination with fulvestrant 500mg q4wk (with loading dose of 500mg at day 1, 14 and 28) in a modified 3+3 design. A dose expansion cohort was conducted at the recommended Phase 2 dose of 6 mg QD. Safety and tolerability of GDC-0032 was assessed, as well as pharmacokinetics (PK), pharmacodynamic (PD) assessment of PI3K pathway inhibition by paired tumor biopsies and by FDG-PET, and anti-tumor activity by RECIST. Results: As of 1 Mar 2013, 17 patients were enrolled onto this study with the completion of dose escalation. No dose limiting toxicities (DLTs) were observed at either the 6 mg or 9 mg dose levels. Adverse events (AEs) assessed by the investigator as related to GDC-0032 in ≥10% of patients, were diarrhea, hyperglycemia, stomatitis, fatigue, asthenia, decreased appetite, nausea, mucosal inflammation and rash. No observed apparent PK interactions were observed between GDC-0032 and fulvestrant. The median number of prior systemic therapies was 6. Metabolic partial responses via FDG-PET (≥ 20% decrease in mSUVmax) were observed in 8 out of 11 patients assessed (73%). Confirmed partial responses by RECIST have been observed at both the 6mg and 9mg GDC-0032 dose levels. These include patients who have had prior treatment with fulvestrant. As of 29 May 2013, enrollment onto the dose escalation and expansion cohort has been completed (n = 27). Updated data on safety, pharmacodynamics, efficacy, and biomarker correlates will be presented. Conclusions: The combination of GDC-0032 and fulvestrant is a well-tolerated regimen with promising preliminary efficacy. GDC-0032 is being further investigated in combination with fulvestrant for patients with hormone receptor-positive advanced breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD1-3.

Abstract B75: A first in-human phase I study to evaluate the MEK1/2 inhibitor GDC-0623 in patients with advanced solid tumors.

Background: Deregulation of the RAS/RAF/MEK/ERK signaling pathway has been implicated in diverse human tumors. GDC-0623 is an orally bioavailable inhibitor of MEK1/2 which has shown antitumor activity in preclinical models (Hatzivassiliou et al. 2013). Methods: An open-label Phase I dose-escalation study using a 3 + 3 design was initiated in patients with advanced solid tumors to evaluate the safety and pharmacokinetic (PK) characteristics of GDC-0623. Patients were administered oral GDC-0623 as a QD or BID regimen on a 21-day on/7-day off dosing schedule in the fasted state (minimum 2 hour fast). In addition, two cohorts were enrolled to examine the effect of food (4 pts) and acidic beverage (3 pts) on GDC-0623 PK. Serial plasma samples for GDC-0623 PK analysis were collected over 24 hours following first dose and after 15 days of continuous dosing. Results: On the QD regimen, 45 pts enrolled in eight successive cohorts (7-160 mg). Dose-limiting toxicities (DLTs) were Grade 4 (G4) creatine phosphokinase (CPK) elevation (90 mg), transient G3 visual disturbance and the serious adverse event (SAE) of G3 dehydration both occurring in the same patient (120 mg), and G3 thrombocytopenia and G3 hyponatremia (160 mg). The maximum tolerated dose was 120 mg (QD cohort). Eight patients enrolled in a single cohort dosing at 45 mg BID. One patient had a DLT of G2 retinal pigment epithelial detachment. Further BID cohorts were not enrolled since the AE profiles between on 90 mg QD and 45 mg BID were comparable. The most frequent adverse events (AE) attributed by the investigator to be GDC-0623-related were rash, visual disturbance - including impaired or blurred vision - which was often associated with sub-retinal fluid, diarrhea, nausea and vomiting, fatigue, elevated CPK, peripheral edema, decreased appetite, headache and dizziness. Preliminarily, GDC-0623 showed dose-proportional PK over the dose range administered. GDC-0623 was rapidly absorbed and distributed, with a terminal half-life of 4-6 hours. Due to its short half-life, GDC-0623 had no accumulation at steady-state following daily oral dosing. Effect of food or acidic beverage on GDC-0623 PK was inconclusive given the inter-patient and intra-patient variability in GDC-0623 PK and very small sample size. One confirmed partial response was observed in a patient with KRAS wild type squamous cell vaginal carcinoma at the QD MTD. Six patients had stable disease ≥ 5 months. Conclusion: GDC-0623 is well-tolerated and showed dose-proportional and time-independent PK. Classic MEK-related AEs, including rash, gastrointestinal symptoms and visual disturbance occurred with similar frequency for QD and BID dosing regimens at the same total daily dose, suggesting comparable intensity of MEK target effect. Updated data will be presented. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B75. Citation Format: Anthony El-Khoueiry, Carla Kurkjian, Thomas Semrad, Luna Musib, Mary Gates, Steve Eppler, Ilsung Chang, Iris Chan, Isabelle Rooney, Johanna Bendell. A first in-human phase I study to evaluate the MEK1/2 inhibitor GDC-0623 in patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B75.

Treatment of Recurrent Metastatic Colon Cancer in the Age of Modern Adjuvant Therapy

The treatment of patients with metastatic colon cancer has evolved tremendously over the past 10 years, with improved overall survival (OS) rates as a result of the advent of several important agents. Following the results of important adjuvant trials, the incorporation of oxaliplatin into the adjuvant setting has significantly increased the disease-free survival and OS rates in patients who undergo curative resection. However, still a significant number of patients will present with recurrent disease after being treated with oxaliplatin-containing chemotherapy regimens. Herein, we present approaches to the chemotherapeutic management of such patients with a review of the literature.

Annexin V-directed enzyme prodrug therapy plus docetaxel for the targeted treatment of pancreatic cancer

Objectives The bleak prognosis associated with pancreatic cancer (PDAC) drives the need for the development of novel treatment methodologies. Here, we evaluate the applicability of 3 enzyme prodrug therapies for PDAC, which are simultaneously targeted to the tumor, tumor vasculature, and metastases via annexin V. In these therapies, annexin V is fused to an enzyme, creating a fusion protein that converts nontoxic drug precursors, prodrugs, into anticancer compounds while bound to the tumor, therefore mitigating the risk of side effects. Methods The binding strength of fusion proteins to the human PDAC cell lines Panc-1 and Capan-1 was measured via streptavidin-horseradish peroxidase binding to biotinylated fusion proteins. Cytotoxic efficacy was evaluated by treatment with saturating concentrations of fusion protein followed by varying concentrations of the corresponding prodrug plus docetaxel. Results All fusion proteins exhibited strong binding to PDAC cells, with dissociation constants between 0.02 and 1.15 nM. Cytotoxic efficacy was determined to be very good for 2 of the systems, both of which achieved complete cell death on at least 1 cell line at physiologically attainable prodrug concentrations. Conclusions Strong binding of fusion proteins to PDAC cells and effective cytotoxicity demonstrate the potential applicability of enzyme prodrug therapy to the treatment of PDAC.