Jeff Evans

Phase I Study of the Poly(ADP-Ribose) Polymerase Inhibitor, AG014699, in Combination with Temozolomide in Patients with Advanced Solid Tumors

Purpose: One mechanism of tumor resistance to cytotoxic therapy is repair of damaged DNA. Poly(ADP-ribose) polymerase (PARP)-1 is a nuclear enzyme involved in base excision repair, one of the five major repair pathways. PARP inhibitors are emerging as a new class of agents that can potentiate chemotherapy and radiotherapy. The article reports safety, efficacy, pharmacokinetic, and pharmacodynamic results of the first-in-class trial of a PARP inhibitor, AG014699, combined with temozolomide in adults with advanced malignancy. Experimental Design: Initially, patients with solid tumors received escalating doses of AG014699 with 100 mg/m2/d temozolomide × 5 every 28 days to establish the PARP inhibitory dose (PID). Subsequently, AG014699 dose was fixed at PID and temozolomide escalated to maximum tolerated dose or 200 mg/m2 in metastatic melanoma patients whose tumors were biopsied. AG014699 and temozolomide pharmacokinetics, PARP activity, DNA strand single-strand breaks, response, and toxicity were evaluated. Results: Thirty-three patients were enrolled. PARP inhibition was seen at all doses; PID was 12 mg/m2 based on 74% to 97% inhibition of peripheral blood lymphocyte PARP activity. Recommended doses were 12 mg/m2 AG014699 and 200 mg/m2 temozolomide. Mean tumor PARP inhibition at 5 h was 92% (range, 46-97%). No toxicity attributable to AG014699 alone was observed. AG014699 showed linear pharmacokinetics with no interaction with temozolomide. All patients treated at PID showed increases in DNA single-strand breaks and encouraging evidence of activity was seen. Conclusions: The combination of AG014699 and temozolomide is well tolerated, pharmacodynamic assessments showing proof of principle of the mode of action of this new class of agents.

Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac): an open-label, randomised, phase 3 trial

BACKGROUND We aimed to assess the efficacy and safety of sequential or simultaneous telomerase vaccination (GV1001) in combination with chemotherapy in patients with locally advanced or metastatic pancreatic cancer. METHODS TeloVac was a three-group, open-label, randomised phase 3 trial. We recruited patients from 51 UK hospitals. Eligible patients were treatment naive, aged older than 18 years, with locally advanced or metastatic pancreatic ductal adenocarcinoma, and Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomly assigned (1:1:1) to receive either chemotherapy alone, chemotherapy with sequential GV1001 (sequential chemoimmunotherapy), or chemotherapy with concurrent GV1001 (concurrent chemoimmunotherapy). Treatments were allocated with equal probability by means of computer-generated random permuted blocks of sizes 3 and 6 in equal proportion. Chemotherapy included six cycles of gemcitabine (1000 mg/m(2), 30 min intravenous infusion, at days 1, 8, and 15) and capecitabine (830 mg/m(2) orally twice daily for 21 days, repeated every 28 days). Sequential chemoimmunotherapy included two cycles of combination chemotherapy, then an intradermal lower abdominal injection of granulocyte-macrophage colony-stimulating factor (GM-CSF; 75 μg) and GV1001 (0·56 mg; days 1, 3, and 5, once on weeks 2-4, and six monthly thereafter). Concurrent chemoimmunotherapy included giving GV1001 from the start of chemotherapy with GM-CSF as an adjuvant. The primary endpoint was overall survival; analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN4382138. FINDINGS The first patient was randomly assigned to treatment on March 29, 2007, and the trial was terminated on March 27, 2011. Of 1572 patients screened, 1062 were randomly assigned to treatment (358 patients were allocated to the chemotherapy group, 350 to the sequential chemoimmunotherapy group, and 354 to the concurrent chemoimmunotherapy group). We recorded 772 deaths; the 290 patients still alive were followed up for a median of 6·0 months (IQR 2·4-12·2). Median overall survival was not significantly different in the chemotherapy group than in the sequential chemoimmunotherapy group (7·9 months [95% CI 7·1-8·8] vs 6·9 months [6·4-7·6]; hazard ratio [HR] 1·19, 98·25% CI 0·97-1·48, p=0·05), or in the concurrent chemoimmunotherapy group (8·4 months [95% CI 7·3-9·7], HR 1·05, 98·25% CI 0·85-1·29, p=0·64; overall log-rank of χ(2)2df=4·3; p=0·11). The commonest grade 3-4 toxic effects were neutropenia (68 [19%] patients in the chemotherapy group, 58 [17%] patients in the sequential chemoimmunotherapy group, and 79 [22%] patients in the concurrent chemoimmunotherapy group; fatigue (27 [8%] in the chemotherapy group, 35 [10%] in the sequential chemoimmunotherapy group, and 44 [12%] in the concurrent chemoimmunotherapy group); and pain (34 [9%] patients in the chemotherapy group, 39 [11%] in the sequential chemoimmunotherapy group, and 41 [12%] in the concurrent chemoimmunotherapy group). INTERPRETATION Adding GV1001 vaccination to chemotherapy did not improve overall survival. New strategies to enhance the immune response effect of telomerase vaccination during chemotherapy are required for clinical efficacy. FUNDING Cancer Research UK and KAEL-GemVax.

A multicentre comparison between Child Pugh and Albumin-Bilirubin scores in patients treated with sorafenib for Hepatocellular Carcinoma

The Albumin‐Bilirubin (ALBI) grade was proposed as an objective means to evaluate liver function in patients with Hepatocellular Carcinoma (HCC). ALBI grade 1 vs 2 were proposed as stratification factors within the Child Pugh (CP) A class. However, the original publication did not provide comparison with the subclassification by points (5–15) within the CP classification.

Dose–Response Relationship in Phase I Clinical Trials: A European Drug Development Network (EDDN) Collaboration Study

Introduction: Because a dose–response relationship is characteristic of conventional chemotherapy, this concept is widely used for the development of novel cytotoxic (CTX) drugs. However, the need to reach the MTD to obtain optimal benefit with molecularly targeted agents (MTA) is controversial. In this study, we evaluated the relationship between dose and efficacy in a large cohort of phase I patients with solid tumors. Experimental Design: We collected data on 1,182 consecutive patients treated in phase I trials in 14 European institutions in 2005–2007. Inclusion criteria were: (i) patients treated within completed single-agent studies in which a maximum-administered dose was defined and (ii) RECIST/survival data available. Results: Seventy-two percent of patients were included in trials with MTA (N = 854) and 28% in trials with CTX (N = 328). The objective response (OR) rate was 3% and disease control at 6 months was 11%. OR for CTX was associated with higher doses (median 92% of MTD); this was not the case for MTA, where patients achieving OR received a median of 50% of MTD. For trials with MTA, patients treated at intermediate doses (40%–80%) had better survival compared with those receiving low or high doses (P = 0.038). On the contrary, there was a direct association between higher dose and better OS for CTX agents (P = 0.003). Conclusion: Although these results support the development of novel CTX based on MTD, we found no direct relationship between higher doses and response with MTA in unselected patients. However, the longest OS was seen in patients treated with MTA at intermediate doses (40%–80% of MTD). Clin Cancer Res; 20(22); 5663–71. ©2014 AACR.

Abstract A218: Pharmacokinetics of orally administered rucaparib in patients with advanced solid tumors.

Background: Oral cancer therapies are often complicated by variable absorption leading to highly variable plasma pharmacokinetics (PK) and thus unpredictable toxicity and efficacy. Rucaparib, a poly (ADP-ribose) polymerase inhibitor (PARPi), is being developed for treatment of tumors associated with homologous recombination repair deficiency with a pre-specified target plasma trough level. While efficacy has been shown for PARPis, dose interruptions/reductions due to adverse events (AEs) are common for PARPis. Here, we report the PK results for oral rucaparib in patients and assess exposure predictability. Methods: Rucaparib PK was studied in two Phase I studies. CO-338-010 (N=39) is an ongoing Phase I/II monotherapy study examining safety, PK, and preliminary efficacy of oral rucaparib administered continuously 40-500 mg once (qd) or 240-600 mg twice daily (bid) (NCT01482715). The effect of a high-fat meal on rucaparib PK was examined at 40 mg (N=3) and 300 mg (N=6). A4991014 (N=53) is an ongoing Phase I study currently assessing rucaparib in combination with carboplatin (CBDCA) (NCT01009190). Patients received lead-in oral rucaparib on Day -5 followed by CBDCA on Day 1 and oral rucaparib qd on Days 1-14 of every 21-day treatment cycle. Patients in earlier cohorts also had a single lead-in dose of intravenous rucaparib for calculating oral bioavailability. Plasma rucaparib levels were determined using a validated LC-MS/MS method. Results: Rucaparib exhibited good oral absorption with a dose-independent oral bioavailability of 36% and median Tmax ranging from 1 to 6 hours. Exposure generally exhibited dose proportional kinetics up to 1200 mg daily dose (600 mg bid). The target trough level of 2 μM was achieved in 100% of patients (n=14) at ≥240 mg bid with low inter-patient variability ( Conclusions: Rucaparib showed desirable dose- and time- independent PK with low inter- and intra- patient variability in exposure compared to published olaparib data. Predictable PK following oral dosing may lead to low rates of over- and under- dosing, potentially minimizing AEs associated with high unpredictable exposures, an important attribute for maintenance therapy. Rucaparib9s low inter-patient variability is beneficial for uniform flat dosing strategies. This will be explored in the two upcoming studies, ARIEL2 and ARIEL3. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A218. Citation Format: Geoffrey Shapiro, Rebecca Kristeleit, Mark Middleton, Howard Burris, L. Rhoda Molife, Jeff Evans, Richard Wilson, Patricia LoRusso, James Spicer, Veronique Dieras, Manish Patel, Erin Dominy, Dayna Simpson, Heidi Giordano, Andrew R. Allen, Sarah S. Jaw-Tsai, Ruth Plummer. Pharmacokinetics of orally administered rucaparib 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 A218.

Abstract A164: Cardiac effects in a first-in-human (FIH), pharmacokinetic (PK), pharmacodynamic (PD) phase I trial of JNJ-26481585, a second-generation oral hydroxamate histone deacetylase inhibitor (HDACi), in patients with refractory cancer.

Background: HDACi have demonstrated activity as anticancer agents and are licensed for use in cutaneous and peripheral T cell lymphoma. Cardiac effects including arrhythmias and QTc prolongation have previously been associated with HDACi administration in humans. This report summarizes the cardiac adverse event (AE) profile observed during the recently completed FIH Phase I trial of JNJ26481585. Methods: Continuous oral daily dosing (QD) of JNJ26481585 in 21-day (D) cycles (C) was investigated initially in 20 patients (pts) demonstrating activity (including 1 partial response, 1 minor response, 1 prolonged stable disease in melanoma) but ventricular arrhythmia (2 pt) and fatigue (1 pt) were dose-limiting. To improve tolerability, 3 intermittent schedules (QD Mon/Wed/Fri (MWF); QD Mon/Tue/Wed/Thu (MTWT); QD Mon/Thu (MT)) also in 21-D C were subsequently explored in 38 (including expansion cohort), 19 and 15 pts respectively. All pts had triplicate 12-lead ECG (tECG), 24 hour ECG (Holter) and echocardiography or MUGA scan for assessment of left ventricular ejection fraction (LVEF) at baseline and during treatment. Analysis of mean QTcF, categorical QTcF and preliminary assessment of cardiac rhythm/morphology was performed. Results: 12mg QD MWF was identified as the recommended Phase II dose (RP2D) based on safety, tolerability, PK predictions and PD activity. Maximum average increase in mean QTcF from baseline ranged from 0 to 8 milliseconds (ms) during cycles 1 and 2 across the 4 schedules. At RP2D, the maximum average increase in mean QTcF observed was 6ms. 1 out of 38 pts (2.6%) treated on the MWF schedule experienced a Grade (G) 3 QTcF prolongation, possibly related to ST-T segment changes identified as a class effect of HDACi. QTcF prolongation G1–2 was rarely observed across schedules and mostly occurred as an isolated reversible observation whilst on study drug. Reversible, non-sustained ventricular tachycardia (NSVT) was observed as a dose limiting toxicity (DLT) in 3 out of 39 pts (7.7%) receiving QD or MTWT dosing but was not observed on the MWF or MT schedules. Other reversible, but dose-limiting, cardiac effects were T-wave inversion (2 pts on MT and MTWT), supraventricular tachycardia (1 pt on MT) and hypertension with raised troponin (1 pt on MWF). Non-specific, reversible, asymptomatic ST-T segment changes were frequently observed. LVEF was unaffected during treatment with JNJ26481585. Conclusion: The RP2D of JNJ26481585 was determined as 12 mg on the MWF schedule and demonstrated an acceptable cardiac safety profile. One pt had QTcF>500 ms but no clinically significant effect on the QTcF interval was observed across schedules. Reversible NSVT was identified as a DLT in some patients on the QD and MTWT dosing schedules but not on the MWF and MT schedules. 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 A164.

Abstract A46: Pharmacodynamic biomarkers for OSI‐906, an insulin‐like growth factor‐1 receptor (IGF‐1R) tyrosine kinase inhibitor, in cancer patients with advanced solid tumors

Background: OSI‐906 is a potent small molecule inhibitor of the insulin-like growth factor 1 receptor (IGF‐1R), a receptor tyrosine kinase that is overexpressed in several human cancer types and implicated in resistance to chemotherapy. Disruption of the growth hormone‐IGF1 signaling axis can affect levels of biomarkers such as IGF1, growth hormone (GH) and insulin and can affect glucose homeostasis, making these potentially useful markers for demonstrating the activity of IGF‐1R inhibitors in solid tissues. Methods: Two phase I dose escalation trials were initiated in cancer patients with advanced solid tumors who received OSI‐906 on either continuous or intermittent dosing schedules. Pharmacodynamic (PD) and pharmacokinetic (PK) assessments were included as secondary objectives of these studies. Circulating biomarkers, including total IGF1, IGFBP3 and non‐fasting GH and insulin levels, were measured at various times during the dosing cycle (21 days for continuous dosing; 14 days for intermittent dosing) and changes were correlated with plasma concentrations of OSI‐906. Results: To date, patients have been treated with up to 450 mg QD and 200 mg BID on the continuous dosing schedule and up to 750 mg QD on the intermittent dosing schedule. Maximum tolerated dose (MTD) was determined to be 400 mg QD and 150 mg BID for continuous dosing and 600 mg QD for intermittent dosing. Preliminary analysis of the PK data suggests that the exposure of OSI‐906 increased with dose. Median plasma concentrations of OSI‐906 at MTD exceeded the predicted concentration required for efficacy based on the preclinical models (1 µM). Total IGF1 concentrations in plasma were increased relative to predose levels at doses ≥ 450 mg QD on the intermittent dosing schedule and ≥ 150 mg QD or 40 mg BID on the continuous dosing schedule. Elevations in non‐fasting plasma insulin levels were also observed in patients with plasma concentrations of OSI‐906 exceeding 5000 ng/mL. PK/PD relationships were observed for IGF1 and insulin. OSI‐906 did not affect plasma IGFBP3 levels in most patients. Analysis of additional biomarkers, including GH, is ongoing. Conclusions: At or below MTD, plasma concentrations of OSI‐906 could be achieved that exceed concentrations required for anti‐tumor efficacy based on the preclinical models. The pharmacodynamic data indicate that pharmacologically‐relevant concentrations of OSI‐906 were achieved in tissues involved in regulating the GH‐IGF1 signaling axis. Together, these PK and PD data indicate that the current recommended dosing regimens may provide sufficient exposure for activity against solid tumors. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A46.