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22. Vermorken JB, Stohlmacher-Williams J, Davidenko I et al. Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamouscell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial. Lancet Oncol 2013; 14: 697–710. 23. Weinberger PM, Yu Z, Haffty BG et al. Molecular classification identifies a subset of human papillomavirus—associated oropharyngeal cancers with favorable prognosis. J Clin Oncol 2006; 24: 736–747. 24. Vermorken JB, Mesia R, Rivera F et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008; 359: 1116–1127. 25. Psyrri A, Licitra L, De Blas B et al. Safety and efficacy of cisplatin plus 5-FU and cetuximab in HPV-positive and HPV-negative recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN): analysis of the phase III EXTREME trial. In ESMO 2012 (Abstr 10180). 26. Vermorken JB, Psyrri A, Mesia R et al. Impact of tumor HPV status on outcome in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck receiving chemotherapy with or without cetuximab: retrospective analysis of the phase III EXTREME trial. Ann Oncol 2014; 25: 801–807. 27. Seiwert T. Accurate HPV testing: a requirement for precision medicine for head and neck cancer. Ann Oncol 2013; 24: 2711–2713.
Annals of Oncology 25: 1416–1421, 2014 doi:10.1093/annonc/mdu157 Published online 15 April 2014
A phase I dose escalation study of oral c-MET inhibitor tivantinib (ARQ 197) in combination with gemcitabine in patients with solid tumors S. Pant1*, M. Saleh2, J. Bendell3, J. R. Infante3, S. Jones3, C. D. Kurkjian1, K. M. Moore1, J. Kazakin4, G. Abbadessa4, Y. Wang4, Y. Chen5, B. Schwartz4 & L. H. Camacho6 1 University of Oklahoma Health Sciences Center, Oklahoma City; 2Georgia Cancer Specialists, Atlanta; 3SCRI, Tennessee Oncology, PLLC, Nashville; 4Arqule, Inc., Woburn; 5BioMarin Pharmaceutical, Inc., Novato; 6St Luke’s Medical Center, Houston, USA
Received 21 December 2013; revised 1 April 2014; accepted 2 April 2014
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/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: 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 *Correspondence to: Dr Shubham Pant, Section of Hematology/Oncology, Peggy and Charles Stephenson Oklahoma Cancer Center, Oklahoma City, OK 73104, USA. Tel: +1-405-271-4022; E-mail: [email protected]
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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20.
cetuximab in patients with locally advanced head and neck cancer. J Clin Oncol 2010; 28: 5294–5300. Wheeler S, Siwak DR, Chai R et al. Tumor epidermal growth factor receptor and EGFR PY1068 are independent prognostic indicators for head and neck squamous cell carcinoma. Clin Cancer Res 2012; 18: 2278–2289. Argiris A, Li Y, Forastiere A. Prognostic factors and long-term survivorship in patients with recurrent or metastatic carcinoma of the head and neck. Cancer 2004; 101: 2222–2229. Zuo Z, Keck MK, Khattri A et al. Multimodality determination of HPV status in head and neck cancers (HNC) and development of an HPV signature. J Clin Oncol 2013; 31 (suppl): abstr 6008. Chung CH, Zhang Q, Kong C et al. p16 expression as a human papillomavirus (HPV)-independent prognostic biomarker in non-oropharyngeal squamous cell carcinoma (non-OPSCC). J Clin Oncol 2013; 31 (suppl): abstr 6007. Fakhry C, Westra WH, Li S et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 2008; 100: 261–269. O’Sullivan B, Huang SH, Siu LL et al. Deintensification candidate subgroups in human papillomavirus-related oropharyngeal cancer according to minimal risk of distant metastasis. J Clin Oncol 2013; 31: 543–550.
Annals of Oncology
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Annals of Oncology
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. Key words: tivantinib, gemcitabine, phase I
introduction
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methods Patients were recruited from four centers in the United States (Georgia Cancer Specialists, Atlanta, GA; Oklahoma University Health Sciences Center, Oklahoma City, OK; Oncology Consultants P.A., Houston, TX; Sarah Cannon Research Institute, Nashville, TN). Key eligibility criteria were histologically or cytologically confirmed advanced-stage solid tumors, age ≥18 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1, measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines, adequate bone marrow (Hgb ≥10 or ≥9 g/ dl for expanded cohort, ANC ≥1.5 × 109/l, Platelets ≥100/l), hepatic (aspartate aminotransferase, alanine aminotransferase ≤2.5× upper limit of normal (ULN) or ≤5× ULN with metastatic liver disease) and renal function (serum creatinine ≤1.5× ULN). Different schedules of drugs administration were tested (Table 1). Tivantinib (ARQ197) was supplied by ArQule, Inc. (Woburn, MA) as 120 mg capsules or tablets and was escalated based on data from previous monotherapy trials (120, 240. 360 mg). The RP2D was defined as the MTD, which is the highest dose of tivantinib in combination with gemcitabine that had no more than 33% probability of causing a dose-limiting toxicity (DLT). The study used a 3 + 3 dose escalation scheme with each cohort starting with three patients. If no DLT was observed, the enrollment commenced at the next higher dose level. A DLT was defined as an adverse event (AE) observed during the first 28-day cycle of therapy according to the following criteria: (i) any ≥grade 3 nonhematologic treatment-related toxicity (except reversible laboratory abnormalities and persistent nausea/vomiting, or diarrhea, despite optimal medical care); (ii) grade 4 neutropenia or anemia for >7 days; (iii) grade 4 thrombocytopenia, or (iv) grade 3 thrombocytopenia in the presence of bleeding. Once the RP2D was established, additional patients were enrolled in an expansion cohort. The first 28 patients were instructed to
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Accumulating evidence has established the role of the MET receptor tyrosine kinase, encoded by the MET proto-oncogene, in tumor development and metastases [1]. Binding of hepatocyte growth factor (HGF) to MET primarily activates the RASMAPK and PI3K-AKT signaling pathways involved in cell growth, proliferation and survival [2]. MET overexpression in cancer is associated with a poor prognosis [3, 4]. Tivantinib (ARQ 197; ArQule, Inc.; Daiichi-Sankyo, Co., Ltd; Kyowa Hakko Kirin (KHK), Co., Ltd) is an oral, selective, smallmolecule MET inhibitor that preferentially inhibits growth and induces apoptosis in human tumor cell lines expressing MET. Tivantinib possesses a unique mechanism of action in that its inhibition of inactive or unphosphorylated form of human c-MET is independent of adenosine triphosphate (ATP) [5, 6]. Preclinical studies in cancer cell lines demonstrated additive or synergistic activity when tivantinib was combined with targeted (erlotinib, sorafenib, gefitinib) or chemotherapeutic agents [docetaxel, gemcitabine, irinotecan, 5-fluorouracil (5-FU)] [7] (Unpublished data, courtesy of ArQule & KHK). Tivantinib is well tolerated and has demonstrated activity in a variety of human tumor xenograft models including breast, colon, gastric, pancreatic and ovarian cancer when administered via daily oral dosing. The antitumor activity was accompanied by the inhibition of c-MET activity as assessed by the level of phosphorylated c-MET [5]. Clinical trials of tivantinib (as monotherapy or in combination with other anticancer agents) demonstrated initial efficacy in MET high patients with hepatocellular carcinoma (HCC), nonsmall-cell lung cancer (NSCLC) and colorectal cancer (CRC) [8–11]. However, a phase III trial in NCSLC [12] and phase II trial in CRC [13] in patients with unselected MET status failed to meet their primary end points. The safety (SAF) profile of tivantinib is well established and common adverse events include anemia, thrombocytopenia, neutropenia, febrile neutropenia, vomiting, dehydration and bradycardia. The recommended dose in capsule formulation is 240 mg twice daily for patients with HCC (increased frequency and severity of ≥grade 3 neutropenia observed in patients receiving 360 mg dose) [9] and at 360 mg twice daily for patients with other malignancies [8, 14]. The antimetabolite gemcitabine is FDA approved for use as a single agent and in combination with other chemotherapeutic agents in pancreatic, NSCLC, advanced ovarian and metastatic breast cancer [15]. The anticancer activity of gemcitabine is mediated through its effects on DNA synthesis during cell division [16]. It causes cellular arrest in the G1/S phase of the cell cycle [15] whereas tivantinib arrests cells in the G2/M phase of the cell cycle, as evidenced by increase in phospho-Histone H3 siRNA [7].
The combination of tivantinib and gemcitabine may be an option for patients with advanced malignancies refractory to standard therapy. Recent preclinical and clinical data suggest that sequential or concurrent administration of anticancer drugs with different mechanisms of action could be more efficacious with an improved toxicity profile [17–19]. To test this hypothesis, a series of preclinical experiments with different dosing schedules were designed in which cells were treated with gemcitabine and tivantinib in continuous, or in pulsatile fashion [7]. Twelve cancer cell lines from different tissue origins including lung, bladder, pancreatic, breast, ovary, uterus and gall bladder were tested. The cells treated on the regimens without a drug holiday inhibited cell growth in a minor subset of the experiments (15%). In contrast, gemcitabine demonstrated synergy with ARQ 197 and inhibited the growth of all 12 cell lines (100%; 12 of 12) tested in the pulsatile regimen with a 2-day drug-free interval. Hence, we translated multiple treatment schedules at the maximal tolerated dose (MTD) (both continuous and sequential) of tivantinib and gemcitabine back to patients in this study.
original articles
Annals of Oncology
Table 1. Dosing schedules Cohort
Tivantinib (ARQ 197) mg b.i.d./frequency of administration
Dose escalation cohorts 0 120/continuously
No. of patients (N = 74; 100%)
Group assignment (N = 74; 100%)
Cycle 1-weekly; cycle 2+ —day 1, 8 and 15
n = 4 (5%)
Group 1 (n = 7; 10%)
240/continuously 240/2 weeks followed by 1 week off
Cycle 1-weekly; cycle 2+ —day 1, 8 and 15 Cycle 1+ —day 8, day 15 and day 22
n = 3 (4%) n = 3 (4%)
C D E
360/2 weeks followed by 1 week off 360/3 weeks continuously followed by 1 week off 360/continuously
Cycle 1+ —day 8, day 15 and day 22 Cycle 1+ —day 8, day 15 and day 22 Cycle 1+ —day 8, day 15 and day 22
n = 4 (5%) n = 7 (10%) n = 8 (11%)
Cycle 1+ —day 8, day 15 and day 22
n = 29 (39%)
Cycle 1+ day 7, day 14 and day 21
n = 16 (22%)
Group 2 (n = 14; 19%)
Group 3 (n = 37; 50%)
Group 4 (n = 16; 22%)
No patients were enrolled in cohort A. The day before and the day of gemcitabine administration.
b
take tivantinib capsules without food. Subsequently, all patients were advised to take tivantinib capsules with meals based on bioavailability/bioequivalence studies in healthy volunteers and cancer patients (NCT 00651638, NCT01149720 and NCT00612209). Toxicity was graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Samples for pharmacokinetic analysis were collected on days 1, 8 and 15. Blood samples and archival tumor tissue (when available) were collected for biomarker analysis. supplementary File S1, available at Annals of Oncology online describes study assessments and detailed pharmacokinetic and pharmacodynamic methodology. All statistical calculations were carried out by using intent-to-treat (ITT), SAF and evaluable (EVAL) analyses. EVAL population was defined as all patients who completed 4 weeks of treatment with both study drugs and who had at least one postbaseline tumor evaluation. ITT population was defined as all patients who received at least one dose of study medication. AEs were evaluated for severity using NCI CTCAE v. 3.0. Overall response rate and the 95% confidence interval (CI) were estimated, as well as the percent of patients in each RECIST response category [e.g. complete response (CR), partial response (PR), stable disease (SD) and progressive disease] and the disease control rate [20]. Progression free survival (PFS) was defined as the time from first dose until disease progression per RECIST or death which ever occurred first.
results patients Seventy-four patients were treated between April 2009 and February 2011. Detailed demographic and baseline characteristics are presented in Table 2. Seventy-three patients received tivantinib and gemcitabine, and one patient received tivantinib only. Overall, the median age was 60.5 years (range, 35–79 years). The majority of the patients were Caucasian (n = 63, 85%), female (n = 44, 59.5%) and had received at least one prior systemic chemotherapy regimen (n = 58, 78%). The median number of prior systemic regimens was 4.0 (range, 0–9). The
| Pant et al.
Table 2. Patient demographics Patients characteristics Gender, n (%) Female Male Age (years) Median (range) Race/ethnicity, n (%) Asian Black or African American Caucasian Other Hispanic or Latino Not Hispanic or Latino ECOG Performance Status, n (%) 0 1 Cancer type Breast cancer Cholangiocarcinoma Endometrial cancer NSCLC Ovarian cancer Pancreatic adenocarcinoma Other Time since initial diagnosis (years) Median (range) Prior anticancer therapies Median (range)
Overall (N = 74) 44 (59.5) 30 (40.5) 60.5 (35–79) 1 (1.4) 5 (6.8) 63 (85.1) 5 (6.8) 8 (10.8) 66 (89.2) 30 (40.5) 44 (59.5) 12 (16.2) 8 (10.8) 4 (5.4) 6 (8.1) 14 (18.9) 21 (28.4) 9 (12.2) 1.8 (0–11) 6 (1–18)
most common primary tumor site was pancreas (n = 21, 28%) followed by ovarian (n = 14, 20%), breast (n = 12, 16%) and cholangiocarcinoma (n = 8, 11%).
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1 Ba
Dose expansion cohorts Expansion 1 360/continuously (Exp 1) Expansion 2 360/5 consecutive days with 2 days (Exp 2) off b ‘pulsatile’ a
Gemcitabine 1000 mg/m2/frequency of administration
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Annals of Oncology
safety
pharmacokinetics The concentration time profile of tivantinib (360 mg b.i.d. capsules) is presented in supplementary Figure S1 and Table S1, available at Annals of Oncology online summarizes the exposure data of tivantinib. Overall, there were no considerable differences in the exposure of tivantinib administered alone or in combination with gemcitabine. Additionally, the exposure of tivantinib observed in this study was in the range of that observed in patients dosed at 360 mg b.i.d. in monotherapy studies. The PK of gemcitabine and 20 ,20 -difluorodeoxyuridine (dFdU) observed in patients treated with 360 mg tivantinib b.i.d. was consistent with the PK results reported in the literature. There was high interpatient variability of both gemcitabine and tivantinib PK parameters. Under steady-state conditions, the AUC 0–12 and Cmax of tivantinib after administration of the 360 mg capsule formulation with food was ∼52% and 56% greater when compared with the fasting state.
pharmacodynamics Plasma was assayed for VEGF, HGF and soluble c-MET. Overall, there were no consistent changes in plasma HGF, VEGF and soluble c-Met levels. The study also evaluated MET tumor biomarkers in archival tumor samples using IHC. Of the 49 assessable patients whose tumor was stained with c-met antibody, 19 (39%) had tumors that were strongly positive, 6 (12%) were focally positive, 9 (18%) were weakly positive and 15 (31%) stained negative. Of the 19 strongly positive patients, 15 were assessed for RECIST with 2 patients achieving PR and 10 SD as their best response. Five other patients with PR as their best response stained negative for MET. Two antibodies were used to
Table 3. Most common (>10%) drug-related adverse events by MeDRA SOC and PT (all grades) System organ class preferred term (%)
All patients (N = 74)
Group 1 (N = 7)
Group 2 (N = 14)
Group 3 (N = 37)
Group 4 (N = 16)
Number (%) of subjects with ≥1 drug-related TEAE Blood and lymphatic system disorders Thrombocytopenia Neutropenia Anemia Febrile neutropenia Gastrointestinal disorders Nausea Vomiting Diarrhea General disorders and administration site conditions Fatigue Pyrexia Metabolism and nutrition disorders Anorexia Skin and subcutaneous tissue disorders Alopecia
71 (95.9) 66 (89.2) 54 (73.0) 51 (68.9) 47 (63.5) 4 (5.4) 42 (56.8) 26 (35.1) 13 (17.6) 11 (14.9) 39 (52.7) 33 (44.6) 9 (12.2) 17 (23.0) 9 (12.2) 16 (21.6) 8 (10.8)
7 (100.0) 5 (71.4) 5 (71.4) 5 (71.4) 2 (28.6) 0 (0.0) 3 (42.9) 2 (28.6) 0 (0.0) 1 (14.3) 4 (57.1) 4 (57.1) 0 (0.0) 4 (57.1) 2 (28.6) 2 (28.6) 0 (0.0)
14 (100.0) 14 (100.0) 9 (64.3) 10 (71.4) 7 (50.0) 1 (7.1) 8 (57.1) 3 (21.4) 3 (21.4) 2 (14.3) 5 (35.7) 4 (28.6) 1 (7.1) 2 (14.3) 0 (0.0) 4 (28.6) 2 (14.3)
34 (91.9) 33 (89.2) 30 (81.1) 24 (64.9) 28 (75.7) 3 (8.1) 21 (56.8) 14 (37.8) 7 (18.9) 6 (16.2) 19 (51.4) 14 (37.8) 6 (16.2) 6 (16.2) 3 (8.1) 7 (18.9) 4 (10.8)
16 (100.0) 14 (87.5) 10 (62.5) 12 (75.0) 10 (62.5) 0 (0.0) 10 (62.5) 7 (43.8) 3 (18.8) 2 (12.5) 11 (68.8) 11 (68.8) 2 (12.5) 5 (31.3) 4 (25.0) 3 (18.8) 2 (12.5)
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All 74 patients received at least one dose of the study drug and were assessable for SAF analysis. Twenty-nine patients were enrolled on the dose escalation phase of the study (Table 1). There were no DLTs observed in the escalation phase. Seventy-one of 74 (96%) patients had at least one treatment emergent adverse event (TEAE) that was considered related to either one or both study drugs. The most common treatment-related AEs were thrombocytopenia (54 of 74; 73%), neutropenia (51 of 74, 69%), anemia (47 of 74; 63.5%), fatigue (33 of 74; 45%), nausea (26 of 74; 35%), vomiting (13 of 74; 18%), diarrhea (11 of 74; 15%), pyrexia (9 of 74; 12%), anorexia (9 of 74; 12%) and alopecia (8 of 74; 11%). Fifty-four (73.0%) of patients experienced at least one treatment-related severe (≥grade 3) TEAE with the most common being neutropenia (43%), anemia (30%), thrombocytopenia (28%) and fatigue (15%). Twelve patients (16%) experienced 13 drug-related serious adverse events including 4 events of anemia, 2 of thrombocytopenia, 2 of febrile neutropenia and 1 event of neutropenia, pancytopenia, interstitial lung disease, respiratory failure and pneumonitis, respectively. The majority of these were reversible, though one patient died of complications of neutropenia and another developed interstitial lung disease possibly related to gemcitabine that resolved with sequelae. Total of 11 (15%) patients discontinued study treatment due to tivantinib and/or gemcitabine-related AEs. Tivantinib was discontinued in 6 (8%) patients and gemcitabine was discontinued in 11 (15%) patients on account of AEs, with the most common AE being neutropenia (4 of 11; 5%). In addition, six (8%) more patients were discontinued due to nontreatment-related AEs. Forty-nine (66%) patients had at least one dose reduction of tivantinib and/or gemcitabine, 34 (69%) of them treated at the RP2D. The most common AEs leading to dose reduction were neutropenia and thrombocytopenia. The distribution of the most common
treatment-related AEs as a function of dose level and NCI CTC grade are presented in Table 3.
original articles detect p-Met. Among assessable patients who were stained for p-FAK, 7 (14%) tumors tested strongly positive, 9 (18%) were focally positive tumors, 11 (22%) were weakly positive and 22 (45%) tumors tested negative. Fourteen patients had HGF testing done on their archival tumor tissue. Eight (57%) were strongly positive and 6 (43%) tumors stained as weakly positive.
efficacy
discussion Tivantinib is an oral, selective, noncompetitive ATP inhibitor of the c-MET tyrosine kinase. It has demonstrated anticancer activity in phase I–II clinical studies with favorable SAF profiles, and promising efficacy results, potentially making it an ideal partner for combination with cytotoxic chemotherapies and other targeted anticancer agents [8, 10, 21]. In this phase I study, patients were treated with escalating doses of tivantinib in combination with gemcitabine. There were no DLTs in the escalation phase. The RP2D was determined as continuous 360 mg b.i.d. of tivantinib in combination with 1000 mg/m2 of gemcitabine administered for 3 weeks on, 1 week off. The pharmacokinetic parameters of tivantinib were assessed following administration of different dose levels in combination with gemcitabine. Overall, there were no consistent differences in the exposure of tivantinib when administered alone or in combination with gemcitabine. The pharmacokinetics of gemcitabine and dFdU observed in this study were consistent with those reported in the literature [15]. The pharmacokinetic parameters of tivantinib were associated with high interpatient variability. The possible sources for this variability are unclear, but could be due to the potential impact of CYP2C19 polymorphisms, drug administration under fed/fasting conditions, API form, body weight, body surface area, gender, ethnicity and hepatic function among others [22]. Exploratory analyses were conducted to
| Pant et al.
identify prognostic and predictive markers. Circulating VEGF, HGF and c-MET were measured in baseline and post-therapy blood samples and, similar to what was observed in other tivantinib studies, failed to correlate with tumor response. It was feasible to detect c-MET tumor biomarkers from tumor tissue using IHC; however, because of the limited number of tumor samples that stained strongly positive (as defined in MET enriched studies), it was difficult to establish correlation between MET status and tumor responses. It is important to note that this was a dosefinding phase I study involving a heterogeneous population with numerous tumor types. Testing for MET expression in a homogenous population should be considered in future prospective trials with MET inhibitors. The incidence and severity of AEs were manageable, with most events being grade ≤2. The most frequently reported drug-related AEs included thrombocytopenia, neutropenia, anemia, fatigue, nausea, vomiting, diarrhea, pyrexia, anorexia and alopecia. The most common drug-related AEs with a severity of ≥grade 3 were neutropenia, anemia, thrombocytopenia and fatigue. Given the known toxicity profile of gemcitabine as monotherapy (hematologic toxicity: leukopenia, neutropenia, thrombocytopenia and anemia; and nonhematologic toxicity: lung toxicity, renal and liver failure, diarrhea, nausea and vomiting [15]), the SAF profile emerging from the combination with tivantinib seems to be acceptable. Disease progression was the primary reason for discontinuation of tivantinib and gemcitabine. Hence, the combination of tivantinib and gemcitabine in this phase I dose escalation study was tolerable and feasible. The efficacy of this combination may warrant further investigation, considering that 11 patients achieved a PR and 26 had SD in the evaluable population. It is interesting to note that 10 of these 37 patients had previously received gemcitabine. There were early signs of efficacy seen in various malignancies including metastatic NSCLC (3 PR and 2 SD; DCR 100%) and ovarian cancer (2 PR and 5 SD; DCR 64%). Initially, the dose of tivantinib in the expansion cohort was 360 mg b.i.d. administered continuously, but based on emerging preclinical data [7] that demonstrated an enhanced antitumor effect by pulsatile treatment, the protocol was amended with patients holding tivantinib the day before and the day of gemcitabine infusion (Table 2, Expansion 2 cohort). Sixteen patients were treated and 12 were assessable in this cohort. Interestingly, though the numbers were small, there was evidence of antitumor activity with 3 PRs and 7 SDs. The SAF profile was similar to the other cohorts (Table 3). However, these numbers are small and further studies are needed to assess the true clinical impact of the pulsatile schedule. The clinical activity seen in metastatic NSCLC, ovarian, cholangiocarcinoma, pancreatic and breast cancer warrant further investigation in these malignancies. Patient selection based on improved techniques to better define MET positivity may enrich the patient population and increase the observed clinical benefit rate in future trials. Furthermore, the combination of tivantinib and gemcitabine may provide benefit to patients who progress following standard gemcitabine treatment. In conclusion, the combination therapy of tivantinib plus gemcitabine demonstrated a favorable SAF profile with manageable toxicities at both continuous and pulsatile schedules.
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Fifty-six patients (46 treated at RP2D of 360 mg b.i.d.) were assessable for efficacy (EVAL). The best response of PR and SD was observed in 11 of 56 (20%) and 26 of 56 (46%) patients, respectively; including 10 patients who received gemcitabine as previous therapy. The overall disease control rate (CR + PR + SD) was 66% (37 of 56). The median PFS was 129 days. PR was observed in patients with the following cancer types: NSCLC (3), ovarian (2), breast (2), endometrial (1), pancreatic (1), cholangiocarcinoma (1) and squamous cell carcinoma of the tongue (1). Of these, two patients (one ovarian and one breast cancer) had SD and progressive disease (per Investigator), respectively, as their response to prior therapy with gemcitabine. Five patients with NSCLC were assessable for response. Three achieved a PR and two SD for >4 months. One of the patients with lung cancer who achieved a PR received tivantinib 240 mg b.i.d. 2 weeks on/1 week off (cohort B). Prior therapies included radiation and chemotherapy (carboplatin plus paclitaxel, erlotinib and an investigational agent). Past medical history of note included smoking for 20 years (former), hypertension, anemia and gout. The patient achieved a PR with a 56% decrease in target lesions after 8 cycles of therapy. The patient progressed after 16 months on study.
Annals of Oncology
Annals of Oncology
disclosure GA, JK, BS and YW are currently employed by ArQule, Inc. and own stock in ArQule, Inc. YC was previously employed by ArQule, Inc. and owns stock in ArQule, Inc. All remaining authors have declared no conflicts of interest.
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Annals of Oncology 25: 1416–1421, 2014 doi:10.1093/annonc/mdu157 Published online 15 April 2014
A phase I dose escalation study of oral c-MET inhibitor tivantinib (ARQ 197) in combination with gemcitabine in patients with solid tumors S. Pant1*, M. Saleh2, J. Bendell3, J. R. Infante3, S. Jones3, C. D. Kurkjian1, K. M. Moore1, J. Kazakin4, G. Abbadessa4, Y. Wang4, Y. Chen5, B. Schwartz4 & L. H. Camacho6 1 University of Oklahoma Health Sciences Center, Oklahoma City; 2Georgia Cancer Specialists, Atlanta; 3SCRI, Tennessee Oncology, PLLC, Nashville; 4Arqule, Inc., Woburn; 5BioMarin Pharmaceutical, Inc., Novato; 6St Luke’s Medical Center, Houston, USA
Received 21 December 2013; revised 1 April 2014; accepted 2 April 2014
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/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: 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 *Correspondence to: Dr Shubham Pant, Section of Hematology/Oncology, Peggy and Charles Stephenson Oklahoma Cancer Center, Oklahoma City, OK 73104, USA. Tel: +1-405-271-4022; E-mail: [email protected]
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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20.
cetuximab in patients with locally advanced head and neck cancer. J Clin Oncol 2010; 28: 5294–5300. Wheeler S, Siwak DR, Chai R et al. Tumor epidermal growth factor receptor and EGFR PY1068 are independent prognostic indicators for head and neck squamous cell carcinoma. Clin Cancer Res 2012; 18: 2278–2289. Argiris A, Li Y, Forastiere A. Prognostic factors and long-term survivorship in patients with recurrent or metastatic carcinoma of the head and neck. Cancer 2004; 101: 2222–2229. Zuo Z, Keck MK, Khattri A et al. Multimodality determination of HPV status in head and neck cancers (HNC) and development of an HPV signature. J Clin Oncol 2013; 31 (suppl): abstr 6008. Chung CH, Zhang Q, Kong C et al. p16 expression as a human papillomavirus (HPV)-independent prognostic biomarker in non-oropharyngeal squamous cell carcinoma (non-OPSCC). J Clin Oncol 2013; 31 (suppl): abstr 6007. Fakhry C, Westra WH, Li S et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 2008; 100: 261–269. O’Sullivan B, Huang SH, Siu LL et al. Deintensification candidate subgroups in human papillomavirus-related oropharyngeal cancer according to minimal risk of distant metastasis. J Clin Oncol 2013; 31: 543–550.
Annals of Oncology
original articles
Annals of Oncology
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. Key words: tivantinib, gemcitabine, phase I
introduction
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methods Patients were recruited from four centers in the United States (Georgia Cancer Specialists, Atlanta, GA; Oklahoma University Health Sciences Center, Oklahoma City, OK; Oncology Consultants P.A., Houston, TX; Sarah Cannon Research Institute, Nashville, TN). Key eligibility criteria were histologically or cytologically confirmed advanced-stage solid tumors, age ≥18 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1, measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines, adequate bone marrow (Hgb ≥10 or ≥9 g/ dl for expanded cohort, ANC ≥1.5 × 109/l, Platelets ≥100/l), hepatic (aspartate aminotransferase, alanine aminotransferase ≤2.5× upper limit of normal (ULN) or ≤5× ULN with metastatic liver disease) and renal function (serum creatinine ≤1.5× ULN). Different schedules of drugs administration were tested (Table 1). Tivantinib (ARQ197) was supplied by ArQule, Inc. (Woburn, MA) as 120 mg capsules or tablets and was escalated based on data from previous monotherapy trials (120, 240. 360 mg). The RP2D was defined as the MTD, which is the highest dose of tivantinib in combination with gemcitabine that had no more than 33% probability of causing a dose-limiting toxicity (DLT). The study used a 3 + 3 dose escalation scheme with each cohort starting with three patients. If no DLT was observed, the enrollment commenced at the next higher dose level. A DLT was defined as an adverse event (AE) observed during the first 28-day cycle of therapy according to the following criteria: (i) any ≥grade 3 nonhematologic treatment-related toxicity (except reversible laboratory abnormalities and persistent nausea/vomiting, or diarrhea, despite optimal medical care); (ii) grade 4 neutropenia or anemia for >7 days; (iii) grade 4 thrombocytopenia, or (iv) grade 3 thrombocytopenia in the presence of bleeding. Once the RP2D was established, additional patients were enrolled in an expansion cohort. The first 28 patients were instructed to
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Accumulating evidence has established the role of the MET receptor tyrosine kinase, encoded by the MET proto-oncogene, in tumor development and metastases [1]. Binding of hepatocyte growth factor (HGF) to MET primarily activates the RASMAPK and PI3K-AKT signaling pathways involved in cell growth, proliferation and survival [2]. MET overexpression in cancer is associated with a poor prognosis [3, 4]. Tivantinib (ARQ 197; ArQule, Inc.; Daiichi-Sankyo, Co., Ltd; Kyowa Hakko Kirin (KHK), Co., Ltd) is an oral, selective, smallmolecule MET inhibitor that preferentially inhibits growth and induces apoptosis in human tumor cell lines expressing MET. Tivantinib possesses a unique mechanism of action in that its inhibition of inactive or unphosphorylated form of human c-MET is independent of adenosine triphosphate (ATP) [5, 6]. Preclinical studies in cancer cell lines demonstrated additive or synergistic activity when tivantinib was combined with targeted (erlotinib, sorafenib, gefitinib) or chemotherapeutic agents [docetaxel, gemcitabine, irinotecan, 5-fluorouracil (5-FU)] [7] (Unpublished data, courtesy of ArQule & KHK). Tivantinib is well tolerated and has demonstrated activity in a variety of human tumor xenograft models including breast, colon, gastric, pancreatic and ovarian cancer when administered via daily oral dosing. The antitumor activity was accompanied by the inhibition of c-MET activity as assessed by the level of phosphorylated c-MET [5]. Clinical trials of tivantinib (as monotherapy or in combination with other anticancer agents) demonstrated initial efficacy in MET high patients with hepatocellular carcinoma (HCC), nonsmall-cell lung cancer (NSCLC) and colorectal cancer (CRC) [8–11]. However, a phase III trial in NCSLC [12] and phase II trial in CRC [13] in patients with unselected MET status failed to meet their primary end points. The safety (SAF) profile of tivantinib is well established and common adverse events include anemia, thrombocytopenia, neutropenia, febrile neutropenia, vomiting, dehydration and bradycardia. The recommended dose in capsule formulation is 240 mg twice daily for patients with HCC (increased frequency and severity of ≥grade 3 neutropenia observed in patients receiving 360 mg dose) [9] and at 360 mg twice daily for patients with other malignancies [8, 14]. The antimetabolite gemcitabine is FDA approved for use as a single agent and in combination with other chemotherapeutic agents in pancreatic, NSCLC, advanced ovarian and metastatic breast cancer [15]. The anticancer activity of gemcitabine is mediated through its effects on DNA synthesis during cell division [16]. It causes cellular arrest in the G1/S phase of the cell cycle [15] whereas tivantinib arrests cells in the G2/M phase of the cell cycle, as evidenced by increase in phospho-Histone H3 siRNA [7].
The combination of tivantinib and gemcitabine may be an option for patients with advanced malignancies refractory to standard therapy. Recent preclinical and clinical data suggest that sequential or concurrent administration of anticancer drugs with different mechanisms of action could be more efficacious with an improved toxicity profile [17–19]. To test this hypothesis, a series of preclinical experiments with different dosing schedules were designed in which cells were treated with gemcitabine and tivantinib in continuous, or in pulsatile fashion [7]. Twelve cancer cell lines from different tissue origins including lung, bladder, pancreatic, breast, ovary, uterus and gall bladder were tested. The cells treated on the regimens without a drug holiday inhibited cell growth in a minor subset of the experiments (15%). In contrast, gemcitabine demonstrated synergy with ARQ 197 and inhibited the growth of all 12 cell lines (100%; 12 of 12) tested in the pulsatile regimen with a 2-day drug-free interval. Hence, we translated multiple treatment schedules at the maximal tolerated dose (MTD) (both continuous and sequential) of tivantinib and gemcitabine back to patients in this study.
original articles
Annals of Oncology
Table 1. Dosing schedules Cohort
Tivantinib (ARQ 197) mg b.i.d./frequency of administration
Dose escalation cohorts 0 120/continuously
No. of patients (N = 74; 100%)
Group assignment (N = 74; 100%)
Cycle 1-weekly; cycle 2+ —day 1, 8 and 15
n = 4 (5%)
Group 1 (n = 7; 10%)
240/continuously 240/2 weeks followed by 1 week off
Cycle 1-weekly; cycle 2+ —day 1, 8 and 15 Cycle 1+ —day 8, day 15 and day 22
n = 3 (4%) n = 3 (4%)
C D E
360/2 weeks followed by 1 week off 360/3 weeks continuously followed by 1 week off 360/continuously
Cycle 1+ —day 8, day 15 and day 22 Cycle 1+ —day 8, day 15 and day 22 Cycle 1+ —day 8, day 15 and day 22
n = 4 (5%) n = 7 (10%) n = 8 (11%)
Cycle 1+ —day 8, day 15 and day 22
n = 29 (39%)
Cycle 1+ day 7, day 14 and day 21
n = 16 (22%)
Group 2 (n = 14; 19%)
Group 3 (n = 37; 50%)
Group 4 (n = 16; 22%)
No patients were enrolled in cohort A. The day before and the day of gemcitabine administration.
b
take tivantinib capsules without food. Subsequently, all patients were advised to take tivantinib capsules with meals based on bioavailability/bioequivalence studies in healthy volunteers and cancer patients (NCT 00651638, NCT01149720 and NCT00612209). Toxicity was graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Samples for pharmacokinetic analysis were collected on days 1, 8 and 15. Blood samples and archival tumor tissue (when available) were collected for biomarker analysis. supplementary File S1, available at Annals of Oncology online describes study assessments and detailed pharmacokinetic and pharmacodynamic methodology. All statistical calculations were carried out by using intent-to-treat (ITT), SAF and evaluable (EVAL) analyses. EVAL population was defined as all patients who completed 4 weeks of treatment with both study drugs and who had at least one postbaseline tumor evaluation. ITT population was defined as all patients who received at least one dose of study medication. AEs were evaluated for severity using NCI CTCAE v. 3.0. Overall response rate and the 95% confidence interval (CI) were estimated, as well as the percent of patients in each RECIST response category [e.g. complete response (CR), partial response (PR), stable disease (SD) and progressive disease] and the disease control rate [20]. Progression free survival (PFS) was defined as the time from first dose until disease progression per RECIST or death which ever occurred first.
results patients Seventy-four patients were treated between April 2009 and February 2011. Detailed demographic and baseline characteristics are presented in Table 2. Seventy-three patients received tivantinib and gemcitabine, and one patient received tivantinib only. Overall, the median age was 60.5 years (range, 35–79 years). The majority of the patients were Caucasian (n = 63, 85%), female (n = 44, 59.5%) and had received at least one prior systemic chemotherapy regimen (n = 58, 78%). The median number of prior systemic regimens was 4.0 (range, 0–9). The
| Pant et al.
Table 2. Patient demographics Patients characteristics Gender, n (%) Female Male Age (years) Median (range) Race/ethnicity, n (%) Asian Black or African American Caucasian Other Hispanic or Latino Not Hispanic or Latino ECOG Performance Status, n (%) 0 1 Cancer type Breast cancer Cholangiocarcinoma Endometrial cancer NSCLC Ovarian cancer Pancreatic adenocarcinoma Other Time since initial diagnosis (years) Median (range) Prior anticancer therapies Median (range)
Overall (N = 74) 44 (59.5) 30 (40.5) 60.5 (35–79) 1 (1.4) 5 (6.8) 63 (85.1) 5 (6.8) 8 (10.8) 66 (89.2) 30 (40.5) 44 (59.5) 12 (16.2) 8 (10.8) 4 (5.4) 6 (8.1) 14 (18.9) 21 (28.4) 9 (12.2) 1.8 (0–11) 6 (1–18)
most common primary tumor site was pancreas (n = 21, 28%) followed by ovarian (n = 14, 20%), breast (n = 12, 16%) and cholangiocarcinoma (n = 8, 11%).
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1 Ba
Dose expansion cohorts Expansion 1 360/continuously (Exp 1) Expansion 2 360/5 consecutive days with 2 days (Exp 2) off b ‘pulsatile’ a
Gemcitabine 1000 mg/m2/frequency of administration
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Annals of Oncology
safety
pharmacokinetics The concentration time profile of tivantinib (360 mg b.i.d. capsules) is presented in supplementary Figure S1 and Table S1, available at Annals of Oncology online summarizes the exposure data of tivantinib. Overall, there were no considerable differences in the exposure of tivantinib administered alone or in combination with gemcitabine. Additionally, the exposure of tivantinib observed in this study was in the range of that observed in patients dosed at 360 mg b.i.d. in monotherapy studies. The PK of gemcitabine and 20 ,20 -difluorodeoxyuridine (dFdU) observed in patients treated with 360 mg tivantinib b.i.d. was consistent with the PK results reported in the literature. There was high interpatient variability of both gemcitabine and tivantinib PK parameters. Under steady-state conditions, the AUC 0–12 and Cmax of tivantinib after administration of the 360 mg capsule formulation with food was ∼52% and 56% greater when compared with the fasting state.
pharmacodynamics Plasma was assayed for VEGF, HGF and soluble c-MET. Overall, there were no consistent changes in plasma HGF, VEGF and soluble c-Met levels. The study also evaluated MET tumor biomarkers in archival tumor samples using IHC. Of the 49 assessable patients whose tumor was stained with c-met antibody, 19 (39%) had tumors that were strongly positive, 6 (12%) were focally positive, 9 (18%) were weakly positive and 15 (31%) stained negative. Of the 19 strongly positive patients, 15 were assessed for RECIST with 2 patients achieving PR and 10 SD as their best response. Five other patients with PR as their best response stained negative for MET. Two antibodies were used to
Table 3. Most common (>10%) drug-related adverse events by MeDRA SOC and PT (all grades) System organ class preferred term (%)
All patients (N = 74)
Group 1 (N = 7)
Group 2 (N = 14)
Group 3 (N = 37)
Group 4 (N = 16)
Number (%) of subjects with ≥1 drug-related TEAE Blood and lymphatic system disorders Thrombocytopenia Neutropenia Anemia Febrile neutropenia Gastrointestinal disorders Nausea Vomiting Diarrhea General disorders and administration site conditions Fatigue Pyrexia Metabolism and nutrition disorders Anorexia Skin and subcutaneous tissue disorders Alopecia
71 (95.9) 66 (89.2) 54 (73.0) 51 (68.9) 47 (63.5) 4 (5.4) 42 (56.8) 26 (35.1) 13 (17.6) 11 (14.9) 39 (52.7) 33 (44.6) 9 (12.2) 17 (23.0) 9 (12.2) 16 (21.6) 8 (10.8)
7 (100.0) 5 (71.4) 5 (71.4) 5 (71.4) 2 (28.6) 0 (0.0) 3 (42.9) 2 (28.6) 0 (0.0) 1 (14.3) 4 (57.1) 4 (57.1) 0 (0.0) 4 (57.1) 2 (28.6) 2 (28.6) 0 (0.0)
14 (100.0) 14 (100.0) 9 (64.3) 10 (71.4) 7 (50.0) 1 (7.1) 8 (57.1) 3 (21.4) 3 (21.4) 2 (14.3) 5 (35.7) 4 (28.6) 1 (7.1) 2 (14.3) 0 (0.0) 4 (28.6) 2 (14.3)
34 (91.9) 33 (89.2) 30 (81.1) 24 (64.9) 28 (75.7) 3 (8.1) 21 (56.8) 14 (37.8) 7 (18.9) 6 (16.2) 19 (51.4) 14 (37.8) 6 (16.2) 6 (16.2) 3 (8.1) 7 (18.9) 4 (10.8)
16 (100.0) 14 (87.5) 10 (62.5) 12 (75.0) 10 (62.5) 0 (0.0) 10 (62.5) 7 (43.8) 3 (18.8) 2 (12.5) 11 (68.8) 11 (68.8) 2 (12.5) 5 (31.3) 4 (25.0) 3 (18.8) 2 (12.5)
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All 74 patients received at least one dose of the study drug and were assessable for SAF analysis. Twenty-nine patients were enrolled on the dose escalation phase of the study (Table 1). There were no DLTs observed in the escalation phase. Seventy-one of 74 (96%) patients had at least one treatment emergent adverse event (TEAE) that was considered related to either one or both study drugs. The most common treatment-related AEs were thrombocytopenia (54 of 74; 73%), neutropenia (51 of 74, 69%), anemia (47 of 74; 63.5%), fatigue (33 of 74; 45%), nausea (26 of 74; 35%), vomiting (13 of 74; 18%), diarrhea (11 of 74; 15%), pyrexia (9 of 74; 12%), anorexia (9 of 74; 12%) and alopecia (8 of 74; 11%). Fifty-four (73.0%) of patients experienced at least one treatment-related severe (≥grade 3) TEAE with the most common being neutropenia (43%), anemia (30%), thrombocytopenia (28%) and fatigue (15%). Twelve patients (16%) experienced 13 drug-related serious adverse events including 4 events of anemia, 2 of thrombocytopenia, 2 of febrile neutropenia and 1 event of neutropenia, pancytopenia, interstitial lung disease, respiratory failure and pneumonitis, respectively. The majority of these were reversible, though one patient died of complications of neutropenia and another developed interstitial lung disease possibly related to gemcitabine that resolved with sequelae. Total of 11 (15%) patients discontinued study treatment due to tivantinib and/or gemcitabine-related AEs. Tivantinib was discontinued in 6 (8%) patients and gemcitabine was discontinued in 11 (15%) patients on account of AEs, with the most common AE being neutropenia (4 of 11; 5%). In addition, six (8%) more patients were discontinued due to nontreatment-related AEs. Forty-nine (66%) patients had at least one dose reduction of tivantinib and/or gemcitabine, 34 (69%) of them treated at the RP2D. The most common AEs leading to dose reduction were neutropenia and thrombocytopenia. The distribution of the most common
treatment-related AEs as a function of dose level and NCI CTC grade are presented in Table 3.
original articles detect p-Met. Among assessable patients who were stained for p-FAK, 7 (14%) tumors tested strongly positive, 9 (18%) were focally positive tumors, 11 (22%) were weakly positive and 22 (45%) tumors tested negative. Fourteen patients had HGF testing done on their archival tumor tissue. Eight (57%) were strongly positive and 6 (43%) tumors stained as weakly positive.
efficacy
discussion Tivantinib is an oral, selective, noncompetitive ATP inhibitor of the c-MET tyrosine kinase. It has demonstrated anticancer activity in phase I–II clinical studies with favorable SAF profiles, and promising efficacy results, potentially making it an ideal partner for combination with cytotoxic chemotherapies and other targeted anticancer agents [8, 10, 21]. In this phase I study, patients were treated with escalating doses of tivantinib in combination with gemcitabine. There were no DLTs in the escalation phase. The RP2D was determined as continuous 360 mg b.i.d. of tivantinib in combination with 1000 mg/m2 of gemcitabine administered for 3 weeks on, 1 week off. The pharmacokinetic parameters of tivantinib were assessed following administration of different dose levels in combination with gemcitabine. Overall, there were no consistent differences in the exposure of tivantinib when administered alone or in combination with gemcitabine. The pharmacokinetics of gemcitabine and dFdU observed in this study were consistent with those reported in the literature [15]. The pharmacokinetic parameters of tivantinib were associated with high interpatient variability. The possible sources for this variability are unclear, but could be due to the potential impact of CYP2C19 polymorphisms, drug administration under fed/fasting conditions, API form, body weight, body surface area, gender, ethnicity and hepatic function among others [22]. Exploratory analyses were conducted to
| Pant et al.
identify prognostic and predictive markers. Circulating VEGF, HGF and c-MET were measured in baseline and post-therapy blood samples and, similar to what was observed in other tivantinib studies, failed to correlate with tumor response. It was feasible to detect c-MET tumor biomarkers from tumor tissue using IHC; however, because of the limited number of tumor samples that stained strongly positive (as defined in MET enriched studies), it was difficult to establish correlation between MET status and tumor responses. It is important to note that this was a dosefinding phase I study involving a heterogeneous population with numerous tumor types. Testing for MET expression in a homogenous population should be considered in future prospective trials with MET inhibitors. The incidence and severity of AEs were manageable, with most events being grade ≤2. The most frequently reported drug-related AEs included thrombocytopenia, neutropenia, anemia, fatigue, nausea, vomiting, diarrhea, pyrexia, anorexia and alopecia. The most common drug-related AEs with a severity of ≥grade 3 were neutropenia, anemia, thrombocytopenia and fatigue. Given the known toxicity profile of gemcitabine as monotherapy (hematologic toxicity: leukopenia, neutropenia, thrombocytopenia and anemia; and nonhematologic toxicity: lung toxicity, renal and liver failure, diarrhea, nausea and vomiting [15]), the SAF profile emerging from the combination with tivantinib seems to be acceptable. Disease progression was the primary reason for discontinuation of tivantinib and gemcitabine. Hence, the combination of tivantinib and gemcitabine in this phase I dose escalation study was tolerable and feasible. The efficacy of this combination may warrant further investigation, considering that 11 patients achieved a PR and 26 had SD in the evaluable population. It is interesting to note that 10 of these 37 patients had previously received gemcitabine. There were early signs of efficacy seen in various malignancies including metastatic NSCLC (3 PR and 2 SD; DCR 100%) and ovarian cancer (2 PR and 5 SD; DCR 64%). Initially, the dose of tivantinib in the expansion cohort was 360 mg b.i.d. administered continuously, but based on emerging preclinical data [7] that demonstrated an enhanced antitumor effect by pulsatile treatment, the protocol was amended with patients holding tivantinib the day before and the day of gemcitabine infusion (Table 2, Expansion 2 cohort). Sixteen patients were treated and 12 were assessable in this cohort. Interestingly, though the numbers were small, there was evidence of antitumor activity with 3 PRs and 7 SDs. The SAF profile was similar to the other cohorts (Table 3). However, these numbers are small and further studies are needed to assess the true clinical impact of the pulsatile schedule. The clinical activity seen in metastatic NSCLC, ovarian, cholangiocarcinoma, pancreatic and breast cancer warrant further investigation in these malignancies. Patient selection based on improved techniques to better define MET positivity may enrich the patient population and increase the observed clinical benefit rate in future trials. Furthermore, the combination of tivantinib and gemcitabine may provide benefit to patients who progress following standard gemcitabine treatment. In conclusion, the combination therapy of tivantinib plus gemcitabine demonstrated a favorable SAF profile with manageable toxicities at both continuous and pulsatile schedules.
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Fifty-six patients (46 treated at RP2D of 360 mg b.i.d.) were assessable for efficacy (EVAL). The best response of PR and SD was observed in 11 of 56 (20%) and 26 of 56 (46%) patients, respectively; including 10 patients who received gemcitabine as previous therapy. The overall disease control rate (CR + PR + SD) was 66% (37 of 56). The median PFS was 129 days. PR was observed in patients with the following cancer types: NSCLC (3), ovarian (2), breast (2), endometrial (1), pancreatic (1), cholangiocarcinoma (1) and squamous cell carcinoma of the tongue (1). Of these, two patients (one ovarian and one breast cancer) had SD and progressive disease (per Investigator), respectively, as their response to prior therapy with gemcitabine. Five patients with NSCLC were assessable for response. Three achieved a PR and two SD for >4 months. One of the patients with lung cancer who achieved a PR received tivantinib 240 mg b.i.d. 2 weeks on/1 week off (cohort B). Prior therapies included radiation and chemotherapy (carboplatin plus paclitaxel, erlotinib and an investigational agent). Past medical history of note included smoking for 20 years (former), hypertension, anemia and gout. The patient achieved a PR with a 56% decrease in target lesions after 8 cycles of therapy. The patient progressed after 16 months on study.
Annals of Oncology
Annals of Oncology
disclosure GA, JK, BS and YW are currently employed by ArQule, Inc. and own stock in ArQule, Inc. YC was previously employed by ArQule, Inc. and owns stock in ArQule, Inc. All remaining authors have declared no conflicts of interest.
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Volume 25 | No. 7 | July 2014
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