A phase I trial of veliparib (ABT-888) and temozolomide in children with recurrent CNS tumors: a Pediatric Brain Tumor Consortium report

Background

A phase I trial of veliparib (ABT-888), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, and temozolomide (TMZ) was conducted in children with recurrent brain tumors to (i) estimate the maximum tolerated doses (MTDs) or recommended phase II doses (RP2Ds) of veliparib and TMZ; (ii) describe the toxicities of this regimen; and (iii) evaluate the plasma pharmacokinetic parameters and extent of PARP inhibition in peripheral blood mononuclear cells (PBMCs) following veliparib.

Methods

TMZ was given once daily and veliparib twice daily for 5 days every 28 days. Veliparib concentrations and poly(ADP-ribose) (PAR) levels in PBMCs were measured on days 1 and 4. Analysis of pharmacokinetic and PBMC PAR levels were performed twice during study conduct to rationally guide dose modifications and to determine biologically optimal MTD/RP2D.

Results

Twenty-nine evaluable patients were enrolled. Myelosuppression (grade 4 neutropenia and thrombocytopenia) were dose limiting. The RP2Ds are veliparib 25 mg/m² b.i.d. and TMZ 135 mg/m²/d. Only 2 out of 12 patients treated at RP2Ds experienced dose-limiting toxicities. Although no objective response was observed, 4 patients had stable disease >6 months in duration, including 1 with glioblastoma multiforme and 1 with ependymoma. At the RP2D of veliparib, pediatric pharmacokinetic parameters were similar to those in adults.

Conclusions

Veliparib and TMZ at the RP2D were well tolerated in children with recurrent brain tumors. A phase I/II trial to evaluate the tolerability and efficacy of veliparib, TMZ, and radiation in children with newly diagnosed brainstem gliomas is in progress.     

Phase 1 study of veliparib with carboplatin and weekly paclitaxel in Japanese patients with newly diagnosed ovarian cancer

This phase 1, open‐label, dose‐escalation study was conducted to determine the safety, tolerability, pharmacokinetics and preliminary efficacy of veliparib with carboplatin and weekly paclitaxel in Japanese women with newly diagnosed, advanced ovarian cancer. Patients received veliparib at 100 or 150 mg b.i.d. on days 1–21 with carboplatin (area under the concentration–time curve 6 mg/mL?min) on day 1 and paclitaxel 80 mg/m² on days 1, 8 and 15 every 3 weeks for up to 6 21‐day cycles. Dose escalation followed a 3 + 3 design to determine dose‐limiting toxicities, maximum tolerated dose and the recommended phase 2 dose. Nine patients (median age 62 [range 27–72] years) received a median of 5 (range 3–6) cycles of treatment (3 at 100 mg, 6 at 150 mg). There were no dose‐limiting toxicities. The most common adverse events of any grade were neutropenia (100%), alopecia (89%), peripheral sensory neuropathy (78%), and anemia, nausea and malaise (67% each). Grade 3 or 4 adverse events were associated with myelosuppression. Pharmacokinetics of carboplatin/paclitaxel were similar at both veliparib doses. Response, assessed in five patients, was partial in four and complete in one (objective response rate 100%). The response could not be assessed in four patients who had no measurable disease at baseline. The recommended phase 2 dose of veliparib, when combined with carboplatin/paclitaxel, is 150 mg b.i.d. Findings from this phase 1 trial demonstrate the tolerability and safety of veliparib with carboplatin/paclitaxel, a regimen with potential clinical benefit in Japanese women with ovarian cancer.     

A phase 1 study of efatutazone,an oral peroxisome proliferator‐activated receptor gamma agonist,administered to patients with advanced malignancies

BACKGROUND:

Efatutazone (CS‐7017), a novel peroxisome proliferator‐activated receptor gamma (PPARγ) agonist, exerts anticancer activity in preclinical models. The authors conducted a phase 1 study to determine the recommended phase 2 dose, safety, tolerability, and pharmacokinetics of efatutazone.

METHODS:

Patients with advanced solid malignancies and no curative therapeutic options were enrolled to receive a given dose of efatutazone, administered orally (PO) twice daily for 6 weeks, in a 3 + 3 intercohort dose‐escalation trial. After the third patient, patients with diabetes mellitus were excluded. Efatutazone dosing continued until disease progression or unacceptable toxicity, with measurement of efatutazone pharmacokinetics and plasma adiponectin levels.

RESULTS:

Thirty‐one patients received efatutazone at doses ranging from 0.10 to 1.15 mg PO twice daily. Dose escalation stopped when maximal impact on PPARγ‐related biomarkers had been reached before any protocol‐defined maximum‐tolerated dose level. On the basis of a population pharmacokinetic/pharmacodynamic analysis, the recommended phase 2 dose was 0.5 mg PO twice daily. A majority of patients experienced peripheral edema (53.3%), often requiring diuretics. Three episodes of dose‐limiting toxicities, related to fluid retention, were noted in the 0.10‐, 0.25‐, and 1.15‐mg cohorts. Of 31 treated patients, 27 were evaluable for response. A sustained partial response (PR; 690 days on therapy) was observed in a patient with myxoid liposarcoma. Ten additional patients had stable disease (SD) for ≥60 days. Exposures were approximately dose proportional, and adiponectin levels increased after 4 weeks of treatment at all dose levels. Immunohistochemistry of archived specimens demonstrated that PPARγ and retinoid X receptor expression levels were significantly greater in patients with SD for ≥60 days or PR (P = .0079), suggesting a predictive biomarker.

CONCLUSIONS:

Efatutazone demonstrates acceptable tolerability with evidence of disease control in patients with advanced malignancies. Cancer 2012. © 2012 American Cancer Society.     

Phase 1 study of capmatinib in MET‐positive solid tumor patients: Dose escalation and expansion of selected cohorts

Capmatinib is an oral, ATP‐competitive, and highly potent, type 1b MET inhibitor. Herein, we report phase 1 dose‐escalation results for capmatinib in advanced MET‐positive solid tumor patients and dose expansion in advanced non‐lung tumors. Capmatinib was well tolerated with a manageable safety profile across all explored doses. Dose‐limiting toxicities (DLT) occurred at 200 mg twice daily (bid), 250 mg bid, and 450 mg bid capsules; however, no DLT were reported at 600 mg bid (capsules). Capmatinib tablets at 400 mg bid had comparable tolerability and exposure to that of 600 mg bid capsules. Maximum tolerated dose was not reached; recommended phase 2 dose was 400 mg bid tablets/600 mg bid capsules; at this dose, C_trough >EC₉₀ (90% inhibition of c‐MET phosphorylation in animal models) is expected to be achieved and maintained. Among the dose‐expansion patients (N = 38), best overall response across all cohorts was stable disease (gastric cancer 22%, hepatocellular carcinoma 46%, other indications 28%); two other indication patients with gene copy number (GCN) ≥6 achieved substantial tumor reduction. Near‐complete immunohistochemically determined phospho‐MET inhibition (H‐score = 2) was shown following capmatinib 450 mg bid capsule in paired biopsies obtained from one advanced colorectal cancer patient. Incidence of high‐level MET GCN (GCN ≥6) and MET‐overexpressing (immunohistochemistry 3+) tumors in the expansion cohorts was 8% and 13%, respectively; no MET mutations were observed. Thus, the recommended phase 2 dose (RP2D) of capmatinib was 600 mg bid capsule/400 mg bid tablet. Capmatinib was well tolerated and showed antitumor activity and acceptable safety profile at the RP2D. (ClinicalTrials.gov Identifier: NCT01324479).     

Phase I study of alpelisib (BYL719), an α‐specific PI3K inhibitor,in Japanese patients with advanced solid tumors

This phase I study aimed to determine tolerability and preliminary efficacy of single‐agent alpelisib (BYL719) in Japanese patients with advanced solid malignancies. The primary objective of the study was to estimate the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of oral alpelisib in patients with advanced solid tumors who had progressed despite standard therapy. The expansion part included patients with PIK3CA mutation/amplification; safety, preliminary efficacy, pharmacokinetic (PK)/pharmacodynamic profile, and food effect on the PK profile of alpelisib at the MTD/RP2D were determined. Oral alpelisib was given as a single agent on a continuous 28‐day treatment cycle once daily. Overall, 33 patients received alpelisib. Dose‐limiting toxicities were observed in 2 patients in the escalation part (at 400 mg/day) and 1 patient in the expansion part (at 350 mg/day). The RP2D of alpelisib was determined as 350 mg/day based on overall safety profile in the dose escalation part and previous data from a Western population; the MTD was not determined. The most common all‐grade treatment‐suspected adverse events were hyperglycemia and maculopapular rash (48.5% each) and diarrhea (45.5%). The PK of alpelisib in the Japanese population was similar to that reported in the Western population. The overall response rate, disease control rate, and median progression‐free survival at 350 mg/day were 3%, 57.6%, and 3.4 months, respectively. Alpelisib as single agent showed a favorable safety profile and encouraging preliminary efficacy in Japanese patients with advanced solid tumors.     

A Dose-finding Study Followed by a Phase II Randomized,Placebo-controlled Trial of Chemoradiotherapy With or Without Veliparib in Stage III Non–small-cell Lung Cancer: SWOG 1206 (8811)

BackgroundWe conducted a 2-part study to evaluate the incorporation of veliparib, a PARP inhibitor, into chemoradiotherapy (CRT) for stage III non–small-cell lung cancer.Patients and MethodsIn the phase I part, patients were treated successively at 3 dose levels of veliparib (40, 80, and 120 mg) twice daily during CRT. In the phase II part, patients were randomized to receive veliparib or placebo during thoracic radiotherapy with concurrent weekly carboplatin and paclitaxel, followed by 2 cycles of consolidation carboplatin and paclitaxel with veliparib or placebo. The study was prematurely discontinued owing to the emergence of adjuvant immunotherapy as standard of care.ResultsOf 21 patients enrolled in phase I, 2 patients developed dose-limiting toxicities (DLTs): 1 grade 3 esophagitis with dysphagia (at 40 mg) and 1 grade 3 esophagitis with dehydration (at 80 mg). No DLTs were seen at veliparib dose of 120 mg twice daily, which was selected for the phase II part that enrolled 31 eligible patients. Progression-free survival (PFS) was not different between the 2 arms (P = .20). For the veliparib and placebo arms, response rates were 56% and 69%, PFS at 1 year 47% and 46%, and overall survival at 1 year 89% and 54%, respectively.ConclusionVeliparib with CRT was feasible and well tolerated. Efficacy could not accurately be determined because of early study closure. Nonetheless, there is enthusiasm for the evaluation of PARP inhibitors in lung cancer as predictive biomarkers are being developed and combinations with immunotherapy are attractive.     

Phase I study of single‐agent ribociclib in Japanese patients with advanced solid tumors

The cyclin D‐CDK4/6‐INK4‐Rb pathway is frequently dysregulated in cancers. Ribociclib, an orally available, selective CDK4/6 inhibitor, showed preliminary clinical activity in a phase I study in the USA and Europe for patients with solid tumors and lymphomas. The present study aimed to determine the single‐agent maximum tolerated dose (MTD) and recommended dose for expansion (RDE) in Japanese patients with advanced solid tumors. Ribociclib safety, tolerability, pharmacokinetic profile, and preliminary antitumor activity were also assessed. Japanese patients with solid tumors that had progressed on prior therapies received escalating doses of single‐agent ribociclib on a 3‐weeks‐on/1‐week‐off schedule. Treatment continued until the development of toxicity or disease progression. A dose escalation was planned for patients with esophageal cancer. In the dose‐escalation phase, 4 patients received 400 mg ribociclib and 13 patients received 600 mg ribociclib. Four patients experienced dose‐limiting toxicities, 3 of whom were in the 600 mg group. The RDE was declared to be 600 mg, and the MTD was not determined. The most frequent adverse events were hematologic and gastrointestinal. Four patients achieved stable disease at the 600 mg dose; no patients achieved complete or partial response. All patients discontinued the study, the majority due to disease progression. No patients discontinued due to adverse events. Dose escalation was not pursued due to lack of observed efficacy in esophageal cancer. At the RDE of 600 mg/d on a 3‐weeks‐on/1‐week‐off schedule, ribociclib showed acceptable safety and tolerability profiles in Japanese patients with advanced solid tumors.     

Phase I and pharmacokinetic study of veliparib,a PARP inhibitor,and pegylated liposomal doxorubicin (PLD) in recurrent gynecologic cancer and triple negative breast cancer with long-term follow-up

Poly(ADP-ribosyl) polymerases (PARPs) are nuclear enzymes with roles in DNA damage recognition and repair. PARP1 inhibition enhances the effects of DNA-damaging agents like doxorubicin. We sought to determine the recommended phase two dose (RP2D) of veliparib with pegylated liposomal doxorubicin (PLD) in breast and recurrent gynecologic cancer patients. Veliparib and PLD were administered in a standard phase 1, 3 + 3 dose-escalation design starting at 50 mg veliparib BID on days 1–14 with PLD 40 mg/mg2 on day 1 of a 28-day cycle. Dose escalation proceeded in two strata: A (prior PLD exposure) and B (no prior PLD exposure). Patients underwent limited pharmacokinetic (PK) sampling; an expansion PK cohort was added. 44 patients with recurrent ovarian or triple negative breast cancer were enrolled. Median age 56 years; 23 patients BRCA mutation carriers; median prior regimens four. Patients received a median of four cycles of veliparib/PLD. Grade 3/4 toxicities were observed in 10% of patients. Antitumor activity was observed in both sporadic and BRCA-deficient cancers. Two BRCA mutation carriers had complete responses. Two BRCA patients developed oral squamous cell cancers after completing this regimen. PLD exposure was observed to be higher when veliparib doses were > 200 mg BID. The RP2D is 200 mg veliparib BID on days 1–14 with 40 mg/m2 PLD on day 1 of a 28-day cycle. Anti-tumor activity was seen in both strata. However, given development of long-term squamous cell cancers and the PK interaction observed, efforts should focus on other targeted combinations to improve efficacy.     

Phase 1 trial of concurrent erlotinib, celecoxib, and reirradiation for recurrent head and neck cancer

BACKGROUND:

Concurrent inhibition of epidermal growth factor receptor (EGFR) and cyclooxygenase‐2 (COX‐2) is an active and well tolerated regimen in recurrent head and neck cancer (HNC). In the current phase 1 trial, the authors sought to determine the maximum tolerated dose (MTD) and efficacy of concurrent erlotinib and celecoxib as a radiosensitizing regimen.

METHODS:

Fourteen patients with previously irradiated HNC with no distant metastases who required reirradiation were eligible. Treatment consisted of daily erlotinib 150 mg and twice daily celecoxib (escalated from 200 mg to 600 mg using a 3 + 3 design with an expanded cohort at the MTD) starting on Day 1 and was continued during radiation. Daily radiation was started on Day 15, and maintenance erlotinib was recommended.

RESULTS:

The recommended phase 2 dose of celecoxib was 400 mg. Three dose‐limiting toxicities included late in‐field orocutaneous fistula (Dose Level 2), osteonecrosis (Dose Level 3), and trismus (Dose Level 3). Acute grade ≥3 toxicities were uncommon and included mucositis (21%) and dermatitis (14%). At a median follow‐up of 11 months, the 1‐year locoregional control, progression‐free survival, and overall survival rates were 60%, 37%, and 55%, respectively.

CONCLUSIONS:

Concurrent erlotinib, celecoxib, and reirradiation was a feasible and clinically active regimen in a population of patients with recurrent HNC who had a poor prognosis. Cancer 2011. © 2011 American Cancer Society.     

Phase 2 open‐label study of single‐agent sorafenib in treating advanced hepatocellular carcinoma in a hepatitis B–endemic Asian population

BACKGROUND:

The current study was a phase 2 open–label study to evaluate the efficacy and tolerability of single‐agent sorafenib in the treatment of advanced HCC patients in a hepatitis B–endemic Asian population.

METHODS:

Patients with advanced hepatocellular carcinoma (HCC) received sorafenib at a dose of 400 mg twice daily in 4‐week cycles. Tumor response was assessed every 3 cycles using Response Evaluation Criteria in Solid Tumors criteria.

RESULTS:

Fifty‐one patients were enrolled in the study and were treated with sorafenib for at least 12 weeks. The median age was 56 years (range, 28‐79 years). Approximately 90% had hepatitis B virus–related HCC. Thirty‐six (71%) patients had underlying Child‐Pugh A cirrhosis, 13 (26%) Child‐Pugh B, and 2 (3%) Child‐Pugh C. Four (8%) patients achieved partial responses, and 9 (18%) patients had stable disease for at least 12 weeks. The median overall survival was 5 months (range, 4‐17 months). Patients without extrahepatic spread, particularly without lung metastasis (P<.01), are more likely to benefit from sorafenib treatment. The most common toxicities were diarrhea (67%), malaise (55%), and hand‐foot‐skin reaction (54%). The majority of patients had transient liver function derangement. Patients with and without underlying portal vein thrombosis had similar therapeutic benefits and likewise shared a similar treatment‐related toxicity profile with sorafenib treatment.

CONCLUSIONS:

Single‐agent sorafenib demonstrates good efficacy and acceptable tolerability in treating an advanced HCC patient population in a hepatitis B–endemic area. The presence of lung metastasis predicts poor response to sorafenib in advanced HCC patients. Cancer 2009. © 2009 American Cancer Society.     

Phase I dose‐escalation study of capmatinib (INC280) in Japanese patients with advanced solid tumors

Capmatinib is a highly specific, potent and selective MET inhibitor. This was an open‐label, multicenter, dose‐escalation, phase I study conducted in Japanese patients with advanced solid tumors (not selected based on their MET status). The primary objective was to determine the maximum tolerated dose (MTD) and/or highest studied dose being safe. Secondary objectives included safety, pharmacokinetics and preliminary antitumor activity. Dose escalation was guided by a Bayesian Logistic Regression Model dependent on dose‐limiting toxicities (DLT) in cycle 1. Of 44 adult Japanese patients with confirmed advanced solid tumors enrolled, 29 received capmatinib capsules (doses ranging from 100 mg once daily [q.d.] to 600 mg twice daily [b.i.d.]) and 15 received tablets (200 mg b.i.d. and 400 mg b.i.d.). DLT occurred in two patients: grade 2 suicidal ideation (600 mg b.i.d. capsule) and grade 3 depression (400 mg b.i.d. tablet). MTD was not reached. The highest studied dose determined to be safe as tablet was 400 mg b.i.d., whereas it is not yet determined for capsules. Most common adverse events suspected to be drug‐related were increased blood creatinine, nausea, decreased appetite, vomiting and diarrhea. Following repeated daily dosing up to day 15 by q.d. or b.i.d. regimen using capsules, median time to reach maximum plasma drug concentration (T_max) was 1.0‐4.0 hours; absorption was more rapid after dosing using tablets, with median T_max of 1.0 hour on both days 1 and 15. Eight patients had a best overall response of stable disease. These data support further clinical development of capmatinib.     

First‐in‐human phase I study of E7090, a novel selective fibroblast growth factor receptor inhibitor,in patients with advanced solid tumors

Fibroblast growth factor receptors (FGFR) are a family of transmembrane receptor tyrosine kinases involved in regulating cellular processes. FGFR mutations are implicated in oncogenesis, representing therapeutic potential in the form of FGFR inhibitors. This phase I, first‐in‐human study in Japan evaluated safety and tolerability of E7090, a potent selective FGFR1‐3 inhibitor, in patients with advanced solid tumors. Dose escalation (daily oral dose of 1‐180 mg) was carried out to assess dose‐limiting toxicity (DLT), maximum tolerated dose, and pharmacokinetics. Pharmacodynamic markers (serum phosphate, fibroblast growth factor 23, and 1,25‐(OH)₂‐vitamin D) were also evaluated. A total of 24 patients refractory to standard therapy or for whom no appropriate treatment was available were enrolled. No DLT were observed up to the 140‐mg dose; one patient in the 180‐mg cohort experienced a DLT (increased aspartate aminotransferase/alanine aminotransferase, grade 3). The maximum tolerated dose was not reached. Dose‐dependent increases in the maximum concentration and area under the curve from time 0 to the last measurable concentration were observed up to 180 mg. Dose‐dependent increases were observed in all pharmacodynamic markers and plateaued at 100‐140 mg, indicating sufficient FGFR pathway inhibition at doses ≥100 mg. In conclusion, E7090 showed a manageable safety profile with no DLT at doses ≤140 mg. Maximum tolerated dose was not determined. The recommended dose for the follow‐up expansion part, restricted to patients with tumors harboring FGFR alterations, was determined as 140 mg, once daily.     

Phase I,multicenter, open‐label,dose‐escalation study of sonidegib in Asian patients with advanced solid tumors

Sonidegib is a selective inhibitor of Smoothened receptor, which is a key regulator of the Hedgehog signaling pathway. The purpose of this study was to determine the maximum tolerated dose based on dose‐limiting toxicity (DLT) and the recommended dose (RD) of sonidegib in Asian patients with advanced solid tumors. This was an open‐label, single‐arm, multicenter, two‐group, parallel, dose‐escalation, phase I study undertaken in Asian patients; group 1 included patients from Japan and group 2 included patients from Hong Kong and Taiwan. Dose escalation was guided by a Bayesian logistic regression model dependent on DLTs in cycle 1 and other safety findings. A total of 45 adult Asian patients with confirmed advanced solid tumors were enrolled. Group 1 included 21 patients (12 treated with 400 mg q.d. [once daily] and 9 treated with 600 mg q.d.) and group 2 included 24 patients (12 treated with 400 mg q.d., 8 treated with 600 mg q.d., and 4 treated with 800 mg q.d.). Elevation in creatine kinase was the DLT in both groups. The most common adverse events suspected to be related to sonidegib in both patient groups were increase in creatine kinase levels, myalgia, fatigue, and abnormal hepatic function. The RD of 400 mg q.d. was defined in both groups. Difference in tolerability was noted between the East Asian patients and Western population. The RD in East Asian patients (400 mg q.d.) was lower than in patients from Europe and the USA (800 mg q.d. and 250 mg twice daily). (Registered with Clinicaltrials.gov : NCT01208831.)     

Dasatinib in imatinib‐resistant or imatinib‐intolerant chronic myeloid leukemia in blast phase after 2 years of follow‐up in a phase 3 study

BACKGROUND:

In a phase 3 study, the authors assessed the effects of dasatinib at doses of 140 mg once daily and 70 mg twice daily in patients who had either chronic myeloid leukemia (CML) in advanced phases or Philadelphia chromosome‐positive acute lymphoblastic leukemia and were resistant or intolerant to imatinib. In the current report, the results for patients with CML in blast phase after 2 years of follow‐up are reported.

METHODS:

Patients were stratified according to whether they had CML in myeloid blast phase (MBP‐CML) or in lymphoid blast phase (LBP‐CML) and were randomized (1:1) within each stratum to receive either oral dasatinib 140 mg once daily or 70 mg twice daily.

RESULTS:

In patients with MBP‐CML, the major hematologic response rate was 28% for both regimens; and, in patients with LBP‐CML, the major hematologic response rate was 42% for once‐daily dasatinib and 32% for twice‐daily dasatinib. The major cytogenetic response rates were 25% for once‐daily dasatinib and 28% for twice‐daily dasatinib in patients with MBP‐CML, and the respective rates in patients with LBP‐CML were 50% and 40%. The overall survival rate at 24 months was 24% for once‐daily dasatinib and 28% for twice‐daily dasatinib in patients with MBP‐CML, and the respective values in patients with LBP‐CML were 21% and 16%. Adverse events indicated a trend toward improved tolerability for the once‐daily regimen.

CONCLUSIONS:

The current results suggested that dasatinib 140 mg once daily had similar efficacy and improved tolerability relative to the 70‐mg twice‐daily regimen in patients with imatinib‐resistant, blast phase CML. Cancer 2010. © 2010 American Cancer Society.     

Dose‐finding study of the checkpoint kinase 1 inhibitor,prexasertib, in Japanese patients with advanced solid tumors

Prexasertib is a novel inhibitor of checkpoint kinase 1. The primary objective of this study was to evaluate prexasertib tolerability in Japanese patients with advanced solid tumors. This nonrandomized single‐arm open‐label phase 1 study of prexasertib consisted of 2 dose levels, 80 mg/m² and the global‐recommended dose based on a US study of 105 mg/m², administered intravenously once every 14 days (n = 6 for each dose). Transition to the higher dose proceeded if the frequency of dose‐limiting toxicity observed in cycle 1 was <33% at the lower dose. Safety measures, pharmacokinetics and antitumor activity were assessed. A total of 12 patients were treated. Two patients, one in each dose group, experienced dose‐limiting toxicities of febrile neutropenia, one grade 4 and the other grade 3; both patients recovered and continued the study treatment. The grade 4 treatment‐emergent adverse events related to study treatment were neutropenia (6 patients [50.0%]), leukopenia (4 patients [33.3%]), and 1 instance each (8.3%) of anemia, febrile neutropenia and thrombocytopenia. Neutropenia was generally transient and reversible; 11 patients (91.7%) required granulocyte colony‐stimulating factor treatment during the study. There were no discontinuations due to adverse events or deaths. The prexasertib pharmacokinetics displayed dose‐independent and time‐independent behavior across both dose levels, similar to the profile observed in the US‐based phase 1 study. Eight patients had a best overall response of stable disease. These data are consistent with the known safety profile for prexasertib and confirm its tolerability in Japanese patients with advanced solid tumors.     

Randomized phase II study evaluating veliparib (ABT-888) with temozolomide in patients with metastatic melanoma

BackgroundVeliparib (ABT-888) is a potent, orally bioavailable, small-molecule inhibitor of the DNA repair enzymes poly ADP-ribose polymerase-1 and -2. Veliparib enhances the efficacy of temozolomide (TMZ) and other cytotoxic agents in preclinical tumor models.Patients and methodsIn this multicenter, double-blind trial, adults with unresectable stage III or IV metastatic melanoma were randomized 1:1:1 to TMZ plus veliparib 20 or 40 mg, or placebo twice daily. Efficacy end points included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR).ResultsPatients (N = 346) were randomized between February 2009 and January 2010. Median [95% confidence interval (CI)] PFS was 3.7 (3.0–5.5), 3.6 (1.9–4.1), and 2 (1.9–3.7) months in the 20-mg, 40-mg, and placebo arms, respectively. Median (95% CI) OS was 10.8 (9.0–13.1), 13.6 (11.4–15.9), and 12.9 (9.8–14.3) months, respectively; ORR was 10.3%, 8.7%, and 7.0%. Exploratory analyses showed patients with low ERCC1 expression had longer PFS when TMZ was combined with veliparib. Toxicities were as expected for TMZ. The frequencies of thrombocytopenia, neutropenia, and leukopenia were significantly increased in the veliparib groups. Grade 3 or 4 adverse events, mainly hematologic toxicities, were seen in 55%, 63%, and 41% of patients in the 20-mg, 40-mg, and placebo arms, respectively.ConclusionsMedian PFS with 20 and 40 mg veliparib almost doubled numerically compared with placebo, but the improvements did not reach statistical significance. OS was not increased with veliparib. Toxicities were similar to TMZ monotherapy, but with increased frequency.     

Phase I and pharmacokinetic study of vorinostat (suberoylanilide hydroxamic acid) in Japanese patients with solid tumors

Vorinostat (suberoylanilide hydroxamic acid), a potent, oral histone deacetylase inhibitor, has demonstrated clinical activity in non-Japanese patients with various hematological and solid tumors. We sought to determine the maximum tolerated dose and a recommended phase II dose for 18 Japanese patients with solid tumors (median age, 58 years; range, 25–72 years) who failed standard therapy. Patients received vorinostat for 14 days followed by a 7-day rest. The initial dose was 100 mg twice daily escalating by 100 mg twice daily. Once-daily dosing was tested at 400 and 500 mg. A maximum tolerated dose could not be identified. Dose-limiting toxicities (thrombocytopenia, anorexia, and fatigue) were observed in two of six patients receiving 200 mg twice daily and in one of six patients receiving 500 mg once daily. In the 100–500 mg dose range, vorinostat area under the concentration–time curve increased in proportion to dose with a pharmacokinetic profile similar to that established in non-Japanese patients. Vorinostat doses of 200 mg twice daily or 500 mg once daily for 14 days followed by a 7-day rest were well tolerated and are candidate doses for phase II trials, although a maximum tolerated dose for vorinostat was not reached. ( Cancer Sci 2009; 100: 1728–1734)     

Patritumab plus trastuzumab and paclitaxel in human epidermal growth factor receptor 2‐overexpressing metastatic breast cancer

Human epidermal growth factor receptor 3 (HER3) expression in lung and breast cancers has a negative impact on survival. Patritumab, a human anti‐HER3 mAb, has shown anticancer activity in preclinical models. This study examined the safety and pharmacokinetics of patritumab in combination with trastuzumab and paclitaxel in patients with HER2‐overexpressing metastatic breast cancer. In this open‐label, multicenter, dose‐escalation, phase Ib study, patients received patritumab 9 or 18 mg/kg plus trastuzumab and paclitaxel at known tolerated doses. Safety and tolerability were assessed based on dose‐limiting toxicities and other non‐life threatening adverse events. The pharmacokinetic profile for patritumab was determined based on the target trough level. Clinical efficacy was evaluated based on the overall response rate and progression‐free survival. Six patients received patritumab 9 mg/kg and 12 received 18 mg/kg. The most common adverse events were diarrhea, alopecia, leukopenia, neutropenia, and maculopapular rash. No dose‐limiting toxicities were observed. The target trough serum concentration was achieved in all patients at a dose of 18 mg/kg. Overall response rate was 38.9% and median progression‐free survival was 274 days. In conclusion, patritumab plus trastuzumab and paclitaxel was tolerable and efficacious at both doses. We recommend the dose level of 18 mg/kg for future phase II studies. (Clinical trial registration: JapicCTI‐121772.)     

Phase‐1 study of abiraterone acetate in chemotherapy‐naïve Japanese patients with castration‐resistant prostate cancer

Persistent androgen synthesis under castration status in adrenal gland, testes and tumor cells is thought to be one of the major causes of development and progression of castration‐resistant prostate cancer (CRPC). Abiraterone acetate (AA), the prodrug of abiraterone, which is an inhibitor of androgen synthesis enzymes, was evaluated for pharmacokinetics, pharmacodynamics, preliminary efficacy and safety in Japanese patients with CRPC in a phase‐1, open‐label and dose‐escalation study. Chemotherapy‐naïve Japanese CRPC patients (N = 27) received one of four AA daily doses (250 mg [n = 9], 500 mg [n = 6], 1000 [1 h premeal] mg [n = 6] and 1000 [2 h postmeal] mg [n = 6]) continuously through 28‐day treatment cycles. In the first cycle, AA monotherapy was given on days 1–7 for pharmacokinetics, and AA plus prednisone (5 mg twice daily) from days 8 to 28. Of 27 patients, 9 continued treatment with AA until the data cut‐off date (18 July 2013). Over the evaluated dose range, plasma abiraterone concentrations increased with dose, with median t_max 2–3 h. At each dose level, mean serum corticosterone concentrations increased, while testosterone and dehydroepiandrosterone sulfate concentrations rapidly decreased following a single AA dose and were further reduced to near the quantification limit on day 8 regardless of the dose. At least 3 patients from each dose‐group experienced ≥50% prostate‐specific antigen reduction, suggesting clinical benefit from AA in Japanese CRPC patients. AA was generally well‐tolerated, and, therefore, the recommended AA dosage regimen in Japanese CRPC patients is 1000 mg oral dose under modified fasting conditions (at least 1 h premeal or 2 h postmeal). This study is registered at ClinicalTrials.gov : NCT01186484.     

First study of the safety, tolerability, and pharmacokinetics of CP-724,714 in patients with advanced malignant solid HER2-expressing tumors.

PURPOSE: To test the tolerability, safety, and recommended phase II dose of CP-724,714, a reversible, highly selective, oral HER2 tyrosine kinase inhibitor in patients with advanced solid tumor malignancies that express HER2. EXPERIMENTAL DESIGN: A phase I trial evaluated escalating doses of CP-724,714, administered daily in 21-day cycles. Pharmacokinetics/pharmacodynamics were evaluated in serial blood samples and in pretreatment and posttreatment tumor and skin biopsies. RESULTS: Thirty female patients [median age, 51 years (range, 37-71); median performance status, 1 (range, 0-1)] received CP-724,714 at four dose levels: 250 mg once daily (4 patients), 250 mg twice daily (15 patients), 250 mg thrice daily (6 patients), and 400 mg twice daily (5 patients). Dosing at 400 mg twice daily and 250 mg thrice daily was not feasible due to reversible, cholestatic liver dysfunction. Treatment-related adverse events were nausea (58%), asthenia (23%), hyperbilirubinemia (27%), elevated transaminases (30%), and skin rash (30%); neither diarrhea nor cardiomyopathy was observed. No objective responses were observed in 28 evaluable patients; 8 (29%) patients had stable disease. Twenty-seven (96%) patients received prior trastuzumab and were heavily pretreated (median prior chemotherapy, 6; range, 1-11). Systemic exposure exceeded the in vivo efficacy threshold required in preclinical studies. CONCLUSIONS: Dose-limiting toxicities included hyperbilirubinemia, elevated alanine aminotransferase, thrombocytopenia and pulmonary embolus. Although the protocol-specified maximum tolerated dose of CP-724,714 was 250 mg thrice daily, the recommended phase II dose was 250 mg twice daily due to excessive late-cycle hepatotoxicity. Despite extensive prior treatment, 29% of patients had stable disease. A phase II trial has been initiated in patients with breast cancer.