Tumoural interstitial hypertension, possibly modulated by platelet-derived and vascular endothelial growth factor receptors (PDGFR and VEGFR), may mediate resistance to chemotherapy.
Forty-eight patients with advanced solid tumours received oral PDGFR inhibitor CP-868,596 (60–100 mg twice daily (BID)) and docetaxel (75–100 mg m–2), or CP-868,596 (60 mg BID), docetaxel (75 mg m–2), and VEGFR inhibitor axitinib (5 mg BID).
The CP-868,596/docetaxel was escalated as above. The CP-868,596/docetaxel/axitinib was not dose escalated because of increased incidence of mucositis-like adverse events (AEs) with concurrent neutropenia relative to that expected for docetaxel. All tested regimens were tolerable, including 100 mg BID CP-868,596 (recommended phase II dose) plus 100 mg m–2 docetaxel (maximum approved dose). Most treatment-emergent AEs were mild–moderate and reversible, commonly including nausea, diarrhoea, vomiting, constipation, fatigue, and anaemia (CP-868,596/docetaxel), and hypertension, lethargy, diarrhoea, and fatigue (CP-868,596/docetaxel/axitnib). Pharmacokinetics were unaffected by co-administration. Twenty-one patients achieved stable disease, including all seven evaluable on CP-868,596/docetaxel/axitinib. All nine CP-868,596/docetaxel/axitinib patients received therapy for a median of six (range, 3–16) cycles.
The CP-868,596/docetaxel was well tolerated, but increased efficacy was not observed. Addition of axitinib delivered greater benefits than expected in the number of patients achieving prolonged stable disease with a moderate increase in AEs.
CP-868,596; docetaxel; axitinib; phase Ib; advanced solid tumours
This phase I first-in-human study was conducted in Japanese patients to investigate the safety, pharmacokinetics (PKs), and determine the maximum tolerated dose (MTD) of oral TAK-285, a novel dual erbB protein kinase inhibitor that specifically targets human epidermal growth factor receptor (EGFR) and HER2.
The TAK-285 dose was escalated until MTD was determined. A second patient cohort received TAK-285 at the MTD for at least 4 weeks.
In all, 26 patients received TAK-285 at doses ranging from 50 to 400 mg once daily (q.d.) or twice daily (b.i.d.); 20 patients made up the dose escalation cohort and the remaining 6 patients were the repeated administration cohort. TAK-285 was well tolerated. Dose-limiting toxicities noted in two patients who received 400 mg b.i.d. were grade 3 increases in aminotransferases and grade 3 decreased appetite. Consequently, the MTD was determined to be 300 mg b.i.d. Absorption of TAK-285 was rapid after oral dosing, and plasma exposure at steady-state increased in a dose-proportional fashion for doses ranging from 50 to 300 mg b.i.d. A partial response was observed for one patient with parotid cancer who received 300 mg b.i.d.
The toxicity profile and PK properties of oral TAK-285 warrant further evaluation.
first-in-human; phase I TAK-285; epidermal growth factor receptor; dual erbB protein kinase inhibitor family; receptor tyrosine kinase inhibitor
A single-agent dose-escalating phase I and pharmacokinetic study on TSU-68, a novel multiple receptor tyrosine kinase inhibitor, was performed to determine the safety profile, maximum-tolerated dose for Japanese patients with advanced solid tumors and to define the recommended dose of phase II studies.
Study design was a dose escalation method on a three-patient cohort. TSU-68 was given orally twice daily (bid) between meals without interruption; the estimation of dose escalation was based on the toxicity within 4 week administration at each dose level.
Fifteen patients were enrolled into the study. Dose levels studied were 200, 400, 800, and 1,200 mg/m2 bid. Grade 3 arrhythmia and anemia/thrombocytopenia were observed in 1 patient each at 800 mg/m2 bid. Three patients discontinued continuous oral administration for 4 weeks at 400 and 800 mg/m2 bid. At 1,200 mg/m2 bid, 2 patients discontinued the treatment over 4 weeks for intolerable fatigue and abdominal pain, respectively. No serious drug-related toxicities have been observed. Grade 1–2 toxicity included urinary/feces discoloration, diarrhea, fatigue, anorexia, abdominal/chest pain, and edema. Tumor shrinkage was observed in 1 patient of NSCLC. In the pharmacokinetics, at any dose levels, Cmax and AUC0–t after repeated administration of TSU-68 on days 8 and 29 were ~2-fold lower that those after the first administration on day 1; these parameters are similar between days 8 and 28. In addition, no obvious dose-dependent increase in plasma exposure to TSU-68 repeatedly administered was observed over the four dose levels, including the higher dose levels.
The tolerable dose in this administration schedule for continuing treatment is thought to be 800 mg/m2 or less bid.
Receptor tyrosine kinase inhibitor; Solid tumors; Phase I; Pharmacokinetic
This phase I study was conducted to determine the maximum tolerated dose (MTD) of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, with 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX4) in patients with advanced colorectal cancer (CRC). Bevacizumab was later included as standard of care at the MTD.
Patients and Methods
Patients received FOLFOX4 with escalating doses of erlotinib: dose level (DL) 1, 50 mg; DL 2, 100 mg; and DL 3, 150 mg once daily continuously. Bevacizumab 5 mg/kg days 1 and 15 was added at the MTD upon Food and Drug Administration approval. Correlative studies included pharmacokinetics, pharmacodynamics was assessed in paired skin biopsies, and fluorodeoxyglucose positron emission tomography scans.
Fifteen patients received 60 cycles (120 FOLFOX treatments). Two dose-limiting toxicities (DLTs) were seen at DL 3: intolerable grade 2 rash (Common Terminology Criteria for Adverse Events version 2) lasting > 1 week, and grade 4 neutropenia. Dose level 2 was expanded to 6 more patients, this time adding bevacizumab, and 1 DLT of grade 3 mucositis occurred. As expected, the primary toxicities were cytopenias, diarrhea, rash, and fatigue. There were 2 occurrences of pneumatosis. One patient experienced an unrelated grade 4 myocardial infarction before starting chemotherapy. No pharmacokinetic drug interactions were observed. The Response Evaluation Criteria in Solid Tumors response rate was 11 of 14 (78%), median progression-free survival was 9.5 months, and median overall survival was 30 months. Three patients are currently alive > 3 years, with 1 having no evidence of disease.
The MTD of erlotinib with FOLFOX4 with or without bevacizumab is 100 mg daily. The regimen appeared to increase toxicity but showed activity in patients with CRC.
Epidermal growth factor receptor; Pharmacokinetics; Tyrosine kinase
This open-label, phase I, dose-escalation study assessed the maximum-tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity of sunitinib in combination with capecitabine in patients with advanced solid tumors.
Patients and Methods
Sunitinib (25, 37.5, or 50 mg) was administered orally once daily on three dosing schedules: 4 weeks on treatment, 2 weeks off treatment (Schedule 4/2); 2 weeks on treatment, 1 week off treatment (Schedule 2/1); and continuous daily dosing (CDD schedule). Capecitabine (825, 1,000, or 1,250 mg/m2) was administered orally twice daily on days 1 to 14 every 3 weeks for all patients. Sunitinib and capecitabine doses were escalated in serial patient cohorts.
Seventy-three patients were treated. Grade 3 adverse events included abdominal pain, mucosal inflammation, fatigue, neutropenia, and hand-foot syndrome. The MTD for Schedule 4/2 and the CDD schedule was sunitinib 37.5 mg/d plus capecitabine 1,000 mg/m2 twice per day; the MTD for Schedule 2/1 was sunitinib 50 mg/d plus capecitabine 1,000 mg/m2 twice per day. There were no clinically significant pharmacokinetic drug-drug interactions. Nine partial responses were confirmed in patients with pancreatic cancer (n = 3) and breast, thyroid, neuroendocrine, bladder, and colorectal cancer, and cholangiocarcinoma (each n = 1).
The combination of sunitinib and capecitabine resulted in an acceptable safety profile in patients with advanced solid tumors. Further evaluation of sunitinib in combination with capecitabine may be undertaken using the MTD for any of the three treatment schedules.
To determine the maximum tolerated dose (MTD), toxicities, and pharmacokinetic-pharmacodynamic profile of the heat shock protein 90 (Hsp90) inhibitor PF-04929113 (SNX-5422) in patients with advanced solid tumors and lymphomas.
This was a single institution, phase I, dose-escalation study of PF-04929113 dosed twice-weekly. Endpoints included determination of dose-limiting toxicities (DLT), MTD, the safety profile of PF-04929113, pharmacodynamic assessment of PF-04929113 on Hsp70 induction, pharmacokinetic (PK) analysis of PF 04928473 (SNX-2112) and its prodrug PF-04929113 and assessment of response.
Thirty three patients with advanced malignancies were treated. Dose escalation was continued up to 177 mg/m2 administered orally twice a week. One DLT (non-septic arthritis) was noted. No grade 4 adverse events (AEs) were seen; grade 3 AEs included diarrhea (9%), non-septic arthritis (3%), AST elevation (3%) and thrombocytopenia (3%). No objective responses were seen in 32 evaluable patients. Fifteen patients (47%) had stable disease; 17 patients (53%) had progressive disease. PK data revealed rapid absorption, hepatic and extra-hepatic clearance, extensive tissue binding and almost linear pharmacokinetics of the active drug PF 04928473. PD studies confirmed inhibition of Hsp90 and a linear correlation between PK parameters and Hsp70 induction.
PF-04929113 administered orally twice weekly is well tolerated and inhibits its intended target Hsp90. No objective responses were seen but long lasting stabilizations were obtained. Although no clinically significant drug-related ocular toxicity was seen in this study the development of PF-04929113 has been discontinued due to ocular toxicity seen in animal models and in a separate phase I study.
JNJ-26483327 is an oral, potent, multi-targeted tyrosine kinase inhibitor, inhibiting kinases of epidermal growth factor receptor (EGFR)-1, -2 and -4, rearranged during transfection (RET) receptor, vascular endothelial growth factor receptor (VEGFR)-3 and Src family (Lyn, Fyn, Yes) at low nanomolar concentrations. This phase I, accelerated titration study assessed maximum tolerated dose, safety, pharmacokinetics and pharmacodynamic effects of JNJ-26483327.
Nineteen patients with advanced cancers received JNJ-26483327 continuous twice daily (BID) in escalating dose cohorts ranging from 100 to 2100 mg. Pharmacodynamic effects were assessed in paired skin biopsies and blood.
JNJ-26483327 was well tolerated in doses up to 1500 mg BID, with target-inhibition-related toxicity such as diarrhoea and skin rash, and other common reported toxicities being nausea, vomiting, anorexia and fatigue. At 2100 mg, two episodes of dose-limiting toxicity were observed, consisting of grade 3 anorexia and a combination of grade 3 anorexia and fatigue, respectively. Pharmacokinetics were dose proportional up to 1500 mg in which plasma levels were obtained showing anti-tumour activity in xenograft mouse models. Pharmacodynamic analysis did not show a substantial effect on expression of Ki-67, p27kip1, phosphorylated mitogen-activated protein kinase, phosphorylated Akt and EGFR, and serum levels of sVEGFR-2, VEGF-C and VEGF-D remained unchanged. Stable disease was noted in six patients (32%).
JNJ-26483327 is well tolerated and shows a predictable pharmacokinetic profile; the recommended dose for further studies is 1500 mg BID.
phase I; JNJ-26483327; pharmacokinetics; pharmacodynamics; tyrosine kinase inhibitor
YN968D1 (Apatinib) selectively inhibits phosphorylation of VEGFR-2 and tumor angiogenesis in mice model. The study was conducted to determine the maximum tolerated dose (MTD), safety profile, pharmacokinetic variables, and antitumor activity in advanced solid malignancies.
This dose-escalation study was conducted according to the Chinese State Food and Drug Administration (SFDA) recommendations in patients with advanced solid tumors to determine the MTD for orally administered apatinib. Doses of continuously administered apatinib were escalated from 250 mg. Treatment continued after dose-escalation phase until withdrawal of consent, intolerable toxicities, disease progression or death.
Forty-six patients were enrolled. Hypertension and hand-foot syndrome were the two dose-limiting toxicities noted at dose level of 1000 mg. MTD was determined to be 850 mg once daily. Pharmacokinetic analysis showed early absorption with a half-life of 9 hours. The mean half-life was constant over all dose groups. Steady-state conditions analysis suggested no accumulation during 56 days of once-daily administration. The most frequently observed drug-related adverse events were hypertension (69.5%, 29 grade 1-2 and 3 grade 3-4), proteinuria (47.8%, 16 grade 1-2 and 6 grade 3-4), and hand-foot syndrome (45.6%, 15 grade 1-2 and 6 grade 3-4). Among the thirty-seven evaluable patients, PR was noted in seven patients (18.9%), SD 24 (64.9%), with a disease control rate of 83.8% at 8 weeks.
The recommended dose of 750 mg once daily was well tolerated. Encouraging antitumor activity across a broad range of malignancies warrants further evaluation in selected populations.
ClinicalTrials.gov unique identifier: NCT00633490
Background This trial evaluated the safety, tolerability and maximum tolerated dose (MTD) of afatinib, a novel ErbB Family Blocker. Methods In this open-label, dose-escalation Phase I study, afatinib was administered continuously, orally, once-daily for 28 days to patients with advanced or metastatic solid tumors. Dose escalation was performed in a 3 + 3 design, with a starting dose of 10 mg/day (d); doses were doubled for each successive cohort until the MTD was defined. The MTD cohort was expanded to a total of 19 patients. Incidence and severity of adverse events (AEs), antitumor activity and pharmacokinetics were assessed. Results Thirty patients received at least one dose of afatinib. Twenty-nine patients were evaluable for response. Dose-limiting toxicities (DLTs) consisting of Grade 3 diarrhea were observed in two out of three patients treated at 60 mg/d. The MTD was determined at 40 mg/d. The most frequent treatment-related AEs were diarrhea and mucosal inflammation reported in 76.7 % and 43.3 % of patients respectively. Five patients had stable disease with a median progression-free survival of 111 days. No objective responses occurred. Pharmacokinetic data showed no deviation from dose-proportionality and steady-state was reached on Day 8 at the latest. Conclusions Afatinib was well tolerated with manageable side effects when administered once-daily, continuously at a dose of 40 mg.
Afatinib; Phase I; ErbB Family Blocker; Dose escalation; Irreversible tyrosine kinase inhibitor
TAS-102 consists of α, α, α-trifluorothymidine (TFT) and an inhibitor of thymidine phosphorylase (TPI). We conducted a dose-escalation phase I study in Japanese patients with advanced solid tumours.
TAS-102 was administered twice daily on days 1–5 and days 8–12 in a 28-day cycle to patients with solid tumours refractory to standard chemotherapy, to determine its maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics (PKs). MTD was evaluated in cycle 1.
Safety and PKs were evaluated in 21 patients treated with TAS-102 at 30, 40, 50, 60, or 70 mg m−2 per day. DLTs, such as grade 4 leucopenia, grade 4 neutropenia, and grade 4 thrombocytopenia, were observed in two patients at doses of 30 and 70 mg m−2. α, α, α-trifluorothymidine and TPI exposures increased dose dependently, and the percentage of decrease in neutrophil count and TFT exposure were significantly correlated. The disease control rate was 50.0% with a median progression-free survival of 2.4 months in 18 colorectal cancer patients. The dose of TAS-102 was not increased above 70 mg m−2 per day because of the increased tendency for grade 3 and 4 neutropenia, and 70 mg m−2 per day was the recommended dose for phase II studies.
TAS-102 at 70 mg m−2 per day was tolerated in Japanese patients with advanced solid tumours. Phase II studies are ongoing in patients with colorectal cancer.
phase I study; pharmacokinetics; TAS-102; TFT; TPI
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.
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.
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.
Efatutazone demonstrates acceptable tolerability with evidence of disease control in patients with advanced malignancies.
efatutazone; CS-7017; PPARγ; phase 1; retinoid; biomarker
We evaluated the safety, maximum tolerated dose, pharmacokinetics, and biologic effects of the combination of the Raf-1, RET, KIT, platelet-derived growth factor receptor (PDGFR) and VEGFR2 kinase inhibitor sorafenib and the farnesyltransferase inhibitor tipifarnib.
A standard 3+3 phase I dose-escalation design was used with a 28-day cycle (sorafenib daily and tipifarnib for 21 days, by mouth).
Fifty patients were treated; 43 reached restaging evaluation after cycle 2. The most common side effects were grade 1–2 rash, hyperglycemia and diarrhea. Dose-limiting toxicity was rash, and the recommended phase II dose is sorafenib 400 mg po qam/200 mg po qpm and tipifarnib po 100 mg BID. Despite the low doses of tipifarnib, one-quarter of patients had ≥50% reduction in farnesyltransferase (FTase) levels. Interestingly, 6 of 8 patients with medullary thyroid cancer (MTC) had durable stable disease (N=3) or partial remissions (N=3), lasting 12 to 26+ months. Five of the six responders had available tissue, and RET gene mutations were identified in them. Prolonged (≥ 6 months) stable disease was also seen in nine patients as follows: papillary thyroid cancer (N=4; 18+ to 27+ months); adrenocortical cancer (N=2; 7 and 11 months); and one each of melanoma (PDGFR mutation-positive) (14 months), renal (6 months) and pancreatic cancer (6 months).
Our study shows that the combination of tipifarnib and sorafenib is well tolerated. Activity was seen, especially in patients with medullary thyroid cancer, a tumor characterized by RET mutations.
tipifarnib; sorafenib; thyroid cancer; RET kinase; Phase I
BIBF 1120 is an oral, potent, tyrosine kinase inhibitor that simultaneously targets vascular endothelial growth factor receptors 1–3, platelet-derived growth factor receptors α and β, and fibroblast growth factor receptors 1–3, as well as FLT3 and Src. Currently, the molecule is in phase III development for second-line non-small cell lung cancer and first-line ovarian cancer patients.
This phase I dose-escalation study assessed the safety and maximum tolerated dose of continuous daily treatment with BIBF 1120 plus standard-dose docetaxel (75 mg m−2, every 3 weeks) and prednisone (5 mg BID) in patients with metastatic, chemo-naive, hormone-refractory prostate cancer (HRPC). Secondary objectives were characterisation of BIBF 1120 and docetaxel pharmacokinetics (PK), and preliminary antitumour activity.
Patients received BIBF 1120 100 mg BID (n=3), 150 mg BID (n=3), 200 mg BID (n=3), and 250 mg BID (n=12). The most frequent drug-related adverse events were diarrhoea (71.4%), asthenia (61.9%), nausea (28.6%), vomiting (28.6%), and alopecia (23.8%). The maximum tolerated dose was 250 mg BID of BIBF 1120. Overall, reversible grade 3/4 liver enzyme elevations occurred in six of twelve patients at this dose level. Among 19 assessable patients, 13 (68.4%) showed a ⩾50% reduction in prostate serum antigen levels from baseline and among 6 evaluable patients with measurable lesions 1 patient experienced a partial response by Response Evaluation Criteria In Solid Tumours criteria. Pharmacokinetic analysis showed no interactions between BIBF 1120 and docetaxel/prednisone.
Based on the overall safety profile, 200 mg BID was the recommended dose for the combination of BIBF 1120 with the standard dose of 75 mg m−2 of docetaxel and prednisone that might be further investigated in HRPC patients. This combination was well tolerated, with preliminary signs of efficacy and no indication of PK interaction between BIBF 1120 and docetaxel.
phase I; multi-kinase inhibitor; prostate cancer
PF299804 is a potent, orally available, irreversible inhibitor of tyrosine kinase human epidermal growth factor receptors (HER) 1 (EGFR), HER2, and HER4. This first-in-human study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF299804 in patients with advanced solid malignancies.
PF299804 was administered once daily continuously (schedule A), and intermittently (schedule B). Dose escalation proceeded until intolerable toxicities occurred. Skin biopsies were taken pre-dose and after 14 days of treatment, to establish a pharmacokinetic/pharmacodynamic relationship. Tumor response was measured once every 2 cycles. Efficacy was correlated with tumor genotypes in non-small cell lung cancer (NSCLC) patients.
121 patients were included (111 in schedule A, 10 in schedule B). The maximum tolerated dose (MTD) was 45 mg/day. Dose-limiting toxicities included stomatitis and skin toxicities. Most adverse events were mild and comprised skin toxicities, fatigue, and gastrointestinal side-effects including diarrhea, nausea, and vomiting. Pharmacokinetic analyses revealed dose-dependent increases in PF299804 exposure associated with target inhibition in skin biopsy samples. Fifty-seven patients with non-small cell lung cancer (NSCLC) were treated in this study. Four patients, all previously treated with gefitinib or erlotinib (2 with exon 19 deletions, 1 with exon 20 insertion, 1 mutational status unknown), had a partial response to PF299804.
The MTD of PF299804 is 45 mg/day. Both continuous and intermittent treatment schedules were well tolerated, and encouraging signs of antitumor activity were observed in gefitinib/erlotinib treated NSCLC patients.
Phase I clinical trial; Non-small cell lung cancer; epidermal growth factor receptor; mutation; kinase inhibitor
The combination of sorafenib (vascular endothelial growth factor receptor 2 inhibitor) and sirolimus (mammalian target of rapamycin inhibitor) might work synergistically.
A phase I dose-escalation study with sorafenib twice a day (b.i.d.) and sirolimus once daily (q.d.) was performed to determine the recommended dose of the combination in patients with solid tumours. Secondary objectives were to determine the safety profile and maximum tolerated dose (MTD), and to evaluate the pharmacokinetics (PK) of the combination.
Dose-limiting toxicities were transaminitis and cutaneous toxicity. The most frequently reported adverse events were elevated transaminases, hypophosphatemia, fatigue, anorexia, diarrhoea, nausea, rash and palmar–plantar erythrodysaesthesia. Sirolimus did not change the PK of sorafenib; in contrast, sorafenib reduced the AUC(0−96) and Cmax of sirolimus. No objective responses were observed; eight patients showed stable disease for a median of 16.3 weeks (range 8–24). The MTD of the combination was sorafenib 200 mg b.i.d. with sirolimus 1 mg q.d.
The combination of sorafenib and sirolimus showed enhanced toxicity, which could not be explained by the PK of both drugs. The relative low doses at the MTD, in combination with the PK results, do not warrant further development of this combination.
phase I; sorafenib; sirolimus; tyrosine kinase inhibitor; mTOR inhibitor
To study the safety, tolerability and pharmacokinetics (PK) of the selective tyrosine kinase inhibitor nilotinib as a single-agent or in combination with imatinib in patients with advanced imatinib-resistant gastrointestinal stromal tumors (GIST).
A Phase I intercohort dose-escalation trial was performed in patients who received either (1) single-agent nilotinib 400 mg bid or (2) escalating doses of nilotinib (200 mg qd, 400 mg qd, or 400 mg bid) plus imatinib 400 mg bid (10- and 14-hour interval daily), or (3) nilotinib 400 mg bid plus imatinib 400 mg qd. Safety, PK and tumor assessments were performed.
Oral clearance (CL/F) of nilotinib was similar across the combination groups (mean CL/F=19.1-25.6 L/h), and lower than in the single-agent cohort (mean CL/F=35.6 L/h). A linear relationship between nilotinib daily dose and peak concentration (Cmax) was observed in the combination cohorts. Observed adverse events (AEs) were mostly non-hematological. Frequently reported AEs were rash (40%), fatigue (38%), abdominal pain (36%) and nausea (36%). Severe AEs (grade 3 or 4) included abdominal pain (13%) and rash (9%), the latter mainly with the combination. Thirty-eight patients had stable disease and two patients achieved partial response with a median progression-free survival of 134 days for the entire group.
Nilotinib alone or in combination with imatinib was well tolerated overall and showed clinical activity in imatinib-resistant GIST patients. This Phase I trial identified single-agent nilotinib 400 mg bid or combined with imatinib 400 mg qd as possible Phase II doses for further evaluation.
nilotinib; imatinib; gastrointestinal stromal tumors (GIST); Phase I; pharmacokinetics (PK)
Background A Phase I study to determine the maximum tolerated dose (MTD) and pharmacokinetics of afatinib (BIBW 2992), a novel irreversible ErbB Family Blocker, administered orally once daily in a 3-week-on/1-week-off dosing schedule. Methods Patients with advanced solid tumors received single-agent afatinib at 10, 20, 40, 55 or 65 mg/day. Safety, antitumor activity, pharmacokinetics and pharmacodynamic modulation of biomarkers were assessed. Results: Forty-three patients were enrolled. Dose-limiting toxicities (DLTs) occurred in five patients in the dose escalation phase (1/8 at 40 mg/day; 1/6 at 55 mg/day; 3/6 at 65 mg/day). The MTD was established at 55 mg/day. In the expansion cohort at the MTD, 6 patients experienced a DLT in the first 28-day treatment period. The most frequent DLT was diarrhea. The most common adverse events were diarrhea, rash, nausea, vomiting and fatigue. Overall, the afatinib safety profile in a 3-week-on/1-week-off dose schedule was similar to that of our daily-continuous schedule. Afatinib displayed dose-dependent pharmacokinetics at doses up to and including 55 mg/day, with a terminal half-life suitable for once-daily dosing. Signs of clinical antitumor activity were observed. In biopsies taken from clinically normal forearm skin, afatinib caused a reduced proliferation rate, with a concomitant increase in differentiation of epidermal keratinocytes. Conclusion Afatinib in a 3-week-on/1-week-off schedule showed a good safety profile. The MTD was 55 mg/day, although excess DLTs in the expansion cohort indicated that the 40 mg/day dose would have an acceptable safety profile for future studies. Dose cohorts between 40 and 55 mg/day were not examined in this study.
Afatinib; Pharmacokinetics; EGFR; HER2
We determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of the oral vascular endothelial growth factor receptor (VEGFR) inhibitor, vatalanib, when administered with imatinib and hydroxyurea on a continuous daily schedule among recurrent malignant glioma patients.
All patients received 500 mg of hydroxyurea twice daily. Imatinib was dosed at 400 mg per day for patients not taking enzyme-inducing antiepileptic drugs (EIAEDs; stratum A) and at 500 mg twice-a-day for patients taking EIAEDs (stratum B). Vatalanib was escalated from 500 mg to 1250 mg twice daily in successive cohorts, independently for each stratum. Pharmacokinetics of each drug were assessed.
Thirty-seven recurrent patients, including 34 (92%) with glioblastoma and 3 (8%) with grade 3 malignant glioma, were enrolled. Nineteen patients (51%) were taking EIAEDs. The MTD of vatalanib for all patients was 1000 mg twice-a-day. DLTs were hematologic, gastrointestinal, renal and hepatic. No patients developed intracranial hemorrhage. Concurrent administration of imatinib and hydroxyurea did not affect vatalanib exposure, but EIAEDs decreased vatalanib and imatinib plasma exposures.
Vatalanib doses up to 1000 mg twice-a-day combined with imatinib and hydroxyurea are well tolerated. Strategies to target tumor blood vessel endothelial cells and pericytes by inhibiting VEGFR and PDGFR, respectively, are safe among recurrent malignant glioma patients and may enhance anti-angiogenesis activity.
Malignant glioma; imatinib mesylate; vascular endothelial growth factor; platelet-derived growth factor; vatalanib; hydroxyurea
To find the maximum tolerated dose (MTD) of OSI-461 in combination with mitoxantrone in patients with advanced solid tumors.
This was a Phase I study using cohort dose escalation of OSI-461 dosed orally twice daily in combination with mitoxantrone 12 mg/m2 given on Day 1 of each 21-day cycle.
OSI-461 dose was escalated to 1,000 mg po bid. One patient experienced a dose-limiting toxicity (DLT). Three patients discontinued the study due to adverse events (AE). Two patients (10%) had a partial response, and ten patients (50%) had stable disease as best response.
The combination of OSI-461 and mitoxantrone was well tolerated. Dose escalation was stopped because of toxicities in a concurrent Phase I trial. The response rate seen in patients with prostate cancer was comparable to response rates seen in trials of mitoxantrone and prednisone alone, and further studies of the combination of OSI-461 and mitoxantrone were not pursued.
Mitoxantrone; OSI-461; Apoptosis; Clinical trial
This study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of the first-in-class dual mammalian target of rapamycin complex (mTORC)1/mTORC2 inhibitor, AZD8055.
Patients with advanced solid malignancies or lymphomas were recruited into this phase I, open-label, dose-escalation study of AZD8055 starting at 10 mg twice-daily oral dosing (BID).
Forty-nine patients received AZD8055. Dose-limiting toxicities were reported at 40 mg (n=1), 90 mg (n=1) and 120 mg (n=3) BID; all were grade 3 rises in transaminases, reversible in all patients, apart from one who had liver metastases. The maximum tolerated dose was defined as 90 mg BID. The most frequent adverse events assessed to be related to AZD8055 were increased alanine aminotransferase (22%), increased aspartate aminotransferase (22%) and fatigue (16%). AZD8055 was rapidly absorbed (median tmax ∼0.5 h) and exposure increased with increasing doses. Seven patients had stable disease for ⩾4 months. Partial metabolic responses, assessed by fluorodeoxyglucose positron emission tomography, were observed at ⩾40 mg BID (n=8 at day 35).
The maximum tolerated dose for AZD8055 is 90 mg BID. Apart from elevated transaminases, which occurred at most dose levels, the drug had an acceptable toxicity profile; however, no RECIST responses were seen.
AZD8055; mTOR inhibitors; phase I
The purpose of this study was to investigate the safety, tolerability, and pharmacokinetics of motesanib when combined with docetaxel or paclitaxel in patients with metastatic breast cancer. In this open-label, dose-finding, phase 1b study, patients received motesanib 50 or 125-mg orally once daily (QD), beginning day 3 of cycle 1 of chemotherapy, continuously in combination with either paclitaxel 90 mg/m2 on days 1, 8, and 15 every 28-day cycle (Arm A) or docetaxel 100 mg/m2 on day 1 every 21-day cycle (Arm B). Dose escalation to motesanib 125 mg QD occurred if the incidence of dose-limiting toxicities (DLTs, primary endpoint) was ≤33 %. If the maximum tolerated dose (MTD) of motesanib was established in Arm B, additional patients could receive motesanib at the MTD plus docetaxel 75 mg/m2. Forty-six patients were enrolled and 45 received ≥1 dose of motesanib. The incidence of DLTs was <33 % in all cohorts; thus, motesanib 125 mg QD was established as the MTD. Seven patients (16 %) had grade 3 motesanib-related adverse events including cholecystitis (2 patients) and hypertension (2 patients). Pharmacokinetic parameters of motesanib were similar to those reported in previous studies. The objective response rate was 56 % among patients with measurable disease at baseline who received motesanib in combination with taxane-based chemotherapy. The addition of motesanib to either paclitaxel or docetaxel was generally tolerable up to the 125-mg QD dose of motesanib. The objective response rate of 56 % suggests a potential benefit of motesanib in combination with taxane-based chemotherapy.
Motesanib; Breast cancer; Angiogenesis; VEGF; Chemotherapy
This phase 1b study assessed the maximum tolerated dose (MTD), safety, and pharmacokinetics of motesanib (a small-molecule antagonist of VEGF receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit) administered once daily (QD) or twice daily (BID) in combination with erlotinib and gemcitabine in patients with solid tumors.
Patients received weekly intravenous gemcitabine (1000 mg/m2) and erlotinib (100 mg QD) alone (control cohort) or in combination with motesanib (50 mg QD, 75 mg BID, 125 mg QD, or 100 mg QD; cohorts 1-4); or erlotinib (150 mg QD) in combination with motesanib (100 or 125 mg QD; cohorts 5 and 6).
Fifty-six patients were enrolled and received protocol-specified treatment. Dose-limiting toxicities occurred in 11 patients in cohorts 1 (n = 2), 2 (n = 4), 3 (n = 3), and 6 (n = 2). The MTD of motesanib in combination with gemcitabine and erlotinib was 100 mg QD. Motesanib 125 mg QD was tolerable only in combination with erlotinib alone. Frequently occurring motesanib-related adverse events included diarrhea (n = 19), nausea (n = 18), vomiting (n = 13), and fatigue (n = 12), which were mostly of worst grade < 3. The pharmacokinetics of motesanib was not markedly affected by coadministration of gemcitabine and erlotinib, or erlotinib alone. Erlotinib exposure, however, appeared lower after coadministration with gemcitabine and/or motesanib. Of 49 evaluable patients, 1 had a confirmed partial response and 26 had stable disease.
Treatment with motesanib 100 mg QD plus erlotinib and gemcitabine was tolerable. Motesanib 125 mg QD was tolerable only in combination with erlotinib alone.
XL184 (cabozantinib) is a potent inhibitor of MET, vascular endothelial growth factor receptor 2 (VEGFR2), and RET, with robust antiangiogenic, antitumor, and anti-invasive effects in preclinical models. Early observations of clinical benefit in a phase I study of cabozantinib, which included patients with medullary thyroid cancer (MTC), led to expansion of an MTC-enriched cohort, which is the focus of this article.
Patients and Methods
A phase I dose-escalation study of oral cabozantinib was conducted in patients with advanced solid tumors. Primary end points included evaluation of safety, pharmacokinetics, and maximum-tolerated dose (MTD) determination. Additional end points included RECIST (Response Evaluation Criteria in Solid Tumors) response, pharmacodynamics, RET mutational status, and biomarker analyses.
Eighty-five patients were enrolled, including 37 with MTC. The MTD was 175 mg daily. Dose-limiting toxicities were grade 3 palmar plantar erythrodysesthesia (PPE), mucositis, and AST, ALT, and lipase elevations and grade 2 mucositis that resulted in dose interruption and reduction. Ten (29%) of 35 patients with MTC with measurable disease had a confirmed partial response. Overall, 18 patients experienced tumor shrinkage of 30% or more, including 17 (49%) of 35 patients with MTC with measurable disease. Additionally, 15 (41%) of 37 patients with MTC had stable disease (SD) for at least 6 months, resulting in SD for 6 months or longer or confirmed partial response in 68% of patients with MTC.
Cabozantinib has an acceptable safety profile and is active in MTC. Cabozantinib may provide clinical benefit by simultaneously targeting multiple pathways of importance in MTC, including MET, VEGFR2, and RET. A global phase III pivotal study in MTC is ongoing (ClinicalTrials.gov number NCT00215605).
We conducted a phase I study of dasatinib, an oral SRC-family tyrosine kinase inhibitor, in combination with paclitaxel and carboplatin in advanced and recurrent epithelial ovarian cancer.
The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included defining toxicity, response rate (RR), pharmacokinetics and pharmacodynamics. Using a “3+3” design, cohorts of 3–6 patients received paclitaxel (175 mg/m2) and carboplatin (AUC 6) every three weeks with escalating doses of dasatinib (100, 120, 150 mg daily), followed by an 8 patient expansion cohort.
Twenty patients were enrolled between 06/07 and 12/09. The median age was 61 years (42–82) with a median of 2 prior regimens (0–6), and 71% had platinum-sensitive disease. There were 3–6 patients in each cohort, and 8 in the expansion cohort. Pharmacokinetics were observed over the first 2 cycles of therapy. One DLT was observed in the 100 mg dasatinib cohort (grade 3 myalgia). Other toxicities in all cycles included neutropenia (95% grade 3–4; 91% in the 150 mg dosing cohort), thrombocytopenia (35% grade 3–4), and fatigue (10% grade 3). The RR was 40% (3 complete responses, (15%); 5 partial responses, (25%)),10 (50%) had stable disease, and 2 were not evaluable. The PFS6-month actuarial estimate was 86%. The median PFS and OS were 7.8 and 16.2 months, respectively.
Due to the high incidence of myelosuppression with subsequent cycles the recommended phase II dose of dasatinib is 150 mg daily in combination with paclitaxel and carboplatin. The combination was safe with evidence of clinical activity.
dasatinib; chemotherapy; ovarian cancer
This phase I study was designed to determine the maximum tolerated dose (MTD) and toxicity profile of the combination of gefitinib, capecitabine, and celecoxib in patients with advanced solid tumors. Patients were treated with escalating doses of gefitinib once daily, capecitabine twice daily (14 of 28 days), and celecoxib twice daily. Plasma samples for biomarkers were obtained at baseline and weekly for the first 2 cycles. Pharmacokinetic variables were correlated with toxicity and presence of biological effect. Tumor biopsies from 5 patients were analyzed for changes in tumor metabolic activity by nuclear magnetic resonance spectroscopy. [18F]fluororodeoxyglucose positron emission tomography was done as a correlate in 6 patients at the MTD. Thirty-nine patients received 168 cycles of therapy. The dose-limiting toxicities observed included nausea, dehydration and nausea, diarrhea, and stomatitis. The MTD was 250 mg/d gefitinib (days 1–14) and 2,000 mg/m2/d capecitabine divided twice daily (days 8–21) every 28 days. Celecoxib was eliminated due to concerns of increased risk for cardiovascular toxicity, although no patients in this study had cardiac events. One patient with cholangiocarcinoma had a confirmed partial response. Fourteen of 39 (36%) patients maintained prolonged stable disease for a median of 4 months (range, 3–24 months). [18F]fluorodeoxyglulucose positron emission tomography scan and metabolomic analyses revealed differences in metabolic response to gefitinib versus capecitabine. The combination of gefitinib and capecitabine is well tolerated and appears to have activity against certain advanced solid tumors, providing a rationale for further evaluation in advanced solid malignancies.