Evaluation of tumor and circulating cell free (cf) DNA mutations in women with hormone refractory metastatic breast cancer (MBC) enrolled in a phase I study of Z-endoxifen (MC093C).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1043-1043
Author(s):  
Matthew P. Goetz ◽  
Vera J. Suman ◽  
Joel M. Reid ◽  
Donald W. Northfelt ◽  
Sarah A Burhow ◽  
...  
Keyword(s):  
Phase I ◽  
Sequence Data ◽  
Metastatic Breast ◽  
Dna Mutations ◽  
Targeted Ngs ◽  
Prognosis And Prediction ◽  
Er Positive ◽  
Hormone Refractory ◽  
Tumor Biopsies ◽  
Dose Levels

1043 Background: In estrogen receptor (ER) positive MBC, mutations (e.g. ESR1), identified from tumor biopsies or cfDNA, confer resistance. The concordance between mutations observed in tumor and cfDNA and the implications for response to Z-endoxifen, a potent anti-estrogen, are unknown. Methods: We previously conducted a phase I trial of Z-endoxifen in endocrine refractory, ER positive MBC. Seven dose levels were considered ranging from 20 to 160 mg/day followed by expansion cohorts (EC) of 40, 80, and 100 mg/day. Pretreatment blood samples (all pts) and fresh tumor biopsies (EC) were collected prospectively. Tumor and cfDNA were evaluated by targeted NGS. Results: 41 pts (38 evaluable) were enrolled. Prior endocrine therapy included aromatase inhibitors (37/38, 97%), fulvestrant (22/38, 58%) and tamoxifen (26/38, 68%). Substantial endoxifen exposure without DLTs at doses above 80 mg/day led to a halt in dose escalation and opening of the EC. Overall clinical benefit (stable > 6 months [7 pts.] or partial response by RECIST criteria [3 pts.]) rate was 26.3% (95%CI: 13.4-43.1%). cfDNA was obtained from 36 pts and mutations were identified in 13 (36%) including ESR1 [ Y537N or D538G] (5), PIK3CA [ H1047R or E542K] (8), TP53 [ K132R, R248Q, R267Q, or H179Y] (4), AKT ( Q79K) (1), and KRAS ( G12D) (1). In 5 pts with cf ESR1 mutations, 4 had additional cfDNA mutations including PIK3CA (3), and TP53 (1). PFS was shorter in pts with cfDNA mutations relative to those without (median: 61 vs.132 days; log-rank p = 0.021). Discordance was observed between tumor and cfDNA mutations where 3/7 PIK3CA tumor mutations were detected by cfDNA, 1/2 TP53 tumor mutations were detected by cfDNA, and 0/1 AKT tumor mutations were detected by cfDNA. Conversely, 2 pts had cfDNA mutations (either ESR1, TP53 or AKT) undetected in tumor. Conclusions: The absence of cfDNA mutations in patients with endocrine resistant, MBC treated with Z-Endoxifen was associated with significantly longer PFS. Given the discordance between tumor and cfDNA sequence data, future studies must determine which approach maximizes prognosis and prediction of benefit for estrogen-targeted therapy. Clinical trial information: NCT01327781.

Phase I Study of a Third-Generation Selective Estrogen Receptor Modulator, LY353381.HCl, in Metastatic Breast Cancer

2001 ◽  
Vol 19 (7) ◽  
pp. 2002-2009 ◽  
Author(s):  
Pamela N. Münster ◽  
Aman Buzdar ◽  
Kapil Dhingra ◽  
Nathan Enas ◽  
Lan Ni ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Metastatic Breast Cancer ◽  
Phase I ◽  
Metastatic Breast ◽  
Median Number ◽  
Third Generation ◽  
Receptor Modulator ◽  
Er Positive ◽  
Dose Levels

PURPOSE: We conducted this phase I trial to determine the safety and toxicity profile of LY353381.HCl—a novel, potent, third-generation selective estrogen receptor modulator (SERM)—because this benzothiophene derivative demonstrated an SERM profile in preclinical studies. PATIENTS AND METHODS: We studied 32 patients with recurrent or metastatic breast cancer. Patients were treated in four cohorts with oral daily doses of 10, 20, 50, and 100 mg. Pharmacokinetic sampling was performed during the first 72 hours following the first dose on day 1 and during the 24 hours after the day 57 dose. Eligibility criteria included Eastern Cooperative Oncology Group performance status of 0 to 2; no significant major organ dysfunction; and at least 3 weeks elapsed since most recent hormonal therapy, chemotherapy, and estrogen replacement therapy. RESULTS: The median patient age was 56 years (range, 30 years to 76 years). The median number of prior chemotherapies for metastatic disease was one (range, zero to four), while the median number of prior hormone regimens for metastatic disease was two (range, zero to five). Receptor status was estrogen receptor (ER) positive and progesterone receptor (PR) positive, 19 patients; ER positive and PR negative, eight patients; ER positive and PR unknown, two patients; and ER and PR unknown, three patients. Dose-limiting toxicity was not observed. Treatment was well tolerated with mild to moderate hot flashes in 18 of 32 patients (56%) at all dose levels. Transvaginal ultrasound performed at baseline and after 12 weeks of treatment showed no endometrial thickening. Of the 32 patients evaluable for response, six patients had stable disease for at least 6 months with a median duration of 7.7 months (range, 6.2 months to 33.8 months). The pharmacokinetics of LY353381.HCl were generally linear with respect to time and studied dose range. CONCLUSION: As predicted in preclinical testing, daily oral LY353381.HCl is safe, is well tolerated at all tested dose levels, and may be clinically beneficial in patients with extensively pretreated metastatic breast cancer. Further studies with LY353381 to evaluate the efficacy in patients with or without prior exposure to tamoxifen and fewer overall prior regimens are under way.

Phase I/II trial of tamoxifen with or without fenretinide, an analog of vitamin A, in women with metastatic breast cancer.

1993 ◽  
Vol 11 (3) ◽  
pp. 474-477 ◽  
Author(s):  
M A Cobleigh ◽  
K Dowlatshahi ◽  
T A Deutsch ◽  
R G Mehta ◽  
R C Moon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Vitamin A ◽  
Phase I ◽  
Mammary Cancer ◽  
Metastatic Breast ◽  
Serum Levels ◽  
Phase Iii ◽  
Antitumor Effects ◽  
Er Positive

PURPOSE Considerable attention has been focused on the chemopreventive properties of fenretinide against carcinogen-induced rodent mammary cancer. Less is known about its direct antitumor effects. The combination of tamoxifen and fenretinide is more effective than tamoxifen or fenretinide alone in prevention of rat mammary cancer. However, the combined toxicity of tamoxifen plus fenretinide in humans is unknown. Therefore, we performed a phase I/II trial in women with estrogen receptor (ER)-positive or progesterone receptor (PR)-positive, previously untreated metastatic breast cancer. PATIENTS AND METHODS Groups of three patients received tamoxifen 20 mg/d, or tamoxifen plus fenretinide 100, 200, 300, or 400 mg/d. Patients who received fenretinide enjoyed a 3-day "drug holiday" every 4 weeks. Serum levels of fenretinide and its major metabolites were monitored. Patients were monitored for known toxicities of tamoxifen and vitamin A analogs, as well as for response. RESULTS There were no significant adverse effects on renal, hepatic, hematologic, or lipid values. Nyctalopia, photophobia, cheilitis, and pruritus were not observed. Improvement or stabilization of disease occurred in 12 of 15 patients. CONCLUSION We conclude that tamoxifen administered with fenretinide is nontoxic. Phase III trials of tamoxifen versus tamoxifen plus fenretinide are warranted.

Pharmacodynamic-guided, modified continuous reassessment method (mCRM)-based, dose finding study of rapamycin in adult patients with solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3020-3020 ◽  
Author(s):  
A. Jimeno ◽  
P. Kulesza ◽  
G. Cusatis ◽  
A. Howard ◽  
Y. Khan ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Dose Finding ◽  
Phase I Trials ◽  
Dose Selection ◽  
Normal Tissues ◽  
Tumor Biopsies ◽  
Dose Levels

3020 Background: Pharmacodynamic (PD) studies, using either surrogate or tumor tissues, are frequently incorporated in Phase I trials. However, it has been less common to base dose selection, the primary endpoint in Phase I trials, in PD effects. We conducted a PD-based dose selection study with rapamycin (Rap). Methods: We used the modified continuous reassessment method (mCRM), a computer-based dose escalation algorithm, and adapted the logit function from its classic toxicity-based input data to a PD-based input. We coupled this design to a Phase I trial of Rap with 2 parts: a dose estimation phase where PD endpoints are measured in normal tissues and a confirmation phase where tumor tissue is assessed. Patients (pts) had solid tumors refractory to standard therapy. Rap was given starting at 2 mg/day continuously in 3-pt cohorts. The PD endpoint was pP70S6K in skin and tumor. Biopsies were done on days 0 and 28 of cycle 1, and a PD effect was defined as ≥ 80% inhibition from baseline. The first 2 dose levels (2 and 3 mgs) were evaluated before implementing the mCRM. The data was then fed to the computer that based on the PD effect calculated the next dose level. The mCRM was set so escalation continued until a dose level elicited a PD effect and the mCRM assigned the same dose to 8 consecutive pts, at which point the effect of that dose will be confirmed in tumor biopsies. Other correlates were PET-CT and pharmacokinetics. Results: Ten pts were enrolled at doses of 2 mg (n = 4), 3 mg (n = 3) and 6 mg (n = 3). Toxicity was anemia (4 G1, 1 G2), leucopenia (1 G1, 2 G2), low ANC (2 G2), hyperglycemia (2 G1, 1 G2), hyperlipidemia (4 G1), and mucositis (1 G1, 1 G2). PD responses were seen in 2 and 1 pt at 2 and 3 mg dose levels. Input of data to the mCRM selected a dose of 6 mg for the third cohort, where PD effect was seen in 1 pt, and thus a fourth dose around 9 mg will be tested. No responses by RECIST occurred, but 2 pts had a response by PET. The PK was consistent with prior data (t1/2 24.6 ± 10.2 h, CL 31.4 ± 12.0 L/h, vol of distribution 235 ± 65 L), and exposure increased with dose. Steady-state concentration were in the 5–20 nM range. Conclusions: mCRM-based dose escalation based on real-time PD assessment is feasible and permits the exploitation of PD effects for dose selection in a rational manner. No significant financial relationships to disclose.

Phase I study of intraperitoneal MHC unrestricted adoptive cell therapy with TALL-104 cells in patients with peritoneal carcinosis

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3054-3054 ◽  
Author(s):  
C. Bengala ◽  
V. Rasini ◽  
R. Sternieri ◽  
M. Dominici ◽  
A. Andreotti ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Mononuclear Cells ◽  
Adoptive Cell Therapy ◽  
Metastatic Breast ◽  
K562 Cells ◽  
Fold Increase ◽  
Breast Cancer Patients ◽  
Peritoneal Carcinosis ◽  
Dose Levels

3054 Background: TALL-104 is an irradiated human leukemic T cell line (CD3+, CD4- CD8+, CD56+, CD16-) grown in IL-2- containing medium, that has the ability to kill tumor cells in preclinical models in a MHC unrestricted way. A phase I trial in metastatic breast cancer patients, has shown that multiple i.v. infusions (infs) of TALL-104 cells can be given safely. In order to optimise the tumor:effector cell ratio, we have designed a phase I study of intraperitoneal infs of γ-irradiated TALL-104 cells. Methods: Patients (pts) with peritoneal carcinosis from ovarian or gastrointestinal tumors not responding to at least 2 lines of chemotherapy were eligible for study entry. The treatment included 5 i.p. infs (day 1, 3, 5, 15, 30) and the study aimed to test three cell dose levels: 1 x 108, 5 x 108, 2.5 x 109. End points of the study were: safety, kinetic of TALL-104 cells on ascites (if present) and peripheral blood (PB) by PCR, levels of cytokines (TGF-β, GM-CSF, IL-2, IL-4, IL-10, IFN-γ, TNF-a and -β, HGF, sIL-2R, sICAM-1) on ascites and serum, and cytotoxicity of autologous PB mononuclear cells (MNC) against K562 cells. Results: So far 10 pts have been treated: 6 with GI and 4 with ovarian cancer; 7 patients had ascites. Five pts have been treated at the 1st and 5 pts at the 2nd dose level. No treatment-related adverse events were observed. TALL-104 cells were detected in ascites (100 % of the pts) and PB (43 % of the pts) up to 48 hrs after the infs. Cytotoxicity of MNC showed a mean 5-fold increase at day 3 through 7 and it was still evident at day 30 in both dose levels. Cytokine levels are available for the first 5 pts. In one pt 18-fold increase of TNF-a was observed in ascites after the first infusion with a peak of 40-fold at day 15. sIL-2R and sICAM-1 showed both a mean 1.2-fold and 1.5-fold increase in serum in ascites respectively up to day 45. TGF-β1 level increased in average 3.3-fold in serum and 1.5-fold in ascites during the same observation period. HGF showed a mean 1.2-fold increase both in serum and ascites. Conclusions: These preliminary results show that the i.p. infusion of TALL-104 is safe. Moreover, the increased autologous cell-mediated cytotoxicity and the levels of soluble cytokines after i.p. infs indicate that TALL-104 cells may elicit potential antitumor activity. No significant financial relationships to disclose.

Phase I study of continuous oral dosing of an irreversible CYP17 inhibitor, abiraterone (A), in castration refractory prostate cancer (CRPC) patients (p) incorporating the evaluation of androgens and steroid metabolites in plasma and tumor

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5063-5063 ◽  
Author(s):  
G. Attard ◽  
T. A. Yap ◽  
A. H. Reid ◽  
C. Parker ◽  
M. Barrett ◽  
...  
Keyword(s):  
Phase I ◽  
Drug Clearance ◽  
Secondary Resistance ◽  
Once Daily ◽  
Elimination Half ◽  
Tumor Biopsies ◽  
Dose Levels ◽  
Anti Tumor Activity ◽  
Post Therapy ◽  
Steroid Precursor

5063 Background: Despite androgen deprivation therapy, recent studies indicate high levels of intra-tumor androgens and continued androgen receptor (AR) signalling in CRPC. Methods: A phase I trial to evaluate the safety and tolerability of A administered once daily at 250, 500, 750, 1,000 and 2,000 mg to chemotherapy-naïve CRPC p. Extensive endocrine evaluation and CTC enumeration were undertaken. Tumor biopsies pre- and post-therapy were evaluated for androgen levels and TMPRSS2/ETS gene translocations. To investigate secondary resistance due to activation of a promiscuous AR by raised precursor steroids upstream of CYP17, all p who progressed were offered combination treatment of A with dexamethasone 0.5mg od (D). Results: 15 p were treated in 3-p cohorts with PSA declines >70% in 9/16 p ( table ) and subsequent expansion of the maximum biologically available dose of 1,000mg (19 p treated to date). All p had progressed on LHRH agonists and antiandrogens, 7/15 on diethylstilboestrol and 7/15 on steroids. No dose limiting toxicities were observed and the only = grade 2 toxicity was reversible hypertension (5 pts) due to CYP17 inhibition. Pharmacokinetics were dose-proportional; mean drug clearance was 803L/hour; mean Vd was 11680L; mean elimination half-life was 10.6 hours. At all dose levels, treatment was associated with increased steroid precursor levels upstream of CYP17, including up to a 300-fold rise in corticosterone levels, as well as loss of detection of adrenal androgens. Circulating testosterone levels were in the castrate range (<50 ng/dl) at baseline, rapidly becoming undetectable (<1 ng/dl) in all p. Conclusion: A can be safely administered to CRPC pts with CYP17 suppression and important anti-tumor activity suggesting that at least 60% of CRPC are still hormone driven. Phase II evaluation of 1,000 mg is ongoing. [Table: see text] [Table: see text]

A phase I study of vorinostat (suberoylanilide hydroxamic acid, SAHA) in combination with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) in patients with advanced colorectal cancer (CRC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3592-3592 ◽  
Author(s):  
M. G. Fakih ◽  
L. Pendyala ◽  
K. Toth ◽  
P. Creaven ◽  
N. Soehnlein ◽  
...  
Keyword(s):  
Phase I ◽  
Liver Metastases ◽  
Stable Disease ◽  
Phase I Study ◽  
Fixed Dose ◽  
Combination Methods ◽  
Disease Stabilization ◽  
Thymidilate Synthase ◽  
Tumor Biopsies ◽  
Dose Levels

3592 Background: Vorinostat is a novel histone deacetylase (HDAC) inhibitor that potentiates 5-FU and platinum antitumor activity. This potentiation is associated with ∼ 40 fold decrease in thymidilate synthase (TS) expression, the main target of 5-FU, in preclinical models. We conducted a phase I study of vorinostat plus FOLFOX in patients with CRC to determine the recommended dose of this combination. Methods: Vorinostat was escalated in a standard 3+3 design. FOLFOX was administered at a fixed dose every 2 weeks: leucovorin 400mg/m2 and oxaliplatin 85mg/m2 over 2 hours followed by 5-FU bolus 400mg/m2 and 5-FU infusion 2400mg/m2 over 46 hours. Vorinostat started 3 days prior to FOLFOX and was given twice daily for 1 week followed by 1 week break. Investigated dose levels of vorinostat (twice daily) include 100, 200, and 300 mg. Tumor biopsies were obtained from patients with accessible liver metastases before and on the 4th day of vorinostat (prior to FOLFOX) to assess TS expression. Results: 9 patients (pts) enrolled (M/F: 8/1; median age: 57, ECOG 0/1: 5/4). All pts had failed prior FOLFOX, irinotecan, and cetuximab therapy. One pt at dose level (DL) 1 was not evaluable due to rapid clinical progression. No dose-limiting toxicities were noted among the 8 evaluable pts. No grade (G) 3 toxicities were noted on the first cycle of treatment (within 2 weeks after 1st FOLFOX) and accrual continues on DL3. Cycle 1 toxicities were attributed to FOLFOX and consisted of 1 G2 neutropenia, 1 G2 mucositis, and 2 G2 nausea/vomiting. Responses were evaluable in 6 pts: 1 pt with peritoneal carcinomatosis on DL 1 has stable disease 5 months + along with a stable CEA; 3 patients at DL2 have stable disease at 2 months along with declining CEA in 2/3 pts. Two pts (DL1) with liver metastases biopsies had a major decrease in TS expression by IHC after 4 days of vorinostat. Conclusions: Vorinostat at 100–200mg PO BID × 1 week every 2 weeks in combination with FOLFOX is well tolerated. The lowest DL of 100 mg PO BID is associated with down-regulation of TS. Disease stabilization in highly refractory patients is promising. The investigation of this regimen in the first or second-line treatment of metastatic CRC is warranted. No significant financial relationships to disclose.

Clinical and safety data of a phase I/II trial with imatinib and vinorelbine for patients with metastatic breast cancer (MBC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13503-e13503
Author(s):  
Christoph Mundhenke ◽  
Christian Schem ◽  
Dirk Olaf Bauerschlag ◽  
Marion T. Weigel ◽  
Antonia Sophie Wenners ◽  
...  
Keyword(s):  
Phase I ◽  
Response Rate ◽  
Kinase Inhibitor ◽  
Safety Data ◽  
Metastatic Breast ◽  
Severe Neutropenia ◽  
Hematological Toxicity ◽  
Study Medication ◽  
Drug Concentrations ◽  
Dose Levels

e13503 Background: Imatinib is a tyrosine kinase inhibitor of bcr-abl, PDGF-R, SCF, c-Kit and abl. In solid tumors it inhibits proliferation and facilitates higher intratumoral cytotoxic drug concentrations. Vinorelbine has good tolerability and efficacy in MBC. This study evaluates the combination of imatinib and vinorelbine. Methods: In aprospective open-label, phase I/II trial 400 mg imatinib p.o. daily (amended from 600 mg) was combined with an escalating dose of vinorelbine i.v. weekly in four dose levels with 10, 15, 20, 25 mg/m² (each n ≥ 5) for pats. with MBC (which express PDGF-R-α and/or -β and/or c-kit). The last pat. of a level was treated > 28 days, before enrolment for the next dose level started. Study endpoints were feasibility and tolerability, incidence of hematological and non-hematological toxicity and clinical efficacy (data cut: 18/11/2011). A translational subprotocol is ongoing. 33 pats. have been enrolled; all dose levels have been fully recruited. 1 patient is still on study medication. Results: 32 pats. are evaluable (ITT population). 11 pats. went off study early (progressive disease, toxicity and withdrawal of consent). 22 pats. were on study >28 days (“ITT>28”). Within the ITT population the response rate (complete (CR) and partial response (PR)) was 9.4% (n=3), the clinical benefit rate CBR (CR+PR+stable disease) 50% (n=16), median time to progression (TTP) 155 days. 21.3% were on study medication >6 months, 15.2% > 12 months (mean 133 days, 15-617 days). Within “ITT>28,” the response rate was 13.6%, CBR 72.7% and median TTP 176 days. Toxicities (ITT population): 21.6% severe leukopenia, 9.1% severe neutropenia (with 1 febrile neutropenia), 1 case of bowel perforation, 36% diarrhea (3% severe), 84.8% nausea (severe 15.2%), 48.5% vomiting (severe 9.1%), 27.3% infections (severe 6.1%), 12.1% periph. neuropathy (severe 9.1%) and 36.4% dyspnea (3% severe). 1 patient on study medication died (non drug related). Conclusions: The combination of imatinib and vinorelbine in MBC appeared to be feasible and tolerable. A CBR of 50% (ITT) in pre-treated pats. proves the efficacy of this combination. Although toxicities were frequent, they appeared to be manageable.

Combination of Trastuzumab and Tanespimycin (17-AAG, KOS-953) Is Safe and Active in Trastuzumab-Refractory HER-2–Overexpressing Breast Cancer: A Phase I Dose-Escalation Study

2007 ◽  
Vol 25 (34) ◽  
pp. 5410-5417 ◽  
Author(s):  
Shanu Modi ◽  
Alison T. Stopeck ◽  
Michael S. Gordon ◽  
David Mendelson ◽  
David B. Solit ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Antitumor Activity ◽  
Phase I ◽  
Metastatic Breast ◽  
Pharmacokinetic Analysis ◽  
Minor Response ◽  
Her 2 ◽  
Dose Levels ◽  
Hsp90 Function

Purpose This phase I study examined whether a heat shock protein (Hsp) 90 inhibitor tanespimycin (17-AAG; KOS-953) could be administered safely in combination with trastuzumab at a dose that inhibits Hsp90 function in vivo in lymphocytes. Patients and Methods Patients with an advanced solid tumor progressing during standard therapy were eligible. Patients were treated with weekly trastuzumab followed by intravenous tanespimycin, assessed in escalating dose levels. Results Twenty-five patients were enrolled onto four tanespimycin dose levels: 225 (n = 4), 300 (n = 3), 375 (n = 8), and 450 mg/m2 (n = 10). Dose-limiting toxicity (DLT) was observed at the third and fourth cohort (1 patient each): more than 2-week delay for grade 4 fatigue/grade 2 nausea and anorexia (375 mg/m2); more than 2-week delay for thrombocytopenia (450 mg/m2). Drug-related grade 3 toxicity included emesis, increased ALT, hypersensitivity reactions (two patients each), and drug-induced thrombocytopenia (n = 1). Common mild to moderate toxicities included fatigue, nausea, diarrhea, emesis, headache, rash/pruritus, increased AST/ALT, and anorexia. Pharmacokinetic analysis demonstrated no difference in tanespimycin kinetics with or without trastuzumab. Pharmacodynamic testing showed reactive induction of Hsp70 (a marker of Hsp90 inhibition) in lymphocytes at all dose levels. Antitumor activity was noted (partial response, n = 1; minor response, n = 4; stable disease ≥ 4 months, n = 4). Tumor regressions were seen only in patients with human epidermal growth factor receptor 2 (HER-2)-positive metastatic breast cancer. Conclusion Tanespimycin plus trastuzumab is well tolerated and has antitumor activity in patients with HER-2+ breast cancer whose tumors have progressed during treatment with trastuzumab. These data suggest that Hsp90 function can be inhibited in vivo to a degree sufficient to cause inhibition of tumor growth.

Paclitaxel in doxorubicin-refractory or mitoxantrone-refractory breast cancer: a phase I/II trial of 96-hour infusion.

1994 ◽  
Vol 12 (8) ◽  
pp. 1621-1629 ◽  
Author(s):  
W H Wilson ◽  
S L Berg ◽  
G Bryant ◽  
R E Wittes ◽  
S Bates ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase I ◽  
Liver Metastases ◽  
Phase Ii ◽  
Phase I Study ◽  
Metastatic Breast ◽  
Minor Response ◽  
Tumor Biopsies ◽  
Mdr 1

PURPOSE A phase I study of paclitaxel infused over 96-hours was performed to determine toxicity, maximum-tolerated dose (MTD), and pharmacokinetics in patients with incurable lymphomas and solid tumors. A phase II study was performed at the MTD of paclitaxel in patients with doxorubicin/mitoxantrone-refractory metastatic breast cancer. PATIENTS AND METHODS In the phase I study, paclitaxel dose levels ranged from 120 to 160 mg/m2, administered on a 21-day cycle. Patients with metastatic breast cancer who had either no response or a partial response (PR) to doxorubicin or mitoxantrone and had measurable disease were eligible for the phase I and II studies. Expression of the multidrug resistance (mdr-1) gene was determined in tumor biopsies by mRNA quantitative polymerase chain reaction. RESULTS Twelve patients received a total of 73 cycles of paclitaxel on the phase I study. Dose-limiting mucositis and/or grade IV granulocytopenia was reached at 160 mg/m2, and 140 mg/m2 was selected as the phase II dose. Thirty-six consecutive patients with metastatic breast cancer were treated, of whom three were not assessable. The median age was 49 years, with disease in the liver and/or lung in 76%. Patients received a median of two prior regimens for metastatic disease, and 73% had no response to prior doxorubicin or mitoxantrone. Of 33 patients treated with paclitaxel, 16 patients (48%) achieved a PR and five (15%) achieved a minor response (MR). With a median potential follow-up duration of 60 weeks, the median progression-free and overall survival durations were 27 and 43 weeks, respectively. No correlation was found between extent of prior treatment or prior response to doxorubicin/mitoxantrone, and response to paclitaxel. Paclitaxel pharmacokinetics showed a correlation between both granulocyte and mucosal toxicity, and serum steady-state concentrations (Css) more than 0.07 mumol/L. Patients with liver metastases had significantly decreased paclitaxel clearance and higher paclitaxel Css. Levels of mdr-1 were uniformly low in all tumor biopsies studied. CONCLUSION The recommended phase II dose of paclitaxel is 140 mg/m2 in patients without liver metastases and 105 mg/m2 in patients with liver metastases. Ninety-six-hour infusions of paclitaxel were effective and well tolerated in patients with doxorubicin/mitoxantrone-refractory breast cancer. Prolonged infusion schedules may be more effective than shorter schedules and deserve further study.

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