A phase I-II and pharmacodynamic (PD) study of the combination of the proteasome inhibitor bortezomib (B) and paclitaxel (P) in patients with taxane-sensitive solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13029-13029
Author(s):  
E. Gallerani ◽  
S. Cresta ◽  
D. Tosi ◽  
C. Sessa ◽  
G. Capri ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Ovarian Cancer ◽  
Antitumor Activity ◽  
Phase I ◽  
Anticancer Agents ◽  
Mononuclear Cells ◽  
Performance Status ◽  
Ecog Performance Status ◽  
Peripheral Blood Mononuclear

13029 Background: Proteasome inhibition blocks the chemotherapy-induced activation of NF-кB increasing chemosensitivity to anticancer agents due to increased apoptosis. NF-кB is frequently aberrantly activated in primary human carcinomas and over-expressed in aggressive breast cancer lines1 supporting the rationale for combining B with P. We designed a phase I-II and PD trial to determine the recommended dose (RD) of the B&P combination, to screen for antitumor activity in patients with potentially taxane-sensitive tumors, to search for drug-induced changes and to identify potential surrogate markers of drug activity and toxicity in peripheral blood mononuclear cells (PBMC). Methods: Eligibility included ECOG performance status < 2, neurotoxicity < 2 and adequate organ functions. Treatment was given Q21 days: B on days 1,4, 8 and 11 and P on days 1 and 8. PBMC for gene expression profiling have been collected on day 1 and 4 before and after therapy. RECIST for response was applied. Results: Twenty-nine patients (20 female, median age 60 yrs) were accrued and 25 are evaluable (breast cancer: 13, ovarian cancer: 7, prostate cancer 1, other 4) ; 16 pts were treated in 4 escalation levels and the RD defined respectively at 1.3 mg/m2/dose & 100 mg/m2/dose for B&P. Neurotoxicity was the main toxicity (G1 36%, G2 20% and 1 case G3) requiring treatment discontinuation in 2 pts at cy 6 & 7. Other toxicities (all grades) were nausea and vomiting (68%), diarrhea (56%, G3 12%), alopecia (52%), asthenia (36%, G2 4%), and myalgia (32%, G2 8%). Antitumor activity consisted of 3 PR in pts with ovarian cancer lasting respectively 14, 8+ and 16 wks; 2 PRs in pts with breast cancer (12+ wks,14+ wks) and 1 PR in a pt with prostate cancer. Conclusions: Thus far the regimen has acceptable toxicity with evidence of antitumor activity. The trial will continue until accrual of four additional patients as planned. Footnotes 1 Adams J Current Opin Oncol 2002, 14:628–634. [Table: see text]

Phase I/II study of GM-CSF gene-transduced allogeneic prostate cancer cellular immunotherapy (GVAX IT) in advanced prostate cancer patients made lymphopenic by chemotherapy and infused with autologous peripheral blood mononuclear cells (MC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14635-14635 ◽  
Author(s):  
B. D. Curti ◽  
I. Assman ◽  
T. Moudgil ◽  
T. Ratzow ◽  
D. Haley ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase I ◽  
Mononuclear Cells ◽  
Performance Status ◽  
Study Groups ◽  
Phase Iii ◽  
Cellular Immunotherapy ◽  
Ecog Performance Status ◽  
Peripheral Blood Mononuclear ◽  
Pre Treatment

14635 Background: GVAX IT has been tested in phase I/ II and is currently being tested in phase III clinical trials of patients (pts) with androgen-independent prostate carcinoma (AIPC). Immunological and PSA responses have been described in men receiving GVAX IT. Preclinical studies have shown that antitumor immune responses induced by GVAX IT could be augmented further by making animals lymphopenic and reconstituting with lymphocytes prior to vaccination. A clinical trial was designed to study the effects of lymphopenic reconstitution in pts with AIPC. Methods: All pts had MC collection by leukapheresis pre-treatment. Study groups were as follows: Arm A - GVAX IT given every two weeks for 6 months; Arm B - Cyclophosphamide (350 mg/m2 IV on days 1–3), MC infusion on day 6, GVAX IT on day 7, then every 2 weeks for 6 months; Arm C - Cyclophosphamide (350 mg/m2 IV on days 1–3) and fludarabine (20 mg/m2 IV on days 1–3), MC infusion on day 6, GVAX IT on day 7, then every 2 weeks for 6 months. Results: Seven pts have been treated thus far and completed at least 2 GVAX IT treatments. Pts had ECOG performance status ≤ 1, castrate testosterone levels, ≤ 1 prior chemotherapy regimen and measurable or evaluable metastatic AIPC. Lymphopenia was induced in all pts enrolled in Arms B and C, with recovery of total granulocytes and lymphocytes within 4 weeks following treatment. Monitoring of humoral and cellular immunological responses is underway and shall be presented. Conclusions: GVAX IT and lymphopenic reconstitution is feasible in men with AIPC. Analysis of clinical and immune response is ongoing. Supported by DAMD grant PC020094 and generous support of Mr. Tom Denhart, the Chiles Foundation and the Murdock Trust. [Table: see text]

Role of gemcitabine along with dendritic cell therapy in advanced-stage pancreatic cancers: Phase I/II trial results in 26 patients from India.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13071-e13071
Author(s):  
Jamal Anono Khan
Keyword(s):  
Dendritic Cell ◽  
Phase I ◽  
Mononuclear Cells ◽  
Performance Status ◽  
Age Groups ◽  
Blood Chemistry ◽  
Advanced Stage ◽  
Ecog Performance Status ◽  
Peripheral Blood Mononuclear ◽  
End Point

e13071^ Background: Pancreatic cancer is the leading cause of cancer deaths worldwide with a very poor survival rate. No adequate therapy allows the patient to have a longer life of even 1 year. Methods: Dendritic cell(DC) based immunotherapy along with gemcitabine chemotherapy is planned to do phase I/II trial in 26 patients of advanced stage adenocarcinoma of pancreas. Inclusion criteria was defined as unresectable disease, ECOG performance status of not more than 2, Blood chemistry and hematocrit within normal range and of all age groups. Peripheral blood mononuclear cells are cultured in GM-CSF/IL-4 in RPMI. At 6th day of culture, the immature dendritic cells are exposed to antigens previously isolated from fresh excised tissue and further matured for 2 days. The cells along with medium are harvested and 1 million mature DC are infused IV by mixing them in 100 ml of dextrose normal saline with ondasnetron 4mg injection. Gemcitabine was given on day 1 and on day 8th and DC on day 15th. The cycle is repeated every month for 3 months followed by DC therapy alone at every 23 days interval till patient survives. The primary end point was overall survival and the secondary end point was improvement in quality quotient. Results: 6 patients survived for 24 months, 10 for 12 months and 3 for 6 months, with radiological improvement in only 4 patients with 25% reduction of disease. The quality quotient of 14 patients improved by second dose of dc therapy with improved appetite and decreased pain in abdomen including cheerfulness in 13 patients. Conclusions: Gemcitabine and DC immunotherapy is a good option for advanced stage pancreas cancer patients.

The addition of prednisone (Pr) to the combination of docetaxel (T) and perifosine (P) decreases the severity of gastrointestinal (GI) toxicity

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13142-13142
Author(s):  
B. Bernhardt ◽  
J. J. Nemunaitis ◽  
B. Ebrahimi ◽  
A. Cervera ◽  
R. Birch ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Stable Disease ◽  
Phase 1 ◽  
Performance Status ◽  
Phase 1 Study ◽  
Ecog Performance Status ◽  
Prior Chemotherapy ◽  
Anticancer Treatment ◽  
Gi Toxicity

13142 Background: Miltefosine (M) is an alkophosholipid with activity as a topical treatment for cutaneous breast cancer lesions. Severe GI toxicity limited its development as a systemic anticancer treatment. P is an equipotent derivative of M with less GI toxicity, but nausea,(N), vomiting (V) & diarrhea (D) are still dose limiting. Methods: This phase 1 study evaluated whether the addition of Pr would enhance the tolerability of P & T in combination. Twenty-five patients (pts) were enrolled. The dose of T was 75 mg/m2 on day 8 of a 21 day cycle and half of the pts were randomized to also receive Pr, 5 mg bid. 50 mg of P was given orally 1, 2 or 3 times a day in successive cohorts on days 1 - 14 of each cycle. Results: Disease sites included lung 9, prostate 7, pancreas 3, ovary 2, breast 1 and other 4. The median age was 63 (range 41 - 80). 18 pts were male & median ECOG performance status was 1 (range 0–2). 22 pts had received a median of 2 prior chemotherapy regimens, 15 a prior taxane and 16 prior radiotherapy. Forty-two cycles of T+P were given without Pr (median 3 & range 1 - 18 per pt) and 84 cycles were given with Pr (median 4.5 cycles & range 1 - 17 per pt). The percentage of pts experiencing various grades (Gr) of N, V & D without and with prednisone are shown in the table below: Five of 12 pts not receiving Pr had gr 2 or 3 toxicities compared to 1 of 13 given Pr. (p<0.05) There were 7 pts evaluable for response not receiving Pr of whom 2 patients with prostate cancer had stable disease for 4+ and 10+ months. There were 9 evaluable pts receiving Pr; 3 partial responses (1 lung & 2, prostate pts) were seen and 1 prostate cancer was stable for 10 months. Patients given prednisone increased their average time on treatment by 50%, and this might be the reason that more responses were seen in this group. Conclusions: These data show that Pr decreases the severity of GI toxicity seen with T & P together and provide a rationale for further studies evaluating the effects of Pr on the toxicities of P either alone or in combination with other drugs. [Table: see text] [Table: see text]

Results from a phase I study of enzalutamide in combination with docetaxel in men with prostate cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5066-5066
Author(s):  
Mark T. Fleming ◽  
Dana E. Rathkopf ◽  
Jackie Gibbons ◽  
Amy C. Peterson ◽  
Alison Hannah ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Phase I ◽  
Phase I Study ◽  
Performance Status ◽  
Safety Data ◽  
Primary Therapy ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status ◽  
Combination Methods

5066 Background: Enzalutamide (ENZA) is a novel androgen receptor (AR) inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC) who had received prior docetaxel (DOC). DOC also prolongs survival in mCRPC and also appears to have anti-tumor effects mediated through the androgen-receptor axis, providing a compelling rationale for combining the two agents. CYP3A4 plays a role in DOC clearance and is induced by ENZA. We therefore conducted a phase I study to explore the PK and safety profiles of this combination. Methods: This study (NCT01565928) evaluated the safety and pharmacokinetics (PK) of DOC co-administered with ENZA in men with mCRPC on androgen deprivation therapy. Pts received DOC (75 mg/m2) by 1-h infusion every 3 weeks with corticosteroids. ENZA (160 mg/d) was started 24 h after the first DOC infusion. Plasma PK samples were collected for 24 h after Cycle (C) 1 and C2 DOC infusions to enable within-subject comparisons of DOC PK ± ENZA. A sample size of 18 pts able to receive ≥ 2 full doses of DOC was specified for PK analyses. Results: Twenty-two pts were enrolled, 4 did not receive 2 full doses of DOC. As of 21 Sept 2012, preliminary PK and C1 and C2 safety data were available from 15 pts. The median age was 65 (range 46-80 yrs); 11 had ECOG performance status 1 (vs 0). Prior primary therapy included surgery (n=2), radiation (n=4) or both (n=5); median PSA was 44.7ng/mL (1.9-585). ANC<1000/mm3 was reported in 14 pts (1 febrile neutropenia), other adverse events in ≥4 pts included fatigue (11), dyspnea (6), alopecia (5), peripheral neuropathy (5), anemia (4) and dysgueusia (4). No seizures were reported. Preliminary PK data (n=15) show similar DOC exposure (within 20%) for DOC in combination with ENZA vs. DOC alone.Final PK and updated tolerability and efficacy data beyond Cycle 2 will be presented. Conclusions: In mCRPC pts, ENZA does not appear to affect tolerability of DOC or have a clinically meaningful impact on DOC PK. Clinical trial information: NCT01565928.

BEZ235 in combination with everolimus for advanced solid malignancies: Preliminary results of a phase Ib dose-escalation study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e13518-e13518 ◽  
Author(s):  
Mohamad Adham Salkeni ◽  
Olivier Rixe ◽  
Nagla Abdel Karim ◽  
Sue Ogara ◽  
Monica Feiler ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Dose Escalation ◽  
Mtor Inhibitor ◽  
Mononuclear Cells ◽  
Performance Status ◽  
Ecog Performance Status ◽  
Dose Escalation Study ◽  
Peripheral Blood Mononuclear ◽  
Phase Ib ◽  
Solid Malignancies

e13518 Background: The mammalian target of rapamycin (mTOR) is a critical signaling pathway in many tumors including cancers of the breast and colon, glioblastoma multiforme, and hepatocellular carcinoma (HCC). Preclinical studies demonstrated the combination of BEZ235, a competitive dual phosphatidylinositide 3-kinase (PI3K)/mTOR inhibitor, and the mTOR inhibitor, everolimus led to greater regression of a carcinogen-induced HCC than treatment with higher doses of either drug alone. Based on this, we initiated a study of BEZ235 combined with everolimus in patients with advanced solid tumors. Methods: A single institution phase Ib dose-escalation study. Patients with advanced solid malignancies, no available standard of care treatment option, and ECOG performance status 0-2 were eligible. Prior treatment with PI3K inhibitors was not allowed. Sequential cohorts of 3-6 patients were treated. The starting dose was everolimus 2.5 mg and BEZ235 200 mg daily in an oral sachet formulation. Cohort 2 received everolimus 2.5 mg and BEZ235 400 mg daily. Pharmacokinetic and pharmacodynamic studies were performed during the first cycle. The phosphorylation of specific downstream effectors of the mTOR pathway was assessed in peripheral blood mononuclear cells (PBMC). Results: Eleven patients, median age 58 (36-73 years) were treated. Tumors included non-small cell lung cancer, colon cancer, and glioblastoma, hepatocellular carcinoma, pancreatic cancer, esophageal cancer, adenoid cystic carcinoma of the larynx, and appendiceal carcinoma. Four patients were treated on cohort 1. None experienced dose-limiting toxicity. Seven patients were treated on the second dose cohort. One patient withdrew necessitating replacement and another developed grade 3 stomatitis from herpes virus requiring cohort expansion. The most common adverse events were thrombocytopenia, lymphopenia, transaminitis, diarrhea, nausea and fatigue. No tumor responses were noted. PBMC showed a decrease in 4E-BP1S65 phosphorylation on day 28 in 2 of 3 patients in cohort 1. Conclusions: The combination of BEZ235 and everolimus was well tolerated at these doses. The trial remains open to accrual. Clinical trial information: NCT01508104.

Tea tree oil presents in vitro antitumor activity on breast cancer cells without cytotoxic effects on fibroblasts and on peripheral blood mononuclear cells

2018 ◽  
Vol 103 ◽  
pp. 1253-1261 ◽  
Author(s):  
Charles Elias Assmann ◽  
Francine Carla Cadoná ◽  
Beatriz da Silva Rosa Bonadiman ◽  
Eduardo Bortoluzzi Dornelles ◽  
Gabriela Trevisan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Antitumor Activity ◽  
Breast Cancer Cells ◽  
Mononuclear Cells ◽  
Tea Tree Oil ◽  
Peripheral Blood Mononuclear ◽  
Cytotoxic Effects ◽  
Tea Tree ◽  
Blood Mononuclear Cells

Phase I trial of a sequence-specific combination of the HDAC inhibitor, vorinostat (SAHA) followed by doxorubicin in advanced solid tumor malignancies

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3502-3502 ◽  
Author(s):  
A. Daud ◽  
M. Schmitt ◽  
D. Marchion ◽  
E. Bicaku ◽  
S. Minton ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patient ◽  
Phase I ◽  
Histone Acetylation ◽  
Phase I Trial ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells ◽  
Grade 3 ◽  
Topo Ii

3502 Background: Preclinical cell culture and xenograft studies suggest that pre-exposure of cancer cells to a histone deacetylase inhibitor (HDACi) may potentiate topoisomerase (topo) inhibitors. The HDACi-induced histone acetylation and chromatin modulation facilitates DNA access and target recruitment for topo II inhibitors. Methods: This Phase I trial explores the safety, tolerability and maximum tolerated dose (MTD) of a weekly schedule of escalating vorinostat doses (twice daily days 1–3) followed by doxorubicin (20 mg/m2) on day 3 (3 out of 4 weeks). Histone acetylation and topo II expression are evaluated in pre-and post-vorinostat peripheral blood mononuclear cells and in tumor cells of the 30 patients treated at the MTD. Results: To date, 15 patients [median age 54 (38–73)] have been treated in 4 vorinostat cohorts: 200, 300, 400, 500 mg bid. Tumor types included: breast (3), melanoma (3), pancreatic (2) and one each of SCLC, sarcoma, endometrial, colon, prostate, renal cell and bladder cancer. Dose-limiting toxicities included a grade 3 thrombocytopenia (1/6) at the 400 mg bid dose. Non-dose limiting Grade 3 and 4 toxicities include neutropenia, thrombocytopenia, fatigue, pulmonary embolus, and anemia (1 pt each). Currently, vorinostat doses of 500 mg bid are being evaluated. One confirmed partial response in a breast cancer patient, as well as minor responses in a melanoma and a prostate cancer patient were seen in 10 evaluable patients. Patients received a median number of 2 (1–9+) treatment cycles. Doxorubicin is stopped after 6 cycles and patients continue on vorinostat alone. H3 and H4 histone acetylation and topo II expression will be correlated with vorinostat dose, plasma concentration and response. Conclusion: A sequence-specific combination of vorinostat and doxorubicin is active without exacerbation of doxorubicin toxicity. The tolerated vorinostat dose exceeds the proposed single agent dose for vorinostat derived from patients with hematological malignancies. Histone hyperacetylation occurs in peripheral blood mononuclear cells at all levels. The anti-tumor activity in breast cancer and melanoma will be further explored. No significant financial relationships to disclose.

ARN-509 in men with high-risk nonmetastatic castration-resistant prostate cancer (CRPC).

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 7-7 ◽  
Author(s):  
Matthew Raymond Smith ◽  
Emmanuel S. Antonarakis ◽  
Charles J. Ryan ◽  
William R. Berry ◽  
Neal Shore ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Phase I ◽  
Phase Ii ◽  
Nuclear Translocation ◽  
Performance Status ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status ◽  
Psa Response ◽  
Psa Progression

7 Background: ARN-509 is a novel second-generation anti-androgen that binds directly to the ligand-binding domain of the androgen receptor, impairing nuclear translocation and DNA binding. The Phase II portion of a multicenter Phase I/II study is evaluating the activity of ARN-509 in 3 distinct patient populations of men with CRPC (high risk non-metastatic CRPC, metastatic treatment-naïve CRPC, and progressive disease after abiraterone acetate). Preliminary results for the cohort of patients with high-risk non-metastatic CRPC are presented here. Methods: All patients had CRPC, no radiographic evidence of metastases (pelvic lymph nodes <3 cm below the iliac bifurcation were allowed), and high risk for disease progression based on PSA value ≥ 8 ng/mL within 3 months of enrollment and/or PSA doubling time ≤ 10 months. Patients received ARN-509 at the recommended Phase II dose of 240 mg/day, previously established in Phase I (Rathkopf et al, GU ASCO 2012). The primary endpoint was PSA response rate at 12 weeks according to the Prostate Cancer Working Group 2 Criteria. Secondary endpoints included safety, time to PSA progression and 1-year metastasis-free survival. PSA assessments were collected every 4 weeks and tumor scans were performed every 16 weeks. Results: Forty-seven patients were enrolled between November 2011 and May 2012. The median age was 71 years (range 51 to 88) and at baseline, patients presented with ECOG performance status 0 (77%), Gleason Score 8-10 (32%), and median PSA of 10.7 ng/mL. All patients received prior treatment with a LHRH analog with or without a first-generation anti-androgen. At a median treatment duration of 20 weeks, three patients discontinued the study. The most common treatment-related adverse events (AE) were fatigue (30%), diarrhea (28%), nausea (17%), rash (13%), and abdominal pain (11%). The incidence of Grade 3 AEs was 6.4%, and no seizures have been observed to date. The 12-week PSA response was 91% and the time to PSA progression has not been reached. Conclusions: In men with high-risk non-metastatic CRPC, ARN-509 is safe and well tolerated with promising preliminary activity based on high PSA response rates. Clinical trial information: NCT01171898.

scholarly journals Phase 1 study of M2698, a p70S6K/AKT dual inhibitor, in patients with advanced cancer

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Apostolia-Maria Tsimberidou ◽  
Jamie V. Shaw ◽  
Dejan Juric ◽  
Claire Verschraegen ◽  
Amy M. Weise ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Cancer ◽  
Mononuclear Cells ◽  
Phase 1 ◽  
Performance Status ◽  
Tumor Therapy ◽  
Objective Response ◽  
Therapy Resistance ◽  
Peripheral Blood Mononuclear ◽  
Dual Inhibitor

Abstract Background The PI3K/AKT/mTOR (PAM) pathway is a key regulator of tumor therapy resistance. We investigated M2698, an oral p70S6K/AKT dual inhibitor, in patients with advanced cancer who failed standard therapies. Methods M2698 was administered as monotherapy (escalation, 15–380 mg daily; food effect cohort, 240–320 mg daily) and combined with trastuzumab or tamoxifen. Results Overall, 101 patients were treated (M2698, n = 62; M2698/trastuzumab, n = 13; M2698/tamoxifen, n = 26). Patients were predominantly aged < 65 years, were female, had performance status 1 and were heavily pretreated. There was a dose- and concentration-dependent inhibition of pS6 levels in peripheral blood mononuclear cells and tumor tissue. M2698 was well tolerated; the most common treatment-emergent adverse events were gastrointestinal, abnormal dreams and fatigue (serious, attributed to M2698: monotherapy, 8.1%; M2698/trastuzumab, 7.7%; M2698/tamoxifen, 11.5% of patients). The recommended phase 2 doses of M2698 were 240 mg QD (monotherapy), 160 mg QD (M2698/trastuzumab) and 160 mg QD/240 mg intermittent regimen (M2698/tamoxifen). In the monotherapy cohort, 27.4% of patients had stable disease at 12 weeks; no objective response was noted. The median progression-free survival (PFS) durations in patients with PAM pathway alterations with and without confounding markers (KRAS, EGFR, AKT2) were 1.4 months and 2.8 months, respectively. Two patients with breast cancer (M2698/trastuzumab, n = 1; M2698/tamoxifen, n = 1) had partial response; their PFS durations were 31 months and 2.7 months, respectively. Conclusions M2698 was well tolerated. Combined with trastuzumab or tamoxifen, M2698 demonstrated antitumor activity in patients with advanced breast cancer resistant to multiple standard therapies, suggesting that it could overcome treatment resistance. Trial registration ClinicalTrials.gov, NCT01971515. Registered October 23, 2013.

Dasatinib plus capecitabine (Cap) for progressive advanced breast cancer (ABC): Phase I study CA180004

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1012-1012
Author(s):  
G. Somlo ◽  
F. Atzori ◽  
L. Strauss ◽  
A. Rybicki ◽  
X. Wu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Phase Ii ◽  
Performance Status ◽  
Combined Treatment ◽  
Breast Cancer Cell Lines ◽  
Ecog Performance Status ◽  
Grade 3 ◽  
Study Laboratory

1012 Background: SRC family kinases (SFK) mediate numerous signal-transduction pathways relevant to breast cancer as well as osteoclast function. Dasatinib, a potent oral inhibitor of SFK and other kinases has preclinical activity in breast models and in vitro synergy with Cap in some breast cancer cell lines (KPL-4 and HCC-70). A phase I trial of dasatinib plus Cap was conducted to define dose-limiting toxicities (DLT), maximum tolerated (MTD), and recommended phase II (RP2D) doses. Methods: Sequential cohorts of pts with ABC were treated with Cap twice daily (BID) on days 1–14 and dasatinib daily in 21-day cycles using dose levels (DL) for Cap (mg/m2) and dasatinib (mg): DL1: Cap 825 + dasatinib 50 BID; DL2: Cap 825 + dasatinib 70 BID; DL3: Cap 1000 + dasatinib 70 BID; DL3a: Cap 1000 + dasatinib 100 once daily (QD). All pts had ECOG performance status 0–1, had prior anthracycline and/or taxane, and received ≤2 regimens in advanced setting. MTD was based on DLT in first cycle and RP2D also based on tolerability of additional cycles. Results: 31 pts with ABC, median age 53 years (range 36–78) were treated. Number of pts treated/evaluable for DLT/reported DLT (event) were DL1: 7/6/1 (headache, grade 3); DL2: 9/7/0; DL3: 6/6/1 (diarrhea, grade 3), and DL3a: 9/9/1 (pneumonia, grade 3). Most frequent AEs related to either drug and occurring at any time on study (n pts) were nausea (12), vomiting (7), diarrhea (6), abdominal pain (2), fatigue (8), headache (7), musculoskeletal pain (1), and pleural effusion (4); hand-foot syndrome (5) was as expected for Cap alone. 11 patients experienced a Grade 3–4 non-hematologic AE at some point during the study. Laboratory abnormalities were uncommon. To date, 20 pts have continued treatment for ≥6 weeks and 9 pts for ≥12 weeks. Number of pts who (at any time) reduced dasatinib/reduced Cap/discontinued for toxicity were DL1: 2/2/1; DL2 2/2/3; DL3: 2/1/2; DL3a: 0/1/1. Updated safety and efficacy data will be presented. Conclusions: Dasatinib + Cap was tolerated without unexpected combined-treatment toxicity; few pts required dose reduction in later cycles. The recommended phase II dose, Cap 1000 plus dasatinib 100 QD, is well tolerated and will be studied for efficacy in an expanded patient cohort. [Table: see text]

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