Romidepsin (HDACi) plus cisplatin and nivolumab triplet combination in patients with metastatic triple negative breast cancer (mTNBC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1076-1076
Author(s):  
Priyanka Sharma ◽  
Vandana G Abramson ◽  
Anne O'Dea ◽  
Lauren Elizabeth Nye ◽  
Ingrid A. Mayer ◽  
...  
Keyword(s):  
Liver Metastasis ◽  
Phase I ◽  
Phase Ii ◽  
Histone Deacetylase Inhibitors ◽  
Objective Response ◽  
Common Grade ◽  
Group 2 ◽  
Grade 3 ◽  
Recognition And Response ◽  
Minimax Design

1076 Background: Histone deacetylase inhibitors (HDACi) upregulate genes involved in antigen presentation machinery and increase expression of natural killer group 2, member D ligands (NKG2DL), thus resulting in enhanced tumor cell recognition and response to PD-1/CTLA-4 blockade. Cisplatin and HDACi combination synergistically induces cytotoxicity, apoptosis, and DNA damage. This phase I-II trial investigated combination of romidepsin (HDACi) plus cisplatin and nivolumab (PD-1 inhibitor) in mTNBC. Patients and Methods: Eligible patients had mTNBC with any number of prior chemotherapies. Phase I was 3+3 dose-escalation design with three dose levels of romidepsin (8, 10, 12mg/m2, D2, 9) plus cisplatin 75mg/m2 D 1 every 21 days. Phase II treatment included romidepsin plus cisplatin plus nivolumab 360mg every 21 days and was designed according to Simon’s two stage minimax design. Primary endpoints were recommended phase 2 dose (RP2D) and objective response rate (ORR). Additional endpoints included safety, PFS, and pharmacokinetics. Results: 51 patients were enrolled (N=13 phase I, N=38 phase II) between 2015-2020. 69% had received ≥1 prior metastatic chemotherapy, 47% had prior platinum, 53% had liver metastasis, 12% had BRCA1/2 mutation, and 11% had PD-L1 positive disease. There were no dose limiting toxicities in phase I. The RP2D was romidepsin 12mg/m2 D2,9 + cisplatin 75mg/m2 D1 + nivolumab 360mg D1 every 21 days. Thrombocytopenia (G3:27%, G4:0%), neutropenia (G3:25%, G4:0%), anemia (G3:22%, G4:0%), nausea (G3:22%, G4:0%), and vomiting (G3:20%, G4:0%) were the most common grade 3/4 adverse events. 21% of patients had immune AEs (G3-4:8%). Among 34 evaluable phase II patients, ORR was 44% (Table), median PFS was 4.4 months, and 1-year PFS was 23%. Median OS was 10.3 months and 1-year OS was 43%. No pharmacokinetic interactions were detected with co-administration of romidepsin-cisplatin-nivolumab. Conclusions: The triplet combination of romidepsin plus cisplatin and nivolumab was well tolerated and shows encouraging efficacy in pretreated mTNBC, including in patients with PD-L1 negative disease and in those with liver metastasis. Correlative biomarker work is ongoing. This combination warrants further evaluation in larger studies. Clinical trial information: NCT02393794 .[Table: see text]

Phase I/II study of oral fluoropyrimidine S-1 plus oral Leucovorin as first-line treatment for metastatic colorectal cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4093-4093 ◽  
Author(s):  
T. Yoshino ◽  
W. Koizumi ◽  
K. Yamaguchi ◽  
Y. Miyata ◽  
T. Kato ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Phase I ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Objective Response ◽  
Oral Fluoropyrimidine ◽  
Common Grade ◽  
Secondary Endpoints ◽  
Adequate Organ Function ◽  
Grade 3

4093 Background: The results of phase I portion of the treatment with the oral S-1 (a new oral fluoropyrimidine) plus oral leucovorin (LV) in patients (pts) with untreated metastatic colorectal cancer (mCRC) was reported at ESMO 2006. Dose limiting toxicities (DLTs) were grade 3 stomatitis/pharyngitis, nausea, diarrhea, ileus and exanthema. The recommended doses (RDs) for this phase II portion were determined to be S-1 40 mg/m2 and LV 25 mg/body orally given twice daily on days 1 to 14 of a 28-day cycle. The PK profiles of S-1 plus LV were similar to those of S-1 monotherapy and UFT plus LV, respectively. The main purpose of this phase II portion is to evaluate the efficacy and safety of S-1 plus LV at RD level in pts with untreated mCRC. Methods: Pts were eligible as follows; unresectable mCRC with no prior chemotherapy or receiving adjuvant chemotherapy completed at least 6 months before, histologically proven adenocarcinoma, PS(ECOG) 0–2, age 20 to 75, measurable lesions, adequate organ function and written informed consent. The pts received 40 mg/m2 of S-1 plus 25 mg/body of LV twice daily as RD in this phase II portion. The primary endpoint was the objective response rates (RRs), and secondary endpoints were time to progression (TTP) and toxicities. Results: Between Sep 2004 and Jun 2006, 56 pts of 65 enrolled pts received the treatment at RD level. The objective RRs were 55% (36 of 65) for all pts and 55% (31 of 56) for pts at RD. Disease control rates (DCRs) were 86% (56 of 65) for all pts and 86% (48 of 56) for pts at RD. Median TTP was 5.5 months for pts at RD, with a median follow-up of 5.5 months. The median survival time is under observation. During the 6 months from starting the treatment, the most common grade 3/4 toxicities at RD were as follows: diarrhea, 23%; stomatitis, 20%; anorexia, 18%; and neutropenia 13%. Conclusions: A combination of S-1 plus oral LV is an effective, well tolerated, and convenient regimen in pts with untreated mCRC, without the addition of either oxaliplatin or irinotecan. The updated results of the objective RRs, DCRs, TTP reviewed extramurally, and detailed safety profile will be presented at the meeting. This trial was supported by Taiho pharmaceutical co., Ltd., Tokyo, Japan. No significant financial relationships to disclose.

Final Results of ECOG1100: A phase I/II study of combined blockade of the ErbB receptor network in patients with HER2- overexpressing metastatic breast cancer (MBC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1033-1033 ◽  
Author(s):  
S. L. Moulder ◽  
A. O’Neill ◽  
C. Arteaga ◽  
M. Pins ◽  
J. Sparano ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Cell Lines ◽  
Dose Level ◽  
Phase Ii ◽  
Prior Exposure ◽  
Prior Chemotherapy ◽  
Group 2 ◽  
Grade 3 ◽  
Group 1

1033 Background: Activation of EGF receptor has been associated with resistance to trastuzumab in breast cancer cell lines. EGFR tyrosine kinase inhibitors inhibit HER2 phosphorylation and synergize with trastuzumab in HER2+ cell lines that co-express EGFR. Methods: Pts with MBC and HER2 overexpression by immunohistochemistry (3+) and/or HER2 gene-amplification by FISH, 0–2 prior chemotherapy regimens for met disease, LVEF 50%, and no prior trastuzumab were treated with trastuzumab 2 mg/kg/wk and gefitinib 250- 500 mg/day until disease progression, unacceptable toxicity or withdrawal of consent. The phase I portion of the trial used a 3+3 design to determine MTD. In the phase II portion of the trial, patients were stratified based upon prior chemotherapy exposure (Group 1= no prior exposure to chemotherapy, Group 2= prior exposure to 1–2 chemotherapy regimens). Response measured using RECIST criteria. The primary endpoint was to increase proportion progression free from 50 to 65% at 6 months in Group 1 and from 50 to 70% at 3 months in Group 2. Results: Phase I: DLT (Grade 3 diarrhea) occurred in 2/3 patients treated at the 500 mg/day dose level of gefitinib in combination with weekly trastuzumab. 0/3 patients treated at the 250 mg/day dose level experienced DLT. This was considered MTD and was the dose selected for the Phase II portion of the trial. Phase II: 36 eligible pts were enrolled. Most patients were ECOG PS of 0 and had visceral organ involvement. Of the patients enrolled in Group 1, one pt achieved a CR, one PR and 7 had SD (≥ 24 weeks). Median time to progression (TTP) was 2.9 months (95% CI, 2.5–4). In Group 2 no responses were observed with a median TTP of 2.5 months (95% CI, 1.5- 2.7). Most common severe toxicities were rash (grade 3, 14%) and diarrhea (grade 3, 30%). No grade 3 cardiac toxicity was encountered. Conclusions: Trastuzumab in combination with gefitinib at doses of 250 mg/day demonstrated an acceptable toxicity profile; however, during planned interim analysis, the TTP did not meet predetermined statistical endpoints required for study continuation. These results do not support the further use of this combination and have implications for other trials using trastuzumab and EGFR TK inhibitors simultaneously. [Table: see text]

A single-arm, open-label, multicenter phase I/II study of the combination of panobinostat (pan) and carfilzomib (cfz) in patients (pts) with relapsed/refractory multiple myeloma (RR MM).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS8115-TPS8115
Author(s):  
Jesus G. Berdeja ◽  
Joseph Mace ◽  
Ruth E. Lamar ◽  
Victor Gian ◽  
Patrick Brian Murphy ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Histone Deacetylase Inhibitors ◽  
Standard Dose ◽  
Objective Response ◽  
Progression Free Survival ◽  
Response To Treatment ◽  
Current Status ◽  
Open Label ◽  
Starting Dose

TPS8115 Background: Despite novel therapies, MM remains an incurable disease. Changes in histone modification are commonly found in human cancers including MM. Preclinical studies demonstrate synergistic anti-MM activity with histone deacetylase inhibitors (HDACi) and proteasome inhibitors (PI) through the dual inhibition of the proteasome and aggresome pathways. Pan is an oral pan-HDACi which has shown synergy with bortezomib in clinical studies. Cfz is a 2nd generation PI which has shown marked anti-MM activity with an improved safety profile. In this trial we evaluate the safety and efficacy of the combination of pan and cfz in pts with RR MM. Methods: This multi-center US study plans to enroll up to 52 adults with RR MM. The phase I study will determine the MTD of the combination of cfz and pan and follow a standard dose escalation design. Pan will be administered orally three times weekly during weeks 1 and 3 of each 28-day cycle (Days 1, 3, 5, 15, 17, 19) at a starting dose of 20 mg. Cfz will be administered intravenously on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Cfz starting dose will be 20mg on days 1,2 of cycle 1 with escalation to the corresponding dose level beginning at 27 mg , if well tolerated. Dose modifications will not be permitted during cycle 1 unless a pt experiences a DLT. A maximum of four dose levels will be evaluated. Approximately 24 pts will be enrolled during the phase I portion to establish the MTD. In the phase II portion of this study, pts with RR MM will receive treatment with the optimal dose of pan and cfz established during phase I. Pts will be assessed for response to treatment after each cycle (4 weeks). Pts with objective response or stable disease will continue treatment until disease progression or unacceptable toxicity occurs. The primary endpoint is to establish the optimal doses of cfz and pan that can be administered to pts with RR MM (phase I) and to evaluate the overall response rate (phase II). Secondary endpoints include time-to-progression, progression-free survival, overall survival and safety. Approximately 25 pts are planned for the phase II portion. Current status: As of 1/27/12 3 patients have been enrolled.

Scoop: Multicenter phase I/II trial of BBI608 and pembrolizumab in patients with metastatic colorectal cancer (EPOC1503).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 107-107 ◽  
Author(s):  
Hiroki Hara ◽  
Akihito Kawazoe ◽  
Yasutoshi Kuboki ◽  
Yoshito Komatsu ◽  
Tomohiro Nishina ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Partial Response ◽  
Phase I ◽  
Metastatic Colorectal Cancer ◽  
Sample Size ◽  
Phase Ii ◽  
Objective Response ◽  
Alternative Hypotheses ◽  
Grade 3 ◽  
Recommended Phase Ii Dose

107 Background: The anti–PD-1 antibody pembrolizumab (P) provides response rates of 28-57% in patients (pts) with MSI-H metastatic colorectal cancer (mCRC) vs 0% in those with non-MSI-H cancers. STAT3 has been previously reported as a potential key driver of immune evasion. This study investigates efficacy and safety for the combination of BBI608 (napabucasin), which blocks phosphorylated STAT3 and downregulates IDO1 and PD-L1, with P, in pts with mCRC. BBI608 480 mg BID with P was determined as the recommended phase II dose in phase I. Methods: Phase II included Cohorts A (MSI-H) and B (non-MSI-H). Pts with mCRC not responding to or intolerant of standard chemotherapies were enrolled. The primary endpoint was immune-related objective response rate (irORR), according to irRECIST. The sample size for Cohort A (10 pts) was derived in an exploratory manner. In Cohort B, assuming null and alternative hypotheses of irORR = 5% and 20% led to an estimated required sample size of 40 pts, with a 1-sided alpha of 5% and power of 90%. Genomic profiles and the consensus molecular subtypes (CMS) of colorectal cancer were determined by whole exome sequencing and RNA sequencing as previously described. Results: From Feb/2017 to Jun/2018, 10 pts were enrolled in Cohort A and 40 in Cohort B. The irORR was 50% (5 of 10 pts) in Cohort A and 10% (95% CI 2.8 to 23.7) (4 of 40 pts) in Cohort B. Of evaluable 19 pts for CMS classification in Cohort B, CMS1, CMS2, CMS3, and CMS4 were detected in 3, 6, 4, and 6 cases, respectively. The irORR was 33% (1 of 3 pts), 0% (0 of 6 pts), 25% (1 of 4 pts), 33% (2 of 6 pts) in CMS1, CMS2, CMS3, and CMS4, respectively. One CMS3 patient with partial response had POLE mutation, while 1 CMS1 and 2 CMS4 pts with partial response did not. The most common grade 3 or higher treatment-related adverse events included fever (10%) in Cohort A, and diarrhea (5%) and appetite loss (7.5%) in Cohort B, without unexpected safety signals. No treatment-related deaths occurred. Conclusions: BBI608 with P showed encouraging anti-tumor activity with acceptable toxicity for non-MSI-H mCRC pts as well as MSI-H mCRC pts. Impact of CMS on the efficacies of this combination warrants further investigation in the additional cohort of this study. Clinical trial information: NCT02851004.

Stage III non small lung cancer (NSCLC): Docetaxel (D), gemcitabine (G), and cisplatin (C) as induction chemotherapy, an Italian phase I study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18201-18201
Author(s):  
S. De Santis ◽  
V. Donato ◽  
M. R. Migliorino ◽  
B. Tedesco ◽  
S. Condo ◽  
...  
Keyword(s):  
Phase I ◽  
Induction Chemotherapy ◽  
Phase Ii ◽  
Phase I Study ◽  
Objective Response ◽  
Stage Iii ◽  
Stage Iiia ◽  
Phase Ii Studies ◽  
Stage Iii Nsclc ◽  
Grade 3

18201 Background: Based on the several clinical trials, combined modality therapy became the standard of care for patients with stage III NSCLC “unresectable” with good performance status (Kathy S. Albain, Educational Book ASCO 2006, 453–461; Thomas E. Stinchcombe, Oncologist 2006, 11, 809–823). The most effective induction chemotherapy has yet to be determined. The objective of this prospective phase I study was to define the maximum tolerated dose (MTD), and to evaluate the activity and safety of one of the third generation triplets as a full dose neoadjuvant regimen in patients (pts) with unresectable Stage III NSCLC. Methods: In this study, chemotherapy-naïve pts with stage IIIA-N2 bulky and IIIB (except malignant pleural effusion) NSCLC were eligible. Inclusion into the trial and treatment decisions were done by multidisciplinary panel involving surgeons, medical oncologists and radiotherapists. All drugs were given intravenously on days 1 and 8, and repeated every 3 weeks up to 2 cycles followed by concurrent chemoradiation. D (30–35 mg/m2) was given first, followed by C (35 mg/m2) and G (1000 mg/m2). Results: From Jan ‘06 to Jul ‘06 twelve eligible pts were enrolled, 10/2 m/f gender; median age 63 (50–72), 1 patient with ECOG PS 0, 11 pts with PS 1; 5 pts with stage IIIA-N2 bulky, 7 pts with stage IIIB NSCLC; nine pts were smokers. All pts were evaluable for toxicity. Toxicity grade 3–4 by CTC criteria was: grade 3 neutropenia in 2/3 patients and grade 3 thrombocytopenia in 1/3 patients on the second dose level of chemotherapy (i.e. docetaxel 35 mg/m2), and was considered dose-limiting. Of 9 pts treated at the MTD (i.e. docetaxel 30 mg/m2), only 1 patient developed grade 4 neutropenia and 1 patient grade 3 thrombocytopenia; 3 patients (30%) had grade 2 neutropenia and grade 2 stomatitis. Of 12 evaluable pts for response, after induction chemotherapy eighty-three percent of patients (9/12 pts) had an objective response and 16,6% (2/9 pts) stable disease. Phase II is continuing for larger patient accrual. Conclusions: The recommended doses for further phase II studies are D (30 mg/m2) followed by C (35 mg/m2) and G (1000 mg/m2) every 3 weeks. This regimen is well tolerated and effective, and appears to be an excellent choice for stage III NSCLC. No significant financial relationships to disclose.

Natural history of diarrhea associated with the anti-CTLA4 monoclonal antibody CP-675,206

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3038-3038 ◽  
Author(s):  
S. Antonia ◽  
J. Sosman ◽  
J. M. Kirkwood ◽  
B. Redman ◽  
T. F. Gajewski ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Dose Range ◽  
Objective Response ◽  
Stage Iv ◽  
Open Label ◽  
Similar Frequency ◽  
Severe Diarrhea ◽  
Grade 3 ◽  
Stage Iv Melanoma

3038 Background: Diarrhea resulting from immune activation has been associated with CTLA4 blockade. For example, in patients (pts) with stage IV melanoma receiving ipilimumab (MDX-010), a number of pts developed grade 3/4 autoimmune enterocolitis and severe diarrhea (Attia et al, 2005). In a single-dose phase I trial of CP-675,206 at doses up to 15 mg/kg in pts with solid tumors (n = 39), 9 instances of diarrhea were reported including 3 grade 3 events (Ribas et al, 2005). The incidence and severity of diarrhea was assessed in pts receiving CP- 675,206 in a large phase I/II study. Methods: An open-label phase I/II trial of CP-675,206 was conducted in pts with stage III (unresectable) or stage IV melanoma and an ECOG PS = 1. Diarrhea was assessed in pts treated at the phase II doses: 10 mg/kg monthly (Q1M) in phase I (n = 22), or 10 mg/kg Q1M (n = 44) or 15 mg/kg every 3 months (Q3M, n = 45) in phase II. Results: Medians of 3.5 doses (range, 1 to 18) at 10 mg/kg Q1M in phase I, 3 doses (range, 1 to 26) at 10 mg/kg Q1M in phase II, and 1 dose (range, 1 to 9) at 15 mg/kg Q3M were administered with 100% dose compliance. Treatment-related diarrhea was reported by 43 (39%) of 111 pts, and grade 3 diarrhea occurred in 14 (13%) pts. One patient had grade 4 colitis resulting in a colectomy. Diarrhea (all grades) occurred with similar frequency in each dose group; however, grade 3 treatment-related diarrhea occurred in 8% of pts treated with 15 mg/kg Q3M compared with 18% of pts treated with 10 mg/kg Q1M in phase I and 14% of pts treated with 10 mg/kg Q1M in phase II. Among 9 pts with an objective response, 8 experienced diarrhea (3 of which were grade 3). The majority of cases (65%) were mild to moderate in severity with a median time to onset of 51 days (range, 1 to 583 days) and resolution of 8 days (range, 1 to 182 days). More than half of pts who reported serious events of diarrhea were treated with steroids. Conclusions: Diarrhea associated with CP-675,206 was primarily mild to moderate in severity, transient, and manageable. In addition, 15 mg/kg Q3M may be better tolerated than 10 mg/kg Q1M. Ongoing clinical trials in pts with advanced melanoma will provide further information about the incidence, severity, and optimal management of diarrhea associated with CP-675,206. No significant financial relationships to disclose.

Phase I study of the IXO regimen, irinotecan (I), capecitabine (X), oxaliplatin (O), as first-line therapy for metastatic colorectal cancer: Final survival results

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4082-4082
Author(s):  
J. Maroun ◽  
D. Jonker ◽  
C. Cripps ◽  
R. Goel ◽  
T. Asmis ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Phase I ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Line Treatment ◽  
First Line ◽  
Common Grade ◽  
Grade 3 ◽  
Ecog Ps ◽  
First Line Treatment

4082 Background: This study was designed to determine the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and efficacy of the IXO regimen when used as first-line treatment for metastatic colorectal cancer (mCRC). Methods: Patients with ECOG PS 0–2, histologically proven, chemo-naïve, non-resectable mCRC were eligible. Phase I starting doses were as follows: I (180 mg/m2 i.v.) d1, X (850 mg/m2 bid orally) d2–15, O (85 mg/m2 i.v.) d1; q3w. Dose escalation (3+3 design) was based on toxicity observed at previous dose levels (DL) until DLT and the MTD were reached. Results: 39 pts (31 male/8 female, median age 58 years, ECOG PS 0–1 in 37, 95%) received a median of 11 cycles (range 1–34) at 8 DLs. 39 pts were evaluable for toxicity. The most common grade 3/4 hematological adverse events (AEs) were granulocytopenia (60%) and fever/febrile neutropenia (18%). The most common grade 3 non-hematological AEs were diarrhea (15%), vomiting (10%), fatigue (8%). No grade 3/4 neuropathy was reported. DLTs: 1 DLT was observed at each of the first 4 DLs, no DLTs at DL5 & 6, 1 at DL7 and 2 at DL8. MTD was reached at DL8. The recommended phase II dose (DL7) is as follows: I (160 mg/m2), X (950 mg/m2), O (100 mg/m2). Efficacy: 38 pts are evaluable for efficacy. The RR is 74% (95% CI 60–89), including 4 CRs, 25 PRs and 6 SDs. The disease control rate is 90% (95% CI 80–100). 10 (26%) pts had subsequent liver surgery with curative intent; 1 had lung resection. Median progression-free survival was 12.3 months (95% CI, 8–17). Overall median survival was 26.4 months (95% CI, 13–36). Conclusions: Diarrhea is the main DLT. Severe neutropenia was of short duration and manageable. The IXO regimen is well tolerated and highly effective as first-line treatment for mCRC. It appears to be particularly effective in downsizing of initially unresectable colorectal cancer liver metastases. A phase II study to confirm the efficacy/safety of IXO in combination with bevacizumab (Avastin) is ongoing. Supported by: Hoffmann La-Roche, Sanofi-Aventis, Pfizer Canada. [Table: see text]

scholarly journals Anlotinib, vincristine, and irinotecan for advanced Ewing sarcoma after failure of standard multimodal therapy: A multicenter, two-cohort, phase Ib/II trial (NCT03416517).

2019 ◽  
Vol 5 (suppl) ◽  
pp. 118-118
Author(s):  
Jie Xu ◽  
Lu Xie ◽  
Wei Guo ◽  
Xin Sun ◽  
Kuisheng Liu ◽  
...  
Keyword(s):  
Phase Ii ◽  
Ewing Sarcoma ◽  
Initial Level ◽  
Objective Response ◽  
Complete Response ◽  
Fixed Dose ◽  
Phase Ib ◽  
Common Grade ◽  
Grade 3 ◽  
Patients Experience

118 Background: Both protracted irinotecan and anti-angiogenesis therapy have shown promising results in Ewing sarcoma. We did this phase Ib/II trial to first define the proper dose of irinotecan in combination with anlotinib in Ewing sarcoma (phase Ib) and then evaluate efficacy (phase II). Methods: Patients diagnosed with recurrent or refractory Ewing sarcoma were enrolled and sub-classified into cohort A (≥16y) or cohort B ( < 16y). In the dose-defining phase Ib portion, anlotinib was given at a fixed dose of 12mg D1-14 every 21 days, while the de-escalated 3+3 design was used to detect the recommended dose of irinotecan in each cohort from an initial level of 20mg/m2/d dx5x2. Recommended phase 2 dose (RP2D) was defined as the highest dose at which no more than 30% patients experience a DLT in the first two courses. In the next dose-expanding phase II portion, the primary endpoint was objective response rate at 12 weeks (ORR12w). Results: 41 patients were finally enrolled with 29 in cohortA and 12 in cohortB. For cohortA, first 5 patients were treated at initial level in phase Ib portion, two of whom subsequently experienced delayed diarrhea as dose-limiting toxicity (DLT). Additional six patients were then treated at a lower dose of 15mg/m2. Since no more DLT was recorded, it was used as RP2D. 23/24 patients in cohort A phase II were available for response evaluation at 12 weeks, with one complete response (CR), 14 partial response (PR) , 2 stable disease (SD) and 6 progressive disease (PD). ORR12wwas 62.5%. For cohort B, no DLT was noticed in the first six patients treated at the initial level which was used as RP2D later. Finally, 12 patients were included in cohort B. ORR12wwas 83.3% with two CR, 8 PR and two PD. Although effective, cohort B were closed because of slow enrollment. Most common grade 3/4 adverse events were leukopenia (28.5%), neutropenia (24.4%), anemia (8.7%) and diarrhea (3.7%). The genotype of UGT1A1*1 and UGT1A1*28 were not associated with the risk of diarrhea. Conclusions: The combination of irinotecan and anlotinib demonstrated an acceptable toxicity profile with promising evidence of clinical efficacy in advanced Ewing sarcoma. Clinical trial information: NCT03416517.

Multicentric phase II trial of gemcitabine plus capecitabine combination in the treatment of previously anthracycline(An)-treated metastatic breast cancer (MBC): SOLTI 0301 study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1051-1051 ◽  
Author(s):  
E. M. Ciruelos ◽  
J. Baselga ◽  
H. Cortes-Funes ◽  
A. Lluch ◽  
J. I. Mayordomo ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Objective Response ◽  
Metastatic Breast ◽  
Hematological Toxicity ◽  
Clinical Activity ◽  
Her2 Overexpression ◽  
Group 2 ◽  
Grade 3 ◽  
Group 1

1051 Background: Based on clinical activity of capecitabine(C) and gemcitabine (G) on the treatment of MBC, we performed a multicentric phase II trial of the combination to test its efficacy and safety profile. Methods: Sample size of 72 evaluable MBC patients (pts) previously An-treated (neoadjuvant 8%, adjuvant 69%, advanced 30%). Median age: 59 years (35–76 years). Estrogen Receptor positive: 47 (65%). HER2 overexpression: 16 (22%). Prior hormonal/trastuzumab allowed. Soft tissue/ganglionar/pleural/bone disease: 19 (26%); visceral metastasis: 53(74%). Stratification: previous chemotherapy (CT) for advanced disease (none: group 1; any: group 2). Study treatment: oral bid C 1,660 mg/m2/day (d) (d1–14) + iv G 1,000 mg/m2/d (d1&8). Cycles repeated every 3 weeks. RECIST/NCI-CTC 2.0 criteria. Primary end point: Objective Response Rate. Results: Response Rates and Clinical Benefit (CB) are detailed in the table . Median follow-up 7.2 months (m) (0.2–18.4). Median time to progression 11.2 m: group 1, 12 m (95%CI: 6.4–14.5); group 2, 8.9 m (95%CI: 6.9–14).Total and median administered cycles/pt: 479 and 8. Delayed cycles: 103(21.5%): 27% due to hematological toxicity, 11% due to non-hematological toxicity, 62% due to other causes. C dose reduced in 27 cycles (5.6%), 12 of them due to non- hematological toxicity. G dose reduced in 169 cycles (35%), mostly on day 8, and due to hematological toxicity (80% of reduced cycles). Grade 3–4 neutropenia: 32 pts (56%), 1 case of febrile neutropenia. Grade 3–4 non-hematological toxicities: asthenia 8 pts (14%), hand- foot syndrome 6 pts (10.5%), mucositis 3 pts (5%), diarrhea 2 pts (3.5%). Conclusions: Combination of C+G in the treatment of previously anthracycline-treated MBC is safe and active, with a manageable toxicity profile and a good clinical activity. [Table: see text] No significant financial relationships to disclose.

Alternating irinotecan with oxaliplatin combined with UFT plus leucovorin (LV) (SCOUT) in patients with advanced colorectal cancer (ACRC): A phase I/II study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4084-4084
Author(s):  
H. Sheikh ◽  
J. W. Valle ◽  
K. Palmer ◽  
G. Wilson ◽  
A. Sjursen ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Objective Response ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Open Label ◽  
Hand Foot Syndrome ◽  
Label Dose ◽  
Grade 3

4084 Background: The feasibility of UFT (tegafur-uracil) plus LV with alternating irinotecan and oxaliplatin was investigated in a two-stage, phase I/II, open-label, dose-finding trial in patients with ACRC. The study is now closed. Here we present results from the phase II cohort and overall results from the phase I/II study. Methods: Eligible patients aged =18 years had histologically confirmed, advanced, inoperable, measurable metastatic disease, no prior chemotherapy other than adjuvant bolus 5-FU administered =6 months previously, and adequate hematologic, hepatobiliary, and renal function. Patients in the phase I study received irinotecan 180 mg/m2 on d1, oxaliplatin 85–100 mg/m2 on d15 plus UFT 200–300 mg/m2/d with LV 90 mg/d on d1–21 of a 28-d cycle. Diarrhea, lethargy, and vomiting were dose limiting. The maximum tolerated dose (MTD) established was irinotecan 180 mg/m2, oxaliplatin 100 mg/m2, UFT 250 mg/m2/d, and LV 90 mg/day. Patients were treated at the MTD in the phase II study. Primary endpoints in the phase II study were objective response rate (ORR) and time to progression (TTP). Results: Forty-five patients (median age 62 [range 24–79] years, median 4 marker lesions) were entered, 16 and 29 patients in the phase I and II studies, respectively. The ORR in all 38 evaluable patients was 66% (95% CI 49–80%), with clinical benefit (CB) in 89% (95% CI 75–97%). At a median follow-up of 10.3 months, median TTP was 8.5 months (95% CI -7.6 to 10.4 months) in 40 evaluable patients and median OS (ITT population; n=45) was 16.8 months (95% CI -11.3 to 28.3 months). In the phase II study (n=29) median TTP was 8.1 months (95% CI -6.7 to 11.3 months) and median OS was 19.6 months (95% CI -7.7 to >25.6 months); ORR in 25 evaluable patients was 68% (95% CI -46.5 to 85.1%) with CB in 100% (95% CI -86.3 to 100%). Of 30 patients with confirmed radiologic progression, 21 (70%) had second-line therapy. At the MTD, 3 patients (10%) had grade 3 diarrhea, 1 patient (3%) had grade 3 neurotoxicity, and 2 patients (7%) had grade 2 alopecia. No hand-foot syndrome (HFS) was seen. Conclusions: UFT plus LV with alternating irinotecan and oxaliplatin is an efficacious first-line treatment for patients with ACRC, with minimal alopecia and neurotoxicity and no HFS. No significant financial relationships to disclose.

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