A phase I dose escalation safety and pharmacokinetic (PK) study of SSR244738 administered as a one-hour intravenous (IV) infusion twice-weekly during a 3-week cycle in patients (pts) with refractory solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2539-2539
Author(s):  
N. Isambert ◽  
G. Spitaleri ◽  
P. Fumoleau ◽  
C. Noberasco ◽  
C. Ramazeilles ◽  
...  
Keyword(s):  
Repeated Administration ◽  
Individual Variability ◽  
Distribution Volume ◽  
Weekly Schedule ◽  
Cell Cycle Inhibitor ◽  
Terminal Half Life ◽  
Heavily Pretreated ◽  
Pretreated Patients ◽  
Grade 3 ◽  
Tumor Types

2539 Background: SSR244738 is a new cytotoxic agent (G2-cell cycle inhibitor). In this first in man study the original schedule of administration was an IV infusion once every 3 weeks (Q3W); and due to the high clearance variability, 1300 mg/m2 was considered the maximum administered dose (MAD). The study was amended to test the twice weekly schedule (D1-D4-D8-D11-D15, every 3 weeks). Methods: Standard escalation was used in cohorts of 3–6 pts. PK profiles (up to T48h or T96h) were obtained in each pt after the 1st and the 5th administration (D1 and D15) of Cycle 1. In the Q3W, there was a trend to lower clearance (CL) in CYP2C9 *3/*3 and *1/*3 genotype pts therefore genotype samples were analyzed at baseline to identify poor metabolizers (PM) and adjust-dosing accordingly. Results: 22 heavily pretreated patients received SSR244738 at doses of 200 (3 pts), 280 (4 pts), 400 (3 pts), 560 (3 pts), 780 (3 pt), 1000 (6 pts; one pt was a PM and received 500 mg/m2). 15 females, 7 males, median age: 60 years (29–82), ECOG: (0:12, 1:9, Unk:1). Main tumor types: ovary, lung, breast, colon and prostate. Nb cycles/pts: > 2 cycles/21 (95%), > 4 cycles/9 (41%), > 6 cycles/6 (27%), > 8 cycles/2 (9%). The most common reason for treatment discontinuation was disease progression. DLT was seen in 2 pts at 1000 mg/m2 dose level: one patient had febrile neutropenia associated with Grade 3 mucositis and the second patient had Grade 3 neutropenia, which caused a treatment delay. Both pts showed high SSR244738 plasma exposures on D15. SD was reported in 11 patients. No CRs or PRs were observed. SSR244738 exhibited an overall low plasma CL (mean [range]: 0.9 [0.3–2.1] L/h). CL slightly decreased with repeated administration. The distribution volume was low [Vss mean (CV%): 11.6 L (30%)] and the terminal half life was long [mean (CV%): 15.6 h (58%)]. No deviation from dose proportionality could be observed, despite the moderate-to-high inter-individual variability (CV<64%) in exposure. Conclusions: SSR244738 is well tolerated with PK profile similar to the Q3W schedule; by changing the schedule of administration we were able to reach the MAD dose (5000 mg/m2/cycle). [Table: see text]

BECAM: A salvage protocol with bevacizumab, capecitabin, and mitomycin C for patients with refractory metastatic colorectal cancer (CRC) or gastric cancer (GC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13554-13554 ◽  
Author(s):  
S. Peinert ◽  
D. Arnold ◽  
R. Siewczynski ◽  
T. Kegel ◽  
C. Heider ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mitomycin C ◽  
Treatment Cycle ◽  
Objective Response ◽  
Tumor Control ◽  
Tumor Site ◽  
Heavily Pretreated ◽  
Pretreated Patients ◽  
Grade 3 ◽  
Tumor Types

13554 Background: Bevacizumab (Bev), a monoclonal antibody targeted against VEGF, has shown to improve efficacy in CRC when combined with chemotherapy. Combination schedules of fluoropyrimidines with mitomycin C (MMC) are active in both CRC and GC. This study was to explore the combination of Bev with a previously reported schedule of Capecitabine (Cap) and MMC (BECAM) in heavily pretreated patients (pts) with GC or CRC. Methods: Pts had to be refractory to at least 3 treatment lines, incl. 5-FU, oxaliplatin, irinotecan, and cetuximab in CRC; 2 lines with 5-FU, platinum, irinotecan or taxane in GC. A treatment cycle consisted of a 1-hour-infusion of Bev 7.5 mg/kg d1, bolus MMC 7mg/m2 d1 and Cap 1000mg/m2 bid d1–14, all qd22. Toxicity was assessed every 3 weeks (wk) and tumor evaluation (CT/MRI) was done every 9 wk. Results: 19 pts were included: m/f 8/11; GC 4, CRC 15, age 63 yrs [42–76], Karnofsky PS 80% [70–100]. Median no. of preceding regimens was 3 [2–6]. A total of 87 cycles were given. Median no. of cycles per pt. was 3 [2–15]. 18 pts were evaluable for toxicity (WHO scale) and efficacy: Grade 3/4 toxicities were thrombocytopenia (5/0), hypertension (1/0), and hemorrhage (0/1). The latter caused cessation of further administration of Bev. Gastrointestinal and other hematologic toxicities did not exceed grade 2. Response: PR was seen in 3 pts (16%; 1/4 GC, 2/14 CRC), stable disease for > 9 wk in 5 pts (1 GC, 4 CRC), leading to a tumor control rate of 44%. Median progression free and overall survival were 3.0 [2–11] and 5.0 [2.5–13] months. However, duration of objective response was remarkable in lasting 7.4–10.0 months. Conclusions: BECAM shows considerable activity in this group of heavily pretreated pts with CRC or GC. Toxicity was generally mild except for MMC-induced thrombocytopenia and (probably) Bev-induced bleeding (gastric tumor site). Despite previous reports of limited activity with Bev/5-FU in refractory pts (NCI TRC trial), BECAM is able to induce long lasting objective responses and therefore merits further investigation in both tumor types. [Table: see text]

Phase II Study of Temsirolimus (CCI-779), a Novel Inhibitor of mTOR, in Heavily Pretreated Patients With Locally Advanced or Metastatic Breast Cancer

2005 ◽  
Vol 23 (23) ◽  
pp. 5314-5322 ◽  
Author(s):  
Stephen Chan ◽  
Max E. Scheulen ◽  
Stephen Johnston ◽  
Klaus Mross ◽  
Fatima Cardoso ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Adverse Events ◽  
Dose Level ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Heavily Pretreated ◽  
Pretreated Patients ◽  
Grade 3 ◽  
Time To Tumor Progression

Purpose In this study, two doses of temsirolimus (CCI-779), a novel inhibitor of the mammalian target of rapamycin, were evaluated for efficacy, safety, and pharmacokinetics in patients with locally advanced or metastatic breast cancer who had been heavily pretreated. Patients and Methods Patients (n = 109) were randomly assigned to receive 75 or 250 mg of temsirolimus weekly as a 30-minute intravenous infusion. Patients were evaluated for tumor response, time to tumor progression, adverse events, and pharmacokinetics of temsirolimus. Results Temsirolimus produced an objective response rate of 9.2% (10 partial responses) in the intent-to-treat population. Median time to tumor progression was 12.0 weeks. Efficacy was similar for both dose levels but toxicity was more common with the higher dose level, especially grade 3 or 4 depression (10% of patients at the 250-mg dose level, 0% at the 75-mg dose level). The most common temsirolimus-related adverse events of all grades were mucositis (70%), maculopapular rash (51%), and nausea (43%). The most common, clinically important grade 3 or 4 adverse events were mucositis (9%), leukopenia (7%), hyperglycemia (7%), somnolence (6%), thrombocytopenia (5%), and depression (5%). Conclusion In heavily pretreated patients with locally advanced or metastatic breast cancer, 75 and 250 mg temsirolimus showed antitumor activity and 75 mg temsirolimus showed a generally tolerable safety profile.

Clinical Response in Heavily Pretreated Mycosis Fungoides with Pembrolizumab: A Case Report

2021 ◽  
pp. 1-3
Author(s):  
Ginevra Lolli ◽  
Beatrice Casadei ◽  
Lisa Argnani ◽  
Alessandro Pileri ◽  
Cinzia Pellegrini ◽  
...  
Keyword(s):  
Mycosis Fungoides ◽  
Assessment Tool ◽  
Therapeutic Option ◽  
Rapid Responses ◽  
Duration Of Response ◽  
Heavily Pretreated ◽  
Stage Ia ◽  
Pretreated Patients ◽  
Grade 3 ◽  
The Moment

Mycosis fungoides (MF) is a disease almost impossible to cure. In the context of heavily pretreated patients, the anti-programmed cell death protein 1 (anti-PD-1) pembrolizumab is a valid therapeutic option. The alteration of the PD-1-PD ligand 1 (PD-L1) axis is often present in MF, and this aspect explains the feasibility of this therapy. We report the case of a 60-year-old woman diagnosed with MF in 2003, Olsen stage IA (T1M0NXBO). Since the moment of the diagnosis, she received 10 lines of therapy, with a short duration of response after each one of them. In April 2020, our patient started pembrolizumab 2 mg/kg every 3 weeks, and she achieved a partial response after the 4th cycle, consistent with the modified severity assessment tool (mSWAT) 1, which she is still maintaining after 10 cycles. No grade ≥3 adverse events were recorded. We conclude that pembrolizumab can induce extremely rapid responses in MF, with very low toxicity.

scholarly journals Pomalidomide-Dexamethasone in the Management of Heavily Pretreated Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 1-1
Author(s):  
Claudio Cerchione ◽  
Lucio Catalano ◽  
Davide Nappi ◽  
Anna Emanuele Pareto ◽  
Gerardo Musuraca ◽  
...  
Keyword(s):  
Oral Administration ◽  
Oral Treatment ◽  
Novel Agents ◽  
Hematologic Toxicity ◽  
Salvage Regimen ◽  
Good Compliance ◽  
Impressive Result ◽  
Heavily Pretreated ◽  
Pretreated Patients ◽  
Grade 3

Background Pomalidomide is a new generation IMID, with a very good compliance, thanks to oral administration, which can be used also in heavily pretreated patients, in a domestic setting. Aims In this retrospective observational trial, It has been evaluated efficacy and tolerance of pomalidomide plus dexamethasone (PD) as salvage regimen in heavily pretreated patients with relapsed and refractory MM (rrMM), whose prognosis is particularly severe. Methods 57 patients (31 M/26 F), with rrMM, median age at diagnosis 69 years (r. 52-86), and median age at start of treatment 76 years (r.56-90) treated with several lines of treatments (median 7, r. 2-11), every refractory to all the drugs previously received (also Bortezomib, Thalidomide and Lenalidomide), received Pomalidomide-Dexamethasone (Pomalidomide 4 mg for 21 days, Dexamethasone 40 mg days 1,8,15,22, pegfilgrastim day +8) every 28 days, until progression. ISS was equally distributed, and cytogenetic at relapse was evaluable in 14 patients. All the patients had previously been treated with schedule containing bortezomib and IMIDs. 63% (36/57) had undergone at least to a single ASCT. All patients were relapsed and refractory to last therapies received before PD. Results Pomalidomide was well tolerated, with grade 3-4 transfusion-dependent anemia in 58% (33/57) of patients, 44% (23/57) grade 3-4 neutropenia (pegfilgrastim in primary prophylaxis was given, no hospitalization was required, no septic shocks were observed), 40% (23/57) grade 3-4 thrombocytopenia without hemorrhagic events and transfusion-dependence. No severe extra-hematologic toxicity was observed. According to IMWG, ORR1 (≥PR) was 47.3% (27/57: 5 CR, 11 VGPR, 7 PR, 4 MR), but, considering that we are evaluating a cohort of heavily pretreated patients, with poor prognosis, another parameter should be considered, ORR2 (≥SD), considering stable disease as a successful result in progressive MM. ORR2 was 77.1% (17 SD). These can be considered as impressive result in this subset of patients. Oral treatment gives a really good compliance, in frail and unfit patients, and response, when present, is always really fast (median time to response: 2 months (r.1-6)), median OS from diagnosis was 94 months (range 21-234), median OS from start of pomalidomide was 9 months (range 1-25). Nine patients have surprisingly achieved a notable response (3 VGPR, 4 PR, 2 MR) after failure of novel agents (i.e. Carfilzomib, Daratumumab and Pomalidomide). Conclusions Pomalidomide-dexamethasone has shown significant efficacy and a very good compliance, thanks to oral administration, in a particularly severe setting of heavily pretreated patients, relapsed and refractory to all available therapeutic resources, also after failure of novel agents. Disclosures Lucchesi: Novartis: Honoraria; Pfizer: Honoraria; Incyte: Honoraria.

CTIM-32. IMMUNE CHECKPOINT INHIBITOR NIVOLUMAB IN PEOPLE WITH RECURRENT SELECT RARE CNS CANCERS: RESULTS OF INTERIM ANALYSIS IN A HEAVILY PRETREATED COHORT

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi57-vi58
Author(s):  
Marta Penas-Prado ◽  
Ying Yuan ◽  
Kathleen Wall ◽  
Elizabeth Vera ◽  
Ukeme Ikiddeh-Barnes ◽  
...  
Keyword(s):  
Safety Profile ◽  
Interim Analysis ◽  
Cns Tumors ◽  
Myxopapillary Ependymoma ◽  
Investigational Drugs ◽  
Heavily Pretreated ◽  
Pretreated Patients ◽  
Grade 3 ◽  
Total Accrual ◽  
Immune Profiling

Abstract INTRODUCTION Standard and experimental therapies for patients with rare CNS tumors are scarce. Nivolumab (PD-1 inhibitor) is approved for several non-CNS cancers. This ongoing Phase II trial (NCT03173950) will determine the efficacy of nivolumab in adults with recurrence/progression of one of 11 selected rare primary CNS tumors. Efficacy is measured by Disease Control Rate (DCR; confirmed CR/PR or durable SD for ≥ 6 months) in 2 cohorts: heavily and non-heavily pretreated patients (heavily pretreated: ≥ 3 prior therapies; non-heavily pretreated: ≤ 2). We report efficacy and safety results of a preplanned interim analysis in the heavily pretreated cohort. METHODS Eligibility includes recurrence/progression of an eligible tumor; age ≥ 18 years; tumor tissue available for histopathology, molecular and immune profiling; KPS ≥ 70; and no steroids at study entry. A total of 150 evaluable patients will be enrolled (75 to each cohort). Prior therapies include radiation and/or standard or investigational drugs. Nivolumab treatment is 240 mg IV every 2 weeks (4 doses); then 480 mg every 4 weeks (14 additional doses). Interim analysis was planned when sample size reached 32 in each cohort. RESULTS As of March 10, 2021, DCR exceeded the minimum required for interim analysis in the heavily pretreated cohort. Among 30 patients, 4 achieved SD &gt; 6 months (medulloblastoma, anaplastic ependymoma, myxopapillary ependymoma, metastatic atypical meningioma). Safety profile (related AEs): grade 3 = 7; grade 4 = 1. Most frequent grade 3-5 AEs regardless of attribution: tumor progression (6); anemia, hydrocephalus, lymphopenia (3 each); cerebral edema, headache (2 each). CONCLUSION DCR exceeded the “go” boundary (i.e., &gt; 2) in the heavily pretreated cohort. Nivolumab showed safety profile consistent with other studies. This cohort will continue to stage 2 and complete total accrual of 75 patients. The trial is currently being expanded to 10 additional sites across the BTTC/NCI-CONNECT consortium.

A phase II trial of bevacizumab and capecitabine combination in metastatic colorectal cancer after failure of irinotecan- and oxaliplatin-containing regimens

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14555-14555
Author(s):  
P. Zoran ◽  
D. Tarabar ◽  
R. Doder
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Drug Regimen ◽  
Survival Duration ◽  
Heavily Pretreated ◽  
Pretreated Patients ◽  
Third Line ◽  
Grade 3

14555 Background: This is a phase II study combination of capecitabine plus bevacizumab for patients with metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-containing regimens. Methods: The dose of capecitabine was 1000 mg/m2, administered twice daily for 14 days every 3 weeks. Bevacizumab was given at a dose of 5mg/kg on day 1 as i.v. infusion every 3 weeks. Treatment was repeated until the occurrence of disease progression or unaccepted toxicity. Results: Twenty-eight patients were enrolled. Of 28 patients, the overall response rate was 14.3% and the disease control rate was 42.9%. With a median follow-up period of 7 months, median time to progression and overall survival duration were 3 months and 14 months, respectively. The 1-year survival rate of all patients was 60.7%. The most common treatment-related grade 3/4 hematological toxicities included leukopenia/neutropenia in 4 patients and thrombocytopenia in 3 patients. Nonhematologic toxicities attributable to bevacizumab included bleeding in 3 patients, hypertension in 4 patients, thromboses in 3 patients, proteinuria in 5 patients, and gastrointestinal perforation in 1 patient. Conclusions: This drug regimen was well tolerated and combination of bevacizumab and capecitabine shows potential as third line chemotherapy in heavily pretreated patients with metastatic colorectal cancer. No significant financial relationships to disclose.

Results of a phase Ib trial evaluating the safety and clinical activity of sapanisertib (TAK 228) in combination with serabelisib (TAK 117) and paclitaxel in patients with advanced ovarian, endometrial, or breast cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3604-3604
Author(s):  
Casey B. Williams ◽  
Kirstin Anne Williams ◽  
Amy K. Krie ◽  
Pradip De ◽  
Nandini Dey ◽  
...  
Keyword(s):  
Clinical Results ◽  
Clinical Activity ◽  
Open Label ◽  
Effective Treatment Option ◽  
Taxane Resistance ◽  
Phase 2 Study ◽  
Heavily Pretreated ◽  
Pretreated Patients ◽  
Grade 3 ◽  
Dose Reductions

3604 Background: The link between taxane resistance and activation of PI3K/AKT/mTOR signaling suggests that by inhibiting this pathway in combination with anti-microtubule agents like paclitaxel may improve treatment outcomes in many malignancies. To investigate this further we combined the TORC 1/2 inhibitor sapanisertib (TAK-228), the PI3Kα isoform inhibitor serabelisib (TAK-117), and paclitaxel in a phase I trial to determine the safety, efficacy, and RP2D. Methods: Open label, cohort study using a traditional 3+3 dose escalation design with a maximum of 5 dosing cohorts. A dose expansion of cohort 4, the recommended RP2D, is planned for February 2020. Results: Enrollment to the DLT evaluation has been completed and the clinical results are summarized in Table. Sixteen patients have been enrolled; a majority were heavily pretreated and resistant to paclitaxel. Overall, the combination was safe and tolerable. One DLT occurred due to renal dysfunction in cohort 5. 360 adverse events have been reported, but only 28 (8%) grade 3 or 4 events. The most common events were leukopenia and non-febrile neutropenia. Two patients required dose reductions as a result of pneumonitis. The ORR is currently 46% in 13 evaluable patients. CBR is 69% and PFS is currently at 10 months. Two patients achieved a CR and three patients remain on treatment. Conclusions: The combination proved to be well tolerated in the doses and schedules used in cohorts 1-4 and exhibited very promising clinical activity in heavily pretreated patients. This regimen could prove to be a highly effective treatment option and a phase 2 study is warranted at the RP2D. Clinical trial information: NCT03154294 . [Table: see text]

scholarly journals Pomalidomide-Dexamethasone in the Management of Heavily Pretreated Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 5022-5022
Author(s):  
Claudio Cerchione ◽  
Lucio Catalano ◽  
Davide Nappi ◽  
Anna Emanuele Pareto ◽  
Fabrizio Pane ◽  
...  
Keyword(s):  
Oral Administration ◽  
Oral Treatment ◽  
Novel Agents ◽  
Hematologic Toxicity ◽  
Salvage Regimen ◽  
Good Compliance ◽  
Impressive Result ◽  
Heavily Pretreated ◽  
Pretreated Patients ◽  
Grade 3

Abstract Pomalidomide is a new generation IMID, with a very good compliance, thanks to oral administration, which can be used also in heavily pretreated patients, in a domestic setting. In this retrospective observational trial, It has been evaluated efficacy and tolerance of pomalidomide plus dexamethasone (PD) as salvage regimen in heavily pretreated patients with relapsed and refractory MM (rrMM), whose prognosis is particularly severe. 57 patients (31 M/26 F), with rrMM, median age at diagnosis 69 years (r. 52-86), and median age at start of treatment 76 years (r.56-90) treated with several lines of treatments (median 7, r. 2-11), every refractory to all the drugs previously received (also Bortezomib, Thalidomide and Lenalidomide), received Pomalidomide-Dexamethasone (Pomalidomide 4 mg for 21 days, Dexamethasone 40 mg days 1,8,15,22, pegfilgrastim day +8) every 28 days, until progression. ISS was equally distributed, and cytogenetic at relapse was evaluable in 14 patients. All the patients had previously been treated with schedule containing bortezomib and IMIDs. 63% (36/57) had undergone at least to a single ASCT. All patients were relapsed and refractory to last therapies received before PD. Pomalidomide was well tolerated, with grade 3-4 transfusion-dependent anemia in 58% (33/57) of patients, 44% (23/57) grade 3-4 neutropenia (pegfilgrastim in primary prophylaxis was given, no hospitalization was required, no septic shocks were observed), 40% (23/57) grade 3-4 thrombocytopenia without hemorrhagic events and transfusion-dependence. No severe extra-hematologic toxicity was observed. According to IMWG, ORR1 (≥PR) was 47.3% (27/57: 5 CR, 11 VGPR, 7 PR, 4 MR), but, considering that we are evaluating a cohort of heavily pretreated patients, with poor prognosis, another parameter should be considered, ORR2 (≥SD), considering stable disease as a successful result in progressive MM. ORR2 was 77.1% (17 SD). These can be considered as impressive result in this subset of patients. Oral treatment gives a really good compliance, in frail and unfit patients, and response, when present, is always really fast (median time to response: 2 months (r.1-6)), median OS from diagnosis was 94 months (range 21-234), median OS from start of pomalidomide was 9 months (range 1-25). Nine patients have surprisingly achieved a notable response (3 VGPR, 4 PR, 2 MR) after failure of novel agents (i.e. Carfilzomib, Daratumumab and Pomalidomide). Pomalidomide-dexamethasone has shown significant efficacy and a very good compliance, thanks to oral administration, in a particularly severe setting of heavily pretreated patients, relapsed and refractory to all available therapeutic resources, also after failure of novel agents. Disclosures Martinelli: Stemline Therapeutics: Consultancy; Incyte: Consultancy; Pfizer: Consultancy, Speakers Bureau; Roche: Consultancy; Celgene /BMS: Consultancy, Speakers Bureau; Daichii Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Abbvie: Consultancy; Astellas: Consultancy, Speakers Bureau.

scholarly journals An Exploration of Trifluridine/Tipiracil in Combination with Irinotecan in Patients with Pretreated Advanced Gastric Cancer

2021 ◽  
Author(s):  
Takuro Mizukami ◽  
Keiko Minashi ◽  
Hiroki Hara ◽  
Tomohiro Nishina ◽  
Yusuke Amanuma ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Treatment Options ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Heavily Pretreated ◽  
Pretreated Patients ◽  
Grade 3 ◽  
Recommended Phase Ii Dose

Abstract Background: Trifluridine/tipiracil (FTD/TPI) and irinotecan are treatment options for heavily pretreated patients with advanced gastric cancer but with limited efficacies. We investigated the combination of FTD/TPI and irinotecan for such patients.Methods: Patients who refractory to fluoropyrimidine, platinum and taxane were enrolled into four cohorts (Level 1A/1B/2A/2B) used an escalated dose of irinotecan [100 (Level 1) or 125 mg/m2 (Level 2) on days 1 and 15] with 2 schedules of FTD/TPI 35 mg/m2/dose: twice daily, on days 1-5 and 8-12 (Level A) or on days 1-5 and days 15-19 (Level B) of a 28-day cycle. The primary and secondary objectives were determination of maximum tolerated dose, dose-limiting toxicities (DLTs), and recommended phase II dose (RP2D) , and evaluation of disease control rate (DCR), respectively. Results: Eleven patients were enrolled; 2 at Level 1A, 3 at Level 1B and 6 at Level 2B. DLTs occurred in 2/2 patient at Level 1A, and 2/6 patients at Level 2B. Grade 3 or higher treatment-related adverse events were neutropenia (90.9%), leukopenia (54.5%), anemia (45.5%) and febrile neutropenia (18.2%). One patient at Level 2B achieved partial response and the DCR was 72.7% (95% CI 39.0- 94.0%). The median progression-free survival and overall survival was 3.0 months (95% CI 0.92- not reached) and 10.2 months (95% CI 2.2- not reached), respectively.Conclusion: The RP2D of FTD/TPI combined with irinotecan was determined to be Level 1B with manageable hematologic toxicities and feasible non-hematologic toxicities. Further evaluation for its efficacy in the RP2D is necessary. Mini-abstract: A phases Ib study of trifluridine/tipiracil in combination with irinotecan for advanced gastric cancer determined the recommended dose with manageable hematologic toxicities and feasible non-hematologic toxicities.

Phase I trial of bortezomib in combination with topotecan in advanced solid tumor malignancies

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12004-12004
Author(s):  
R. Morgan ◽  
F. Valdes-Albini ◽  
T. Synold ◽  
G. Somlo ◽  
S. Shibata ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Phase I Trial ◽  
Hematologic Toxicity ◽  
Weekly Schedule ◽  
Clinical Testing ◽  
Advanced Solid Tumor ◽  
Advanced Malignancies ◽  
Grade 3 ◽  
Tumor Types

12004 Background: Bortezomib (B) and topotecan (T) have been shown in pre-clinical testing to be synergistic. Based on this data we have performed a phase I study to determine the maximally tolerated dose and toxicities (tox) of B and T delivered sequentially. Methods: 24 pts (KPS<ECOG 3) with advanced malignancies were treated with T (2.0, 2.5, 3.0 or 3.5 mg/m2 in sequential cohorts) IV on days 1 and 8 of each three week cycle. B 1.3 mg/m2 iv was administered six hours following T on days 1 and 8, and alone on days 4 and 12. Pts were treated in cohorts of 3, the MTD dose was expanded to include 10 additional pts for PK analysis. There was no limit on prior therapies. DLT was defined as any gr 3 or 4 non-hematologic toxicity not reversible in 48h or any gr 3 thrombocytopenia lasting >7 days or associated with bleeding or any gr 4. Results: Tumor types included: breast (4), ovary (5), lung (3), others (12). 24 pts were entered (11M 13F). The median age was 55 (range: 34–83). DLT was thrombocytopenia, observed in two pts at 3.5 mg/m2 and one pt at 3.0 mg/m2 (MTD). Other grade 3 or 4 tox included fatigue, lymphopenia, hypomagnesemia, and hypertriglyceridemia. Of the 24 enrolled pts, stable disease was observed in 4 (4 or 5 cycles), 9 progressed, 5 were inevaluable and 6 are too early. PK analysis is pending. Conclusions: T and B delivered sequentially are well tolerated on a weekly schedule. DLT is thrombocytopenia. PK will be presented.(Supported by NCI Grant CA33572). [Table: see text]

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