Result of the feasibility study of lidocaine (LDC) for peripheral venous pain induced by oxaliplatin (L-OHP).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e21624-e21624
Author(s):  
Daisuke Sakai ◽  
Miwako Uemori ◽  
Takashi Sugiura ◽  
Toshihiro Kudo ◽  
Miwa Boku ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Concomitant Administration ◽  
Hematological Toxicity ◽  
Peripheral Vein ◽  
Port Placement ◽  
Level 1 ◽  
Grade 3 ◽  
Vascular Pain ◽  
First Time ◽  
Level 2

e21624 Background: For the patients with colorectal cancer, CapeOx or SOX, combination of L-OHP with oral fluoropyrimidines Capecitabine or S-1, is commonly used in clinical practice. These regimens, different from FOLFOX, do not necessarily require central venous port placement and can be administered via peripheral vein. However, peripheral vascular pain induced by administration of L-OHP was discussed. Methods: LDC was concomitantly administered through the lateral duct of drip route from 30 minutes before to end of L-OHP administration, to patients with colorectal cancer who are to be administered L-OHP (100 mg/m2 or more) via the peripheral vein for the first time. LDC dose was set at two levels of 0.5 (Level 1) and 1.5 (Level 2) mg / kg / Hr. Safety, symptoms of pain and pharmacokinetics of LDC were evaluated. The DLT criteria were (1) an allergic reaction of Grade 2 or higher, (2) non-hematological toxicity of Grade 3 or more related to LDC, (3) cessation of administration of L-OHP or LDC, (4) higher than 5 mcg / mL of blood concentration of LDC. Results: A total of nine patients were enrolled (Level 1: 3, Level 2: 6). No DLTs were observed. The average Cmax of LDC was 0.4 (range: 0.3 - 0.5) mcg/ml at Level 1 and 1.3 (0.5 - 2.3) mcg / ml at Level 2. In the pain assessment (VAS score), in Level 1, 2 cases did not feel pain, 1 case was 3/10. In Level 2, there were no pain in 4 cases and 2/10 in the remaining 2 cases. Conclusions: To alleviate vascular pain caused by peripheral intravenous administration of L-OHP, concomitant administration of LDC could be safe and effective. Clinical trial information: UMIN000011393.

A phase I study of modified irinotecan (CPT-11) plus cisplatin (CDDP) [m-IP] against paclitaxel/carboplatin [TC] -resistant and recurrent ovarian cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 13015-13015
Author(s):  
T. Suzuki ◽  
M. Morishita ◽  
M. Matsuura ◽  
T. Fujimoto ◽  
R. Tanaka ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase I Study ◽  
Phase Ii Study ◽  
Recurrent Ovarian Cancer ◽  
Hematological Toxicity ◽  
Prior Chemotherapy ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

13015 Background: CPT-11/CDDP is effective regimen for ovarian cancer. Particularly against ovarian cancer resistant to prior chemotherapy, a 40% response rate was reported (Sugiyama T Cancer Letters, 1998). However, every 4 weeks treatment with CPT-11 day 1, 8, and 15, administration on day 15 was skipped in about 60% due to toxicity, and the relative dose intensity of IP was 66.7% in non-small cell lung cancer (Saito H Am J Clin Oncol 2006). We planed Phase I study, in consideration of the effect of prior chemotherapy in TC-resistant ovarian cancer, a modified CPT-11 (day 1, 8) and CDDP (day 1) for every 4 weeks treatment (m-IP). The aim of this study conducted to examine the dose limiting toxicity (DLT), to evaluate the maximum tolerated dose (MTD), and define the recommended dose (RD) for a phase II study. Methods: Patients with TC-resistant ovarian cancer having a PS 0–1, age 30–75 years, normal organ functions, and written informed consent. CPT-11 was administered intravenously over 90 minutes on day 1 and day 8, plus CDDP was day 1, repeated every 4 weeks. The dose escalation schedule was defined: Doses of CPT-11/CDDP (mg/m2) were 60/60 at level 1, 70/60 at level 2 and 70/70 at level 3. DLT were determined as Grade 4 hematological toxicity and = Grade 3 non-hematological toxicity occurred, and when dosing on day 8 was delayed for more than 8 days due to toxicity. Results: Nine patients were enrolled (level 1/2/3: 3/3/3). DLTs, at level 1 and 2, no patients developed. At level 3, grade 3 nausea and vomiting and delayed treatment on day 8 due to anorexia, were observed in all of 3 patients. Therefore, MTD was determined to be level 3 and RD was determined to be level 2 (CPT-11: 70mg/m2, CDDP: 60mg/m2). Major =Grade 3 toxicities observed were leukopenia, neutropenia, nausea, and vomiting. No Grade 4 hematological toxicities were observed. Diarrhea was mild. Antitumor effect at RD was observed in 1 patient with CR, 1 patient with PR and 1 patient with PD. Conclusions: The MTD of m-IP was CPT-11 70mg/m2 and CDDP 70mg/m2 (level 3), the RD was CPT-11 70mg/m2 and CDDP 60mg/m2 (level 2). Preliminary response are promissing associated with tolerable toxicity for TC-resistant and recurrent ovarian cancer. A Phase II study is currently conducted. No significant financial relationships to disclose.

scholarly journals Phase I-II Study of Sequential Therapy with Decitabine Followed By Clofarabine, Idarubicin, and Cytarabine (DAC-CIA regimen) in Relapsed/Refractory Acute Myeloid Leukemia (AML)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5283-5283
Author(s):  
Nitin Jain ◽  
Farhad Ravandi ◽  
Guillermo Garcia-Manero ◽  
Gautam Borthakur ◽  
Tapan Kadia ◽  
...  
Keyword(s):  
Stem Cell ◽  
Dose Level ◽  
Stem Cell Transplant ◽  
Hematological Toxicity ◽  
Cell Transplant ◽  
Hypomethylating Agents ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2 ◽  
Refractory Aml

Abstract Background: Patients (pts) with relapsed/refractory AML have dismal outcomes with currently available chemotherapy regimens. Preclinical and clinical evidence suggests that the use of hypomethylating agents such as decitabine prior to standard chemotherapy may be synergistic (Qin et al. Clin Can Res 2007; Scandura et al. Blood 2011; Clozel et al. Cancer Discov 2013). Methods: Pts aged ≥18 to 65 years with relapsed or refractory AML (up to salvage 2) were eligible. Prior therapy with hypomethylating agents was allowed. The chemotherapy regimen was as follows: TableDoseDays INDUCTIONDecitabine20 mg/m2 IVDays 1-5Clofarabine15 mg/m2 IVDays 6-9 (Dose level 1) Days 6-10 (Dose level 2)Idarubicin10 mg/m2 IVDays 6-8Cytarabine1 gm/m2 IVDays 6-10CONSOLIDATIONDecitabine20 mg/m2 IVDays 1-5Clofarabine15 mg/m2 IVDays 6-8Idarubicin8 mg/m2 IVDays 6-7Cytarabine1 gm/m2 IVDays 6-8 Results: Eighteenpts (female, n=4) have been treated so far. Median age was 43 years (range 20-61). Majority of the pts (10/18, 56%) were in salvage 2. Four had a prior allogeneic stem cell transplant (SCT). Cytogenetics were diploid (n=4), complex (n=11), 11q abnormality (n=2), trisomy 8 (n=1). Five pts had a TP53 mutation and 3 pts had an NRAS mutation. Median number of cycles administered was 1 (range 1-2). Grade 3-4 non-hematological toxicity included grade 3 mucositis (DLT) in 2 pts during the induction cycle. Due to mucositis and prolonged cytopenias (prolonged cytopenias didn’t meet the DLT definition), dose level 2 was not pursued, and all patients were treated at dose level 1. Grade 3 transaminitis was seen in 4 pts. Fifteen pts had one or more infections. Six (33%) pts achieved CR, of whom 5 were able to proceed to SCT (one pt with CR opted not to pursue SCT). Median time to CR was 35 days. An additional 3 pts had a >50% decrease in bone marrow blast count (marrow response) and all three proceeded with SCT. All 4 patients with diploid cytogenetics achieved CR. Only 1/5 (20%) patients with mutated TP53 achieved a CR. Two patients have relapsed (one 3 months after SCT and the other after consolidation cycle 1). Six patients are alive (4 after stem cell transplant, 2 are receiving further salvage regimens after DAC-CIA failure). Median survival of the entire group is 7.2 months (see figure 1). Conclusions: The sequential treatment of decitabine followed by chemotherapy is safe and effective with a CR rate of 33% and with 8/18 patients able to proceed to an allogeneic SCT. The phase II part of the study is enrolling patients at this time. FIGURE 1 FIGURE 1. Disclosures Off Label Use: Decitabine and clofarabine are not approved for AML..

Quadruplet regimen with capecitabine, irinotecan, oxaliplatin, and bevacizumab in chemo-naive patients with metastatic colorectal cancer: Results from the safety lead-in of QUATTRO-II study.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 57-57
Author(s):  
Hideaki Bando ◽  
Daisuke Kotani ◽  
Masahito Kotaka ◽  
Akihito Kawazoe ◽  
Toshiki Masuishi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Braf V600e ◽  
Phase Iii ◽  
Fixed Dose ◽  
Wild Type ◽  
Randomized Phase Ii ◽  
Level 1 ◽  
Grade 3

57 Background: FOLFOXIRI plus bevacizumab (BEV) is regarded as the standard of care for selected patients (pts) with metastatic colorectal cancer (mCRC), despite the high incidence of neutropenia and diarrhea. The AXEPT phase III study showed that the modified capecitabine (CAP) + irinotecan (IRI) + BEV (CAPIRI+BEV) [CAP 1600 mg/m2, IRI 200 mg/m2, and BEV 7.5 mg/kg q3wk] treatment was non-inferior to FOLFIRI+BEV, with a lower incidence of hematologic toxicity. We hypothesized that the modified CAPIRI combined with oxaliplatin (OX) and BEV (CAPOXIRI+BEV) would be more feasible than FOLFOXIRI+BEV, without compromising efficacy. Methods: The QUATTRO-II study is an open-label, multicenter, randomized phase II study. In Step 1, the recommended doses (RD) of OX and IRI were investigated as a safety lead-in. In Step 2, pts are randomized to either the RD of CAPOXIRI+BEV or FOLFOXIRI+BEV. In Step 1, four dose levels of CAPOXIRI (fixed dose of CAP 1600 mg/m2 and BEV 7.5 mg/kg plus escalated or de-escalated doses of OX and IRI, q3wk) were investigated in a 3+3 manner. A dose level of ≤ 2/6 of dose-limiting toxicity (DLT) cases was expected as the RD. Results: A total of 9 pts (3 at Level 0, 6 at Level 1) were included in Step 1. The baseline characteristics were as follows: the median age was 62 years; 6 were male; 6 presented with a left-sided tumor; 8 had a performance status of 0; all wild type/ RAS mutant/ BRAF V600E mutant were 8/1/0; and UGT1A1 wild type/*6 single hetero/*28 single hetero were 7/0/2. In Level 0 (IRI 200 mg/m2, OX 100 mg/m2), one grade 4 neutropenia and one grade 3 anorexia were observed, but without DLT. In Level 1 (IRI 200 mg/m2, OX 130 mg/m2), two grade 4 neutropenia and one grade 3 colitis were observed, with 1 DLT (febrile neutropenia) case, fully recovered without G-CSF administration. No treatment-related deaths were observed. Although dose modifications were needed in 4 of the 6 pts, no further safety concerns related to treatment continuity were observed in the 2nd or subsequent cycles. Thus, we determined that the dose administered in Level 1 is the RD for Step 2. According to the preliminary efficacy results at 8 weeks after initiating study treatment, 6 pts achieved a partial response (2 in Level 0 and 4 in Level 1). Conclusions: The RD of CAPOXIRI+BEV was 200 mg/m2 IRI, 130 mg/m2 OX, 1600 mg/m2 CAP, and 7.5mg/kg BEV. The randomized phase II Step (Step 2) of QUATTRO-II is ongoing. Clinical trial information: NCT04097444.

scholarly journals Beneficial Treatment Management with Trifluridine/Tipiracil in a Patient with Metastatic Colorectal Cancer and Pronounced Hematological Event History during Previous Treatments

2018 ◽  
Vol 11 (1) ◽  
pp. 43-48 ◽  
Author(s):  
Volker Kaechele ◽  
Jürgen Hess ◽  
Wolfgang Schneider-Kappus
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Dose Reduction ◽  
Performance Status ◽  
Recommended Dose ◽  
Hematological Toxicity ◽  
Ecog Performance Status ◽  
History Of ◽  
Grade 3

Trifluridine/tipiracil (FTD/TPI) significantly improves overall survival in patients with metastatic colorectal cancer (mCRC). The most common treatment-related event (grade ≥3) was hematological toxicity. We here report long-term disease-stabilizing FTD/TPI treatment of an mCRC patient (KRAS wild-type, ECOG performance status 1 at baseline and at the end of FTD/TPI therapy) with multifocal synchronous metastases and a longstanding history of extensive hematological events during previous treatments. Finally, this 62-year-old male patient was treated for 10 months with FTD/TPI by consecutive alteration of treatment parameters: (i) initial daily dose reduction to 80 mg (72% of the recommended dose), (ii) 20 days dose delay, (iii) a second and later third dose reduction to 70 mg and 60 mg (about 64% and 55%, respectively, of the recommended dose), and (iv) 30 µg per day of granulocyte colony-stimulating factor administration first for 3 days, and later for 5 days, for each treatment cycle.

A Phase I Study of the HDAC Inhibitor LBH589 in Combination with Imatinib for Patients with CML in Cytogenetic Remission with Residual Disease Detectable by Q-PCR.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2194-2194 ◽  
Author(s):  
Ravi Bhatia ◽  
David S. Snyder ◽  
Allen Lin ◽  
Jennifer Arceo ◽  
Linda Seymour ◽  
...  
Keyword(s):  
Stem Cells ◽  
Phase I ◽  
Research Funding ◽  
Residual Disease ◽  
Leukemia Stem Cells ◽  
Gi Symptoms ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2 ◽  
Dose Limiting Toxicity

Abstract Abstract 2194 Poster Board II-171 Imatinib mesylate (IM) is effective in inducing remission and improving survival in CML patients. However IM-treated patients continue to harbor residual leukemia stem cells (Blood 101:4701, 2003). Most patients relapse if treatment is discontinued, and it is generally recommended that treatment with IM be continued indefinitely. The inability of IM to cure CML, the potential for side effects and the financial burden of life-long treatment provide an impetus to develop approaches to eliminate residual leukemia stem cells. We have shown in preclinical studies that treatment with the HDAC inhibitor LBH589 (LBH) combined with IM effectively eliminates CML stem cells resistant to IM alone. The safety and MTD of LBH589 in combination with Imatinib has not been previously evaluated. We have initiated a phase I, open label clinical trial to determine the safety and tolerability of LBH589 given in combination with IM in CML patients, and to determine the MTD and dose-limiting toxicity (DLT). CML patients in chronic phase (CP) treated with IM 400mg/d for >1 year with major or complete cytogenetic response and residual disease on Q-PCR are eligible. LBH589 is administered in combination with IM 400mg PO daily in 28 day cycles, with successive cohorts of patients receiving escalating doses of LBH 3 times a week (level 1: 10mg; level 2: 15mg; level 3: 20mg). Treatment is scheduled for 6 cycles of 28 days each. Five patients have been enrolled thus far (Table). No dose limiting toxicity (DLT), defined as Grade 3 hematological or non-hematological toxicity in the first 28 days, was observed in 3 patients enrolled at dose level 1. DLT (Grade 3 thrombocytopenia) was observed in 1 of the 2 patients enrolled at dose level 2. Other toxicities included thrombocytopenia (Grade 3 [n=2]; Grade 1-2 [n=4]), hypophosphatemia (Grade 3 [n=1]; Grade 2 [n=2]), fatigue (Grade 1 [n=3]), hypocalcemia (Grade 1 [n=2] and Grade 1-2 GI symptoms (diarrhea [n=2]; nausea [n=3]; anorexia [n=2]; vomiting [n=3]; constipation [n=1]). Of note, significant QTc prolongation was not observed on intensive EKG monitoring. IM did not require to be held for any of these toxicities. Two patients have completed 6 cycles of treatment, with one opting to receive an additional 3 cycles, 2 are currently receiving treatment, and one withdrew after 1.5 cycles because of fatigue and GI symptoms. Bone marrow aspirates for assessment of BCR-ABL status were performed at the end of cycles 3 and 6 of treatment. Q-PCR analyses showed reduction in BCR-ABL levels in patient #2 (LBH 10mg) after 3 months, which was not sustained at 6 months. Patient #4 (LBH 15mg), followed for 5 months so far, had undetectable BCR-ABL after 3 months of treatment. These results suggest that LBH589 can be safely administered in combination with IM. Reduction in BCR-ABL levels was seen in two patients but the durability is unclear as yet. We are continuing accrual of patients to define the MTD and safety of this combination. Disclosures: Bhatia: Novartis: Consultancy, Research Funding. Snyder:Novartis: Consultancy, Honoraria, Speakers Bureau. Deininger:Novartis: Consultancy. Radich:Novartis: Consultancy, Honoraria, Research Funding.

Oxaliplatin, Fludarabine, Cytarabine, and Rituximab Combination Therapy Induces High Response Rates in Agressive Chronic Lymphocytic Leukemia (CLL) and Richter's Syndrome (RS).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3443-3443 ◽  
Author(s):  
Apostolia-Maria Tsimberidou ◽  
William Wierda ◽  
William Plunkett ◽  
Susan O'Brien ◽  
Thomas J. Kipps ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Research Funding ◽  
Response Rates ◽  
Off Label ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Abstract 3443 Poster Board III-331 Introduction The first Phase I-II clinical trial of oxaliplatin, fluradabine, cytarabine (Ara-C), and rituximab (OFAR1) demonstrated significant activity in refractory CLL and RS (Tsimberidou et al, J Clin Oncol, 2008;26:196). To enhance the response rate and decrease myelosuppression, the dose of oxaliplatin was increased to 30mg daily, the dose of Ara-C was decreased to 0.5g/m2 daily and the optimal number of days of fluradabine and Ara-C administration was explored (OFAR2). Methods In a Phase I-II study of OFAR2, patients were treated with oxaliplatin 30mg/m2, D1-4; fludarabine 30mg/m2, Ara-C 0.5g/m2; rituximab 375mg/m2, D3; and pelfigrastim 6mg, D6. Fludarabine and Ara-C were given on D2-3 (dose level 1) D2-4 (dose level 2) or D2-5 (dose level 3); courses were repeated every 4 weeks. Patients received prophylaxis for tumor lysis, DNA viruses, and PCP. A “3+3” design was used and the planned number of patients in the Phase II was 90 (CLL, 60; RS, 30). Results Ninety-one patients (CLL, 67; RS, 24) have been treated to date: Phase I, 12 patients (by dose level: 1, n=3; 2, n=6; and 3, n=3). DLTs were noted in 2 of 3 patients on dose level 3 (G4 diarrhea, 1; G4 neutropenic sepsis, 1); thus, dose level 2 was the MTD. Seventy-nine patients (relapsed CLL, 58; RS, 19) have been treated in the Phase II portion of the study. Patient characteristics were as follows: age > 60 years, 65%; 17p deletion, 38%; 11q deletion, 13%; 13q deletion, 16%; trisomy 12, 21%; no findings, 12%; unmutated IgVH, 80%; ZAP70-positive, 75%; and CD38 ≥30%, 58%. Response in patients treated in the Phase II recommended dose is shown in Table (evaluable, 67). The overall response rates in patients with 17p and 11q deletions were 48% and 55%, respectively. The median survival duration was 21 months (CLL, 21 months; RS, 9.5 months). At 18 months, the survival rates in patients with 17p and 11q deletions were 66% and 76%, respectively. Twelve patients underwent stem cell transplantation after OFAR2 (as post-remission therapy, n=10; as salvage, n=2). Overall, 196 cycles were administered. Grade 3-4 neutropenia, thrombocytopenia, and anemia were noted in 63%, 72%, and 39% of patients and in 57%, 70%, and 25% of cycles and Grade 3-4 infections in 19% of patients. Conclusion Preliminary results demonstrated that OFAR2 induced response in 40% of patients with RS and 63% of patients with relapsed/refractory CLL. OFAR2 had antileukemic activity in patients with 17p deletion. Clinical outcomes appeared to be superior to those of OFAR1 in refractory CLL, whereas results of OFAR1 appeared to be superior to those of OFAR2 in RS. Accrual is ongoing. Disclosures Tsimberidou: ASCO: ASCO Career Development Award; Sanofi: Research Funding. Off Label Use: Oxaliplatin is used off-label. Wierda:Genentech: Honoraria; Bayer, Sanofi-Aventis, Abbott, GSK: Research Funding; GSK, Trubion, Ligand, Genentech, Medimmune, Abbot: Consultancy; Celgene: Speakers Bureau. Plunkett:Sanofi-Aventis: Research Funding. O'Brien:Genentech: Research Funding; Sanofi: Consultancy. Kipps:NCI: Grant P01CA-81534.

T3 : A Multicenter Phase IB Dose Escalation Study to Evaluate the Safety, Feasibility and Efficacy of the Temsirolimus (Torisel™)-CHOP-Rituximab (T-R-CHOP), Temsirolimus (Torisel™)-FC-Rituximab (T-R-FC) and Temsirolimus (Torisel™)- DHA-Rituximab (T-R-DHA) for the Treatment of Patients with Relapsed/Refractory Mantle Cell Lymphoma (MCL), a Lysa Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4426-4426
Author(s):  
Steven Le Gouill ◽  
Krimo Bouabdallah ◽  
Guillaume Cartron ◽  
Remy Gressin ◽  
Thierry Lamy ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Chemotherapy Regimen ◽  
Cell Lymphoma ◽  
Dose Escalation Study ◽  
Phase Ib ◽  
Multicenter Phase ◽  
Mantle Cell ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract The T3 trial is a multicenter Phase IB dose escalation study that evaluates the safety, feasibility and efficacy of three Temsirolimus-based chemotherapy regimens: Temsirolimus(Torisel™)-CHOP-Rituximab (T-R-CHOP), Temsirolimus(Torisel™)-FC-Rituximab (T-R-FC) and Temsirolimus(Torisel™)-Dexamethasone-aracytine-Rituximab (T-R-DHA) for the treatment of patients with relapsed/refractory Mantle Cell Lymphoma (MCL). The choice of the chemotherapy regimen was left to the decision of local investigator. The primary objective of the T3 was to assess the feasibility and incidence of dose limiting toxicities (DLT) during the two first cycles for each chemotherapy regimen in order to determine the maximal tolerate dose (MTD) in a 3+3 dose escalating design. Dose levels of Temsirolimus (administrated at D2, 8 and 15) were as followed: 25mg level 1; 50mg level 2 and 75mg level 3 and 15 mg in level -1. Patients were planned to receive at least 4 cycles. After 4 cycles, response was evaluated and then patients could continue treatment for 2 additional cycles or receive another treatment according to investigator’s decision. The T3 trial started in November 2011 and so far 38 patients have been enrolled (32 patients are evaluable to date; median age of 69y; range 56 -79). Before inclusion into the T3 trial, patients had received a median of 1 (range 1-3) line of treatment including autologous stem cell transplantation in 15 cases. Nine patients were included in the R-CHOP group (ORR after 4 cycles was 55,6%). In level 1, two patients out of 3 experimented DLT (grade 3: lymphopenia and GI hemorrhage). In level -1 (n=6), one DLT has been reported (grade 3 thrombocytopenia). In the T-R-FC group (n=12; ORR after 4 cycles was 41,7%), 6 patients were included in level 1 and 3 experimented DLT (grade 3: thrombocytopenia and leukopenia). In cohort -1 (n=6), 4 DLTs were reported. Eleven patients were included in the T-R-DHA group (ORR after 4 cycles was 80%). One DLT was suspected during toxicity review in level 1 (n=3) and was not confirmed as a DLT by the Safety Committee, hence the decision to pass to superior dose level. Then 6 patients (3+3) were included in level 2 (50mg) where 1 DLT was reported. However, only one patient received complete schema of temsirolimus with 3 injections because of hematology toxicity. Thus, it has been decided to add 3 additional patients at level 1 (25mg). These patients are currently under treatment. In conclusion, hematological toxicity grade 3 was the major concern of the three temsirolimus-based chemotheprapy regimen. Administration of Temsirolimus at D15 was frequently skipped. However, 51,6% of patients reached at least a PR after 4 cycles and the T-R-DHA group was the safest, in which, 50% of patients reached CR after 4 cycles. Thus, Temsirolimus plus high dose aracytine based-chemotherapy regimens provides good disease control with an acceptable tolerability profile for patients with relapsed MCL. Disclosures Le Gouill: pfizer: Honoraria; mundipharma: Honoraria; roche: Honoraria; celgene: Consultancy, Honoraria; janssen-cilag: Honoraria. Coiffier:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Preliminary Safety and Efficacy of the Combination of Brentuximab Vedotin and Ipilimumab in Relapsed/Refractory Hodgkin Lymphoma: A Trial of the ECOG-ACRIN Cancer Research Group (E4412)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 585-585 ◽  
Author(s):  
Catherine S. Diefenbach ◽  
Fangxin Hong ◽  
Jonathon B. Cohen ◽  
Michael J. Robertson ◽  
Richard F. Ambinder ◽  
...  
Keyword(s):  
Dose Level ◽  
Dose Escalation ◽  
Research Funding ◽  
Checkpoint Inhibitor ◽  
Sensory Neuropathy ◽  
Peripheral Sensory Neuropathy ◽  
Level 1 ◽  
Grade 3 ◽  
Peripheral Sensory ◽  
Level 2

Abstract Background: Despite advances in chemotherapy, R/R HL remains a significant clinical problem with over 1,000 primarily young lives lost annually. HL is a unique tumor in which a small number of malignant Hodgkin Reed-Sternberg (HRS) cells propagate an immunosuppressive microenvironment that augments HRS growth and survival. We hypothesized that immune checkpoint inhibitor therapy could activate the tumor immune microenvironment, while the CD30 expressing HRS cells could be targeted by brentuximab vedotin (BV), thereby overcoming tumor cell resistance and deepening clinical responses. E4412 is a phase 1 ECOG-ACRIN sponsored study of the combination of BV and the checkpoint inhibitors ipilimumab (IPI) and nivolumab (NIVO) in patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL). Here we report the data on the patients treated with BV + IPI, the first cohort of the study. Methods: Patients with biopsy proven R/R HL were treated with BV 1.8mg/kg and two escalating doses of IPI: 1 mg/kg or 3mg/kg. After safety was determined an expanded cohort was treated with BV 1.8mg/kg IV and IPI 3mg/kg IV. The schedule consisted of BV administered every 21 days for 16 cycles and IPI every 21 days x 4 doses and thereafter every 3 months for up to a year. Dose limiting toxicity (DLT) was defined for purposes of dose escalation within the first cycle of therapy. Patients are followed for toxicity up to 30 days beyond their last treatment. Results: As of 7/2015 19 of 23 planned patients have been treated with BV + IPI. We report the data on the full dose escalation population (13 patients: Dose level 1 (6), Dose level 2 (7)). The median age was 33 years (range: 20-49). Seven patients were male. Patients were heavily pretreated with a median of 4 prior therapies (2-13). Fourpatients had prior treatment with BV; 8 patients had prior SCT (7 autologous, 1 allogeneic). Safety: Overall the regimen of BV + IPI was extremely well tolerated with no DLTs noted during dose escalation. Toxicities considered at least possibly related to drug during any cycle of treatment are shown according to grade in Table 1. The most common treatment related adverse events were: diarrhea, rash, and peripheral sensory neuropathy. Other AEs of interest included: alopecia, transaminitis, and uveitis. Grade 3 and 4 treatment related adverse events (AEs) included: Dose level 1: one grade 3 infusion reaction, which led to a protocol amendment to include premedication, no further grade 3 infusion reactions were noted; Dose level 2: one each: grade 3 rash, vomiting, and peripheral sensory neuropathy, and one grade 4 thrombocytopenia in patient with pre-existing thrombocytopenia. Response: For the 12 evaluable patients, the overall response (ORR) for the combination of BV + IPI was 67% with a complete response (CR) rate of 42% (5 of 12 patients). An additional 2 patients had stable disease (SD) giving a clinical benefit rate of 83%. Three of 5 of the CRs occurred at dose level 1 (1mg dose of IPI). The median progression free survival (PFS) is 0.74 years with a median follow-up of 0.66 years. Conclusion: In this first reported study of the combination of checkpoint inhibitor and ADC, toxicity was low, primarily grades 1 and 2. In a heavily pretreated patient population, 33% of whom had had prior BV and 67% of whom were s/p ASCT, the ORR of 67% and CR rate of 42% suggests a potential deepening of response compared to monotherapy. More than half of these CRs occurred at 1mg of IPI suggesting that in combination with ADC, low doses of immune stimulation may be highly active. Optimization of this combination strategy is planned with ongoing accrual to cohorts receiving BV + NIVO, and BV + IPI + NIVO. Data will be updated to include the full BV + IPI cohort by the time of the annual meeting. Table 1. Common and Immune Toxicities Toxicity Type Dose Level 1 (n=6) Dose Level 2 (n=7) Grade Grade 1,2 3 4 5 1,2 3 4 5 (n) (n) (n) (n) (n) (n) (n) (n) Fatigue 5 - - - 3 - - - Fever 1 - - - 3 - - - Pain 2 - - - 3 - - - Alopecia 2 - - - 1 - - - Pruritus 1 - - - 2 - - - Rash maculo-papular 4 - - - 2 1 - - Diarrhea 4 - - - 4 - - - Dyspepsia 2 - - - 1 - - - Nausea 6 - - - 4 - - - Vomiting 3 - - - 2 1 - - Papulopustular rash 1 - - - 1 - - - Alanine aminotransferase increased 3 - - - 3 - - - Aspartate aminotransferase increased 3 - - - 2 - - - Platelet count decreased - - - - - - 1 - Anorexia 3 - - - - - - - Headache 2 - - - 2 - - - Peripheral sensory neuropathy 5 - - - 4 1 - - Dry eye 2 - - - - - - - Uveitis 1 - - - - - - - Cough 2 - - - 1 - - - Disclosures Diefenbach: Molecular Templates: Research Funding; Immunogen: Consultancy; Celgene: Consultancy; Idera: Consultancy; Jannsen Oncology: Consultancy; Gilead: Equity Ownership, Research Funding, Speakers Bureau; Incyte: Research Funding; Genentech: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Off Label Use: Presentation will discuss the experimental use of the checkpoint inhibitor Ipilimumab in relapsed/refractory Hodgkin lymphoma.. Cohen:Celgene: Consultancy; Millennium: Consultancy; Pharmacyclics: Consultancy; Seattle Genetics: Consultancy; BMS: Research Funding; Janssen: Research Funding. Robertson:Eli Lilly: Equity Ownership. Fenske:Pharmacyclics: Honoraria; Seattle Genetics: Honoraria; Millennium/Takeda: Research Funding; Celgene: Honoraria. Kahl:Roche/Genentech: Consultancy; Seattle Genetics: Consultancy; Millennium: Consultancy; Cell Therapeutics: Consultancy; Celgene: Consultancy; Infinity: Consultancy; Pharmacyclics: Consultancy; Juno: Consultancy. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding.

Docetaxel and capecitabine for previously treated metastatic colorectal cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13579-13579
Author(s):  
T. E. O’Brien ◽  
E. Newton ◽  
J. Trey ◽  
E. Crum
Keyword(s):  
Colorectal Cancer ◽  
Phase I ◽  
Dose Level ◽  
Low Dose ◽  
Metastatic Breast ◽  
Human Colon Cancer ◽  
Level 3 ◽  
Previously Treated ◽  
Level 1 ◽  
Level 2

13579 Background: Docetaxel (D) induces human colon cancer cell lines to upregulate thymidine phosphorylase, an enzyme which activates capecitabine (C) to its cytotoxic form. This provided rationale for adding low dose D to C in patients with colorectal cancer (CRC). Although this combination has been established in metastatic breast cancer, it has not been evaluated in CRC. Because of concerns of toxicity in a pretreated population, we performed a phase I trial in patients with previously treated CRC. Methods: Eligibility: At least 1 prior treatment for metastatic disease; ECOG PS 0–1; adequate organ function. Design: Phase I, dose escalation. D, IV, days 1 & 8, and C, PO BID days 5–18, repeated q21days. Dose Level 1: D=15mg/m2, C=1000mg/m2; Level 2: D= 15 mg/m2, C= 1100 mg/m2; Level 3: D= 20 mg/m2, C= 1100 mg/m2; Level 4: D=20mg/m2, C=1250mg/m2. Results: 13 patients have thus far been treated. 11 are evaluable for toxicity and 10 for response (1 at dose level 4 was taken off study due to non-compliance before completion of cycle 1; another died of progressive cancer before completing cycle 1 at dose level 4; another is evaluable for toxicity but not yet for response). 9 with colon, 4 with rectal primary sites. Median follow-up= 5 mo (1–19 mo). Med age= 59 (30–75); #prior regimens for met disease 1–2, all of which were 5-FU based. Toxicities No dose limiting toxicities (DLT) until Dose Level 4. Dose Level 1: 1/3 developed grade 2 diarrhea and hand-foot syndrome and delayed grade 3 hand-foot; Dose Level 2: 2/3 developed grade 2 toxicities (hand-foot in one and diarrhea in the other); Dose Level 3: 1/3 developed delayed grade 2 hand-foot; Dose Level 4: 1 patient with delayed grade 2 hand-foot and grade 1 eye tearing; another developed DLT (grade 4 stomatitis/dehydration). Response 6/10 patients progressed after 2 cycles; 2 pts had stable disease, one lasting 4.6 mo; 2 patients had a partial response, one of which lasted 9 mo. The latter case had refractory disease to FOLFOX 4 but a 78% reduction in her liver metastases to D+C. Conclusions: The combination of low dose docetaxel, used as chemosensitizing agent, with capecitabine in this pretreated group of patients with metastatic CRC appears to be well tolerated, with no DLTs seen until Dose Level 4, and has modest activity. MTD determination awaits further accrual. No significant financial relationships to disclose.

Phase I study of vorinostat (suberoylanilide hydroxamic acid, SAHA) in patients (pts) with non-Hodgkin lymphoma (NHL) in Japan

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18521-18521 ◽  
Author(s):  
K. Tobinai ◽  
T. Watanabe ◽  
Y. Kobayashi ◽  
S. Yamasaki ◽  
Y. Morita-Hoshi ◽  
...  
Keyword(s):  
Phase I ◽  
Cell Lymphoma ◽  
International Workshop ◽  
B Cell Lymphoma ◽  
Clinical Activity ◽  
Non Hodgkin Lymphoma ◽  
T Cell Lymphomas ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

18521 Background: Vorinostat (Zolinza™), a potent histone deacetylase inhibitor, has demonstrated clinical activity in pts with cutaneous T-cell lymphomas (CTCL) and other NHL subtypes. However, the clinical activity and PK profile in Japanese pts with NHL was unknown. Methods: Japanese pts with NHL were sequentially enrolled in two dose levels ranged from 100 (Level 1) - 200 mg (Level 2) BID, PO for 14 consecutive days every 3 wks. Higher doses were not tested as other phase I studies had established that 300 mg BID for 14 consecutive days every 3 wks exceeded the MTD. PK profiles were analyzed in serum and urine samples. Response was also evaluated according to the international workshop criteria. Results: Ten pts were enrolled: 9 were evaluable for toxicity. One was excluded due to noncompletion of the 1st cycle. All were evaluable for PK. Median age was 60 yrs (range 52–74). Four pts had follicular lymphoma (FL), 2 mantle cell lymphoma (MCL), 2 diffuse large B-cell lymphoma and 2 CTCL. Median no. of prior regimens was 3 (1–4). In the 1st cycle, none of 3 pts at Level 1 and 1 of 6 pts at Level 2 developed DLTs (anorexia and hypokalemia of grade 3), indicating Level 2 to be the MTD in this setting. PK was not greatly affected by multiple doses. Intact drug was hardly excreted in urine (<1% of dose). PK profile is similar to that established in US pts. As of Dec 2006, 4 pts were continuing treatment (median 5 mos [1–15]). Two pts with FL showed PR for 8+ and 2+ mos, respectively, and the remaining 1 pt with FL and 1 of 2 pts with MCL showed tumor reduction greater than 30%. Conclusions: Oral vorinostat was well tolerated up to 200 mg BID for 14 consecutive days every 3 wks in Japanese pts with NHL. Preliminary observations of clinical efficacy warrant further investigations for NHL focusing on FL and MCL. No significant financial relationships to disclose.

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