scholarly journals Phase I Trial of Rituximab, Cladribine and Temsirolimus (RCT) for Initial Therapy of Mantle Cell Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3661-3661 ◽  
Author(s):  
David J. Inwards ◽  
Paul Fishkin ◽  
Betsy R. LaPlant ◽  
Matthew T. Drake ◽  
Paul Kurtin ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Mantle Cell Lymphoma ◽  
Dose Level ◽  
Cell Lymphoma ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Mantle Cell ◽  
Grade 3 ◽  
Dose Levels

Abstract Abstract 3661 Objective: We conducted this trial to determine the maximum tolerated dose (MTD) and schedule of temsirolimus added to an established regimen comprised of rituximab and cladribine for the initial treatment of mantle cell lymphoma and to generate preliminary information on the toxicity and efficacy of this combination. Methods: A standard phase I cohort of 3 study design was utilized. MTD was defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients (at least 2 of a maximum of 6 new patients). DLT was defined as grade 4 ANC (<500) for ≥5 days, grade 4 ANC (<500) associated with fever (>100.5 F) and/or active infection, PLT <25,000, grade 4 infection, or ≥grade 3 non-hematologic toxicity during the first cycle of therapy as per NCI Common Terminology Criteria for Adverse Events v3.0. The fixed doses of rituximab and cladribine were 375 mg/m2 IV day 1 and 5 mg/m2/d IV days 1–5 of a 28 day cycle, respectively, as previously published. There were 5 planned temsirolimus IV dose levels: 15 mg day 1; 25 mg day 1; 25 mg days 1 and 15; 25 mg days 1,8 and 15; and 25 mg days 1,8,15, and 22. The fifth dose level is as previously published in combination with rituximab. Results: A total of 17 patients were treated: 3 each at dose levels 1–4 and 5 at dose level 5 (25 mg temsirolimus days 1,8,15, and 22). The median age was 75 years (52–86). There were 11 males and 6 females. At presentation 88% had stage IV disease, and 94% had extranodal disease. MIPI scores were low in 6% (1 patient), intermediate in 59% (10 patients), and high in 35% (6 patients). There was a single DLT recorded at dose level 3 based on the initial DLT criteria, though this cytokine release syndrome was clearly rituximab related, and occurred prior to the first dose of temsirolimus. Five patients were treated at the highest planned temsirolimus dose level (25 mg days 1,8,15, and 22) with no DLT observed. No further dose escalation was planned, and this level was determined to be tolerated, though higher levels may be tolerable. All patients were evaluable for adverse events. Hematologic toxicity was frequent, with grade 3 anemia in 12% of patients, grade 3 thrombocytopenia in 35%, grade 4 thrombocytopenia in 30%, grade 4 lymphopenia in 47%, grade 3 neutropenia in 24%, and grade 4 neutropenia in 18% of patients. There were 3 thrombotic episodes, 2 of which were attributed to therapy, and 3 episodes of pneumonitis. The overall response rate was 94% with 53% CR and 41% PR. The median progression free survival was 18.7 months. Conclusions: Temsirolimus 25 mg IV weekly may be safely added to rituximab and cladribine at 375 mg/m2 IV day 1 and 5 mg/m2/d IV days 1–5 of a 28 day cycle, respectively. This regimen had promising preliminary activity in an elderly cohort of patients with mantle cell lymphoma. Disclosures: Off Label Use: Temsirolimus for mantle cell lymphoma.

scholarly journals A Phase I Trial of Ibrutinib Plus Palbociclib in Patients with Previously Treated Mantle Cell Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 150-150 ◽  
Author(s):  
Peter Martin ◽  
Kristie Blum ◽  
Nancy L. Bartlett ◽  
Steven I. Park ◽  
Kami J. Maddocks ◽  
...  
Keyword(s):  
Phase I ◽  
Mantle Cell Lymphoma ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Hematological Toxicity ◽  
Mantle Cell ◽  
Previously Treated ◽  
Grade 3 ◽  
Dose Levels

Abstract Background Single-agent ibrutinib confers a response rate of 77%, including a complete response (CR) rate of 19% in patients with previously treated mantle cell lymphoma (MCL); however, with a median progression-free survival (PFS) of 14.6 months and 1-year response duration (RD) rate of 69%, nearly half of all patients experience treatment failure during the first year. We previously demonstrated that prolonged early G1 cell cycle arrest induced by the oral, specific CDK4/6 inhibitor palbociclib can overcome ibrutinib resistance in primary human samples and MCL cell lines with wild-type BTK (Chiron et al. Cancer Discovery 2014). We conducted a phase I trial to evaluate the safety and preliminary activity of palbociclib plus ibrutinib in patients with previously treated mantle cell lymphoma. Methods Adult patients who were ibrutinib and CDK4/6 inhibitor-naïve who had previously treated MCL were eligible to participate. The primary objective was to estimate the maximum tolerated dose of the combination. Consenting patients were enrolled to one of five dose levels, shown in Table 1. Patients were treated in 28 day cycles, with ibrutinib administered daily and palbociclib administered on days 1-21. (Table 1). Patients could continue to receive study treatment until progression, unacceptable toxicity, or withdrawal of consent. Doses were escalated according to a standard phase I 3+3 design. Patients were evaluated for efficacy at the end of cycles 3 and 6, and every 6 cycles thereafter. All CRs, as documented by CT, required confirmation by PET/CT; bone marrow biopsy and endoscopy were also required in patients with known marrow or GI tract involvement, respectively. Additional objectives included pharmacokinetics and evaluation of pretreatment samples for biomarkers of response or resistance. Results From August 2014 to June 2016 a total of 20 patients (15 males, 5 females) were enrolled (DL1 n=3, DL2 n=3, DL3 n=6, DL4 n=3, DL5 n=5). The patients' MIPI risk distribution were 7 low, 7 intermediate, and 6 high. The median number of prior therapies was 1 (range 1-5). Six patients were refractory to their last prior therapy. Three patients experienced dose limiting toxicity: One patient treated at DL3 experienced grade 4 thrombocytopenia lasting more than 7 days, and grade 3 rash was seen in two patients at DL5. Grade 3-4 hematological toxicity included thrombocytopenia (28%), neutropenia (22%), and lymphopenia (17%). Grade 3-4 non-hematological toxicity regardless of attribution included one patient with each of the following: lung infection, ALT/AST increase, encephalitis, hyponatremia, sinus tachycardia, pneumonitis. Grade 1-2 adverse events related to treatment and occurring in at least 2 patients included the following: diarrhea (50%), fatigue (44%), rash (39%), bruising (17%), nausea (17%), fever (11%), dyspepsia (11%), and myalgia (11%). Other than the two patients that experienced grade 3 rash at DL5, no patients have required dose reductions; 6 patients required dose interruptions. Thirteen subjects continue on study therapy. The reasons for stopping treatment were disease progression (n=4), adverse event (elevated liver enzymes, n=1; and prolonged cytopenias, n=1), and allogeneic stem cell transplantation (n=1). Of the 18 patients that have had at least one response evaluation to date, 12 (67%) patients responded to treatment and 8 (44%) achieved a CR. The median time to CR was 3 cycles and no responding patients have progressed on study. With a median follow up of 11 months, the estimated 1-year PFS and RD are 68% and 100%, respectively (Figure 1). Conclusions The mechanism-based combination of ibrutinib plus palbociclib is well tolerated and active. Toxicity is primarily related to myelosuppression of grade 1-2 severity, although grade 3 rash was observed at the highest doses evaluated. In this small group of patients, the combination produced responses at all dose levels, with a CR rate of 44% and a median time to CR of 3 months. No responding patients have progressed to date. These preliminary CR, PFS, and RD rates appear better than those reported in other studies of single-agent ibrutinib although the numbers of patients was very small. A phase II multi-center clinical trial to evaluate time to progression is planned. Biomarker studies to evaluate mechanisms of primary resistance are ongoing. Disclosures Martin: Janssen: Consultancy, Honoraria, Other: travel, accommodations, expenses; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Other: travel, accommodations, expenses; Novartis: Consultancy; Acerta: Consultancy; Teva: Research Funding. Ruan:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics, LLC, an AbbVie Company: Research Funding, Speakers Bureau; Janssen: Research Funding.

Phase I Study of Noscapine for Patients with Non-Hodgkin’s Lymphoma or Chronic Lymphocytic Leukemia Refractory to Chemotherapy.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3341-3341
Author(s):  
Anil Tulpule ◽  
Alexandra M. Levine ◽  
Nancy E. Berman ◽  
Lynne Smith ◽  
Alan Auerbach ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Phase I ◽  
Mantle Cell Lymphoma ◽  
Dose Level ◽  
Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Hodgkin's Lymphoma ◽  
Mantle Cell ◽  
Grade 3 ◽  
Grade Iii

Abstract Noscapine is an alkaloid derived from opium, which lacks sedative, euphoric, analgesic or respiratory depressant properties. Antitumor activity of Noscapine has been demonstrated both in vivo, against human lymphoid tumor cells, and in vitro, in human tumors implanted in athymic mice. Noscapine induces conformational changes in tubulin, which results in altered microtubule assembly. In this Phase I trial, cohorts of subjects with relapsed/refractory non-Hodgkin’s lymphoma (NHL) or chronic lymphocytic leukemia (CLL/SLL) were treated at three different dose levels of total daily doses of 1 g, 2 g, and 3 g. At each dose level the drug was administered orally on a three times a day schedule. The total duration of treatment was 49 days. Results: Twelve subjects with a median age of 65 years (range 38–71) have been accrued. Four subjects had CLL/SLL, 2 had mantle cell lymphoma, one had follicular grade III, 4 had DLC, and one had lymphoplasmacytic low grade lymphoma. 10 subjects are evaluable for response. Partial response was seen in 1 subject with follicular grade III disease. The duration of this PR is 56+ months. Stable disease was seen in a case of mantle cell lymphoma (duration 30 days) and a case of DLC (duration 77 days). The remaining 7 subjects had progression of disease. Noscapine has been well tolerated, with no grade 3 or 4 hematological toxicities. One grade 3 neurotoxicity consisting of depressed level of consciousness was experienced at the 3 g dose level. We conclude that a larger study of Noscapine is warranted to evaluate the efficacy of the compound in patients with lymphoma. The oral formulation, suggestion of efficacy and relative lack of toxicity make Noscapine an attractive candidate for further study.

Rituximab, Lenalidomide, and Bortezomib in the First-Line or Second-Line Treatment of Patients with Mantle Cell Lymphoma a Phase I/II Trial.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2748-2748 ◽  
Author(s):  
Ian W. Flinn ◽  
Mark Mainwaring ◽  
Nancy Peacock ◽  
Dianna Shipley ◽  
Edward Arrowsmith ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Mantle Cell Lymphoma ◽  
Phase Ii ◽  
Cell Lymphoma ◽  
Drug Regimen ◽  
Prior Treatment ◽  
Hematologic Toxicity ◽  
Mantle Cell ◽  
Grade 3

Abstract Abstract 2748 Background: Mantle cell lymphoma (MCL) is a relatively rare but aggressive form of B-cell non-Hodgkin lymphoma (NHL) which is incurable with standard chemotherapy. Treatment options range from observation to allogeneic hematopoetic stem cell transplantation. The optimal therapy remains to be defined. Combination cytotoxic chemotherapy regimens containing anthracyclines such as R-CHOP or R-hyperCVAD used in other forms of lymphoma are clearly active. However, there appears to be a trade-off between intensity of the treatment and durability of the remission making delivery of the higher intensity, durable regimens difficult in some populations such as the elderly. Bortezomib (BOR) and lenalidomide (LEN) are commonly used in multiple myeloma and have also demonstrated activity in lymphoma including MCL. Rituximab (RIT) is effective in a broad array of CD20 positive lymphomas. The purpose of this study was to develop an effective, non-anthracycline containing treatment regimen that could be delivered to a broad patient population. Methods: Eligible patients had biopsy-proven MCL, ≤1 prior therapy, ECOG performance status of 0, 1, or 2, and adequate organ and bone marrow function. A brief phase I portion established the MTD. Dose limiting toxicities were defined as: grade 4 neutropenia or febrile neutropenia, grade 4 thrombocytopenia or platelet transfusion, uncontrolled grade 3 nausea or diarrhea, any clinically significant grade 3/4 treatment-related non-hematologic toxicity, or the inability to start Cycle 2 due to treatment related toxicity. Dose limiting toxicity in the phase I portion of this study occurred at 15mg of LEN on days 1–14 followed by 7 days of rest: 1pt with grade 4 neutropenia and grade 3 neuropathy, and 1 pt with grade 3 total body rash resulting in hospitalization. Based on these events phase II dosing was established at: LEN 10mg PO daily on days 1–14, BOR 1.3mg/m2 IV (days 1, 4, 8 and 11), and RIT 375mg/m2 (days 1, 8, and 15 of cycle 1; 375mg/m2on day 1 of subsequent cycles). Treatment was repeated every 21 days for a maximum of 6 cycles. Patients were assessed for response by International Lymphoma Response Criteria (Cheson 2007) after completing cycles 3 and 6. Phase II study objectives included: assessments of safety and tolerability of this three-drug regimen, and a preliminary estimate of efficacy. Results: Between June 2008 and May 2012, 22 patients were enrolled with a median age 66 years; (range 18–80) and are included in this analysis. Eighteen patients (82%) were stage IV at diagnosis, and 16 (78%) patients had not received prior treatment. At the time of this analysis, 11 patients (50%) completed treatment, and 3 additional patients (14%) remain active. Grade 3/4 thrombocytopenia and neutropenia were reported in 5 (23%) and 4 (18%) patients, respectively. Treatment related Grade 3/4 non-hematologic toxicity included: rash (32%), neuropathy (18%), dehydration (14%), and fatigue (14%). Three patients (14%) discontinued treatment due to toxicity (1 each: septic shock, neuropathy, cardiac ischemia/infarction). Eighteen patients were evaluable for response. The overall response rate was 82% (CR 32%, PR 50%). Of the 16 patients that received no prior treatment, the ORR was 75% (CR 25%, PR 50%). The median FU was 16 months (1–38) months. Kaplan-Meier estimates of all patients for progression-free and overall survival at 18 months are 61% and 79% respectively. Conclusion: The MTD of LEN in combination with BOR and RIT is less than LEN and BOR combinations in multiple myeloma. The three-drug regimen of RIT, BOR, and LEN is feasible in older as well as younger patients with MCL. Given the incidence of neuropathy, subcutaneous or less frequent IV dosing of BOR is worthy of investigation rather than the twice-weekly IV BOR used in this study. Preliminary estimates of efficacy indicate that this regimen is active, and warrants further study. Disclosures: Off Label Use: Off-lable use of Lenalidomide, and Bortezomib in the treatment of Mantle Cell Lymphoma.

scholarly journals Temsirolimus in Combination with Three Different Immuno-Chemotherapy Regimens in Relapse and Refractory Mantle Cell Lymphoma, Final Results of the T3 Phase IB Trial of the Lysa Group

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2987-2987 ◽  
Author(s):  
Steven Le Gouill ◽  
Krimo Bouabdallah ◽  
Barbara Burroni ◽  
Thierry Lamy ◽  
Remy Gressin ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Board Of Directors ◽  
Dose Level ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Maximum Tolerated Dose ◽  
Advisory Committees ◽  
Phase Ib ◽  
Mantle Cell ◽  
Grade 3

Abstract Temsirolimus has shown clinical activity in heavily pretreated patients with mantle cell lymphoma (MCL) leading to evaluate tolerability and efficacy of combinations regimens. The T3 trial is a multicenter, Phase IB, dose escalation study (3+3) of Temsirolimus administered in combination with three chemotherapy regimens in relapse or refractory (R/R) mantle cell lymphoma (MCL) patients. The primary objective was to determine the maximum tolerated dose (MTD). DLT was assessed during the first two cycles. Study design: Temsirolimus was added for 6 cycles to R-CHOP (R-CHOP-T) administered every 3 weeks or to or R-FC (R-FC-T) and R plus high dose cytarabine and dexamethasone (R-DHA-T) administered every 4 weeks. Temsirolimus was administered IV at day 2, 8 and 15. Three dose levels of Temsirolimus was tested: 15 mg, 25 mg (starting dose) and 50 mg. Patients were treated with one of these 3 chemotherapy regimens according to the choice of local investigator and no randomization was performed. LYSARC was the sponsor and the trial was conducted with a financial support of Pfizer Results: forty-one patients (R-CHOP-T n=10; R-FC-T n=14 and R-DHA-T, n=17)were enrolled. At time of inclusion, median age of patients was 68y (56-79), 32 patients were male, median time from last therapy to inclusion was 23,1m (2-143), MIPI score was low in 8, intermediate in 13 and high in 19 cases (missing=1). Previous lines of treatment included autologous stem cell transplantation in 18 patients. Among patients treated in the R-CHOP-T arm, all patients (n=4) presented grade 3 toxicities at the 25mg dose level. At the 15mg dose level (n=6), one DLT occurs (Thrombopenia). Consequently, the maximum tolerated dose (MTD) of Temsirolimus in the R-CHOP-T was 15 mg. Among patients of the R-FC-T arm (n=14) and R-DHA-T, the recommended dose of Temsirolimus has not been found because of toxicities that occurred at all Temsirolimus doses (25 and 15mg). Hematologic grade 3/4 toxicities were the most frequent, mainly thrombocytopenia (n=28). In term of efficacy, ORR (CR/CRu/PR) during treatment period was 40% for R-CHOP-T including 2 patients who reached CR, 35,7% for R-FC-T including 3 patients who reached CR and 47,1% for R-DHA-T including 6 patients who reached CR. For all patients, mFU is 30.5 m (23-39). The mPFS and mOS according to treatment arms and for all patients (n=41) are as followed: 15,1m and not reached for R-CHOP-T (n= 10); 8.6m and 17.8 m for R-FC-T (n=14) ; 11.9m and 24.2m for R-DHA-T (n=17). In conclusion, the recommended dose of Temsirolimus for R-CHOP-T is 15mg D1,8,15. We are not able to recommend a dose of Temisrolimus for both R-DHA-T and R-FC-T. Hematologic toxicity was the main concern in all arms. A good efficacy in term of response rates PFS and OS was observed in all arms suggesting that Temsirolimus-based chemotherapy regimen should be further investigated in prospective trials but dose of Temsirolimus should be carefully investigated. Disclosures Cartron: Roche: Consultancy, Honoraria; Celgene: Honoraria; Gilead: Honoraria; Jansen: Honoraria. Thieblemont:Roche: Consultancy; Gilead: Consultancy; Janssen: Consultancy. Haioun:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Casasnovas:ROCHE: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria. Hermine:AB science: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Celgene: Research Funding; Novartis: Research Funding; Alexion: Research Funding.

scholarly journals Ibrutinib, Obinutuzumab And Venetoclax In Relapsed and Untreated Patients with Mantle-Cell Lymphoma, a phase I/II trial

Blood ◽  
2020 ◽  
Author(s):  
Steven Le Gouill ◽  
Franck Morschhauser ◽  
David Chiron ◽  
Krimo Bouabdallah ◽  
Guillaume Cartron ◽  
...  
Keyword(s):  
Phase I ◽  
Mantle Cell Lymphoma ◽  
Residual Disease ◽  
Cell Lymphoma ◽  
Quantitative Polymerase Chain Reaction ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Positron Emission ◽  
Mantle Cell ◽  
Grade 3

Ibrutinib, obinutuzumab plus venetoclax demonstrate synergy in pre-clinical models of mantle-cell lymphoma (MCL). OAsIs (NCT02558816), a single-arm multi-center prospective phase I/II trial, aimed to determine the maximum tolerated dose (MTD) of venetoclax in combination with fixed doses of ibrutinib and obinutuzumab, in relapsed MCL patients. At the venetoclax MTD, extension cohorts were opened for relapsed and untreated patients. Safety and efficacy were secondary objectives. Minimal residual disease (MRD) was assessed by allele-specific oligonucleotide-quantitative polymerase chain reaction (ASO-qPCR). Between Oct 14, 2015 to May 29, 2018, forty-eight patients were enrolled. No dose limiting toxicity (DLT) was reported, and venetoclax at 400mg per day was chosen for extension. Eighteen (75%) relapsed and 8 (53%) untreated patients experienced grade 3/4 adverse events (AEs). The complete response rate assessed by positron-emission tomography at the end of cycle 6 was 67% in relapsed and 86.6% in untreated patients. MRD clearance for evaluable patients was seen in 71.5% of relapsed (10 out of 14) and 100% of untreated MRD-evaluable patients (n=12), at the end of three cycles. The median follow-up (mFU) for relapsed patients was 17 months (range, 10 to 35). The 2-years PFS was 69.5% (95% CI, 52.9- 91.4%) and 68.6% (95% CI, 49.5- 95.1%) for OS. The mFU was 14 months (range, 5 to 19) for untreated patients, the 1-year PFS was 93.3% (95% CI, 81.5- 100%). Obinutuzimab, ibrutinib and venetoclax combination is well tolerated and provides high response rates including at the molecular level in relapsed and untreated MCL patients.

Phase I study of temozolomide in children and adolescents with recurrent solid tumors: a report from the Children's Cancer Group.

1998 ◽  
Vol 16 (9) ◽  
pp. 3037-3043 ◽  
Author(s):  
H S Nicholson ◽  
M Krailo ◽  
M M Ames ◽  
N L Seibel ◽  
J M Reid ◽  
...  
Keyword(s):  
Phase I ◽  
Children And Adolescents ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Cancer Group ◽  
Grade 3 ◽  
Dose Levels ◽  
Dose Limiting Toxicity

PURPOSE The Children's Cancer Group conducted a phase I trial of temozolomide stratified by prior craniospinal irradiation (CSI). PATIENTS AND METHODS Children and adolescents with recurrent or progressive cancer were enrolled. Temozolomide was administered orally daily for 5 days, with subsequent courses administered every 21 to 28 days after full hematologic recovery. Dose levels tested included 100, 150, 180, 215, 245, and 260 mg/m2 daily. RESULTS Twenty-seven patients on the non-CSI stratum were assessable for hematologic toxicity. During the first three dose levels (100, 150, and 180 mg/m2 daily), only grades 1 and 2 hematologic toxicity occurred. One patient at 215 mg/m2 daily had grade 3 hematologic toxicity. Three of eight patients (38%) treated at 245 to 260 mg/m2 daily had dose-limiting toxicity (DLT), which included both neutropenia and thrombocytopenia. Twenty-two patients on the CSI stratum were assessable for hematologic toxicity. Hematologic DLT occurred in one of six patients (17%) at 100 mg/m2 daily and in two of four patients (50%) at 215 mg/m2 daily. No nonhematologic DLT occurred; nausea and vomiting occurred in more than half of the patients. After two courses of temozolomide, 10 patients had stable disease (SD), and three patients had a partial response (PR), one of whom subsequently had a complete response (CR) that persists through 24 months of follow-up. CONCLUSION The maximum-tolerated dose (MTD) of temozolomide for children and adolescents without prior CSI is 215 mg/m2 daily and for those with prior CSI is 180 mg/m2 daily for 5 days, with subsequent courses that begin on day 28. Temozolomide is well tolerated and should undergo phase II testing in children and adolescents.

Phase I-II Trial of Oral Cyclophosphamide, Prednisone and Lenalidomide (Revlimid®) (CPR) for the Treatment of Patients with Relapsed and Refractory Multiple Myeloma.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1723-1723
Author(s):  
Donna E. Reece ◽  
Esther Masih-Khan ◽  
Arooj Khan ◽  
Peter Anglin ◽  
Christine Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Oral Cyclophosphamide ◽  
Varicella Zoster ◽  
Refractory Multiple Myeloma ◽  
Grade 3 ◽  
Dose Levels

Abstract Oral cyclophosphamide and prednisone is a convenient regimen in relapsed and refractory multiple myeloma (MM), with a partial response (PR) rate of 40% and median progression-free survival of 19 months in our retrospective analysis of patients in first or second relapse after autologous stem cell transplantation (ASCT) (Trieu Y, et al, Mayo Clin Proc2005; 80: 1582). We sought to enhance the efficacy of this regimen by adding oral lenalidomide (Revlimid®), a potent anti-myeloma agent, in a phase I-II trial. The CPR regimen consisted of cyclophosphamide on days 1, 8 and 15, lenalidomide on days 1–21, and prednisone 100 mg every other day in a 28-day cycle. ASA 81 mg/day was given to all patients (pts) as prophylaxis for DVT. Three dose levels were evaluated using a 3 by 3 dose escalation design. Between 11/2007–07/2008, 15 pts with relapsed/refractory MM were entered onto study. Median age was 60 (45–78) years and 60% were male. Immunoglobulin subtype was IgGκ:λ in 10:1; IgA κ:λ in 2:1 and κ light chain in 1. Median number of prior regimens was 2 (1–3) and 14 had undergone previous ASCT, including double transplants in 2 pts. Prior therapy also included thalidomide in 3 (20%) and bortezomib in 6 (40%). FISH cytogenetics were available in 9, but none had 13q deletion, t(4;14) or p53 deletion. At the time of protocol entry, median β2-microglobulin level was 222 (92–325) nm/L, albumin 38 (35–46) g/L, creatinine 78 (50–100) μmol/L, platelet count 230 (93–318) x 109/L and ANC 2.5 (1.9–9.0) x 109/L. Protocol treatment is summarized in Table 1. Dose level N Cyclophosphamide dose (mg/m2) Lenalidomide dose (mg) Prednisone dose (mg) Median # cycles given 1 3 150 15 100 9 2 3 150 25 100 6 3 6 300 25 100 4 3 (expanded) 3 300 25 100 1 Dose limiting toxicity was not observed during cycle 1 at any of the dose levels and the maximum tolerated dose of this regimen has not yet been reached at the highest dose level planned; all pts remain on active therapy. Grade 3/4 thrombocytopenia was seen in 1 pt (cohort 2) and neutropenia in 4 pts (1 in cohort 1, 1 in cohort 2 and 2 in cohort 3) and were managed with dose reduction and/or growth factor support. No episodes of febrile neutropenia occurred in any pt. Only 1 pt experienced varicella zoster; routine antiviral prophylaxis was not used. Other grade 3/4 non-hematologic toxicities were uncommon and included abdominal pain/bacteremia in 1 pt in cohort 1, hypokalemia in 1 pt in cohort 2, and DVT in 1 pt in cohort 3. Mild grade 1/2 constipation (47%), muscle cramps (33%) and fatigue (33%) were also noted. To date, best response includes the following: dose level 1 (1 near complete remission [nCR], 2 PR); dose level 2 (3 PR); dose level 3 (4 PR, 2 minimal response [MR]); expanded cohort 3 (1 MR, 2 too early). We conclude: 1) the combination of full doses of the agents in CPR can be given in a 28-day cycle with minimal toxicity; 2) the overall response rate (nCR + PR + MR) in 13 evaluable pts to date is 87%; 3) no pts have progressed in this preliminary analysis; 4) longer follow-up is required to assess the long-term efficacy of this regimen.

Final Results of a Phase I Study of the Fc Engineered CD19 Antibody XmAb®5574 (MOR00208) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2894-2894 ◽  
Author(s):  
Jennifer A. Woyach ◽  
Farrukh Awan ◽  
Ian W. Flinn ◽  
Rolondo Enoch ◽  
Paul A. Foster ◽  
...  
Keyword(s):  
High Risk ◽  
Febrile Neutropenia ◽  
Adverse Events ◽  
Phase I ◽  
B Cell ◽  
Dose Level ◽  
Phase I Trial ◽  
Hematologic Toxicity ◽  
B Cell Malignancies ◽  
Dose Levels

Abstract Abstract 2894 Antibody (Ab) therapies such as the CD20 monoclonal abs rituximab and ofatumumab are commonly used in CLL alone and in combination with chemotherapy, however, CD20 density is low on CLL cells, suggesting this may not be the ideal target. CD19, which is ubiquitously expressed on CLL cells and those of other B cell malignancies is a reasonable candidate for ab targeting. XmAb5574 is a novel humanized IgG1 CD19 monoclonal ab with an engineered Fc region to enhance Fc gamma receptor binding affinity. In vitro, this ab demonstrates direct cytotoxicity and antibody dependent cellular phagocytosis similar to rituximab, however, shows enhanced natural killer antibody dependent cellular cytotoxicity compared to other therapeutic abs used in CLL (Awan, FT Blood 2009). We have performed a first in human trial of this ab as a single agent in relapsed or refractory (R/R) CLL, and present the results in this report. This study is a multi-institutional phase I trial of XmAb5574 in patients (pts) with R/R CLL. Eligible pts were those with CLL who had at least 1 prior therapy and required treatment by International Working Group on CLL (IWCLL) 2008 Guidelines (Hallek, M Blood 2008), had Eastern Cooperative Oncology Group Performance Status <3, had platelets ≥50,000/mm3, and had adequate organ function. Primary endpoints were to determine maximal tolerated dose (MTD), describe toxicity, and characterize pharmacokinetics (PK). A secondary endpoint was to explore efficacy. An accelerated titration design was used in which 1 pt was accrued to the first two dose levels provided there were no dose limiting toxicities (DLT) or ≥ grade 2 adverse events (AE), and then a standard 3×3 design was employed from dose level 3 forward. Dose levels included 0.3, 1, 3, 6, 9, and 12 mg/kg with an expansion to a total of 16 pts at the MTD. XmAb5574 was administered as an intravenous infusion on days 1, 4, 8, 15, and 22 of cycle (C) 1, and on days 1, 8, 15, and 22 of C2. Toxicity was assessed using the National Cancer Institute's Common Criteria for Adverse Events v4.0 for non-hematologic toxicity, and IWCLL 2008 guidelines for hematologic toxicity. Disease response assessment by physical exam was performed on C1D28, C2D28, and 4, 8, and 12 weeks after the end of C2. Radiographic assessment was performed C2D28. 27 pts were enrolled to this phase I trial. The median age of all pts was 66 years (range 40–84). The pts were generally high risk: 14 (52%) had high-risk disease by Rai stage, 8 (30%) had del(11q22.3) and 10 (37%) had del(17p13.1) by FISH, and 24 (89%) had IgVH unmutated disease. The median number of prior therapies was 4 (range 1–14). Toxicity with this agent was modest. Dose escalation continued without dose limiting toxicity (DLT) until the highest dose level, in which one patient experienced grade 4 neutropenia associated with febrile neutropenia which required dose discontinuation. 100% of patients experienced any AE, with the majority of AE being grade 1–2. The most common AEs were infusion reactions in 18 patients (67%), all of which were grade 1 or 2. Treatment-related Grade 3 or 4 AEs occurred in 5 pts (19%), and included neutropenia (n=3), thrombocytopenia (n=2), increased aspartate aminotransferase (AST) (n=1), febrile neutropenia (n=1), and tumor lysis syndrome (n=1). All were on the 12 mg/kg dose level except one pt receiving 1mg/kg who experienced neutropenia. Overall response rate by IWCLL 2008 criteria is 11%, all of which have been partial responses (PR). Using IWCLL 1996 response criteria which does not include CT scan assessment of disease resulted in a PR in 13 pts (42%). Only 2 pts had PD at the 8 week evaluation point. Responses occurred at the 6, 9, and 12 mg/kg dose levels. All objective responses were in pts categorized as CLL as opposed to SLL, and no patients with lymph nodes >5cm responded. PK was best modeled by a two-compartment model. Half-life was 14 days, with clearance 5mL/day/kg that was not dose-dependent. Across the dose range, area under the curve increased in a dose-proportional manner, while maximum concentration increased in a less than proportional manner. A steady-state was reached at or before infusion 9. XmAb5574 shows acceptable toxicity and signs of preliminary efficacy in patients with high-risk, heavily pretreated CLL. These results justify movement into phase II study in CLL as well as other B cell malignancies. Modest toxicity, in particular infectious toxicity, will potentially allow combinations with other active agents in CLL. Disclosures: Enoch: Xencor, Inc.: Employment. Foster:Xencor, Inc: Consultancy.

scholarly journals Safety Results from the United States Cohort of the Ibrutinib Early Access Treatment Protocol (EAP: MCL4001) in Patients with Relapsed or Refractory Mantle Cell Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4461-4461
Author(s):  
Peter Martin ◽  
Andre Goy ◽  
Radhakrishnan Ramchandren ◽  
Lucille Ferrante ◽  
Vijay Reddy ◽  
...  
Keyword(s):  
Adverse Events ◽  
Mantle Cell Lymphoma ◽  
Progressive Disease ◽  
Cell Lymphoma ◽  
Serious Adverse Events ◽  
Major Hemorrhage ◽  
Once Daily ◽  
Mantle Cell ◽  
The Us ◽  
Grade 3

Abstract Background: Bruton’s tyrosine kinase (BTK) is a critical signaling molecule in the B-cell receptor pathway. Ibrutinib is a first-in-class, once daily, oral covalent inhibitor of BTK that was approved in the US (November 2013) based on an international multi-center Phase 2 study in patients with relapsed or refractory mantle cell lymphoma (MCL), with an ORR of 68% (CR 21% and PR 47%) and median progression free survival of 13.9 months (Wang et al. NEJM 2013). This EAP was conducted in a similar patient population to provide access to ibrutinib prior to market authorization and to collect additional safety data. The results of the US cohort are reported here. Methods: This was an open-label EAP in patients with relapsed or refractory MCL, who resided in areas where ibrutinib was not available and were ineligible for ongoing ibrutinib trials. Key entry criteria were as follows: age ≥ 18 years, relapsed or refractory MCL, and no prior ibrutinib therapy. Patients received ibrutinib 560mg orally once daily in 28 day cycles until progressive disease, unacceptable toxicity, no further benefit or end of study (US approval). Adverse events (Grade ≥ 3), serious adverse events, and adverse events of interest (major hemorrhage, intracranial hemorrhage) were collected. Results: In total,149 patients participated in the EAP at 46 US sites from May 2013 to April 2014. Median age was 68 years (range: 39-90 years) and 89% were white. Median treatment exposure was 3.65 months (range: 0.0-7.7 months), with approximately 26% of patients receiving treatment for more than 6 months. Of the 149 patients, 58.5% had refractory disease and 66.7% had received ≥3 prior lines of therapy. Adverse events grade ≥3 were reported in 59 patients (39.6%), the most common of which were neutropenia (6.7%), dyspnea (4%), anemia (3.4%) and thrombocytopenia (3.4%). Serious adverse events were reported in 46 patients (30.9%). Adverse events of interest were reported in two patients (1.3%): 1 major hemorrhage (0.7%) and 1 intracranial hemorrhage (0.7%). Ten patients (6.7%) discontinued treatment due to adverse events. The primary reason for discontinuation was progressive disease in 20 patients (13.4%) and death in 12 patients (8.1%). The majority of patients (66%) continued on therapy until the end of study (US approval). Conclusions: The safety profile observed in this US cohort of the EAP was consistent with that observed during the registration trial for MCL. No new safety signals were observed in this predominantly refractory population of patients. Moreover, this EAP provided an important mechanism for patients to receive ibrutinib prior to US approval. Disclosures Martin: Janssen: Honoraria. Ferrante:Janssen Scientific Affairs, LLC: Employment. Reddy:Janssen Scientific Affairs, LLC: Employment. Londhe:Janssen Scientific Affairs, LLC: Employment. Wildgust:Janssen Global Services: Employment. McGowan:Janssen Scientific Affairs, LLC: Employment.

Phase I/II trial of bortezimib and pemetrexed in patients with advanced non-small cell lung cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18145-18145 ◽  
Author(s):  
R. B. Natale ◽  
M. McKinley ◽  
J. Hilger ◽  
T. Myers
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Finding ◽  
Mantle Cell ◽  
Finding Study ◽  
Heavily Pretreated ◽  
Level 3 ◽  
Previously Treated Patients ◽  
Grade 3 ◽  
Dose Levels

18145 Background: Bortezomib (Vc) is a novel proteosome inhibitor with activity in several malignancies including multiple myeloma, mantle cell lymphoma, and NSCLC. In NSCLC, Vc has additive activity combined with carboplatin and gemcitabine in first line and with docetaxel in second line treatment. Pemetrexed (P) is active in NSCLC and preclinical data suggests a pro-apoptotic synergy between Vc and P. Therefore, we initiated a phase I/II dose finding study of Vc + P in previously-treated patients (pts) with advanced or metastatic NSCLC. Methods: Fifteen pts have been accrued to 3 of 4 planned dose levels of Vc + P. Starting doses (and # pts treated) were Vc 1.4 mg/m2 day 1 & 8 + P 400 mg/m2 day 1 every 3 weeks (3 pts). The 2nd and 3rd dose levels were Vc 1.6 mg/m2 day 1 & 8 + P 500 mg/m2 day 1 (8 pts, 5 new + 3 from dose level 1) and Vc 1.8 mg/m2 day 1 & 8 + P 500 mg/m2 day 1 (7 pts). Results: 15 pts are evaluable for response and toxicity and include 8 males, 7 females, median age 67 (range, 55–82), PS 0/1 (3/12 pts), median of 2 prior therapies (range 1–3). Confirmed PRs occurred in 2 pts (13%) and stable disease in 5 (33%). Dose limiting toxicities consisted of grade 4 fatigue (1 pt) and neutropenia/fever (1 pt) at dose level 2, and grade 3 abdominal pain and fatigue (1 pt) and grade 3 diarrhea and vomiting (1 pt) at dose level 3. Conclusions: The above combination is safe at the doses tested thus far and active in pts with heavily pretreated, advanced NSCLC. We are currently exploring Vc 2.0 mg.m2 Day 1 & 8 + P 500 mg/m2 day 1 every 3 weeks to determine the MTD and plan a multi-site Phase II study to determine response rate and survival in a larger pt population. No significant financial relationships to disclose.

Sign in / Sign up

Export Citation Format

Share Document