Rituximab, Cyclophosphamide, Bortezomib and Prednisone (R-CBorP): Final Results of a Phase I Trial Evaluating Two Dosing Schedules and the Safety of Overlapping Pegfilgrastim in Patients with Relapsed/Refractory Indolent and Mantle Cell Lymphomas.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3708-3708 ◽  
Author(s):  
John Gerecitano ◽  
Carol S. Portlock ◽  
Paul A. Hamlin ◽  
Craig H Moskowitz ◽  
Ariela Noy ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Single Agent ◽  
Response Rates ◽  
Neutropenic Fever ◽  
Significant Activity ◽  
Weekly Schedule ◽  
Mantle Cell ◽  
Grade 3 ◽  
Weekly Group

Abstract Abstract 3708 Poster Board III-644 Aim To determine the safety and efficacy of substituting bortezomib (Bor) for vincristine in standard ‘R-CVP’. A separate safety analysis evaluated the safety of pegfilgrastim (PegG) overlapping with Bor administration. Rationale Vincristine has marginal activity in indolent lymphomas, while preclinical and clinical data suggest that single agent Bor has significant activity in indolent and mantle cell (MCL) non-Hodgkin Lymphoma (NHL), and may also be synergistic with rituximab (R) and DNA-damaging agents. Methods In this phase I trial, Bor and cyclophosphamide (C) were alternately escalated. R (375 mg/m2) and C (750 mg/m2 or 1000 mg/m2) were dosed on day one, and prednisone (P) (100 mg daily) on days 2-6. In schedule 1, Bor was given on days 2 and 8, with doses escalated from 1.3 to 1.8 mg/m2. In schedule 2, Bor was given on days 2, 5, 9 and 12 with doses escalated from 1.1 to 1.5 mg/m2. Due to 2 neutropenic fevers in schedule 2 (twice-weekly Bor), the protocol was amended to allow for filgrastim (G) support, administered in between Bor dosing days. This allowed accrual to the highest planned dosing level. A separate cohort of 10 patients was added at the twice-weekly Bor 1.3 mg/m2 + C 1000 mg/m2 level to assess the safety of administering overlapping PegG instead of G. In this cohort, PegG was given with Bor on day 2. Patients with PR or SD after 4 cycles received 4 further cycles, those with CR got 2 further cycles. Toxicity was assessed using NCI-CTC, v. 3.0. No DLT was seen at maximum doses of Bor and C in either schedule. Schedule 1 accrued 15 patients, with one DLT requiring cohort expansion at the second dose level. Schedule 2 accrued 40 patients. Results Demographic variables were similar between the two groups, and both schedules were well tolerated with similar toxicity profiles. Most hematologic toxicities (HTs) and non-HTs across all dose levels and cycles were grade 1-2. Grade 3-4 non-HTs in the weekly treatment cohorts included grade 3 diarrhea (n=1), dehydration (n=1), neutropenic fever (n=1), infection (n=2) and anal incontinence (n=1, likely unrelated). Grade 3 toxicities in the twice-weekly groups included fatigue (n=3), neutropenic fever (n=2), fever (n=1), hypoxia (n=1) and neuropathy (n=2), along with one grade 4 neuropathy. Of the patients who developed neuropathy above baseline, resolution to baseline occurred in 8 of 9 (89%) of patients in the weekly group after a median of 0.7 months, and in 15 of 26 (58%) of patients in the twice-weekly group after a median of 4 months. To evaluate the safety of pegfilgrastim overlapping with 4 doses of Bor, toxicities and CBCs for patients in the PegG group were compared with those of patients treated at identical doses of R-CBorP given non-overlapping G support. All toxicities and CBC trends were similar, with the exception of a significant but mild decline in platelets in the PegG group. Overall response rates in the 13 evaluable weekly and 33 evaluable twice-weekly patients were 46% (23% CR) and 64% (36% CR), respectively. Conclusions R-CBorP is a well-tolerated and promising new regimen in patients with NHL. The safety of administering PegG overlapping with Bor has been established, and simplifies this regimen. Although response rates appeared to be greater in the twice-weekly schedule, a randomized study will be required to determine the true difference. Grade 3-4 neuropathy was seen only in the twice-weekly dosing group, and seemed to be less reversible and longer-lasting than in the weekly group. A randomized phase II study will soon begin enrollment to compare the toxicity and efficacy of these two dosing schedules in a larger group of patients with follicular lymphoma. Disclosures: Gerecitano: Genentech: Speakers Bureau; Biogen Idec: Speakers Bureau. Off Label Use: bortezomib in combination with other active agents for indolent and mantle cell non-Hodgkin lymphomas. Hamlin:Genentech: Speakers Bureau; Biogen Idec: Speakers Bureau. Zelenetz:Millenium Advisory board: Membership on an entity's Board of Directors or advisory committees.

Schedule of bortezomib administration may be an important determinant of single-agent activity in patients with relapsed or refractory follicular (FL) lymphoma and mantle cell lymphoma (MCL)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8051-8051 ◽  
Author(s):  
O. O'Connor ◽  
P. Hamlin ◽  
C. Moskowitz ◽  
D. Straus ◽  
A. Noy ◽  
...  
Keyword(s):  
Cell Lymphoma ◽  
Important Determinant ◽  
Single Agent ◽  
Dose Intensity ◽  
Significant Activity ◽  
Weekly Schedule ◽  
Mantle Cell ◽  
Grade 3 ◽  
Multi Center Study

8051 Background: We previously demonstrated the significant activity of bortezomib for the treatment of FL and MCL. The activity in MCL has been confirmed in a multi-center study leading to the recent approval by the FDA. The demonstrated activity was observed on the twice weekly schedule. Recent data using bortezomib in combination with rituximab suggested that weekly bortezomib was less toxic and possibly equally as efficacious as twice weekly bortezomib. This study does not allow a determination of weekly single agent activity alone. We sought to evaluate the single agent activity of bortezomb in FL and MCL administered on a weekly schedule. Methods: Pts with FL and MCL were treated with bortezomib at a dose of 1.8 mg/m2 weekly for 4 of 6 consecutive weeks. To date, 20 pts (12 FL, 8 MCL) have been treated on this schedule, of which 18 are assessable for response. Two pts were inevaluable: 1 pt received steroids for bronchitis (MCL); and 1 pt (FL) with grade 2 diarrhea withdraw consent making her data inaccessible. Results: The range of cycles administered was 1 to 8, with a median of 2. The weekly dosing schedule was well tolerated with 1 pt. developing neuropathy (grade 3). Fourteen pts completed at least two cycles of therapy and underwent restaging. Two pts had a PR (both FL), 8 had SD (5 FL, 3 MCL) and 4 had POD (2 FL, 2 MCL). The other 4 evaluable patients are now being restaged. Conclusions: These data suggest weekly dosing with bortezomib may not be as effective as twice weekly. Typically, bortezomib administered on the twice weekly schedule has an ORR of 30% in MCL and 50% in FL. Additionally, the frequency of pts. experiencing POD appears to be less common on the twice weekly schedule. One difference in the schedules is the dose intensity and dose density. A cycle of twice weekly bortezomib administers 1.7 mg/m2/week, while a weekly schedule administers only 1.2 mg/m2/week, a 30% difference in dose intensity and a 100% difference in dose density (1.33 × per week vs. .67 × per week). What remains unclear from a pharmacologic perspective is the relative importance of high Cmax vs high AUC exposures, and their impact on both toxicity and efficacy. These data suggest that schedule is critical in the activity of bortezomib. No significant financial relationships to disclose.

Activity of Combined Flavopiridol and Lenalidomide in Patients with Cytogenetically High Risk Chronic Lymphocytic Leukemia (CLL): Updated Results of a Phase I Trial,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3910-3910
Author(s):  
Kristie A. Blum ◽  
Lai Wei ◽  
Jeffrey A. Jones ◽  
Leslie A Andritsos ◽  
Joseph M. Flynn ◽  
...  
Keyword(s):  
High Risk ◽  
Combination Therapy ◽  
Phase I ◽  
Dose Escalation ◽  
Phase I Trial ◽  
Single Agent ◽  
Significant Activity ◽  
Upper Respiratory Tract ◽  
Off Label ◽  
Grade 3

Abstract Abstract 3910 Background: The cyclin dependent kinase inhibitor, flavopiridol, and the immunomodulatory agent, lenalidomide, are active in heavily pre-treated CLL patients (pts) with bulky adenopathy and adverse cytogenetics, although dose escalation of these two agents has been limited by tumor lysis syndrome (TLS) and tumor flare. Furthermore, these agents do not deplete T-cells, and combination therapy may result in greater efficacy and less infectious toxicity than observed with fludarabine or alemtuzumab combinations. Methods: We conducted a phase I trial of combined flavopiridol and lenalidomide in pts with CLL relapsed after at least 1 prior therapy, WBC < 150,000/mm3, ANC > 1000/mm3, platelets > 30,000/mm3, and creatinine < 1.5 mg/dL. Treatment consisted of flavopiridol alone, 30 mg/m2 bolus + 30–50 mg/m2 4-hour continuous IV infusion (CIVI) days 1, 8, and 15 of cycle 1. Starting in cycle 2, flavopiridol 30 mg/m2 bolus + 30–50 mg/m2 4-hour CIVI days 3, 10, and 17 was combined with lenalidomide 2.5, 5.0, 7.5, 10, 15, or 25 mg days 1–21 every 35 days. All pts received 20 and 4 mg of dexamethasone 30 minutes prior to and 24 hours after flavopiridol, respectively, to minimize cytokine release symptoms. Pegfilgrastim was administered on day 18 of cycles 2–8. Results : Thirty pts (18 males) with a median age of 60 (range 42–74) previously treated with a median of 3 prior therapies (range 1–10) were enrolled. All pts received prior fludarabine and 40% were fludarabine refractory. Seventy-three percent of patients were Rai stages III-IV, 60% pts had bulky adenopathy > 5 cm, 60% pts had del(17p13.1), 37% pts had del(11q22.3), and 83% pts had a complex karotype. Twenty-five pts completed two or more cycles of therapy (median 3.5, range 1–8). Five pts completed only one cycle of therapy and were removed prior to receiving lenalidomide due to progressive disease (n=2), TLS requiring dialysis (n=2), and grade 4 thrombocytopenia (n=1). Pts received 2.5 mg (n=6), 5.0 mg (n=7), 7.5 mg (n=4), and 10 mg (n=3) of lenalidomide with 30 mg/m2 bolus + 30 mg/m2 4-hour CIVI flavopiridol and 5 patients have received 10 mg of lenalidomide with 30 mg/m2 bolus + 50 mg/m2 4-hour CIVI flavopiridol. DLT consisting of grade 3–4 transaminitis persisting > 7 days occurred in 2 pts treated with 2.5 mg (n=1) and 5.0 mg of lenalidomide (n=1), respectively. Grade 3–4 toxicities consisted of thrombocytopenia (60%), diarrhea (57%), transient transaminitis (47%), neutropenia (47%), hyperglycemia (47%), infection (43%, pneumonia in 5 pts, upper respiratory tract infection in 2 pts, cellulitis in 1 pt, herpes simplex stomatitis in 1 pt, oral candidiasis in 1 pt, catheter-associated in 1 pt, and febrile neutropenia without a source in 2 pts), hypokalemia (37%), anemia (33%), hypophosphatemia (33%), hypocalcemia (17%), hyperkalemia (17%), TLS requiring dialysis (7%), tumor flare (3%), and rash (3%). In 23 evaluable pts who completed 1 or more cycles of combined lenalidomide and flavopiridol, partial responses were observed in 13 pts (57%), including 7 pts with del(17p13.1), 6 pts with del(11q22.3), 9 pts with complex cytogenetics, 5 fludarabine-refractory pts, and 6 pts with bulky lymphadenopathy. Six pts were able to proceed to allogeneic transplant after 1–3 cycles, and 4 of these pts remain in remission. Median PFS and OS are 7 months (range 0–24 months; 95% CI 5, 11) and 23 months (range 0–27 months; 95% CI 13, 27), respectively. No significant differences have been observed in the single agent and combination PK parameters (AUC, Cmax, T ½, and Clearance) of lenalidomide and flavopiridol. Conclusions: Combined flavopiridol and lenalidomide is well tolerated without increased risks of TLS or tumor flare, with significant activity in pts with bulky, cytogenetically high-risk CLL. This combination regimen could be utilized to de-bulk high risk pts prior to stem cell transplantation or prior to other oral therapies. The MTD has not been reached and dose escalation continues at a lenalidomide dose that exceeds the single agent MTD in CLL of 5 mg (Maddocks et al, Blood 114: abstract 3445, 2009). Future evaluation of continued maintenance lenalidomide after initial combination therapy is planned. This trial is supported by NCI 1R21 CA133875, NCI P50-CA140158, NCI K23 CA109004, NCI U01 CA076576, LLS SCOR 7080–06, and the D. Warren Brown Foundation. Disclosures: Off Label Use: Flavopiridol and lenalidomide are off-label for the treatment of CLL.

Phase I Trial Examining Addition of Gemcitabine to CHOP in Intermediate Grade NHL.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4765-4765
Author(s):  
John L. Reagan ◽  
James N. Butera ◽  
Alan G. Rosmarin ◽  
Ahmed Nadeem ◽  
Fred J. Schiffman ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Phase I Trial ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Chop Chemotherapy ◽  
Intermediate Grade ◽  
Chemotherapeutic Regimen ◽  
Grade 3 ◽  
Dose Limiting Toxicity

Abstract Abstract 4765 BACKGROUND Gemcitabine induces a 20% response as single agent therapy in patients with relapsed or refractory NHL. We report phase I findings of gemcitabine in combination with standard CHOP chemotherapy with G-CSF support for intermediate grade NHL. The protocol was modified during enrollment to include rituximab in CD 20+ lymphomas. METHODS Patients received CHOP plus gemcitabine at 500 mg/m2 (Cohort 1) or 750 mg/m2 (Cohort 2) on days 1,4 of each 21 day cycle. Accrual was suspended once each cohort was filled. Dose escalation occurred after all patients in the cohort were determined to not have a dose limiting toxicity. RESULTS Between 4/02 and 5/04 10 patients were enrolled and completed the study treatment (6 in cohort 1, 4 in cohort 2). In Cohort 1, grade 3 toxicities included neutropenia, anemia, neuropathy, and constipation. Grade 4 toxicities were febrile neutropenia, and thrombocytopenia. In Cohort 2, grade 3 toxicities included neutropenia, thrombocytopenia, mucositis, anemia and intestinal obstruction. Grade 4 toxicities included febrile neutropenia, neutropenia, and thrombocytopenia. One patient developed MDS 36 months after chemotherapy. Three of four patients in Cohort 2 developed dose limiting toxicities (mucositis and thrombocytopenia) requiring dose reduction of gemcitabine after cycle 1. Overall, the survival rate at 2.5 years was 71%. CONCLUSIONS This Phase I trial concludes that gemcitabine 500mg/m2 on days 1 and 4 of each 21 day cycle is the maximum tolerated dose when combined with standard CHOP chemotherapy with G-CSF support for intermediate grade NHL. Response rates are encouraging for this novel chemotherapeutic regimen. Disclosures: Off Label Use: Gemcitabine was added to standard CHOP chemotherapy in this trial.. Sikov:Eli Lilly: Honoraria.

Phase I trial of escalating doses of weekly everolimus (RAD001) in combination with docetaxel for the treatment of metastatic breast cancer (MBC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1066-1066
Author(s):  
S. L. Moulder ◽  
E. Rivera ◽  
J. Ensor ◽  
A. Gonzalez-Angulo ◽  
M. Christofanilli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase I ◽  
Phase I Trial ◽  
Single Agent ◽  
Metastatic Breast ◽  
Maximum Tolerated Dose ◽  
Entire Group ◽  
Interpatient Variability ◽  
Grade 3

1066 Background: Inhibition of mTOR with everolimus (E) may improve efficacy in combination with docetaxel (D), but both drugs are metabolized by CYP3A4, thus a pharmacokinetic (PK) interaction may also exist. Methods: 15 patients (pts) with MBC were treated with docetaxel and everolimus using the continuous reassessment method (CRM) to determine maximum tolerated dose (MTD). Docetaxel doses were 40–75 mg/m2 IV on day 1 of a 21 day cycle. Everolimus doses were 20–50 mg PO on days 1 and 8 of a 21 day cycle (except cycle 2, where only day 8 was given to allow single agent PK analyses of both drugs). Response was measured every 2 cycles using RECIST. Results: Median age= 58 years and 77% of pts had >2 prior chemotherapies for MBC. Initially 2 of 2 pts treated (D= 75 mg/m2, E= 30 mg) developed DLT (neutropenic fever/infection), prompting a mandatory PK evaluation for all pts enrolled in subsequent cohorts. A second cohort of 3 patients (D=60 mg/m2, E=20mg) had no DLT, but no pts received day 8 of E due to grade 3–4 neutropenia. PK analyses demonstrated a 42% lowered (-42%) D clearance at the 60 mg/m2 in the presence of E (n=1). Subsequent cohorts were accrued at D=40 mg/m2 with escalating doses of E (Table). For the entire group, an 18% decrease (-18%) in D clearance was observed when D was administered concomitantly with E. High interpatient variability of D clearance was observed (range +16% to -135%). No pts had CR/PR, but 6 had SD>4 cycles and 2 had SD=8 cycles. Conclusions: Weekly everolimus appears to cause widely variable and unpredictable changes in docetaxel clearance making this combination unfeasible. [Table: see text] No significant financial relationships to disclose.

scholarly journals Phase 1 Study of Bisthianostat, an Orally Efficacious Pan-HDAC Inhibitor: Part Results of Safety, Pharmacokinetics and Efficacy in Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5591-5591
Author(s):  
Hong-Hui Huang ◽  
Jian Hou ◽  
Yang-Ming Zhang ◽  
Yu-Bo Zhou ◽  
Li Jia ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Hdac Inhibitor ◽  
Phase 1 ◽  
Single Agent ◽  
Human Study ◽  
Weekly Schedule ◽  
Phase 1 Study ◽  
Expansion Phase ◽  
Grade 3

Background: Multiple myeloma (MM) is the second most common hematological malignancy. This disease remains incurable as nearly all patients will relapse and become refractory to established MM therapy. Thus, new treatment option for relapsed or refractory (R/R) MM is needed, particularly those with different mechanisms of action. One such approach is to inhibit histone deacetylase (HDAC) and produce synergistic anti-myeloma activity via mechanisms of epigenetic modulations. In 2015, panobinostat was approved by US FDA as the first HDACi to treat R/R MM in combination with bortezomib and dexamethasone. Bisthianostat is a novel bisthiazole-based HDACi evolved from the thiazole-thiazoline cap group in natural product Largazole (Nan et al., ACS Med Chem Lett. 2014). It is orally available and displayed inhibition against a series of MM cell lines. Here we presented preliminary in-human findings from CH-020PI study, an ongoing phase 1 study of bisthianostat. (Trial registered at ClinicalTrial.gov: NCT03618602) Methods: CH-020PI is a first-in-human study to investigate the safety, tolerability, pharmacokinetics, and efficacy of bisthianostat in R/R MM patients. It is a single center, open-label, single arm, dose escalating phase I study. A standard 3+3 cohort design with 100mg as the starting dose was used to determine the maximum tolerated dose of bisthianostat. This study comprised two phases: a pharmacokinetics phase and an expansion phase. In the pharmacokinetics phase, a single-dose of bisthianostat was administered on day 1, and then multiple-dose was administered on a twice-weekly schedule for 4 consecutive weeks. Patients in the expansion phase received continuous bisthianostat twice weekly until progressive disease or unacceptable toxicities. Results: Until 30 June 2019, 8 patients were enrolled at 3 dose levels from 100 to 400mg. The median age at enrollment was 62 years (range, 51-70 years). The median number of previous lines of therapy was 5 (range, 2-6). Per protocol, all of 8 patients were evaluable for pharmacokinetics, toxicities and efficacy. In the pharmacokinetic evaluation, for all the 8 patients tested at day 1, the peak concentration of bisthianostat was reached within 2.3 hours; half life time were around 4 hours; bisthianostat uptake represented by AUClast were in good proportion to the level of dose as 100, 200 and 400mg, respectively. Similar results were observed at day 28. Any grade hematological treatment-related adverse events (AEs) occurred in 4 of 8 patients (50%), while grade 3/4 hematological AEs occurred in 2 (25%) patients. Any grade non-hematological treatment-emergent AEs were observed in 3 (37.5%) patients; no grade 3/4 non-hematological AEs were reported. No patient discontinued the treatment of bisthianostat due to AEs. Except patient 007 (200mg cohort) experienced a grade 2 nausea, no patients experienced diarrhea, nausea, or vomiting. It is worthy to note that gastrointestinal toxicity is common with the use of panobinostat, a FDA-approved HDAC inhibitor. Overall single-agent efficacy was modest, and stable disease (SD) was observed in 4 (50%) patients. At the time of data cut-off for statistical analysis, no dose-limiting toxicity has been observed. Conclusions: Bisthianostat proved to be well absorbed and tolerated. It exhibited modest anti-tumor efficacy in our cohort of heavily pretreated patients with R/R MM. This phase I clinical trial is currently ongoing, and future trials should compare different doses and schedules of the combination in order to optimize the treatment tolerability and enhance its efficacy. Disclosures No relevant conflicts of interest to declare.

scholarly journals Temsirolimus in Combination with Bendamustine and Rituximab for the Treatment of Relapsed Mantle Cell and Follicular Lymphoma: Report on an Ongoing Phase I/II Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3930-3930
Author(s):  
Georg Hess ◽  
Ulrich Keller ◽  
Johannes Atta ◽  
Ulrich Bitz ◽  
Christian Lerchenmueller ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Research Funding ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Response Rates ◽  
Phase Iii ◽  
Mtor Inhibition ◽  
Grade 3 ◽  
Ongoing Phase

Abstract Background: mTOR inhibition has been shown to be effective in various subtypes of malignant lymphomas. In relapsed MCL a phase III trial could prove superiority of Temsirolimus to standard options. Furthermore, in patients with follicular and diffuse large B-cell lymphoma, promising response rates could be observed (Smith et al, JCO 2010). Whereas combination to single agent Rituximab (R) improved efficacy (Ansell et al, Lancet Oncology 2011), there is limited information of the feasibility and efficacy in combination with chemotherapy. Bendamustine (B) has been shown to be effective in various lymphoma entities and has a beneficial side effect profile (Rummel et al, JCO, 2005). In the phase I of this trial, we have established that 50mg of Temsirolimus given 3 times weekly in a four week cycle could be safely added to BR (Hess, Leukemia, 2015). Here we report for the first time combined results of phase I and II of this trial. Methods: this is a multicenter, national, prospective trial. Inclusion criteria: patients were eligible if they had histologically proven FL or MCL, 1-3 prior treatment lines, no curative option available, no refractoriness to Bendamustine, measurable disease, ECOG < 3, sufficient bone marrow reserve, no severe concomitant diseases and given informed consent. Treatment consisted of Bendamustine 90mg/m² day 1-2, Rituximab 375mg/m² day 1 and Temsirolimus 50 mg day 2, 8, 15 of a 28d cycle. A total of 4 cycles was planned with interim staging after 2 cycles. Results: Overall 34 patients (pts) have been included until now (15 pts phase I, 19 pts phase II). Concerning clinical characteristics, median age was 71 years, with 25 MCL and 9FL, and a median number of 2 pretreatments (1-3). Overall the treatment was well tolerated, and toxicity was predominantly hematologic. In 118 evaluable cycles of chemotherapy the following hematologic grade 3 / 4 toxicities were noted: leukopenia (11 pts, 32%), neutropenia (8 pts, 24%), and thrombocytopenia (7 pts, 21%). Non-hematologic grade 3 / 4 observed in at least two patients were angioedema and decrease in blood potassium, infection, metabolic (4 events). AE's of special interest: pulmonary: rate of cough (4; 12%) and pneumonitis (1; 3%); gastrointestinal: diarrhea (6; 18%), nausea (13, 38%); general: fatigue (16; 47%), mucositis (13, 38%); bleeding: epistaxis (4; 12%), which all were predominantly grade 1 or 2. Response: currently, best responses were 8 CR (31%), 16 PR (62%) and 2 SD (8%) in 26 patients evaluable so far. Updated results will be presented at the meeting. Overall responses were 94% in MCL (7 CR, 10 PR, 1 SD) and 88% in FL (1 CR, 6 PR, 1 SD). After a median follow up of 13 months (mean: 21 months) median PFS is 18.6 months for the entire cohort, with 22 months for MCL and not reached in FL. Summary: In this ongoing phase II trial 50mg Temsirolimus (day 1,8,15) in combination with Bendamustine and Rituximab was well tolerated and feasible. A moderate dose of Temsirolimus to standard chemotherapy might be the optimal way to achieve the maximum efficacy with mTOR inhibitors; in fact excellent response rates suggest an additive effect of mTOR inhibition to BR. Even after the BTK inhibitor Ibrutinib has entered the clinical arena of MCL, this combined treatment represents a valuable additional option especially for patients with relapsed MCL Disclosures Hess: Pfizer, Janssen, Roche, Mundipharma: Honoraria, Research Funding; Janssen, Roche, , Celgene, Novartis: Consultancy. Keller:Roche: Consultancy, Honoraria; Pfizer: Consultancy. Witzens-Harig:Roche: Honoraria; Pfizer: Honoraria, Research Funding.

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 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]

Phase I Trial of Bortezomib (NSC 681239) and Flavopiridol (NSC 649890) in Patients with Recurrent or Refractory Indolent B-Cell Neoplasms.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1573-1573 ◽  
Author(s):  
Steven Grant ◽  
Daniel Sullivan ◽  
David Roodman ◽  
Robert K Stuart ◽  
Edward Perkins ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Phase Ii ◽  
Phase I Trial ◽  
Treatment Plan ◽  
Human Leukemia ◽  
Mantle Cell ◽  
Grade 3 ◽  
Nf Kappab ◽  
Dose Levels

Abstract Preclinical studies suggest that neoplastic cells may be particularly sensitive to simultaneous interruption of cell-cycle and survival signaling pathways. In accord with this concept, we have shown that flavopiridol (F), a CDK inhibitor, interacts with bortezomib (B), a proteasome inhibitor, to induce mitochondrial injury and apoptosis in human leukemia, myeloma, and lymphoma cells (Dai et al, Oncogene22:7108, 2003; Dai et al, Blood104:509, 2004). These actions were associated with inhibition of NF-kappaB DNA binding, increased expression of phospho-JNK, and downregulation of XIAP and Mcl-1. Based on these findings, a phase I trial has been initiated to identify appropriate doses of B+F for further investigation. Eligible patients (pts) include those with multiple myeloma or indolent B-cell neoplasms, and recurrent or refractory disease following at least 1 prior systemic therapy (excluding allogeneic stem cell transplantation). In the initial stage of the trial, pts received B (iv push) immediately followed by F bolus (1- hour infusion) on d1, 4, 8, and 11 out of a 21-day (d) cycle. Dose levels were, in mg/m2 (B/F): 1.0/15, 1.3/15, 1.3/22, 1.3/30, 1.3/40, 1.3/50, and 1.3/60. Subsequently, a “hybrid” F infusion schedule (30 minute load followed by a 4-hour infusion) was adopted based on evidence of activity of this schedule in chronic lymphocytic leukemia. With the hybrid schedule, all pts receive B (iv push) 1.3 mg/m2 on d1, 4, 8 and 11. Targeted F dose levels using the hybrid schedule are (Fload/Finfusion; mg/m2): 20/20 on d1 and 8; 30/30 on d1 and 8; 30/50 on d1 and 8; 30/30 on d1, 4, 8 and 11; 30/50 on d1, 4, 8 and 11. Dose limiting toxicity (DLT) is defined as NCI CTCAE grade 4 ANC/platelets for &gt; 1 week or grade ≥ 3 non-heme toxicity. 38 pts have been enrolled. 29 pts were treated at 7 dose levels with the bolus schedule, after which development of the hybrid schedule was begun. With the hybrid schedule, 11 pts have been treated at 3 dose levels. To date, one DLT (grade 3 lower back pain) was observed at level 5 of the bolus schedule and one DLT (grade 3 fatigue) was seen at the 1st hybrid dose level. The MTD of the hybrid schedule has not been reached. Non-DLT toxicities include herpes zoster (2 disseminated), peripheral neuropathy, fatigue, postural hypotension, syncope, diarrhea and ≤ grade 3 cytopenias. Of 35 pts evaluable for response, there have been 2 complete responses (1 lymphoma and 1 mantle cell lymphoma), 7 partial responses (5 myeloma and 2 lymphoma), 3 minor responses (2 myeloma and 1 extramedullary plasmacytoma), 15 patients with stable disease (5 myeloma, 7 lymphoma, 1 Waldenstrom’s and 2 mantle cell lymphomas). Of the 3 pts who had received prior bortezomib, 2 had minor responses and 1 had disease progression. To date, hyperacute tumor lysis has not occurred with the hybrid schedule, but aggressive prophylaxis and monitoring are integral to the treatment plan. Correlative laboratory studies involving bone marrow CD138+ cells from patients with myeloma revealed a reduction in post-treatment NF-kappaB nuclear localization in 4 of 5 evaluable patients. Variable effects on myeloma cell expression of phospho-JNK, Mcl-1, and XIAP have been observed. Collectively, these findings indicate that a regimen combining bortezomib and flavopiridol, including the use of a hybrid flavopiridol schedule, is well tolerated in patients with progressive B-cell malignancies, and has clear activity in some patients refractory to standard therapy. Pending identification of the MTD and RPTD (recommended phase II dose), phase II evaluation of this therapeutic strategy should define its activity more definitively.

Plerixafor, G-CSF and Azacitidine For The Treatment Of MDS: Results Of a Phase I Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2816-2816
Author(s):  
Mark A. Schroeder ◽  
Marcus Grillot ◽  
Teresa Reineck ◽  
Meagan A Jacoby ◽  
Rizwan Romee ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Phase I ◽  
Research Funding ◽  
Phase I Trial ◽  
Response Rates ◽  
Response To Treatment ◽  
Hematologic Toxicity ◽  
Oncology Research ◽  
Grade 3

Abstract Azacitidine has been shown to prolong survival and delay progression to leukemia in intermediate-2 and high risk myelodysplastic syndrome (MDS) in a randomized study compared to best supportive care. The combination of G-CSF and plerixafor is synergistic in increasing the release of stem and progenitor cells from the bone marrow through disruption of critical bone marrow stromal interactions including the CXCR4 / CXCL12 axis. The interaction of bone marrow stromal cells with the MDS tumor clone may play a roll in pathogenesis and response to treatment. We hypothesized that resistance of MDS to azacitidine may be related to MDS tumor and BM-stromal cell interactions, and disruption of these interactions by treatment with plerixafor + G-CSF could enhance sensitivity to azacitidine, thus improving complete and partial response rates. We conducted a phase I trial to investigate the safety and tolerability of plerixafor + G-CSF in combination with azacitidine in adult (18 years or older) MDS patients. Secondary objectives included response rates and biologic correlates evaluating: kinetics, phenotype, cell cycle status and kinetics of mobilization of MDS blasts compared to normal stem cells in select patients with informative cytogenetics. Major inclusion criteria included MDS defined by WHO criteria, 5 – 20% blasts on bone marrow aspirate, and at least one cytopenia in one cell lineage. Subjects receiving prior hypomethylating therapy were allowed. A standard 3+3 trial with 3 cohorts (320, 440, and 560 mcg/kg/day SC) was conducted. Dose limiting toxicity was defined as grade 3 or higher non-hematologic toxicity and hematologic toxicity of leukostasis or tumor lysis. Myelosuppression, infection, grade III nausea, fatigue, weight loss and electrolyte abnormalities were not considered dose limiting. Subjects initially received G-CSF 10 mcg/kg subcutaneous (SC) daily D1 – D8, plerixafor SC daily D3 – D8 and azacitidine 75mg/m2 SC D3 – D8, 4 hours after plerixafor administration. The trial was amended after the first 3 subjects to reduce G-CSF dose and administration to 5 days. Results Two of the first three subjects enrolled in cohort 1 (320 mcg/kg/d plerixafor) had leukocytosis. The trial was amended to reduce the G-CSF dose (10 mcg/kg to 5 mcg/kg) and duration (8 days to 5 days) because of this. One subject had symptoms of leukostasis with a WBC reaching nearly 100K/uL and a subsequent subject developed hyperleukocytosis (WBC = 80K/uL) without leukostasis. The trial was amended to reduce the G-CSF to 5 days concurrent with plerixafor and azacitidine along with defining dose holding parameters for G-CSF and plerixafor if the peripheral blood WBC exceeded 40K/uL or if absolute blast count exceeded 10K/uL. Since amendment of the trial, 64 subjects have been screened and 20 subjects have been enrolled and are evaluable. Subjects included 65% males, median age 67, and MDS diagnosis at study entry including 6/18 (33%) RAEB-1 and 12/18 (67%) RAEB-2. 5/18 subjects (28%) had plerixafor and G-CSF held during treatment because of leukocytosis. 9/18 subjects (50%) had received no prior treatment for their MDS. DLTs were experienced in Cohort 1 related to thrombocytosis (n =1) and in Cohort 2 related to atrial fibrillation (n = 1) with near syncope. Major non-hematologic grade 3 or 4 adverse events included epistaxis, hypocalcemia, GI bleed, headache, dyspnea, infection with neutropenia, and bone pain. The MTD was determined to be 560mcg/kg plerixafor SC with no subjects (n = 6) in this cohort experiencing a DLT. The median number of cycles completed was 3. Reasons for stopping treatment included progression to leukemia (n = 6), physician choice (n = 2), withdrawal of consent (n = 1), adverse event (n = 2). Best response in those evaluable after completing 2 cycles of treatment (n = 14) showed marrow CR in 5/14 (36%, 3 in those not previously treated for MDS), stable disease in 5/14 (36%) and progressive disease 4/14 (29%). Conclusion Plerixafor plus G-CSF in combination with azacitidine was well tolerated in the studied MDS patients when given over 5 days and may be associated with encouraging response rates. Correlative studies are ongoing to evaluate changes in cell cycle, apoptosis and preferential mobilization of blasts using this regimen. We are currently enrolling an expanded cohort of 7 subjects at the MTD dose to evaluate preferential mobilization of blasts with plerixafor alone in cases using informative cytogenetics. Disclosures: Schroeder: Celgene: Research Funding; Sanofi Oncology: Research Funding. Off Label Use: Plerixafor and G-CSF for the treatment of MDS. Welch:Eisai: Research Funding. Stockerl-Goldstein:Millennium: Speakers Bureau; Celgene : Speakers Bureau.

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